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1693240 | 33,737,590 | Ultrastructural and immunohistochemical study of epithelioid hemangioendothelioma of bone: coexpression of epithelial and endothelial markers | Four cases of epithelioid hemangioendothelioma of bone--a borderline malignant tumor of vascular origin--were studied ultrastructurally and immunohistochemically. The epithelioid tumor cells were positive for vimentin, polyclonal and monoclonal cytokeratins, and the endothelial markers factor VIII-related antigen (FVIII:RAg) and Ulex europaeus agglutinin I. The coexpression of polyclonal cytokeratin and FVIII:RAg was demonstrated by means of step sections in the same tumor cells. The endothelial origin of epithelioid tumor cells was supported ultrastructurally by identification of Weibel-Palade bodies. | Gold Standard | clinical characteristics or disease pathology | 0 |
2068012 | 39,595,153 | Epithelioid angiosarcoma of the adrenal gland associated with chronic arsenical intoxication? | Epithelioid angiosarcoma is a rare tumor quite recently described. There is no accurate epidemiological study of this tumor. Among the internal organs, the liver is the one most frequently affected with angiosarcoma while there is no reference to the adrenal gland as a primary site. It is well known that the direct exposure to arsenicals (especially of vineyard cultivators) may be an important causative factor in the pathogenesis of the disease. A 59-year-old male vineyard cultivator with an epithelioid angiosarcoma of the right adrenal gland is described. The histologic characteristics as well as the immunohistochemical profile of the tumor are presented and the literature is briefly reviewed. | Gold Standard | clinical characteristics or disease pathology | 0 |
3176552 | 30,077,314 | [Changed manifestation of fluorosis as an occupational disease within the past 15 years]. | characteristics, laboratory findings, and genetic results of 46 patients with genetically diagnosed PCD through whole-exome sequencing at our single center from a total of 265 patients with PCD within a 5-year period. Genetic analysis revealed pathogenic variants in DNAH5 (n = 12 individuals, 12 families), CCDC40 (n = 9 individuals, six families), RSPH4A (n = 5 individuals, three families), DNAH11 (n = 4 individuals, four families), HYDIN (n = 5 individuals, five families), CCNO (n = 4 individuals, four families), DNAI1 (n = 2 individuals, one family), ARMC4 (n = 2 individuals, two families), TTC25 (n = 1), DNAH1 (n = 1), and CCDC39 (n = 1) genes. Although not statistically significant, the age at diagnosis was lower (median: 3 years; range, 6 months-4 years) in patients with CCNO pathogenic variants due to the early reporting of symptoms, and the median body mass index (BMI) and BMI z scores were lower in patients at 18.7 and 16 kg/m2 , and -0.78 and -1.2 with CCDC40 and CCNO pathogenic variants, respectively. The median forced expiratory flow in 1 second (FEV1%), forced vital capacity (FVC%), and forced expiratory flow (FEF)25-75% were 53%, 64%, and 28%, respectively; these parameters were also lower in the CCDC40 group than in the other groups. There was no significant correlation between the genetic results and symptoms, radiologic findings, and microbiologic data of patients with PCD. In PCD, there was significant heterogeneity of lung disease, patients who had pathogenic variants in CCNO presented earlier, and those with CCDC40 and CCNO had worse lung disease, and poorer nutritional status compared with the other subgroups. We hope that whole genotype-phenotype and clinical relationships will be identified in PCD. | Gold Standard | disease mechanism | 2 |
10706650 | 21,310,249 | Sedation for intractable distress of a dying patient: acute palliative care and the principle of double effect | Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. The case presented is of a young man dying of recurrent epithelioid hemangioendothelioma, distressed with stridor and severe pain, whose poorly controlled symptoms were successfully treated with an infusion of propofol, titrated to provide effective comfort in the last few hours of the patient's life. The tenet of double effect, which allows aggressive treatment of suffering in spite of foreseeable but unintended consequences, is reviewed. The patient's parents were invited and contributed to the Rounds, providing compelling testimony to the power of the presence of clinicians at the time of death and the importance of open communication about difficult ethical issues. | Gold Standard | therapeutics in the clinic | 3 |
11233615 | 22,791,609 | Magnetic resonance imaging in the investigation of sensorineural hearing loss: is contrast enhancement still necessary? | High resolution T2-weighted magnetic resonance (MR) imaging has been proposed as a rapid, inexpensive means of investigating patients with sensorineural deafness, particularly to exclude vestibular schwannomas. Whether the accepted 'gold standard' of contrast-enhanced T1-weighted images can be omitted, however, remains controversial. Over a 22-month period the use of axial turbo-spin echo T2-weighted images (T2W) were prospectively compared with contrast-enhanced T1-weighted spin echo scans in the evaluation of 513 patients presenting with audiovestibular symptoms. A 2-D T2W turbo spin echo (TSE) sequence with 3 mm slices was used in 340 patients while a 3-D sequence with overlapping 1 mm slices was used in 173 patients. The T2-weighted image findings were documented and subsequently compared with contrast-enhanced images. With the 2-D sequence 24 patients (25 lesions) had internal auditory meatus (IAM)/cerebello-pontine angle (CPA) masses identified by contrast-enhanced T1-weighted images, all of which were seen on the T2-weighted TSE sequence; there was one false positive 'mass' on the T2-weighted scans and one false negative case of IAM dural enhancement on T1-weighted imaging; six were considered normal initially on the T2-weighted images although three were subtly abnormal in retrospect. With the 3-D sequence three acoustic neuromas were all identified correctly with no false positive and only one false negative result (labyrinthitis). The 2-D and 3-D images were judged technically inadequate for clinical assessment in 15 and nine per cent respectively. We conclude that mass lesions of the IAM/CPA can be reliably identified on T2W TSE imaging but labyrinthine lesions may be missed without contrast enhancement. This is of particular importance in planning the management of neurofibromatosis type 2. Non-neoplastic disorders of the inner ear are also likely to be missed. | Gold Standard | clinical characteristics or disease pathology | 0 |
15630586 | 19,411,982 | Value of 123I-IMT SPECT for diagnosis of recurrent non-astrocytic intracranial tumours | The value of single-photon emission tomography (SPECT) using iodine-123-alpha-methyl-tyrosine (IMT) for the diagnosis of recurrent or residual gliomas is well established. In the current study we investigated whether IMT-SPECT could also be useful in the follow-up of brain metastases and other intracranial tumours of non-astrocytic origin. The study included 22 patients with suspected recurrent intracranial tumours of non-astrocytic origin (12 brain metastases, one supratentorial primitive neuroendocrine tumour (PNET), one rhabdoid tumour, two clivus chordomas, three ependymomas, two pituitary tumours, one anaplastic meningioma) who had previously been treated by surgery and/or radio/chemotherapy. SPECT results were correlated with clinical and MRI follow-up data. The study was true positive in 13 patients, true negative in five, false positive in one and false negative in three patients. Notably, all false negative findings were <13 mm. The resulting sensitivity of the IMT-SPECT was 81%. We concluded that the IMT-SPECT is a promising complementary imaging tool for the detection of recurrences of non-astrocytic intracranial tumours and their distinguishing from treatment-induced changes. The limitation of the IMT-SPECT is its low sensitivity for the detection of small lesions. | Gold Standard | clinical characteristics or disease pathology | 0 |
17432352 | 8,766,909 | Intra-nasal scanning of tumors in nasal cavity and paranasal sinus with endoscopic ultrasonography | To evaluate endoscopic ultrasonography for masses in nasal cavity and paranasal sinus. Under the guidance of nasal endoscope, sonographic scan of 18 masses within nasal cavity and paranasal sinus was performed by using 10 MHz catheter transducer with diameter of 3.3 mm under local anesthesia. Twelve of them were benign tumors and 6 of them were malignant ones, which were confirmed by pathological examination of resected specimens. Under the guidance of nasal endoscope, masses could be observed accurately with catheter transducer. On gray scale ultrasound, most masses were heterogeneous hypoechoic, tumors with rich blood vessels were lower hypoechoic, and some showed irregular anechoic area due to dilated vascular net. Neurofibroma was with well-defined and regular border and entire capsule; chordoma was without distinct edge and capsule. A giant pituitary tumor eroding bone of sphenoid sinus and intruding into nasal cavity. The relationship between mass and internal carotid artery could be demonstrated using color Doppler flow imaging (CDFI). Blood flowing signals in masses could be detected by CDFI, and spectral Doppler could discriminate arterial or venous blood flowing signals and measure its velocity. The rich blood supply was observed in fibroangioma, the rich flow signals and high velocity could be detected in malignant tumors. Nasal endoscope-guided sonography for soft tissue masses in nasal cavity is of exact location, clear image and high resolution, which can reveal blood flow signals sensitively, differentiate arterial and venous blood signals and measure the velocity of them. It provides a new imaging modality for masses within nasal cavity, sinuses and skull base. | Gold Standard | clinical characteristics or disease pathology | 0 |
19308961 | 205,325,122 | A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability | Prolidase deficiency (PD) is a rare, pan-ethnic, autosomal recessive disease with a broad phenotypic spectrum. Seventeen causative mutations in the PEPD gene have been reported worldwide. The purpose of this study is to characterize, clinically and molecularly, 20 prolidase deficient patients of Arab Moslem and Druze origin from 10 kindreds residing in northern Israel. All PD patients manifested developmental delay and facial dysmorphism. Typical PD dermatological symptoms, splenomegaly, and recurrent respiratory infections presented in varying degrees. Two patients had systemic lupus erythematosus (SLE), and one a novel cystic fibrosis phenotype. Direct DNA sequencing revealed two novel missense mutations, A212P and L368R. In addition, a previously reported S202F mutation was detected in 17 patients from seven Druze and three Arab Moslem kindreds. Patients homozygous for the S202F mutation manifest considerable interfamilial and intrafamilial phenotypic variability. The high prevalence of this mutation among Arab Moslems and Druze residing in northern Israel, and the presence of an identical haplotype along 500,000 bp in patients and their parents, suggests a founder event tracing back to before the breakaway of the Druze from mainstream Moslem society. | Gold Standard | clinical characteristics or disease pathology | 0 |
19403253 | 206,875,492 | Hereditary hemorragic telangiectasia and hepatic abcess | We report the case of a 27-year-old man presenting with a hepatic abscess and hereditary hemorrhagic telangiectasia (HHT). The association between HHT and an infectious disease seemed to be induced by arteriovenous malformations and maybe also by a deficit of polymorphonuclear cells, a monocyte oxidative burst and phagocytosis. This diagnosis should be suggested in case of serious infections in young patients. Prevention is based on screening for and destroying infection, antibioprophylaxis and embolization of arteriovenous malformations. | Gold Standard | clinical characteristics or disease pathology | 0 |
19410311 | 6,635,056 | Two vascular arteriovenous malformations with left-to-right shunting and right-heart failure in a single patient | Arteriovenous malformations may lead to right-heart failure in cases of hemodynamically significant left-to-right shunting. Here, we report the case of a 37-year-old female who presented with congestive heart failure related to an isolated anomalous connection of the left pulmonary vein to the left brachiocephalic vein (partial anomalous pulmonary venous connection). After successful reconnection to the left appendage and clinical improvement, the patient once again developed progressive signs of heart failure. Several arteriovenous malformations were identified in the liver as the underlying cause of the patient's high-output heart failure, and the patient was retrospectively diagnosed with hereditary hemorrhagic telangiectasia. Target embolization led to right-ventricular remodeling, and persistent clinical improvement. To our knowledge, this is the first report of two rare AV-malformations with left-to-right shunting and progressive right-heart failure in a single individual. | Gold Standard | clinical characteristics or disease pathology | 0 |
19840971 | 2,693,778 | A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia | Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for the diagnosis of primary ciliary dyskinesia (PCD). We report our extensive experience of TEM analysis in a large series of patients in order to evaluate its feasibility and results. TEM analysis performed in 1,149 patients with suspected PCD was retrospectively reviewed. Biopsies (1,450) were obtained from nasal (44%) or bronchial (56%) mucosa in children (66.5%) and adults (33.5%). TEM analysis was feasible in 71.4% of patients and showed a main defect suggestive of PCD in 29.9%. TEM was more feasible in adults than in children, regardless of the biopsy site. Main defects suggestive of PCD were found in 76.9% of patients with sinopulmonary symptoms and in only 0.4% of patients with isolated upper and 0.4% with isolated lower respiratory tract infections. The defect pattern was similar in children and adults, involving dynein arms (81.2%) or central complex (CC) (18.8%). Situs inversus was never observed in PCD patients with CC defect. Kartagener syndrome with normal ciliary ultrastructure was not an exceptional condition (10.2% of PCD). In conclusion, TEM analysis is feasible in most patients and is particularly useful for PCD diagnosis in cases of sinopulmonary syndrome of unknown origin. | Gold Standard | clinical characteristics or disease pathology | 0 |
19923167 | 19,970,651 | CFTR is essential for sperm fertilizing capacity and is correlated with sperm quality in humans | Our previous studies have demonstrated the cystic fibrosis transmembrane conductance regulator (CFTR) is important for capacitation and male fertility in mouse and guinea pig spermatozoa. However, the exact function of CFTR on human sperm fertilizing capacity, and correlation with sperm quality has not been established. The present study may shed light on some unexplained male infertility, and on a possible new method for diagnosis of male infertility and strategy for male contraception. To assess the effect of CFTR on human sperm fertilizing capacity, we examined sperm capacitation and the acrosome reaction using chlortetracycline staining, analyzed sperm hyperactivation by computer-assisted semen analysis (CASA), measured intracellular cAMP levels using ElA and evaluated sperm penetration of zona-free hamster eggs assay in fertile men. The percentage of spermatozoa expressing CFTR from fertile, healthy and infertile men (mainly teratospermic, asthenoteratospermic, asthenospermic and oligospermic) was conducted by indirect immunofluorescence staining. Progesterone significantly facilitated human sperm capacitation and ZP3 triggered the acrosome reaction, both were significantly inhibited by CFTR inhibitor-172 (CFTRinh-172; 10 nM-1 microM) in a dose-dependent manner. The presence of 100 nM CFTRinh-172 markedly depressed intracellular cAMP levels, sperm hyperactivation and sperm penetration of zona-free hamster eggs. In addition, the percentage of spermatozoa expressing CFTR in the fertile men was significantly higher than healthy and infertile men categories (P < 0.01). CFTR is essential for human sperm fertilizing capacity and the impairment of CFTR expression in spermatozoa is correlated with a reduction of sperm quality. These results suggest that defective expression of CFTR in human sperm may lead to the reduction of sperm fertilizing capacity. | Gold Standard | disease mechanism | 2 |
19953662 | 20,321,962 | Ethmoid mucocele: a new feature of primary ciliary dyskinesia | Primary ciliary dyskinesia (PCD) is a rare congenital autosomal recessive disease that produces impairment of mucosal ciliary movement. Children with this disorder usually manifest recurrent and chronic infections of the upper and lower airways. We describe the history of a 12-month-old boy in whom the correct diagnosis of PCD was achieved after the occurrence of ethmoid mucocele associated with omolateral proptosis. A careful description of this new feature of PCD and its dangerous complications are also presented. | Gold Standard | clinical characteristics or disease pathology | 0 |
20004858 | 43,485,084 | Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes | For treatment of intractable epilepsies, there are no data comparing conventional adrenocorticotropic hormone and pulsatile corticoid therapy with dexamethasone. A retrospective comparison of efficacy was therefore conducted for both forms of application. Between 1989 and 2001, a series of 11 children with West syndrome and 3 with Lennox-Gastaut syndrome were treated with adrenocorticotropic hormone (group 1); between 2003 and 2006, 7 children with West syndrome, 5 with electrical status epilepticus during slow sleep, and 2 with Lennox-Gastaut syndrome were treated with pulsatile corticoid therapy (group 2). In group 1 (n = 14), 9/11 West syndrome patients became seizure free, but none with Lennox-Gastaut syndrome (0/3). In group 2 (n = 14), 4/7 West syndrome patients became seizure-free, 1/2 with Lennox-Gastaut syndrome exhibited seizure-frequency reduction, and 2/5 patients with electrical status epilepticus during slow-wave sleep exhibited significant improvement according to electroencephalograms. In West syndrome, pulsatile corticoid therapy was an effective alternative treatment to adrenocorticotropic hormone, whereas in Lennox-Gastaut syndrome in general steroids did not lead to a significant seizure reduction. In electrical status epilepticus during slow-wave sleep, treatment with pulsatile corticoid therapy seems to be effective and should be investigated in a larger group of patients. | Gold Standard | therapeutics in the clinic | 3 |
20008422 | 4,836,738 | Resective pediatric epilepsy surgery in Lennox-Gastaut syndrome | The objective of this study was to evaluate the role of resective pediatric epilepsy surgery for Lennox-Gastaut syndrome (LGS). We analyzed clinical data of 27 children and adolescents who had LGS and underwent resective epilepsy surgery despite abundant (>30% of preoperative interictal and/or ictal epileptiform discharges) generalized or generalized contralateral maximal and multiregional electroencephalogram abnormalities. On high-resolution MRI, cerebral lesions were noted in 23 (85.2%) patients but not in 4 (14.8%) patients. The age of patients at the time of surgery was between 1.7 and 17.3 years (mean: 7.8 years). Surgeries were lobar or multilobar resection in 21 (77.8%) patients and hemispherotomy in 6 (22.2%). At a mean of 33.1 months' postoperative follow-up, 16 (59.3%) patients had no seizures and 4 (14.8%) had infrequent seizures. Of 4 patients without brain abnormalities found on MRI, 2 patients became seizure-free after resective surgery was performed on the basis of electrophysiologic studies and concordant results in other multimodal neuroimages. Malformation of cortical development was the most common pathology and was seen in 20 (74.1%) patients, but 2 (7.4% patients) did not show any abnormal pathology. Sixteen (72.7%) patients, including 14 who had no seizures and 2 who had infrequent seizures after surgery, showed an increase in developmental quotient. No clinical profile was significantly associated with postoperative seizure-free rate. Resective epilepsy surgery should be considered for children with LGS, despite abundant generalized and multiregional electroencephalogram abnormalities. | Gold Standard | therapeutics in the clinic | 3 |
20030794 | 11,213,716 | Acute cellular rejection and Epstein-Barr virus-related post-transplant lymphoproliferative disorder in a pediatric lung transplant with low viral load | We report the case of an 18-year-old male who underwent bilateral lung transplantation for end-stage cystic fibrosis. No Epstein-Barr virus (EBV) or cytomegalovirus serology mismatch was detected on pre-transplant evaluation (donor and recipient were both positive). Two months after lung transplantation a computed tomography scan showed multiple nodules throughout both lungs. At that time a low EBV DNA blood level was detected (<300 copies/100,000 lymphomonocytes). Scheduled follow-up transbronchial biopsy (TBB) revealed a prevalent finding characterized by perivascular lymphoid infiltrates with endothelitis. Extensive tissue coagulative necrosis with peripheral areas of dense aggregates of larger lymphoid cells were detected in the trans-thoracic fine needle core biopsy (FNCB) performed on the largest nodule. The immunophenotypic profile characterized the perivascular lymphoid cells in TBB as mainly composed of T lymphocytes (CD3 positive) while the larger number of lymphocytes in FNCB as B cells (CD20 positive). In situ hybridization for EBV (EBER mRNA) was negative in TBB while it was positive in many lymphocytes of the FNCB. Real-time polymerase chain reaction (PCR) for EBV was performed on paraffin-embedded FNCB and detected a high quantity of EBV genomes (1260 copies/cell). IgH gene rearrangement using a fragment size PCR technique revealed a monoclonal B-cell population in FNCB. Morphological and molecular findings suggest a final diagnosis of acute cellular rejection and a post-transplant lymphoproliferative disorder (PTLD) EBV-related in a lung transplant recipient with a low EBV DNA blood level. A possible coexistence of PTLD and acute rejection should be considered both for diagnosis and treatment. EBV PCR in the peripheral blood is a useful screening tool in transplant recipients; however, rare cases with PTLD may not have detectable levels of EBV DNA. This aspect should be taken into consideration to avoid false negatives. | Gold Standard | therapeutics in the clinic | 3 |
20032308 | 3,104,991 | Interplay between ER exit code and domain conformation in CFTR misprocessing and rescue | Multiple mutations in cystic fibrosis transmembrane conductance regulator (CFTR) impair its exit from the endoplasmic reticulum (ER). We compared two processing mutants: DeltaF508 and the ER exit code mutant DAA. Although both have severe kinetic processing defect, DAA but not DeltaF508 has substantial accumulation in its mature form, leading to higher level of processing at the steady state. DAA has much less profound conformational abnormalities. It has lower Hsp70 association and higher post-ER stability than DeltaF508. The ER exit code is necessary for DeltaF508 residual export and rescue. R555K, a mutation that rescues DeltaF508 misprocessing, improves Sec24 association and enhances its post-ER stability. Using in situ limited proteolysis, we demonstrated a clear change in trypsin sensitivity in DeltaF508 NBD1, which is reversed, together with that of other domains, by low temperature, R555K or both. We observed a conversion of the proteolytic pattern of DAA from the one resembling DeltaF508 to the one similar to wild-type CFTR during its maturation. Low temperature and R555K are additive in improving DeltaF508 conformational maturation and processing. Our data reveal a dual contribution of ER exit code and domain conformation to CFTR misprocessing and underscore the importance of conformational repair in effective rescue of DeltaF508. | Gold Standard | disease mechanism | 2 |
20041940 | 19,860,002 | The natural history of epilepsy in tuberous sclerosis complex | Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission. Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome. | Gold Standard | clinical characteristics or disease pathology | 0 |
20042709 | 19,600,214 | Spontaneous adult-onset pulmonary arterial hypertension attributable to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia | Loss-of-function mutations in genes coding for transforming growth factor-beta/bone morphogenetic protein receptors and changes in nitric oxide(_) (NO(_)) bioavailability are associated with hereditary hemorrhagic telangiectasia and some forms of pulmonary arterial hypertension. How these abnormalities lead to seemingly disparate pulmonary pathologies remains unknown. Endoglin (Eng), a transforming growth factor-beta coreceptor, is mutated in hereditary hemorrhagic telangiectasia and involved in regulating endothelial NO(_) synthase (eNOS)-derived NO(_) production and oxidative stress. Because some patients with pulmonary arterial hypertension harbor ENG mutations leading to haplo insufficiency, we investigated the pulmonary vasculature of Eng(+/-) mice and the potential contribution of abnormal eNOS activation to pulmonary arterial hypertension. Hemodynamic, histological, and biochemical assessments and x-ray micro-CT imaging of adult Eng(+/-) mice indicated signs of pulmonary arterial hypertension including increased right ventricular systolic pressure, degeneration of the distal pulmonary vasculature, and muscularization of small arteries. These findings were absent in 3-week-old Eng(+/-) mice and were attributable to constitutively uncoupled eNOS activity in the pulmonary circulation, as evidenced by reduced eNOS/heat shock protein 90 association and increased eNOS-derived superoxide ((_)O(2)(-)) production in a BH(4)-independent manner. These changes render eNOS unresponsive to regulation by transforming growth factor-beta/bone morphogenetic protein and underlie the signs of pulmonary arterial hypertension that were prevented by Tempol. Adult Eng(+/-) mice acquire signs of pulmonary arterial hypertension that are attributable to uncoupled eNOS activity and increased (_)O(2)(-) production, which can be prevented by antioxidant treatment. Eng links transforming growth factor/bone morphogenetic protein receptors to the eNOS activation complex, and its reduction in the pulmonary vasculature leads to increased oxidative stress and pulmonary arterial hypertension. | Gold Standard | disease mechanism | 2 |
20052366 | 1,654,046 | The L441P mutation of cystic fibrosis transmembrane conductance regulator and its molecular pathogenic mechanisms in a Korean patient with cystic fibrosis | Cystic fibrosis (CF) is an autosomal recessive disorder usually found in populations of white Caucasian descent. CF is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. A 5-yr-old Korean girl was admitted complaining of coughing and greenish sputum. Chest radiographs and computed tomographic (CT) scan revealed diffuse bronchiectasis in both lungs. The patient had chronic diarrhea and poor weight gain, and the abdominal pancreaticobiliary CT scan revealed atrophy of the pancreas. Finally, CF was confirmed by the repeated analysis of the quantitative pilocarpine iontophoresis test. The chloride concentration of sweat samples taken from both forearms of the pateint was an average of 88.7 mM/L (normal value <40 mM/L). After a comprehensive search for mutations in the CFTR gene, the patient was found to carry the non-synonymous L441P mutation in one allele. Molecular physiologic analysis of the L441P mutation of CFTR revealed that the L441P mutation completely abolished the CFTR Cl(-) channel activity by disrupting proper protein folding and membrane trafficking of CFTR protein. These results confirmed the pathogenicity of the L441P mutation of CFTR circulating in the Korean population. The possibility of CF should be suspected in patients with chronic bronchiectasis, although the frequency of CF is relatively rare in East Asia. | Gold Standard | disease mechanism | 2 |
20067780 | 34,887,756 | Reduced plasma levels of Ang-2 and sEng as novel biomarkers in hereditary hemorrhagic telangiectasia (HHT) | Hereditary hemorrhagic telangiectasia (HHT; OMIM 187300) is an autosomal dominant vascular disorder characterized by telangiectases and internal arteriovenous malformations caused by mutations in certain elements of the TGF-beta receptor complex. In the case of HHT1 mutations in the endoglin gene are responsible, whereas mutations in the ALK1 gene (an activin receptor-like kinase 1), lead to HHT2. Another two loci found at chromosome 5 and chromosome 7, whose target genes remain unidentified, lead to types 3 and 4 of the disease, respectively. Mutations in the MADH4/SMAD4 gene, another member of the TGF-beta signalling pathway, lead to a combined syndrome of familial juvenile polyposis associated with HHT. In an attempt to identify some soluble components differentially expressed in the plasma of HHT patients, angiopoietin-2 and soluble endoglin concentrations were analyzed with standard quantitative sandwich ELISA. Angiopoietin-2 and soluble endoglin levels are reduced in plasma of HHT patients compared to control individuals, and a diagnostic algorithm for HHT based on these protein levels is proposed. Down-regulated protein levels of angiopoietin-2 and soluble endoglin in plasma represent novel HHT biomarkers that could be useful in the biochemical diagnosis of HHT facilitating the rapid identification of potential HHT patients. | Gold Standard | clinical characteristics or disease pathology | 0 |
20087969 | 11,451,779 | An epistaxis severity score for hereditary hemorrhagic telangiectasia | Hereditary hemorrhagic telangiectasia (HHT)-related epistaxis leads to alterations in social functioning and quality of life. Although more than 95% experience epistaxis, there is considerable variability of severity. Because no standardized method exists to measure epistaxis severity, the purpose of this study was to determine factors associated with patient-reported severity to develop a severity score. Prospective, survey-based study. HHT care providers and a focus group of patients were interviewed to determine epistaxis-associated factors. From this, an electronic survey was developed and administered to patients with HHT. Descriptive analyses were performed with calculations of means and medians for continuous and proportions for categorical variables. Multiple ordinal logistic and linear regression models were developed to determine risk factors for epistaxis severity. Nine hundred respondents from 21 countries were included. Eight hundred fifty-five (95%) subjects reported epistaxis. The mean (standard deviation) age was 52.1 (13.9) years, and 61.4% were female. Independently associated risk factors for self-reported epistaxis severity included epistaxis frequency (odds ratio [OR] 1.57), duration (OR 2.17), intensity (OR 2.45), need for transfusion (OR 2.74), anemia (OR 1.44), and aggressiveness of treatment required (OR 1.53, P < .001 for all). Risk factors for increasing epistaxis severity in patients with HHT include frequency, duration, and intensity of episodes; invasiveness of prior therapy required to stop epistaxis; anemia; and the need for blood transfusion. From these factors, an epistaxis severity score will be presented. | Gold Standard | clinical characteristics or disease pathology | 0 |
20093376 | 37,483,851 | Swarming motility, secretion of type 3 effectors and biofilm formation phenotypes exhibited within a large cohort of Pseudomonas aeruginosa clinical isolates | Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen capable of acutely infecting or persistently colonizing susceptible hosts. P. aeruginosa colonizes surfaces in vitro by either biofilm formation or swarming motility. The choice of behaviour is influenced by the physical properties of the surface and specific nutrient availability, and subject to regulatory networks that also govern type 2 and type 3 protein secretion. Biofilm formation by clinical isolates has been well-studied. However, the swarming behaviour of human isolates has not been extensively analysed. We collected isolates from 237 hospitalized patients without cystic fibrosis and analysed motility and secretion phenotypes of each isolate. We found biofilm formation and swarming to be negatively associated, while swarming was positively associated with the secretion of both proteases and type 3 exoenzymes. Most isolates were capable of type 3 secretion and biofilm formation, even though these traits are considered to favour distinct modes of pathogenesis. Our data demonstrate that while clinical isolates display diverse motility, biofilm and secretion phenotypes, many of the predicted relationships between swarming motility and other phenotypes observed in laboratory strains also hold true for bacteria isolated from human patients. | Gold Standard | disease mechanism | 2 |
20093519 | 41,267,898 | Pancreatic involvement in hereditary hemorrhagic telangiectasia: assessment with multidetector helical CT | To evaluate and describe pancreatic involvement by using multidetector computed tomography (CT) in patients with a diagnosis of hereditary hemorrhagic telangiectasia (HHT). Institutional review board approval was obtained, and all patients provided informed consent. Across 12 months, all consecutive adult patients with a confirmed diagnosis of HHT referred to our pluridisciplinary HHT center for evaluation were enrolled prospectively in the study and underwent contrast material-enhanced multidetector CT of the abdomen. Pancreatic telangiectases and arteriovenous fistulas were noted, and their characteristics were described. Genetic mutation was also investigated. Thirty-five patients (19 women, 16 men; mean age, 48.4 years) were included. All patients were asymptomatic. A genetic mutation was identified in 28 (80%) patients, including endoglin in 16 (57%), activin type-II-like receptor kinase 1 (ALK1) in 11 (39%), and SMAD4 in one (4%). Eleven (31%) patients exhibited pancreatic involvement. Fifty-four percent of patients with ALK1 mutation had pancreatic involvement. Twenty-three pancreatic telangiectases were identified during the arterial phase in nine patients. Seven pancreatic arteriovenous malformations (AVMs) were identified in four patients. Pancreatic involvement commonly is found in patients with HHT (31% in our study), mainly in patients with ALK1 mutation; pancreatic telangiectases or AVMs are only diagnosed duringthe arterial phase at multidetector CT. | Gold Standard | disease mechanism | 2 |
20097527 | 10,817,877 | Ventricular rotation is independent of cardiac looping: a study in mice with situs inversus totalis using speckle-tracking echocardiography. | of a mutant mouse model with a Dnah5 mutation to determine whether cardiac mechanics may be affected by reversal of cardiac situs. This mutant is a bona fide model of primary ciliary dyskinesia, with surviving homozygous mice showing either situs solitus (SS) or situs inversus totalis (SI). High-frequency ultrasound interrogations of 27 neonatal and infant Dnah5 mutant mice, 16 with SS and 11 with SI, were conducted using an ultra-high-frequency biomicroscope. Electrocardiographic and respiratory gating were used to reconstruct high-resolution two-dimensional cines at 1,000 Hz, with speckle-tracking echocardiography used to further analyze midchamber and apical rotation. All SS mice exhibited the expected counterclockwise apical rotation as viewed caudocranially, and surprisingly, the same counterclockwise motion was also observed in SI mice. Speckle-tracking analysis confirmed counterclockwise systolic rotation in both SS and SI mice, and this increased in magnitude from the subepicardium to the endocardium and from the papillary muscles to the apex. The magnitude of apical endocardial rotation was not different for SS and SI mice (5.64+/-0.75 degrees and 5.76+/-1.90 degrees, respectively, P=.93). The anatomic segments responsible for the largest components of apical endocardial systolic rotation differed between the SS and SI hearts (P=.004). In both, the two largest contributors to rotation were offset 180 degrees from each other, but the anatomic regions differed between them. In SS hearts, maximal regional rotation occurred at the anterior mid-septum and posterolateral free wall, while in SI hearts, it was derived from the posterior septum and the anterolateral free wall. Analysis by episcopic fluorescence image capture histology of representative SI and SS mice showed normal intracardiac and segmental anatomy ({S,D,S} or {I,L,I}) without intracardiac defects. These results show that mirror-image cardiac looping did not result in mirror-image rotation of the morphologic left ventricle. These findings suggest that further studies are warranted to evaluate whether fiber orientation and cardiac mechanics may be abnormal in individuals with reversal of cardiac situs. The results of this study indicate that cardiac looping and myofiber orientation may be independently regulated. | Gold Standard | disease mechanism | 2 |
20099136 | 8,164,561 | Heterologous expression of membrane proteins for structural analysis | Membrane proteins (MPs) are responsible for the interface between the exterior and the interior of the cell. These proteins are involved in numerous diseases, like cancer, cystic fibrosis, epilepsy, hyperinsulinism, heart failure, hypertension and Alzheimer disease. However, studies of these disorders are hampered by a lack of structural information about the proteins involved. Structural analysis requires large quantities of pure and active proteins. The majority of medically and pharmaceutically relevant MPs are present in tissues at low concentration, which makes heterologous expression in large-scale production-adapted cells a prerequisite for structural studies. Obtaining mammalian MP structural data depends on the development of methods that allow the production of large quantities of MPs. This review focuses on the heterologous expression systems now available to produce large amounts of MPs for structural proteomics, and describes the strategies that allowed the determination of the structure of the first heterologously expressed mammalian MPs. | Gold Standard | disease mechanism | 2 |
20100611 | 20,887,356 | A healthy birth after intracytoplasmic sperm injection using ejaculated spermatozoa from a patient with Kartagener's syndrome | To report a healthy birth that was achieved by intracytoplasmic sperm injection (ICSI) with use of ejaculated spermatozoa from a patient with Kartagener's syndrome. Case report. Private infertility clinic. Couple with male factor infertility due to Kartagener's syndrome. Intracytoplasmic sperm injection with ejaculated sperm. Semen characteristics, sperm motility, fertilization, pregnancy, and birth after ICSI. With ejaculated sperm, the fertilization rates were 73% in the first stimulation cycle and 100% in the second cycle. Intracytoplasmic sperm injection was successful. The pregnancy resulted in birth of a single healthy child. With ejaculated sperm, successful pregnancy after ICSI in couples with Kartagener's syndrome is possible. Kartagener's syndrome is a heterogeneous group of disorders with similar clinical presentations, and treatment should be individualized depending on sperm motility. | Gold Standard | therapeutics in the clinic | 3 |
20141966 | 5,534,683 | Thoracic endografting in a patient with hereditary hemorrhagic telangiectasia presenting with a descending thoracic aneurysm | A 53-year-old woman with no classic risk factors for aneurysm disease presented with the sudden onset of chest pain and dyspnea. A large descending thoracic aortic aneurysm with focal type B dissection was identified and excluded by emergency thoracic endografting. Further postoperative evaluation revealed a history of epistaxis, perioral telangiectasias, hepatic hypervascularity, and a mutation in the gene expressing activin receptor-like kinase 1 (ALK1), leading to a diagnosis of hereditary hemorrhagic telangiectasia. Aortic aneurysms associated with hereditary hemorrhagic telangiectasia are extremely rare, and to our knowledge, this is the first report of thoracic endografting in this patient population. | Gold Standard | therapeutics in the clinic | 3 |
20142516 | 1,932,232 | Regulation of conductance by the number of fixed positive charges in the intracellular vestibule of the CFTR chloride channel pore | Rapid chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is dependent on the presence of fixed positive charges in the permeation pathway. Here, we use site-directed mutagenesis and patch clamp recording to show that the functional role played by one such positive charge (K95) in the inner vestibule of the pore can be "transplanted" to a residue in a different transmembrane (TM) region (S1141). Thus, the mutant channel K95S/S1141K showed Cl(-) conductance and open-channel blocker interactions similar to those of wild-type CFTR, thereby "rescuing" the effects of the charge-neutralizing K95S mutation. Furthermore, the function of K95C/S1141C, but not K95C or S1141C, was inhibited by the oxidizing agent copper(II)-o-phenanthroline, and this inhibition was reversed by the reducing agent dithiothreitol, suggesting disulfide bond formation between these two introduced cysteine side chains. These results suggest that the amino acid side chains of K95 (in TM1) and S1141 (in TM12) are functionally interchangeable and located closely together in the inner vestibule of the pore. This allowed us to investigate the functional effects of increasing the number of fixed positive charges in this vestibule from one (in wild type) to two (in the S1141K mutant). The S1141K mutant had similar Cl(-) conductance as wild type, but increased susceptibility to channel block by cytoplasmic anions including adenosine triphosphate, pyrophosphate, 5-nitro-2-(3-phenylpropylamino)benzoic acid, and Pt(NO(2))(4)(2-) in inside-out membrane patches. Furthermore, in cell-attached patch recordings, apparent voltage-dependent channel block by cytosolic anions was strengthened by the S1141K mutation. Thus, the Cl(-) channel function of CFTR is maximal with a single fixed positive charge in this part of the inner vestibule of the pore, and increasing the number of such charges to two causes a net decrease in overall Cl(-) transport through a combination of failure to increase Cl(-) conductance and increased susceptibility to channel block by cytosolic substances. | Gold Standard | disease mechanism | 2 |
20149600 | 2,994,446 | Lennox-Gastaut syndrome in adulthood: clinical and EEG features | We performed a retrospective study to investigate seizure, EEG, social and cognitive outcome in adult LGS subjects. We retrospectively evaluated 27 LGS patients aged 40-59 years. We assessed in particular the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. During the early stages of the disease, all patients presented tonic seizures (TS) during wakefulness and sleep, 20/27 had atypical absences (AA), more rarely other seizure types. EEG showed slow background activity in 21/27 patients, diffuse slow spike-wave discharges (DSSW) during wakefulness in 22/27, and bursts of diffuse fast rhythms (DFR) in sleep in all patients. At last observation, 11 patients only had TS during wakefulness, but all still presented TS during sleep; AA persisted in 6 patients. EEG showed normal BA in 12/27 patients; only 7/27 still presented DSSW. On the contrary, sleep EEG showed the persistence of DFR in all. A moderate to severe cognitive impairment was observed in 26/27 patients. In adult LGS patients TS during sleep remain the major seizure type; moreover, a standard waking EEG may be normal. Thus, polysomnography represents the most important mean of investigation also in adult LGS patients. | Gold Standard | clinical characteristics or disease pathology | 0 |
20167855 | 32,667,407 | Lung function in patients with primary ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study | Early diagnosis and treatment is considered important to prevent lung damage in primary ciliary dyskinesia (PCD). Few studies have addressed long-term evolution of lung function after PCD diagnosis. We investigated whether long-term lung function was dependent on age or level of lung function at PCD diagnosis. An observational, single-center, cross-sectional, and three-decade longitudinal study of FEV(1) and FVC related to age at diagnosis until current age was performed. Linear regression was used to describe the relation between first measured lung function values and age at diagnosis across the cohort. Courses of lung function after diagnosis and the according slopes were used to group patients into increasing, stable, or decreasing courses. Additionally, slopes from courses of 10 years of follow-up were related to age at diagnosis and initial level of lung function, respectively, using linear regression. Seventy-four children and adults with PCD were observed for median 9.5 (range, 1.5-30.2) years during which 2,937 lung function measurements were performed. First measured FEV(1) was less than 80% of predicted in one-third of preschool-diagnosed children. During observation, 34% of patients lost more than 10 percentage points, 57% were stable, and 10% improved more than 10 percentage points in FEV(1). Courses of lung function after diagnosis were related to neither age at diagnosis nor initial level. Our study strongly suggests that PCD is a disease of serious threat to lung function already at preschool age, and with a high degree of variation in courses of lung function after diagnosis that was not linked to either age or level of lung function at diagnosis. Early diagnosis did not protect against decline in lung function. | Gold Standard | clinical characteristics or disease pathology | 0 |
20167933 | 207,553,696 | Prostaglandin E₂regulation of cystic fibrosis transmembrane conductance regulator activity and airway surface liquid volume requires gap junctional communication | Stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by protease-activated receptors (PARs) at the basolateral membranes and by adenosine receptors (ADO-Rs) at the apical membrane maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Both pathways involve the release of prostaglandin E₂ (PGE₂) and the stimulation of their basolateral receptors (EP-Rs). We sought to determine whether gap junctions contribute to the coordination of these pathways for modulating CFTR activity and mucus hydration. We used RT-PCR and Western blotting to determine connexin (Cx), CD73, and EP-R expression in a Calu-3 airway epithelial cell line grown on Transwell (Corning Costar, Cambridge, MA) inserts. We used dye coupling to evaluate gap junctional intercellular communication (GJIC). We used Ussing chamber studies and X-Z confocal microscopy to monitor Cl(-) secretion and ASL volume regulation. We found that connexin 43 (Cx43)-mediated GJIC was increased either by endogenous ADO after the hydrolysis of purine nucleotides by CD73 or by the direct activation of ADO-Rs. Inhibition of phospholipase A2 and cyclooxygenase prevented ADO-dependent increases in GJIC, suggesting the involvement of PGE₂. PGE₂ was found to increase GJIC markedly by stimulating EP4-Rs. The modulation of ADO signaling also affected the PAR-dependent activation of CFTR. The reduction of GJIC by CD73 or Cx43 inhibition prevented PAR-evoked CFTR currents in Ussing chambers. The inhibition of GJIC resulted in a failure of PGE₂ to increase ASL volume in Calu-3 cells and in primary cultures of well-differentiated human airway epithelial cells. Thus, gap junctions coordinate a signaling network comprising CFTR, ADO-Rs, PARs, and EP-Rs, and are required for ASL volume homeostasis. | Gold Standard | disease mechanism | 2 |
20169970 | 30,551,849 | Anesthetic management of a child with Lennox-Gastaut syndrome | General anesthesia was given twice to a 9-year-old girl with Lennox-Gastaut syndrome (LGS). LGS is one of the catastrophic forms of childhood epilepsy, and very few reports describe its anesthetic management. The anesthetic concern in LGS patients is a possibility of perioperative epilepsy due to proconvulsive effects of anesthesia-related drugs and due to the interaction between anesthetics and therapeutic drugs. Fortunately, her perioperative course was uneventful. The patients having LGS should be placed under careful observation postoperatively. | Gold Standard | therapeutics in the clinic | 3 |
20170910 | 205,048,931 | High diagnostic and clinical impact of small-bowel capsule endoscopy in patients with hereditary hemorrhagic telangiectasia with overt digestive bleeding and/or severe anemia | Patients with hereditary hemorrhagic telangiectasia (HHT) often present with recurrent anemia because of epistaxis or GI bleeding in relation to telangiectases mostly located in the stomach or small bowel. Capsule endoscopy is considered a major diagnostic tool for small-bowel diseases, but the impact of capsule endoscopy imaging on patient management in HHT is poorly understood. To clarify the contribution of capsule endoscopy in selected patients with HHT. Prospective, descriptive study. Multicenter, two university hospital tertiary-care centers, from January 2003 to June 2007. This study involved 30 patients with HHT and severe anemia (hemoglobin <9 g/dL; normal: 11-15 g/dL) and minimal epistaxis or moderate anemia but overt GI bleeding. Capsule endoscopy investigation. Clinical characteristics and capsule endoscopy results and their clinical consequences. Capsule endoscopy detected gastric and small-bowel telangiectases in 14 (46.7%) and 26 (86.7%) cases, respectively. Active bleeding was present in 36.7% of cases. Diffuse telangiectases were detected in 42.3% without correlation with age, sex, or type of HHT mutation. Further investigations were carried out as a consequence of the capsule endoscopy results in 67% of cases. Treatment, consisting mostly of endoscopic argon plasma coagulation, was scheduled in 46.7% of patients. Our population was essentially composed of patients with the ALK1 mutation. This study shows that there is a high diagnostic yield for capsule endoscopy in selected patients with HHT. Capsule endoscopy makes possible precise mapping of lesions and has a considerable impact on the management of these selected patients by using a predefined algorithm: a limited number of accessible lesions is suitable for endoscopic treatment, whereas innumerable diffuse lesions require a medical approach. We suggest that capsule endoscopy could be a first-line, noninvasive, digestive tract examination in selected patients with HHT. | Gold Standard | clinical characteristics or disease pathology | 0 |
20198988 | 34,894,848 | Endovascular treatment of hereditary hemorrhagic telangiectases of the tongue | Hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu disease, is an autosomal dominant disorder involving vascular abnormalities of various organs. Telangiectases are frequently observed, predominantly on the nasal and oral mucosa. We present a case a of 53-year-old man with the tonge hemorrhagic telangiectases and epistaxis. Selective catheterization and embolization of the right lingual artery led to size redution and no bleeding from tongue telangiectases. | Gold Standard | therapeutics in the clinic | 3 |
20199521 | 31,185,652 | Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study | This open-label extension evaluated the long-term efficacy and tolerability of rufinamide in patients with Lennox-Gastaut syndrome (LGS) who had previously completed a 12-week double-blind study. In total, 124 patients (aged 4-37 years), receiving 1-3 concomitant antiepileptic drugs, were treated with rufinamide approximately 25-60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests. Overall, patients were treated with rufinamide for a median (range) of 432 (10-1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had > or = 50% reduction in total and tonic-atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%). In this open-label extension, rufinamide appeared to be an effective long-term adjunctive therapy for the treatment of LGS-associated seizures in children and young adults. | Gold Standard | patient-based therapeutics | 4 |
20202952 | 32,249,931 | Hemothorax due to rupture of pulmonary arteriovenous malformation: an interventional emergency | Spontaneous hemothorax as a result of a ruptured pulmonary arteriovenous malformation (PAVM) is a life-threatening event and requires immediate interventional therapy. We present two patients who survived following emergent embolization. Definitive thoracentesis was delayed until embolization was performed. The tamponade provided by the hemothorax may have prevented exsanguination, suggesting to us that drainage of blood from the pleural space should be delayed until the PAVM has been treated. Hemorrhage from a PAVM may be the first manifestation of hereditary hemorrhagic telangiectasia. Genetic testing and screening for other family members should be considered. | Gold Standard | therapeutics in the clinic | 3 |
20224041 | 12,887,435 | Pathogenesis of arteriovenous malformations in the absence of endoglin | Arteriovenous malformations (AVMs) result in anomalous direct blood flow between arteries and veins, bypassing the normal capillary bed. Depending on size and location, AVMs may lead to severe clinical effects including systemic cyanosis (pulmonary AVMs), hemorrhagic stroke (cerebral AVMs) and high output cardiac failure (hepatic AVMs). The factors leading to AVM formation are poorly understood, but patients with the familial disease hereditary hemorrhagic telangiectasia (HHT) develop AVMs at high frequency. As most HHT patients have mutations in ENG (endoglin) or ACVRL1 (activin receptor-like kinase 1), a better understanding of the role of these genes in vascular development is likely to reveal the etiology of AVM formation. Using a mouse with a conditional mutation in the Eng gene, we investigated the sequence of abnormal cellular events occurring during development of an AVM. In the absence of endoglin, subcutaneous Matrigel implants in adult mice were populated by reduced numbers of new blood vessels compared with controls, and resulted in local venous enlargement (venomegaly). To investigate abnormal vascular responses in more detail, we turned to the more readily accessible vasculature of the neonatal retina. Endoglin-deficient retinas exhibited delayed remodeling of the capillary plexus, increased proliferation of endothelial cells and localized AVMs. Muscularization of the resulting arteriovenous shunts appeared to be a secondary response to increased blood flow. AVMs develop when an angiogenic stimulus is combined with endoglin depletion. Moreover, AVM formation appears to result from the combination of delayed vascular remodeling and an inappropriate endothelial cell proliferation response in the absence of endoglin. | Gold Standard | disease mechanism | 2 |
20309575 | 36,483,599 | The characterization of the first anti-mouse Muc6 antibody shows an increased expression of the mucin in pancreatic tissue of Cftr-knockout mice | Gel-forming mucins are large high-molecular weight secreted O-glycoproteins responsible for the gel-properties of the mucus blanket. Five orthologous gel-forming mucins have been cloned in human and mouse. Among them, the mucin MUC6 has been less studied, particularly in rodents and no anti rodent-Muc6 antibody has been reported yet. In order to further study Muc6 in mice, our aims were to obtain a specific Muc6 antibody, to validate it and to test it in Cftr deficient mice. A polyclonal serum named CP4 was isolated from a rabbit immunized by a mouse Muc6 peptide. In Western blot experiments, the antibody detected a high-molecular weight molecule secreted by the gastric tissue. Using immunohistochemistry, we showed that the antibody reacted strongly with deep glands of duodenum and ileum and mucous neck cells of gastric body. CP4 also recognized Muc6 protein secreted at the surface of the stomach and renal collecting tubules. The centroacinar cells of pancreatic tissue also reacted with the antibody. Cftr-/- mice showed a higher expression of Muc6 at both protein and RNA levels compared with their control Cftr+/+ littermates suggesting that as in the human disease, Muc6 may contribute to the formation of materials that block pancreatic acini and ducts in mouse models of cystic fibrosis. The rabbit anti-mouse Muc6 polyclonal antibody seems highly specific to the mouse mucin and will be useful to study pancreatic pathology in cystic fibrosis. | Gold Standard | disease mechanism | 2 |
20335083 | 10,169,843 | Value of nasal nitric oxide in the diagnosis of primary ciliary dyskinesia | The aim of this study is to report nasal nitric oxide (nNO) values in children with primary ciliary dyskinesia (PCD) and to compare them with nNO values in healthy children, asthmatic children, children with cystic fibrosis and children with post infectious bronchiectasis. We determined nNO values in 9 children with PCD, 36 asthmatic children, 31 children with cystic fibrosis, 8 children with post infectious bronchiectasis and 37 healthy children. We compared nNO values between these different conditions and calculated sensitivity and specificity of nNO to diagnose PCD. All children with PCD - except one (nNO 348 ppb) - had nNO values below 112 ppb, mean 88 ppb (95%CI 9.6-166). The nNO mean was 898 ppb (95%CI 801-995) in healthy children, 1023 ppb (95%CI 911-1137) in asthmatic children, 438 ppb (95%CI 367-508) in cystic fibrosis children and 361 ppb (95%CI 252-470) in children with post infectious bronchiectasis. The mean concentration of nNO was lower (P<0.05) in PCD patients, compared to the other groups. The measurement of nasal NO in our study population showed, at a cut-off level of < or =112 ppb, a sensitivity of 88.9% and a specificity of 99.1% in the diagnosis of PCD [ROC 0.98 (95%CI 0.94-0.99); P<0.0001; probability ratio 95.1]. The measurement of nasal NO appears to be a useful tool for screening children for PCD, in which a cut-off level of < or =112 ppb suggests the disease, although nNO above 112 ppb does not exclude PCD. | Gold Standard | clinical characteristics or disease pathology | 0 |
20345938 | 38,802,020 | Infantile epileptic encephalopathy with late-onset spasms: report of 19 patients | Late-onset spasms (LOS) are epileptic spasms starting after the first year of life. Our aim was to assess the electroclinical features and the follow-up of the patients with this particular type of epileptic seizure. We retrospectively included all patients with LOS confirmed by electroencephalography between 1989 and 2008. Clinical and electroencephalographic findings at diagnosis and during follow-up were collected. The Vineland scale was used to evaluate the neuropsychological outcome. We report 19 patients with LOS of 240 patients with recorded epileptic spasms. Eighteen patients had an epileptic encephalopathy with late-onset spasms. The ictal electroencephalography (EEG) showed a focal or generalized discharge of triphasic slow-waves, slow-spikes, or slow spikes-waves with fast activities. The interictal EEG usually showed focal or generalized slow-waves or slow spikes-waves without hypsarhythmia. LOS were controlled in only six patients. Three developed typical Lennox-Gastaut syndrome and 10 had a severe epileptic encephalopathy. Neuropsychological outcome was evaluated in 15 patients with the Vineland scale. Cognitive functions were normal in only one patient, whereas severe cognitive delay was observed in 12 of 15. Epileptic spasms may appear after the age of one. They are more frequently observed in patients with epileptic encephalopathy. In few patients this type of seizure was observed before the patients fulfill Lennox-Gastaut syndrome criteria. In one patient, we diagnosed a focal epilepsy with seizures occurring in cluster. When LOS are related to an epileptic encephalopathy, this epileptic syndrome seems to be linked to refractory epilepsy and severe cognitive outcome unrelated to the etiology. | Gold Standard | clinical characteristics or disease pathology | 0 |
20346358 | 38,289,608 | Chloride channels and transporters in human corneal epithelium | Transport of water and electrolytes is critical for corneal clarity. Recent studies indicate another important function of transport of ions and electrolytes - establishing wound electric fields that guide cell migration. We found chloride (Cl(-)) flux is a major component of the corneal wound electric current. In order to elucidate the mechanisms of Cl(-) transport, we studied Cl(-) channels and transporters in human corneal epithelial (HCE) cells. We tested a transformed human corneal epithelial cell line (tHCE), primary cultures of human corneal epithelial cells (pHCE), and human donor corneas. We first used RT-PCR to determine expression levels of mRNA of CLC (Cl(-) channels/transporters of CLC gene family) family members and CFTR (cystic fibrosis transmembrane conductance regulator) in HCE cells. We then confirmed protein expression and distribution of selected CLC family members and CFTR with Western blot and immunofluorescence confocal microscopy. Finally, Cl(-) currents were recorded with electrophysiological techniques. The mRNAs of CLC-2, CLC-3, CLC-4, CLC-5, CLC-6, and CFTR were detected in the HCE cell line. CLC-1 and CLC-7 were not detectable. Western blot and immunostaining confirmed protein expression and distribution of CLC-2, CLC-3, CLC-4, CLC-6 and CFTR in human corneal epithelium. CLC-2 preferentially labeled the apical and basal layers, while CLC-3 and CLC-4 labeled only the superficial layer. CLC-6 and CFTR labeling showed a unique gradient with strong staining in apical layers which gradually decreased towards the basal layers. Corneal endothelium was positive for CLC-2, CLC-3, CLC-4, CLC-6 and possibly CFTR. Human corneal epithelial cells demonstrated voltage dependent Cl(-) currents. HCE cells express functional Cl(-) channels and transporters. CLC-2, CLC-3, CLC-4, CLC-6, and CFTR had distinct expression patterns in human corneal epithelium. Those molecules and their distribution may play important roles in maintaining resting Cl(-) fluxes and in regulating Cl(-) flux at corneal wounds, which may be a major contributor to wound electrical signaling. | Gold Standard | disease mechanism | 2 |
20350728 | 162,411 | Primary ciliary dyskinesia in Amish communities | Primary ciliary dyskinesia is an autosomal recessive multigenic disease that results in impaired mucociliary clearance. We have diagnosed 9 subjects with primary ciliary dyskinesia from geographically dispersed Amish communities, on the basis of clinical characteristics and ciliary ultrastructural defects. Despite consanguinity, affected individuals had evidence of genetic heterogeneity. | Gold Standard | clinical characteristics or disease pathology | 0 |
20368796 | 13,890,898 | Intensity-modulated radiotherapy for a rendu-osler-weber disease patient with recurrent severe epistaxis: a case report | We present a case of a Rendu-Osler-Weber disease patient with recurrent life threatening epistaxis demanding multiple blood transfusions despite of repetitive endoscopic laser and electrocoagulations, endovascular embolisation, septodermoplasty, and long-term intranasal dressings. As alternative treatment modalities repeatedly failed and the patient became almost permanently dependent on nasal dressing, we performed a highly conformal intensity-modulated radiotherapy of the nasal cavity; a total dose of 50 Gy in 2 Gy single fractions was applied. The therapy was very well tolerated, no acute toxicities occurred. Two weeks after the last radiation dose had been applied, the nasal dressing could be removed without problems. Endoscopical control revealed an almost avascular white mucosa without any trace of bleeding spots; previously existing hemangiomas and crusts had disappeared. After a 1-year-follow up, the patient had no significant recurrent epistaxis. | Gold Standard | therapeutics in the clinic | 3 |
20384723 | 34,623,865 | Frameshift mutations of the ARX gene in familial Ohtahara syndrome | Ohtahara syndrome is one of the most severe and earliest forms of epilepsy and is frequently associated with brain malformations, such as hemimegalencephaly. Recently, longer expansion of the first polyalanine tract of ARX was found to be causative for Ohtahara syndrome without brain malformation, whereas premature termination mutations of ARX were found to cause severe brain malformations, such as lissencephaly or hydranencephaly. Both are designated as ARX-related interneuronopathies. We investigated the molecular basis of Ohtahara syndrome in two families, comprising six male patients in two generations demonstrating X-linked inheritance. Novel frameshift mutations in the terminal exon of the ARX gene (Ala524fsX534 and E536fsX672) were identified in two patients (2 and 13 years, each) from both families. Two patients developed West syndrome, and one of these later developed Lennox-Gastaut syndrome. Brain magnetic resonance imaging (MRI) of all patients showed no brain malformations in contrast to the patients with a premature termination mutation in other exons of ARX. The etiology of Ohtahara syndrome is heterogeneous; however, the molecular analysis of ARX should be considered in sporadic or familial male patients with Ohtahara syndrome. | Gold Standard | disease mechanism | 2 |
20414677 | 5,743,541 | Update on molecular diagnosis of hereditary hemorrhagic telangiectasia | Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disease hallmarked by the development of arteriovenous malformations (AVMs). Germline mutations in two genes, endoglin (ENG) and activin receptor like kinase 1 (ACVRL1), have been implicated in this disease. This report describes molecular diagnosis in a consecutive series of 600 individuals with clinical features of HHT disease. Each coding exon and flanking intronic regions of ENG and ACVRL1 genes was sequenced. Exonic copy number was quantified in probands without a coding sequence mutation. Novel nonsynonymous variants were further analyzed to predict functional consequences. In addition, common single nucleotide polymorphisms genotypes and haplotypes for the two genes were compared between individuals with and without mutations. The highest mutation detection rate (87% [95% CI 80.2-91.5]) was observed in probands who met all four Curacao criteria (epistaxis, telangiectases, AVMs and family history). More than 30% of identified mutations were novel; however, only 6% were variants of unknown significance. Determining the significance of novel mutations as related to disease presents additional challenges. Detection of multiple alterations in the same proband also requires careful evaluation for disease association. In conclusion, the sensitivity of molecular diagnosis is highest in probands with a clinically confirmed diagnosis of HHT. However, a substantial fraction of probands in this group do not carry an identifiable mutation in the coding exons of these two genes. This suggests alternate mechanisms of gene inactivation or involvement of alternate loci, and it requires further investigation. | Gold Standard | disease mechanism | 2 |
20458853 | 27,514,989 | Fatal hypoxic hepatitis in a patient with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber's disease) | Hypoxic (ischemic) hepatitis generally requires the concurrence of an underlying condition which chronically exposes the liver to some degree of hypoxia (for example, congestive heart failure) combined with a triggering event (for example, arrhythmia) which further decreases the oxygen supply. We report a case of hypoxic hepatitis in which hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber's disease) constituted this underlying condition and gastrointestinal hemorrhage was the triggering event. To our knowledge, this is the first reported case of hypoxic hepatitis in hereditary hemorrhagic telangiectasia with the exception of therapeutic ligation or embolization of the hepatic artery so as to decrease shunting of liver blood. Hemodynamic mechanisms are proposed to explain this particular outcome. | Gold Standard | clinical characteristics or disease pathology | 0 |
20463179 | 22,296,052 | Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation | Patients with cystic fibrosis periodically experience pulmonary exacerbations. Previous studies have noted that some patients' lung function (FEV(1)) does not improve with treatment. To determine the proportion of patients treated for a pulmonary exacerbation that does not recover to spirometric baseline, and to identify factors associated with the failure to recover to spirometric baseline. Cohort study using the Cystic Fibrosis Foundation Patient Registry from 2003-2006. We randomly selected one pulmonary exacerbation treated with intravenous antibiotics per patient and compared the best FEV(1) in the 3 months after treatment with the best FEV(1) in the 6 months before treatment. Recovery to baseline was defined as any FEV(1) in the 3 months after treatment that was greater than or equal to 90% of the baseline FEV(1). Multivariable logistic regression was used to estimate associations with the failure to recover to baseline FEV(1). Of 8,479 pulmonary exacerbations, 25% failed to recover to baseline FEV(1). A higher risk of failing to recover to baseline was associated with female sex; pancreatic insufficiency; being undernourished; Medicaid insurance; persistent infection with Pseudomonas aeruginosa, Burkholderia cepacia complex, or methicillin-resistant Staphylococcus aureus; allergic bronchopulmonary aspergillosis; a longer time since baseline spirometric assessment; and a larger drop in FEV(1) from baseline to treatment initiation. For a randomly selected pulmonary exacerbation, 25% of patients' pulmonary function did not recover to baseline after treatment with intravenous antibiotics. We identified factors associated with the failure to recover to baseline, allowing clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment. | Gold Standard | therapeutics in the clinic | 3 |
20466398 | 207,213,368 | Brain abscess as the first clinical manifestation of isolated pulmonary arteriovenous malformation without Rendu-Osler disease | Brain abscesses occur in 5 to 13 % of patients with pulmonary arteriovenous malformation (PAVM), more often present in Rendu-Osler-Weber disease or hereditary hemorrhagic telangiectasia (HHT). A 51-year-old man with a history of transient Parinaud syndrome at 37 years complained of **headache** for 2 months before **acute onset of a left cerebellar syndrome without fever.** CT-scan and **MRI of the head revealed a heterogeneous left cerebellar lesion.** **A brain abscess was drained and all signs resolved.** CT-scan of the chest revealed a left lingual PAVM; occlusion was incomplete after **coil embolization.** He had no feature of HHT and no mutation in ENG and ACVRL1 genes. A **second embolization** was performed 5 months later, but the malformation was not occluded at 6 months. We report the seventh case of PAVM complicated by a cerebellar abscess. The right to left shunt in PAVM results in hypoxemia, secondary polycythemia and paradoxical embolization of infective organisms bypassing the pulmonary filter. Combining different MRI techniques (in particular diffusion and proton MR spectroscopy) provides invaluable data for the diagnosis of brain abscess. Careful search for PAVM must be undertaken, particularly in adults with cryptogenic abscess, to avoid further abscess formation or stroke. | Gold Standard | clinical characteristics or disease pathology | 0 |
20481640 | 11,282,719 | Drug metabolite-specific lymphocyte responses in sulfamethoxazole allergic patients with cystic fibrosis | Sulfamethoxazole (SMX) is an important antibiotic in the management of patients with cystic fibrosis, but allergic reactions may develop thus restricting therapy. The aim of this study was to utilize drug (metabolite) antigens to diagnose SMX-mediated allergic reactions in patients with cystic fibrosis. Lymphocytes from 2/12 allergic patients were stimulated to proliferate strongly with the SMX metabolite nitroso SMX (SMX-NO). In contrast, responses to SMX were weak. The introduction of an antigen-driven T-cell enrichment step prior to the analysis of proliferation increased the sensitivity of the assay. SMX-NO responses were detected with lymphocytes from all patients with cutaneous signs. | Gold Standard | clinical characteristics or disease pathology | 0 |
20495106 | 44,727,235 | Predictors of influenza vaccination in the Cystic Fibrosis Foundation patient registry, 2006 through 2007 | Influenza vaccination is recommended for all persons with cystic fibrosis (CF). Despite this recommendation, no study has been performed to determine factors associated with receipt of influenza vaccination among persons with CF. We conducted a 2-year cohort study from 2006 through 2007 using the CF Foundation (CFF) Patient Registry to assess predictors of influenza vaccination with logistical regression modeling. In 2006, the cohort consisted of 16,435 persons with vaccination data seen at CFF care centers. Vaccination rates were high for children aged < 5 years (90.5%), children 5 to < 18 years (91.1%), and adults (87.9%). In 2006, decreased odds of vaccination were seen among adults with other or unknown insurance (0.37; 95% CI, 0.15-0.87). Among children 5 to < 18 years and adults, decreased odds of vaccination were seen among Hispanics (children, 0.74; 95% CI, 0.55-0.98; adults, 0.67; 95% CI, 0.46-0.98) and with use of oxygen therapy (children, 0.55; 95% CI, 0.38-0.78; adults, 0.68; 95% CI, 0.55-0.86), whereas four or more clinic visits annually was associated with increased odds of vaccination (children, 2.33; 95% CI, 1.92-2.84; adults, 2.05; 95% CI, 1.71-2.47). Findings associated with decreased vaccine receipt remained significant in sensitivity analyses that assumed missing vaccination data were vaccine positive. Overall influenza vaccination rates are very high in the US CF population. Knowledge of influenza vaccination predictors among persons with CF may aid clinicians in targeting patients at greater risk for influenza infection. These data may have important implications for the evolving pandemic 2009 influenza A(H1N1). | Gold Standard | therapeutics in the clinic | 3 |
20519934 | 25,317,320 | SPLUNC1 expression reduces surface levels of the epithelial sodium channel (ENaC) in Xenopus laevis oocytes | Throughout the body, the epithelial Na+ channel (ENaC) plays a critical role in salt and liquid homeostasis. In cystic fibrosis airways, for instance, improper regulation of ENaC results in hyperabsorption of sodium that causes dehydration of airway surface liquid. This dysregulation then contributes to mucus stasis and chronic lung infections. ENaC is known to undergo proteolytic cleavage, which is required for its ability to conduct Na+ ions. We have previously shown that the short, palate lung and nasal epithelial clone (SPLUNC1) binds to and inhibits ENaC in both airway epithelia and in Xenopus laevis oocytes. In this study, we found that SPLUNC1 was more potent at inhibiting ENaC than either SPLUNC2 or long PLUNC1 (LPLUNC1), two other PLUNC family proteins that are also expressed in airway epithelia. Furthermore, we were able to shed light on the potential mechanism of SPLUNC1's inhibition of ENaC. While SPLUNC1 did not inhibit proteolytic activity of trypsin, it significantly reduced ENaC currents by reducing the number of ENaCs in the plasma membrane. A better understanding of ENaC's regulation by endogenous inhibitors may aid in the development of novel therapies designed to inhibit hyperactive ENaC in cystic fibrosis epithelia. | Gold Standard | disease mechanism | 2 |
20537283 | 30,640,323 | Role of adenylate kinase type 7 expression on cilia motility: possible link in primary ciliary dyskinesia | Adenylate kinase 7 (AK7) mediates the reaction 2ADP <--> ATP + AMP, providing energy for the beating of cilia. A study recently showed that AK7 expression may be correlated with the primary ciliary dyskinesia (PCD) phenotype in mice. In this study, we characterized AK7 expression in vitro in an air-liquid interface (ALI) model and in middle nasal turbinate biopsy specimens from a cohort of patients with PCD to elucidate whether AK7 expression is correlated with ciliary malfunction. AK7 expression was measured by real-time reverse-transcription polymerase chain reaction and Western blotting. In vitro differentiated nasal human epithelial cell siRNA experiments were performed to investigate the effect of AK7 expression on ciliary beat frequency (CBF). Ciliary motility and ultrastructure were evaluated in a cohort of 29 patients with PCD (PCD, n = 17; Kartagener's syndrome, n = 12) and 26 healthy control donors. AK7 expression was mainly located on the apical surface of differentiated nasal ALI cells, and targeted suppression of the AK7 gene decreased CBF by 41%. AK7 expression was diminished significantly in patients with PCD (0.54 +/- 0.1-fold; p < 0.05) compared with healthy controls (1.1 +/- 0.08-fold). Furthermore, AK7 expression was correlated with CBF in patients with PCD (r = 0.5; p = 0.009). AK7 expression was correlated with CBF in vitro and in nasal biopsy specimens from patients with PCD, which may have contributed to the ciliary malfunction observed in our patients with PCD. | Gold Standard | disease mechanism | 2 |
20542434 | 39,039,282 | Lennox-Gastaut syndrome and idiopathic intracranial hypertension | Lennox-Gastaut Syndrome is a severe childhood epilepsy syndrome characterised by the diagnostic triad of a slow spike and wave pattern on electroencephalogram, multiple seizure types and developmental delay. Idiopathic intracranial hypertension is a syndrome characterised by raised cerebrospinal fluid pressure in the absence of an intracranial mass lesion or ventricular dilatation and often headache. We present the first reported case of Lennox-Gastaut Syndrome associated with symptomatic idiopathic intracranial hypertension in a 15 year old male, requiring cerebrospinal fluid diversion by means of ventriculoperitoneal shunting. | Gold Standard | clinical characteristics or disease pathology | 0 |
20564725 | 2,027,821 | Characteristics of chloride transport in nasal mucosa from patients with primary ciliary dyskinesia | Primary ciliary dyskinesia (PCD) is an inherited disorder that produces lifelong difficulties with chronic airway inflammation. Little is known about the role of chronic airway inflammation on chloride ion transport properties in PCD. This study assessed the cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl) ion transport properties of freshly excised nasal mucosa from PCD compared with normal and chronic rhinosinusitis (CRS). Electrophysiology study utilizing Ussing type hemi-chamber technique with three different types of nasal tissue (normal, CRS, PCD) obtained from patients during endoscopic surgery at a tertiary referral center. Nasal tissues were examined under short-circuit conditions, and gradient-driven Cl currents were continuously recorded. The cAMP elevating agonist (forskolin) was added to stimulate cystic fibrosis transmembrane conductance regulator-mediated Cl secretion. To prevent misinterpretation of flux measurement, Cl transport inhibitors were used at the end of all experiments. Basal Cl currents (I(Cl)) and changes in I(Cl) to forskolin (DeltaI(Cl)) were compared between normal, CRS, and PCD nasal tissues. Forskolin stimulated Cl currents across all different types of nasal epithelia. The Cl secretory response was effectively blocked by the Cl ion transport inhibitors. I(Cl) were significantly higher in normals (155.0 +/- 9.3 microA/cm(2)) compared to CRS (79.1 +/- 15.0 microA/cm(2)) and PCD (70.9 +/- 20.4 microA/cm(2)) (P = .005). DeltaI(Cl) in CRS (14.8 +/- 2.3 microA/cm(2)) and PCD (12.2 +/- 2.4 microA/cm(2)) were markedly diminished compared to normals (28.3 +/- 4.7 microA/cm(2)) (P = .024). PCD tissues were characterized by impaired I(Cl) and DeltaI(Cl). Both parameters were reduced by 54.3% and 56.9% in PCD when compared to normals. | Gold Standard | disease mechanism | 2 |
20569877 | 205,002,626 | Tolerance and efficacy of ceftazidime in combination with aztreonam for exacerbations of cystic fibrosis | Antibiotic therapy for acute pulmonary exacerbations in patients with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility. This can be difficult when bacteria are multiresistant. The objective of this retrospective study was to evaluate the tolerance and efficiency of ceftazidime and aztreonam combination (+/-tobramycin, +/-ciprofloxacin) in the treatment of acute exacerbations in cystic fibrosis patients who were chronically colonized with multiresistant P. aeruginosa. Seventeen severe patients, with FEV(1)=1070+/-66 mL and BMI=18+/-0.6 kg/m(2), who had chronic colonisation with P. aeruginosa with intermediate sensitivity or resistance to ceftazidime and aztreonam, were studied between June 2003 and March 2007. Oxygen saturation, dyspnoea, weight, FEV(1), FVC, and tolerance were evaluated before and after antibiotic courses. Forty-two courses of treatment, administered between June 2003 and March 2007 were studied: Patients increased their FEV(1) and FVC (p=0.01). One antibiotic course was stopped after four days because of cutaneous side effects. The median delay until the next exacerbation was 101+/-10 days. These courses were compared with other combinations of antibiotics that the patients had received before. The combination of ceftazidime and aztreonam was more effective in patients receiving less than four courses per year for acute pulmonary exacerbation. In chronically P. aeruginosa colonised cystic fibrosis patients, ceftazidime and aztreonam combination (+/-tobramycin, +/-ciprofloxacin) is well tolerated and efficient. This treatment suggests a clinical and functional benefit is possible, even in patients with severe disease. | Gold Standard | therapeutics in the clinic | 3 |
20597077 | 37,947,006 | Measurement of airway ion transport assists the diagnosis of cystic fibrosis | The nasal potential difference (PD) demonstrates the increased Na absorption and decreased Cl secretion typically found in cystic fibrosis (CF). It provides useful information for diagnostic purposes and measures the effect of new treatments on the ion transport defects found in CF. This study summarizes the nasal PD results in the respiratory tract of different groups of subjects, examines the responses in squamous epithelia and evaluates new ways to consider nasal PD results.Nasal PD was tested using the standard protocol of baseline, amiloride, low chloride, and isoproterenol solutions in 40 healthy non-CF volunteers, 46 CF subjects, and 78 subjects referred for investigation of possible CF. Nasal PD was also measured in the squamous epithelium at the anterior nares in six non-CF subjects.Baseline PD was elevated in the CF (47.5 (1.7) mV) compared with non-CF subjects: (14.0 (0.8) mV, P < 0.00001). Combined [Cl + Isop] responses were smaller in the CF (-0.1 (0.4) mV) compared with the non-CF subjects (26.2 (1.2) mV, P < 0.00001). In the diagnostic cohort 58 were given a non-CF diagnosis, 16 had CF confirmed, but 4 remained indeterminate. Separate consideration of Na and Cl transport was easily portrayed through X-Y plots. Finally, the nasal PD responses of squamous epithelium showed high baseline values, but little response to amiloride and low chloride solutions.The nasal PD provides useful information in the diagnostic algorithm of CF, and in the delineation of the two ion transport defects characteristically found in the respiratory epithelium. Avoidance of the squamous epithelium remains an important consideration for those performing and interpreting nasal PD responses. | Gold Standard | clinical characteristics or disease pathology | 0 |
20598586 | 16,565,240 | Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy--the Austrian experience | To evaluate the long-term efficacy/tolerability of the ketogenic diet (KD) in paediatric drug-resistant epilepsies. Data from children who were treated between 1999 and 2008 and had continuous follow-up of at least 6 months after initiation of the KD were analysed retrospectively. Response was defined as > or = 50% seizure reduction. Treatment effects on EEG, developmental outcome and the "outcome-predictive" value of various clinical factors were also assessed. 50 children (22 boys; mean age 4.5 years+/-3.55) were included. Mean follow-up was 3.93+/-2.95. 50% of the patients were responders, 48% of them became seizure free. 50% were non-responders, 20% of them deteriorated. In responders, EEG background activity improved significantly (p=0.014) and a significantly lower rate of epileptic discharges (p=0.009) was seen after 6 months. In addition, neurological examination findings demonstrated significant developmental progress (p=0.038). Favourable treatment outcome was associated with a shorter disease duration (p=0.025) and generalised tonic clonic seizures (p=0.059). No further significant outcome predictors were detected. However, response was 44% in patients with infantile spasms, 62.5% in those with Dravet syndrome and 50% in Lennox-Gastaut-syndrome. Side effects occurred in 28%, but discontinuation of the KD was not required in any case. They most often observed with concomitant topiramate (p=0.001) and valproate (p=0.046). Despite the retrospective nature of the study and the inhomogeneous patient sample, we found good long-term effects of the KD on seizure frequency, EEG and neurological development. | Gold Standard | therapeutics in the clinic | 3 |
20610118 | 34,957,305 | Infantile spasms: does season influence onset and long-term outcome? | To study whether onset of infantile spasms manifests seasonal variation, as previously reported, and whether any such seasonality is associated with treatment response and long-term outcome, data for 57 patients were retrospectively reviewed. The data were collected from hospital files and through a mail survey of children with infantile spasms born from 1980 to 2002 and monitored at the University Children's Hospital of Berne, Switzerland. The mean age at time of onset of infantile spasms was 7 months (range, 0.75-40), at diagnosis 8 months (range, 1-42) and at follow-up 11.3 years (range, 1-23 years). In 77% of participants, the etiology of infantile spasms was known (symptomatic); in the remaining 23% it was not known (nonsymptomatic). In contrast to previous findings, onset of infantile spasms was not associated with calendar month, photoperiod, or global solar radiation. Long-term prognosis was poor: 4 of the 57 (7%) children died; 49 (86%) had cognitive impairment and 40 (70%) had physical impairment; 31 (54%) had cerebral palsy, 37 had (65%) persistent seizures, and 9 (16%) had Lennox-Gastaut syndrome. Symptomatic infantile spasms were associated with worse cognitive outcome (P < 0.001), but treatment modality and overall duration of infantile spasms were not. There was no association of calendar month or photoperiod at onset with cognitive outcome or treatment response. | Gold Standard | clinical characteristics or disease pathology | 0 |
20618411 | 25,636,384 | Outcome of vagus nerve stimulation for epilepsy in Budapest | Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients with intractable epilepsy. Better clinical outcomes were recorded in nonfocal and Lennox-Gastaut syndrome (LGS). We conducted a 2-year, open label, prospective study to measure the seizure outcome of 26 VNS patients. The seizure numbers were assessed using clinician's global impression scale (CGI) and patient diaries. The average seizure reduction was 23% at the first year and 22% at the second year. Seizure reduction was more pronounced among patients with nonfocal than with focal epilepsy. The response rate was 50% at first year and 30% at the second year. The best CGI record for clinically significant improvement was 15% in the LGS group. The only statistically significant result was the reduction of the generalized tonic-clonic seizures (GTCS). The side-effect profile was good; however, the large number of mild and reversible effects influenced the stimulation parameters and thus probably the effectiveness of the therapy. We suggest that VNS is an optional treatment mostly in cases of therapy-resistant Lennox-Gastaut syndrome. Patients with GTCS may experience improvement such as reduction of seizure severity. We conclude that VNS is a safe neuromodulatory treatment, but future developments of neuromodulatory approaches are needed. | Gold Standard | patient-based therapeutics | 4 |
20618958 | 16,301,773 | Isolation and characterization of microparticles in sputum from cystic fibrosis patients | Microparticles (MPs) are membrane vesicles released during cell activation and apoptosis. MPs have different biological effects depending on the cell from they originate. Cystic fibrosis (CF) lung disease is characterized by massive neutrophil granulocyte influx in the airways, their activation and eventually apoptosis. We investigated on the presence and phenotype of MPs in the sputum, a rich non-invasive source of inflammation biomarkers, of acute and stable CF adult patients. Spontaneous sputum, obtained from 21 CF patients (10 acute and 11 stable) and 7 patients with primary ciliary dyskinesia (PCD), was liquefied with Sputasol. MPs were counted, visualized by electron microscopy, and identified in the supernatants of treated sputum by cytofluorimetry and immunolabelling for leukocyte (CD11a), granulocyte (CD66b), and monocyte-macrophage (CD11b) antigens. Electron microscopy revealed that sputum MPs were in the 100-500 nm range and did not contain bacteria, confirming microbiological tests. CF sputa contained higher number of MPs in comparison with PCD sputa. Levels of CD11a+-and CD66b+-, but not CD11b+-MPs were significantly higher in CF than in PCD, without differences between acute and stable patients. In summary, MPs are detectable in sputa obtained from CF patients and are predominantly of granulocyte origin. This novel isolation method for MPs from sputum opens a new opportunity for the study of lung pathology in CF. | Gold Standard | clinical characteristics or disease pathology | 0 |
20620301 | 12,323,173 | Primary lung tumors in children and adolescents: a 90-year experience | Primary lung tumors in children are rare. A wide range of histopathologic tumor types occurs. The incidence of these lesions and their outcomes are still largely unknown. **This study aims to determine the incidence of different primary lung tumors in children and to contribute data leading to the development of evidence-based treatment models. **A single institution retrospective **review** was performed with institutional review board approval. Patients were included if they had primary, nonhematologic lung tumors. Simple squamous papillomas subjected to endoscopic biopsy and not resected, and vascular lesions associated with multisystem lesions, such as hereditary hemorrhagic telangiectasia, were excluded. Medical records and pathologic material for patients from 1918 to 2008 were reviewed. Forty patients were identified (23 boys, 17 girls) with a mean age of 9.6 years (range, 3 months to 19 years). Fourteen distinct** histopathologic tumor** types were identified. The most common tumor types were carcinoid (8), inflammatory myofibroblastic tumor (7), and pleuropulmonary blastoma (6). Rare pediatric lung tumors including small cell carcinoma, adenocarcinoma, and pulmonary capillary hemangiomatosis were also seen. The mortality rate was 17.5% (7) in our series. **Chemotherapy** was used in 23% (9) and **radiation** in 20% (8) of the patients. Of the 33 survivors, 28 had follow-up with a median duration of 29.5 months (mean, 63.2 months; range, 1-471 months). Primary lung tumors in children are rare and histopathologically diverse. The tumor spectrum involves many types not seen in adults, and unlike adults, patients rarely have a history of exposure to external predisposing factors. Although complete resection remains the standard for treatment of most tumors, addition of adjuvant therapy is dependent on both tumor stage and histopathologic type. | Gold Standard | clinical characteristics or disease pathology | 0 |
20622729 | 206,086,329 | Unsuspected polymicrobial brain abscess arising from an intra-abdominal source in a patient with hereditary hemorrhagic telangiectasia | The unusual and unprecedented occurrence of a patient with hereditary hemorrhagic telangiectasia (HHT) and a polymicrobial abscess with three different organisms, including fungi, is reported. The patient was a 48-year-old woman with human immunodeficiency virus (HIV) infection and HHT who was brought to the hospital after a motor vehicle accident with altered mental status. Computed tomography did not reveal evidence of acute brain injury but showed a left frontal brain abscess. The patient underwent neurosurgical drainage of the abscess. On culture the abscess yielded methicillin-resistant Staphylococcus aureus, Streptococcus intermedius, and Candida guilliermondii. | Gold Standard | clinical characteristics or disease pathology | 0 |
20631900 | 8,657,496 | Triple-vessel percutaneous coronary revascularization in situs inversus dextrocardia | Dextrocardia with situs inversus occurs in approximately one in 10,000 individuals of whom 20% have primary ciliary dyskinesia inherited as an autosomal recessive trait. These patients have a high incidence of congenital cardiac disease but their risk of coronary artery disease is similar to that of the general population. We report what is, to our knowledge, the first case of total triple-vessel coronary revascularization by percutaneous stent implantation in a 79-year-old woman with situs inversus dextrocardia. We describe the successful use of standard diagnostic and interventional guide catheters with counter rotation and transversely inversed image acquisition techniques. The case also highlights that the right precordial pain may represent cardiac ischemia in this population. | Gold Standard | therapeutics in the clinic | 3 |
20650983 | 12,335,630 | Agenesis of paranasal sinuses and nasal nitric oxide in primary ciliary dyskinesia | Agenesis of paranasal sinuses has only been described in case reports of patients with primary ciliary dyskinesia (PCD). As agenesis of paranasal sinuses may contribute to low nasal nitric oxide levels, a common finding in PCD, we speculated that this condition might frequently occur in PCD patients. Patients referred for PCD evaluation were consecutively recruited for 30 months. In addition to standard diagnostic testing for PCD, a computed tomography (CT) scan of paranasal sinuses was performed in all subjects. 86 patients (46 children aged 8-17 yrs) were studied. PCD was diagnosed in 41 subjects and secondary ciliary dyskinesia (SCD) was diagnosed in the remaining 45 subjects. Frontal and/or sphenoidal sinuses were either aplastic or hypoplastic on CT scans in 30 (73%) out of 41 PCD patients, but in only 17 (38%) out of 45 with SCD (p = 0.002). There was a significant inverse correlation between the score for aplasia/hypoplasia of each paranasal sinus and nasal NO values in the PCD patients (p = 0.008, r = -0.432) but not in SCD (p = 0.07, r = -0.271). The findings of aplasia/hypoplasia of the frontal and or sphenoidal sinuses may be part of the spectrum of PCD and this finding should prompt exclusion of this condition. | Gold Standard | clinical characteristics or disease pathology | 0 |
20651854 | 41,856,093 | Characterization of clonal strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients in Ontario, Canada | Pseudomonas aeruginosa is an opportunistic pathogen that can form biofilms in the lungs and airways of cystic fibrosis (CF) patients, resulting in chronic endobronchial infection. Two clonal strains of P. aeruginosa, named type A and type B, have recently been identified and have been found to infect more than 20% of CF patients in Ontario, Canada. In this study, 4 type A and 4 type B isolates retrieved from 8 CF patients in Ontario, Canada, were characterized. All 8 isolates grew well in rich medium and formed biofilms in vitro. Antibiotic resistance profiles of bacteria grown in biofilms and planktonic culture were studied via minimal bactericidal concentration assays for tobramycin, gentamicin, and ciprofloxacin. Compared to laboratory strains of P. aeruginosa, all 8 isolates showed increased resistance to all antibiotics studied in both biofilm and planktonic assays. Gene expression analysis of mexX, representing the MexXY-OprM efflux pump, and mexA, representing MexAB-OprM, revealed that these genes were up-regulated in the 8 clinical isolates. These results suggest clonal type A and type B isolates of P. aeruginosa isolated from CF patients in Ontario, Canada, show a multidrug resistance pattern that can be partially explained as being due to the increased expression of common antibiotic efflux systems. | Gold Standard | disease mechanism | 2 |
20666130 | 3,463,183 | Treatment of childhood epilepsies: Japanese Expert Consensus study and a comparison of the results with those of the USA and EU | We conducted a Japanese Expert Consensus (EC) study for the treatment of childhood epilepsies following the method reported from the USA and EU (Wheless JW, et al., 2005, 2007), and compared the results to reveal differences in the choice of antiepileptic drugs (AEDs). The subjects were 41 pediatric board-certified epileptologists who responded to the 23 questionnaires. A 9-point scale was used to grade each AED, in which 9 was the best whereas 1 was the worst for appropriateness of choice for each epileptic syndrome. Lamotrigine (LTG) is frequently used for idiopathic generalized epilepsy except for valproate sodium (VPA) in both the USA and EU, while VPA and clonazepam were the main AEDs in Japan. For cryptogenic complex partial epilepsy and benign focal epilepsy, carbamazepine was a first-line AED among the USA, EU, and Japan, although other first-line AEDs were oxcarbamazepine (OCBZ), LTG, and levetiracetam (LEV) in both the USA and EU, while it was zonisamide in Japan. Regarding the treatment for symptomatic generalized epilepsy, West syndrome and Lennox-Gastaut syndrome, VPA and ACTH were first-line AEDs commonly used in the USA, EU, and Japan, while the other first-line AEDs were topiramate (TPM) and LTG in the USA and EU, and CZP and clobazam in Japan. This Japanese EC study demonstrated the difference in the selection of AEDs for epileptic syndromes between the USA and EU, which use more newly-introduced AEDs including TPM, LTG, OCBZ and LEV as first-and second-line AEDs, and Japan. | Gold Standard | therapeutics in the clinic | 3 |
20666837 | 30,396,165 | Rufinamide in refractory childhood epileptic encephalopathies other than Lennox–Gastaut syndrome | Background: To report on the first multicenter Italian experience with rufinamide as adjunctive drug in children, adolescents and young adults with refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. | Gold Standard | patient-based therapeutics | 4 |
20667149 | 8,168,304 | Repeatability of the 6-minute walk test in adolescents and adults with cystic fibrosis | To determine the repeatability of the 6-minute walk test (6MWT) in adolescents and adults with cystic fibrosis (CF). This was a prospective cross-sectional study. We included consecutive patients ages>or=15 years attending an adult CF program. The patients underwent the 6MWT, pulmonary function tests, and clinical evaluation. The second 6MWT was performed following a rest period of 60 min. Thirty-one patients were included. The mean+/-SD age was 23.5+/-6.7 y, and the mean FEV1 was 61+/-28% of predicted. The mean+/-SD walked distance in the first 6MWT was 583.6+/-68.6 m and in the second 6MWT was 590.0+/-72.2 m. The mean difference between the first and second 6MWT was -6.5 m, with limits of agreement between -74.9 m and 61.9 m, and the coefficient of variation was 4.3%. The mean oxygen desaturation in the first 6MWT was 2.5+/-4.5%, and in the second test it was 1.8+/-4.0%. The mean difference between the first and second test was 0.6%, and the coefficient of variation was 104%. Although the 6MWT distance was reproducible, the wide limits of agreement exceeded the minimum important difference for this test. These findings indicate that, in the routine evaluation of CF patients, at least two 6MWTs are required on any testing occasion to obtain a reliable estimate of the 6MWT distance. | Gold Standard | clinical characteristics or disease pathology | 0 |
20682136 | 24,571,852 | Nasal nitric oxide and pulmonary radioaerosol mucociliary clearance as supplementary tools in diagnosis of primary ciliary dyskinesia | Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive inherited disorder, characterized by abnormalities in ciliary structure and/or function. Frequent, intermittent or chronic airway infections precipitated by impaired airway mucociliary clearance may cause permanent lung damage and reduced lung function. Early diagnosis is considered important for the prevention of lung damage, but diagnosis is probably often delayed or even missed since diagnosis of PCD is both complex and time consuming, and yet not always exact. The aims of this PhD thesis were to evaluate the discriminative capacity and "real-life" clinical application of two candidates for supplemental diagnostic testing for PCD: Nasal nitric oxide (nNO) measurement placed as a first line test to point out probable PCD patients for further investigation or exclude patients, regardless of age, Pulmonary radioaerosol mucociliary clearance (PRMC) as a second line test for PCD investigation in children from 5 years of age. And additionally, Proposing an algorithm for the pathway of diagnosing PCD based on these two studies and recommendations from the literature. Nasal NO and PRMC demonstrated to be two highly valid supplementary diagnostic tools to be placed in each end of the diagnostic pathway when investigating selected patients referred for PCD work up. Nasal NO measurement demonstrated to have an obvious place as a first line test in the pathway of PCD investigation and PRMC as second line test as a supplement to ciliary function test and EM-test in cases of difficult diagnoses. Neither of these tests can stand alone in diagnosis or excluding of PCD. PCD remains to be a diagnosis that should be made at a tertiary PCD centre, as clinical evaluation of referred patients is crucial before excluding the disease. | Gold Standard | clinical characteristics or disease pathology | 0 |
20692461 | 39,388,301 | Case report: cystic fibrosis, lung transplantation, and the novel H1N1 flu | The H1N1 pandemic flu is a significant risk factor for both patients with chronic disease who need organ transplantation and transplant recipients. This population needs special care regarding comorbidities and related complications. MB, a 38-year-old Italian cystic fibrosis male patient with lung and pancreatic involvement, was referred to our division in July 2009 for fever-associated arthromyalgia, headache, and rhinitis. Lung transplantation had been performed in September 2005, and he was subsequently treated with immunosuppressive therapy: tacrolimus, everolimus, and prednisolone. In the past, chronic respiratory colonization with Pseudomonas aeruginosa and intermittent infection with Aspergillus flavus, chronic renal failure, hypertension, and diabetes mellitus complicated his clinical history. He started antiviral treatment with oseltamivir despite no travel history and no respiratory symptoms. H1N1 swab was positive. Three days later, the patient was admitted to the hospital for the persistence of fever and the onset of cough. Chest x-ray showed a left lower pneumonia, which was confirmed by computerized tomography. Broad-spectrum antibiotic therapy led to an improvement of the clinical condition. The patient was discharged 8 days later; a control swab was negative. This case report suggests some general considerations regarding solid organ recipients: 1) Flu-related complications require early treatment (both antiviral and antibiotic); 2) active microbiologic surveillance is important to prevent lethal infections (ie, invasive aspergillosis); 3) evaluation of immunosuppressant blood levels is necessary for drug-drug interactions. Active prevention is the best option for decreasing morbidity and mortality in the transplanted patient. | Gold Standard | therapeutics in the clinic | 3 |
20717170 | 242,550,250 | p | Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, 26 patients (5 having CF, 10 CBAVD (congenital bilateral absence of the vas deferens) and 11 with CF-like symptoms) and 14 healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from >2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution, give several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD. | Gold Standard | disease mechanism | 2 |
20797703 | 42,585,916 | A sperm viability test using SYBR-14/propidium iodide flow cytometry as a tool for rapid screening of primary ciliary dyskinesia patients and for choosing sperm sources for intracytoplasmic sperm injection | Spermatozoa viability tests based on dual-color flow cytometry after staining with Sybr-14/propidium iodide were performed on 44 men with complete asthenospermia for primary ciliary dyskinesia (PCD) screening, and seven were identified with PCD by electron microscopy of ultrastructural ciliary defects. Six PCD patients underwent eight intracytoplasmic sperm injection therapy cycles using ejaculated sperm or testicular sperm, obtaining a mean fertilization rate of 46.6%, with three healthy babies born and one in utero at the time of writing. | Gold Standard | therapeutics in the clinic | 3 |
20802934 | 22,184,169 | High prevalence of methicillin-resistant Staphylococcus aureus with SCCmec type III in cystic fibrosis patients in southern, Brazil | Bacterial colonization of the lungs is the main cause of morbidity in cystic fibrosis (CF). Pathogens such as Staphylococcus aureus are very well adapted to the pulmonary environment and may persist for years in the same patient. Genetic determinants of these bacteria, such as the presence of SCCmec have recently emerged as a problem in this population of patients. Staphylococcus aureus isolates obtained from different clinical materials coming from CF and non-CF patients attended at a cystic fibrosis reference hospital were compared according to SCCmec type and antibiotic susceptibility profile. Three hundred and sixty-four single-patient Staphylococcus aureus isolates were collected, of which 164 (45%) were from CF patients. Among the latter, 57/164 (44.5%) were MRSA, and among the non-CF patients, 89/200 (35%) were MRSA. Associated pathogens were found in 38 CF patients. All 57 MRSA from CF patients harbored the multiresistant cassette type III. In contrast, 31/89 MRSA from non-CF patients harbored SCCmec type I (35%) and 44/89 harbored type III (49%). The antibiotic susceptibility pattern was similar between CF and non-CF patients. The high prevalence of multiresistant SCCmec type III among CF patients compared with non-CF patients in our institution may make it difficult to control disease progression through antibiotic therapy for promoting the survival of this kind of patient. | Gold Standard | clinical characteristics or disease pathology | 0 |
20823030 | 206,548,744 | Experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation | We report our experience in a cohort of patients with hyperphenylalaninemia in a tertiary care referral center in Lebanon. Forty-one sequential patients were studied: 34 classical phenylketonuria (PKU), 3 hyperphenylalaninemia (non-PKU), and 4 biopterin metabolism defects. The majority of cases were clinically diagnosed at variable ages with variable neurological outcomes. Only 29.3% were detected by neonatal screening. Two unusual cases were observed in the context of inadequate treatment in 1 and delayed therapy in the other: a newborn with PKU developed severe keratomalacia; and a 5-year-old girl with dihydropteridine reductase deficiency due to a novel mutation identified in the quinoid dihydropteridine reductase gene developed Lennox-Gastaut syndrome and white matter changes with periventricular cysts. Part of our experience parallels that in the West. However, the clinical manifestations observed in our patients emphasize the importance of a national newborn screening program with efficient management of diagnosed cases. | Gold Standard | disease mechanism | 2 |
20842588 | 8,601,564 | New antiepileptic drugs: lacosamide, rufinamide, and vigabatrin | The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms. | Gold Standard | therapeutics in the clinic | 3 |
20868986 | 22,672,725 | Primary ciliary dyskinesia: Kartagener syndrome with central giant cell granuloma | A case report. This paper describes a clinical case of both giant cell granuloma and Kartagener syndrome in a 15-year-old male patient, with emphasis on the radiographic aspects of this extremely unusual pathology. To our knowledge, the presence of these 2 rare clinical conditions in the same patient has not been previously reported. | Gold Standard | clinical characteristics or disease pathology | 0 |
20888268 | 17,372,464 | Rufinamide in children and adults with Lennox–Gastaut syndrome: First Italian multicenter experience | adolescents and adults with Lennox-Gastaut syndrome. The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3-21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10mg/kg body weight, evenly divided in two daily doses and then increased by 10mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day. After a mean follow-up period of 12.3 months (range 3-21 months), the final mean dose of rufinamide was 33.5mg/kg/24h (range 11.5-60) if combined to valproic acid, and of 54.5mg/kg/24h (range 21.8-85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50-99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25-50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count. Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritability and loss of appetite. In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox-Gastaut syndrome and produced only mild or moderate adverse side effects. | Gold Standard | patient-based therapeutics | 4 |
20927127 | 11,520,009 | PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients | Cystic fibrosis (CF) is a common life-threatening autosomal recessive disorder in the Caucasian population, and the gene responsible is the CF transmembrane conductance regulator (CFTR). Patients with CF have repeated bacterial infection of the airways caused by Pseudomonas aeruginosa (PA), which is one of the predominant pathogen, and endobronchial chronic infection represents a major cause of morbidity and mortality. Pentraxin 3 (PTX3) is a gene that encodes the antimicrobial protein, PTX3, which is believed to have an important role in innate immunity of lung. To address the role of PTX3 in the risk of PA lung colonization, we investigated five single nucleotide polymorphisms of PTX3 gene in 172 Caucasian CF patients who were homozygous for the F508del mutation. We observed that PTX3 haplotype frequencies were significantly different between patients with PA colonization, as compared with noncolonized patients. Moreover, a protective effect was found in association with a specific haplotype (odds ratio 0.524). Our data suggest that variations within PTX3 affect lung colonization of Pseudomonas in patients with CF. | Gold Standard | disease mechanism | 2 |
20933420 | 51,809,318 | Cse1l is a negative regulator of CFTR-dependent fluid secretion | Transport of chloride through the cystic fibrosis transmembrane conductance regulator (CFTR) channel is a key step in regulating fluid secretion in vertebrates [1, 2]. Loss of CFTR function leads to cystic fibrosis [1, 3, 4], a disease that affects the lungs, pancreas, liver, intestine, and vas deferens. Conversely, uncontrolled activation of the channel leads to increased fluid secretion and plays a major role in several diseases and conditions including cholera [5, 6] and other secretory diarrheas [7] as well as polycystic kidney disease [8-10]. Understanding how CFTR activity is regulated in vivo has been limited by the lack of a genetic model. Here, we used a forward genetic approach in zebrafish to uncover CFTR regulators. We report the identification, isolation, and characterization of a mutation in the zebrafish cse1l gene that leads to the sudden and dramatic expansion of the gut tube. We show that this phenotype results from a rapid accumulation of fluid due to the uncontrolled activation of the CFTR channel. Analyses in zebrafish larvae and mammalian cells indicate that Cse1l is a negative regulator of CFTR-dependent fluid secretion. This work demonstrates the importance of fluid homeostasis in development and establishes the zebrafish as a much-needed model system to study CFTR regulation in vivo. | Gold Standard | disease mechanism | 2 |
20938370 | 25,804,761 | Skeletal muscle metabolism in cystic fibrosis and primary ciliary dyskinesia | Previous studies have reported differences in muscle function and metabolism between patients with cystic fibrosis (CF) and healthy controls (HC), but it is currently unknown whether these abnormalities are specific to CF or also seen in other airway diseases. In this study, we used magnetic resonance spectroscopy (MRS) during exercise to assess muscle metabolism in CF patients. Twenty patients with CF and 20 age, gender, and habitual activity-matched HCs and a respiratory disease comparison group with primary ciliary dyskinesia (PCD; n = 10) were studied. Phosphorus MRS (P-MRS) was used to characterize muscle bioenergetic metabolism at rest and after high-, moderate-, and low-intensity exercise. CF patients exhibited lower resting ATP/phosphocreatine (PCr) ratio and significantly higher end-exercise pH values compared with both HC and PCD patients. Both CF and PCD patients demonstrated significantly slower PCr recovery time constants after high-intensity exercise. Our results suggest that not only there are specific abnormalities of muscle metabolism in CF patients but also there is a nonspecific impact of respiratory disease on muscle function. | Gold Standard | clinical characteristics or disease pathology | 0 |
20947455 | 11,981,299 | Lactate in cystic fibrosis sputum | Antibiotic therapy is thought to improve lung function in patients with cystic fibrosis (CF) by decreasing neutrophil-derived inflammation. We investigated the origin and clinical significance of lactate in the chronically inflamed CF lung. Lactate was measured in sputa of 18 exacerbated and 25 stable CF patients via spectrophotometry and gaschromatography. Lung function was assessed via spirometry. Seven patients with chronic obstructive pulmonary disease (COPD) and three patients with acute lung inflammation served as control groups. Neutrophil and bacterial lactate production was assessed under aerobic and anaerobic conditions. In sputum specimens of patients with respiratory exacerbations lactate concentrations decreased significantly (p<0.005) from 3.4±2.3mmol/L to 1.4±1.4mmol/L after 2-3 weeks of intravenous antibiotics. Successful treatment was reflected in 16 patients (88.9%) by FVC increase associated with lactate decrease (p<0.05). In every single sputum lactate was detectable (3.0±3.1mmol/L, range 0.2-14.1mmol/L). Lactate was lower (1.6±0.8mmol/L) in sputa from seven COPD patients, and it was below the detection limit in three patients with acute lung inflammation. Neutrophil lactate production accumulated up to 10.5mmol/L after 4 days, whereas bacterial lactate production did not appear to contribute substantially to sputum lactate concentrations. Successful antibiotic therapy is reflected by a decrease in lactate concentrations. Neutrophils are the most likely source for lactate in sputum of CF patients. Therefore lactate may be used to monitor responses to antibiotic therapy as an adjunct to lung function measurements. | Gold Standard | therapeutics in the clinic | 3 |
20961363 | 41,560,815 | Potential of ceragenin CSA-13 and its mixture with pluronic F-127 as treatment of topical bacterial infections | Ceragenin CSA-13 is a synthetic mimic of cationic antibacterial peptides, with facial amphiphilic morphology reproduced using a cholic acid scaffold. Previous data have shown that this molecule displays broad-spectrum antibacterial activity, which decreases in the presence of blood plasma. However, at higher concentrations, CSA-13 can cause lysis of erythrocytes. This study was designed to assess in vitro antibacterial and haemolytic activity of CSA-13 in the presence of pluronic F-127. CSA-13 bactericidal activity against clinical strains of bacteria associated with topical infections and in an experimental setting relevant to their pathophysiological environment, such as various epithelial tissue fluids and the airway sputum of patients suffering from cystic fibrosis (CF), was evaluated using minimum inhibitory and minimum bactericidal concentration (MIC/MBC) measurements and bacterial killing assays. We found that in the presence of pluronic F-127, CSA-13 antibacterial activity was only slightly decreased, but CSA-13 haemolytic activity was significantly inhibited. CSA-13 exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa present in CF sputa, and biofilms formed by different Gram (+) and Gram (-) bacteria. CSA-13 bactericidal action is partially compromised in the presence of plasma, but is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid. The synergistic action of CSA-13, determined by the use of a standard checkerboard assay, reveals an increase in CSA-13 antibacterial activity in the presence of host defence molecules such as the cathelicidin LL-37 peptide, lysozyme, lactoferrin and secretory phospholipase A (sPLA). These results suggest that CSA-13 may be useful to prevent and treat topical infection. Combined application of CSA-13 with pluronic F-127 may be beneficial by reducing CSA-13 toxicity. | Gold Standard | disease mechanism | 2 |
20970386 | 11,549,209 | Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases | Lennox-Gastaut syndrome is an intractable epileptic encephalopathy, with most patients experiencing daily seizures despite therapy with multiple antiepileptic drugs. New treatments need to be tested to define their efficacy in this syndrome. Lacosamide is a new antiepileptic drug recently approved for the treatment of partial-onset seizures. We describe three patients with Lennox-Gastaut syndrome resistant to conventional antiepileptic drugs whose seizures were aggravated by lacosamide. | Gold Standard | therapeutics in the clinic | 3 |
21030607 | 27,154,811 | Physiological relevance of cell-specific distribution patterns of CFTR, NKCC1, NBCe1, and NHE3 along the crypt-villus axis in the intestine | We examined the cell-specific subcellular expression patterns for sodium- and potassium-coupled chloride (NaK2Cl) cotransporter 1 (NKCC1), Na(+) bicarbonate cotransporter (NBCe1), cystic fibrosis transmembrane conductance regulator (CFTR), and Na(+)/H(+) exchanger 3 (NHE3) to understand the functional plasticity and synchronization of ion transport functions along the crypt-villus axis and its relevance to intestinal disease. In the unstimulated intestine, all small intestinal villus enterocytes coexpressed apical CFTR and NHE3, basolateral NBCe1, and mostly intracellular NKCC1. All (crypt and villus) goblet cells strongly expressed basolateral NKCC1 (at approximately three-fold higher levels than villus enterocytes), but no CFTR, NBCe1, or NHE3. Lower crypt cells coexpressed apical CFTR and basolateral NKCC1, but no NHE3 or NBCe1 (except NBCe1-expressing proximal colonic crypts). CFTR, NBCe1, and NKCC1 colocalized with markers of early and recycling endosomes, implicating endocytic recycling in cell-specific anion transport. Brunner's glands of the proximal duodenum coexpressed high levels of apical/subapical CFTR and basolateral NKCC1, but very low levels of NBCe1, consistent with secretion of Cl(-)-enriched fluid into the crypt. The cholinergic agonist carbachol rapidly (within 10 min) reduced cell volume along the entire crypt/villus axis and promoted NHE3 internalization into early endosomes. In contrast, carbachol induced membrane recruitment of NKCC1 and CFTR in all crypt and villus enterocytes, NKCC1 in all goblet cells, and NBCe1 in all villus enterocytes. These observations support regulated vesicle traffic in Cl(-) secretion by goblet cells and Cl(-) and HCO(3)(-) secretion by villus enterocytes during the transient phase of cholinergic stimulation. Overall, the carbachol-induced membrane trafficking profile of the four ion transporters supports functional plasticity of the small intestinal villus epithelium that enables it to conduct both absorptive and secretory functions. | Gold Standard | disease mechanism | 2 |
21038076 | 6,484,746 | Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients | Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis. We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (_2 and _17 alleles) on voriconazole exposure and maintenance dose and side effects. Heterozygous carriers of the CYP2C19_2-deficient allele required lower maintenance doses (440 ± 107 mg/day) compared with wild-type and CYP2C19_17-allele carriers (633 ± 197 mg/day and 600 ± 193 mg/day, respectively, P<0.05). The time to achieve the therapeutic range and the proportion of out-of-range concentrations were significantly higher in the CYP2C19_2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19_1 and CYP2C19_17 groups, respectively) or CYP2C19_17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19_1 and CYP2C19_2 groups, respectively) (P<0.01). No relationship was found between voriconazole toxicity and CYP2C19 status. In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels. | Gold Standard | disease mechanism | 2 |
21039067 | 11,330,164 | Chronic hepatitis C treatment in a cystic fibrosis patient in the pulmonary pre-transplant stage | The standard treatment of chronic hepatitis C, pegylated interferon and ribavirin (pegI/R), has many limitations in both effectiveness and secondary effects, which makes it unsuitable or even contraindicated for some patients. In hepatitis C virus-infected cystic fibrosis patients this treatment could increase respiratory infections with subsequent pulmonary function deterioration. On the contrary, hepatitis C virus (HCV) infection may make lung transplant (LT) unfeasible. We present the case of a cystic fibrosis-young man diagnosed with HCV infection during LT assessment who was treated with pegI/R. In spite of the lung function worsening and respiratory infections, he managed to complete treatment and even sustained virological response (SVR). At present he is on LT waiting list. | Gold Standard | therapeutics in the clinic | 3 |
21131972 | 22,366,493 | CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs | Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex. | Gold Standard | disease mechanism | 2 |
21146944 | 38,440,608 | Uncovered primary seizure foci in Lennox-Gastaut syndrome after corpus callosotomy | Corpus callosotomy (CC) is a palliative surgical procedure to control atonic, tonic, or generalized tonic-clonic seizure in Lennox-Gastaut syndrome (LGS). Here, we report patients with LGS who underwent resective surgery, following CC better delineating the presumed seizure foci localized in one hemisphere. We retrospectively reviewed seven patients with LGS who underwent CC and subsequent cortical resection. The median follow-up duration after lobectomy was 20 months (range, 15-54 months) and three patients had follow-up periods over 24 months. The findings of video electroencephalography (EEG) monitoring, structural and functional neuroimagings were compared between pre- and post-CC. Four patients had Engel class I and one patient had Engel class II outcomes following cortical resection; post-CC, compared to pre-CC, showed better localized ictal/interictal epileptiform discharges in the unilateral frontal area in two patients, in the unilateral parieto-temporo-occipital areas in one patient and in the unilateral fronto-temporal areas in the remaining two patients. Two patients had Engel Class III outcome following cortical resection; post-CC EEG continued to show multifocal epileptiform discharges but predominantly arising from a unilateral frontal area. Following CC, positron emission tomography showed localized glucose hypometabolism of which location was concordant with post-CC EEG abnormalities in all patient. Similarly, ictal/interictal single photon emission computed tomography also showed localized abnormalities concordant with post-CC EEG abnormalities in five of the six patients. Pathological assessment revealed cortical dysplasia in six patients, whereas no pathological abnormality was found in the remaining patient, who obtained Engel Class I outcome following cortical resection. CC could change EEG findings, glucose metabolisms and cerebral blood flows, and it is sometimes helpful in delineating the primary seizure focus in patients with LGS. | Gold Standard | therapeutics in the clinic | 3 |
21169497 | 12,328,525 | Pseudomonas aeruginosa enhances production of an antimicrobial in response to N-acetylglucosamine and peptidoglycan | Pseudomonas aeruginosa is an opportunistic pathogen often associated with chronic lung infections in individuals with the genetic disease cystic fibrosis (CF). Previous work from our laboratory revealed that five genes predicted to be important for catabolism of N-acetylglucosamine (GlcNAc) are induced during in vitro growth in CF lung secretions (sputum). Here, we demonstrate that these genes comprise an operon (referred to as the nag operon) and that NagE, a putative component of the GlcNAc phosphotransferase system, is required for growth on and uptake of GlcNAc. Using primer extension analysis, the promoter of the nag operon was mapped and shown to be inducible by GlcNAc and regulated by the transcriptional regulator NagR. Transcriptome analysis revealed that in addition to induction of the nag operon, several P. aeruginosa genes encoding factors critical for extracellular antimicrobial production are also induced by GlcNAc. Finally, we show that the GlcNAc-containing polymer peptidoglycan induces production of the antimicrobial pyocyanin. Based on this data, we propose a model in which P. aeruginosa senses surrounding bacteria by monitoring exogenous peptidoglycan and responds to this cue through enhanced production of an antimicrobial. | Gold Standard | disease mechanism | 2 |
21204804 | 10,339,015 | STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study | We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct-sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause. | Gold Standard | disease mechanism | 2 |
21225838 | 36,432,273 | High yield technique to diagnose immotile cilia syndrome: a suggested algorithm | To determine the efficacy of our nasal brush biopsy technique to diagnose primary ciliary dyskinesia. Retrospective chart review at an urban children's hospital. We obtained medical records of all patients who underwent an endoscopic guided ciliary brush biopsy from January 2000 to June 2008. Data recorded included the procedure date, biopsy location, presence of motility on light microscopy, and whether specimen was sent for electron microscopy and those results. Sixty pediatric patients between the ages of 16 months and 17.3 years with chronic sinusitis (35 males, 25 females) were identified. Three were excluded because biopsies were taken from a non nasal location. Forty-seven specimens had light microscopy evaluation only, as normal motile cilia were identified. Ten had haphazard or absent motility and required further evaluation with electron microscopy. Electron microscopy ruled out defects for three samples, was non-diagnostic for five, and the remaining two reports could not be found. Overall, in 47/57 (82%) cases, light microscopy alone ruled out primary ciliary dyskinesia (PCD). Using both methods, there was a 91% success rate in ruling out PCD. Obtaining an endoscopic biopsy with a cytosoft cytology brush (Camarillo California) from the posterior portion of the inferior turbinate gave sufficient specimen to examine for PCD. Light microscopy alone or in concert with evaluation by electron microscopy confirmed normal cilia in 91% of specimens ruling out the diagnosis of PCD. The algorithm suggested is simple and has high success in allowing the clinician to exclude the diagnosis of PCD in the patient with chronic or recurrent upper respiratory infections. | Gold Standard | clinical characteristics or disease pathology | 0 |
21227654 | 10,045,056 | Interictal epileptiform discharges and asystole | We describe a case of a patient with Lennox-Gastaut syndrome who had asystole and sinus bradycardia during interictal epileptiform abnormalities on EEG. Video-EEG/EKG monitoring prior to corpus callosotomy recorded consistent prolongation of the R-R interval on the EKG during bursts of epileptiform abnormalities (generalized paroxysmal fast activity), which became transiently more pronounced after surgery. These findings reveal that interictal epileptiform abnormalities may cause significant cardiac arrhythmias in some individuals. | Gold Standard | clinical characteristics or disease pathology | 0 |
21243535 | 40,614,789 | Cerebellar atrophy in a child with valproate toxicity | In the treatment of epilepsy, selecting an appropriate antiepileptic drug for each individual patient requires matching the patient's clinical needs with the agent's specific pharmacological attributes. In many situations, the final choice of an antiepileptic drug may need a change due to the agent's side-effect profile. The authors report a ten-year-old child with Lennox Gastaut syndrome who developed recurrence of seizures, hyperammonemic encephalopathy and cerebellar atrophy on valproate therapy. Valproate was discontinued and lamotrigine was added followed by good control of seizures. Cerebellar atrophy as a serious adverse side effect of valproate therapy, has been infrequently reported. | Gold Standard | therapeutics in the clinic | 3 |
21256770 | 15,909,132 | A prospective open-labeled trial with levetiracetam in pediatric epilepsy syndromes: continuous spikes and waves during sleep is definitely a target | Although LVT is currently extensively prescribed in childhood epilepsy, its effect on the panel of refractory epilepsy syndromes has not been entirely evaluated prospectively. In order to study the efficacy and safety of LVT as adjunctive therapy according to syndromes, we included 102 patients with refractory seizures (6 months to 15 years) in a prospective open-labeled trial. The responder rate was respectively 36% and 32% at 3 and 6 months with 6% and 7% patients becoming seizure free. Among the responders at 6 months (n=33), seizure frequency decreased by 66% and 79% at 3 and 6 months LVT compared to baseline. The highest benefit was for CSWS patients with 2/3 responders, 50% seizure free and no aggravation. LVT provided respectively 39% and 42% responders in focal and absence epilepsies. Infantile spasms and Dravet syndrome experienced the lowest efficacy. No patient with myoclonic-astatic epilepsy or Lennox-Gastaut syndrome was aggravated. LVT dose over 40 mg/kg/d was associated with a lower response rate. Tolerability was excellent. In spite of a small sample, we assume that CSWS is a good candidate for a randomized-controlled trial with LVT. | Gold Standard | patient-based therapeutics | 4 |
21259449 | 30,219,779 | Screening for symptoms of depression and anxiety in adolescents and young adults with cystic fibrosis | Although studies have assessed symptoms of depression and anxiety in individuals with cystic fibrosis (CF), few have been conducted since the advent of new medical treatments (e.g., nebulized antibiotics, ThAIRpy Vest). Study objectives were to: (1) document symptoms of depression and anxiety for adolescents and young adults with CF and compare with normative values, (2) examine the associations among depressive/anxiety symptoms and gender, age, lung function, and body mass index, and (3) determine the relations between adolescent and caregiver symptoms of depression and anxiety. Patients and caregivers completed the Hospital Anxiety and Depression Scale (HADS) anytime (e.g., beginning or end) during routine CF clinic appointments. Participants included 59 adolescents/young adults with CF (M(age) = 15.8 years, 54% female, 98% Caucasian, M(FEV1% predicted) = 84.6) and caregivers of 40 adolescents. Although symptom scores were in the normative range for patients with CF (M(Depression) = 2.27 and M(Anxiety) = 5.59), 3% and 32% exhibited clinically elevated symptoms of depression and anxiety, respectively. Symptoms of depression and anxiety were significantly associated with age (r = 0.28, 0.36). Symptoms of depression and anxiety were also positively correlated (r = 0.48). Females endorsed higher anxiety symptoms than males. While adolescent and caregiver anxiety scores were not related, higher caregiver depressive symptoms were associated with older patient age and worse lung function. Data from the current study suggest low levels of depressive symptoms and substantial levels of anxiety symptoms in adolescents and young adults with CF. Consistent with prior literature, depressive symptoms appear higher in older patients and are significantly associated with anxiety symptoms. Caregiver symptomology appears to be more affected by an adolescent's health status, suggesting a need to screen caregivers when health begins to decline. | Gold Standard | clinical characteristics or disease pathology | 0 |
21273388 | 15,513,315 | Nasal nitric oxide and nitric oxide synthase expression in primary ciliary dyskinesia | No study has evaluated the correlation between different expression of nitric oxide synthase (NOS) isoforms in nasal epithelial cells and nasal NO (nNO) level in primary ciliary dyskinesia (PCD). Gene expression of endothelial (NOS3) and inducible NOS (NOS2) and their correlation with nNO level, ciliary function and morphology were studied in patients with PCD or secondary ciliary dyskinesia (SCD). NOS3 gene polymorphisms were studied in blood leukocytes. A total of 212 subjects were studied (48 with PCD, 161 with SCD and three normal subjects). nNO level correlated with mean ciliary beat frequency (p = 0.044; r = 0.174). The lower the nNO level the higher was the percentage of immotile cilia (p<0.001; r = -0.375). A significant positive correlation between NOS2 gene expression and nNO levels was demonstrated in all children (p = 0.001; r = 0.428), and this correlation was confirmed in patients with PCD (p = 0.019; r = 0.484). NOS2 gene expression was lower in PCD than in SCD (p = 0.04). The NOS3 isoform correlated with missing central microtubules (p = 0.048; r = 0.447). nNO levels were higher in PCD subjects with the NOS3 thymidine 894 mutation, and this was associated with a higher ciliary beat frequency (p = 0.045). These results demonstrate a relationship between nNO level, NOS mRNA expression and ciliary beat frequency. | Gold Standard | disease mechanism | 2 |
21284095 | 42,083,654 | Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: a multicenter experience | Examination of ciliary ultrastructure remains the cornerstone diagnostic test for primary ciliary dyskinesia (PCD), a disease of abnormal ciliary structure and/or function. Obtaining a biopsy with sufficient interpretable cilia and producing quality transmission electron micrographs (TEM) is challenging. Methods for processing tissues for optimal preservation of axonemal structures are not standardized. This study describes our experience using a standard operating procedure (SOP) for collecting nasal scrape biopsies and processing TEMs in a centralized laboratory. We enrolled patients with suspected PCD at research sites of the Genetic Disorders of Mucociliary Clearance Consortium. Biopsies were performed according to a SOP whereby curettes were used to scrape the inferior surface of the inferior turbinate, with samples placed in fixative. Specimens were shipped to a central laboratory where TEMs were prepared and blindly reviewed. Four hundred forty-eight specimens were obtained from 107 young children (0-5 years), 189 older children (5-18 years), and 152 adults (> 18 years), and 88% were adequate for formal interpretation. The proportion of adequate specimens was higher in adults than in children. Fifty percent of the adequate TEMs showed normal ciliary ultrastructure, 39% showed hallmark ultrastructural changes of PCD, and 11% had indeterminate findings. Among specimens without clearly normal ultrastructure, 72% had defects of the outer and/or inner dynein arms (IDA), while 7% had central apparatus defects with or without IDA defects. In summary, nasal scrape biopsies can be performed in the outpatient setting and yield interpretable samples, when performed by individuals with adequate training and experience according to an SOP. | Gold Standard | clinical characteristics or disease pathology | 0 |
21290179 | 2,327,166 | Natural History and Outcome of Hepatic Vascular Malformations in a Large Cohort of Patients with Hereditary Hemorrhagic Teleangiectasia | BackgroundHereditary hemorrhagic telangiectasia is a genetic disease characterized by teleangiectasias involving virtually every organ. There are limited data in the literature regarding the natural history of liver vascular malformations in hemorrhagic telangiectasia and their associated morbidity and mortality.AimThis prospective cohort study sought to assess the outcome of liver involvement in hereditary hemorrhagic telangiectasia patients.MethodsWe analyzed 16 years of surveillance data from a tertiary hereditary hemorrhagic telangiectasia referral center in Italy. We considered for inclusion in this study 502 consecutive Italian patients at risk of hereditary hemorrhagic telangiectasia who presented at the hereditary hemorrhagic telangiectasia referral center and underwent a multidisciplinary screening protocol for the diagnosis of hereditary hemorrhagic telangiectasia. Of the 502 individuals assessed in the center, 154 had hepatic vascular malformations and were the subject of the study; 198 patients with hereditary hemorrhagic telangiectasia and without hepatic vascular malformations were the controls. Additionally, we report the response to treatment of patients with complicated hepatic vascular malformations.ResultsThe 154 patients were included and followed for a median period of 44 months (range 12–181); of these, eight (5.2%) died from VM-related complications and 39 (25.3%) experienced complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively. The median overall survival and event-free survival after diagnosis were 175 and 90 months, respectively. The rate of complete response to therapy was 63%.ConclusionsThis study shows that substantial morbidity and mortality are associated with liver vascular malformations in hereditary hemorrhagic telangiectasia patients. | Gold Standard | clinical characteristics or disease pathology | 0 |
21300824 | 559,413 | CCL20/CCR6 feedback exaggerates epidermal growth factor receptor-dependent MUC5AC mucin production in human airway epithelial (NCI-H292) cells | Mucous hypersecretion is an important feature of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Multiple stimuli induce mucin production via activation of an epidermal growth factor receptor (EGFR) cascade, but the mechanisms that exaggerate mucin production in obstructive airway diseases remain unknown. In this study, we show that binding of CCL20, a G protein-coupled receptor (GPCR) ligand that is upregulated in the airways of subjects with obstructive airway diseases, to its unique GPCR CCR6 induces MUC5AC mucin production in human airway epithelial (NCI-H292) cells via metalloprotease TNF-α-converting enzyme (TACE)-dependent EGFR activation. We also show that EGFR activation by its potent ligand TGF-α induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating mucin production in the NCI-H292 cells. In NCI-H292 cells, TGF-α stimulation induced two phases of EGFR phosphorylation (EGFR-P). The second EGFR-P was TACE-dependent and was responsible for most of the total mucin induced by TGF-α. Binding of endogenously produced CCL20 to CCR6 increased the second EGFR-P and subsequent mucin production induced by TGF-α. In NHBE cells, TGF-α-induced EGFR activation did not lead to significant CCL20 production or to EGFR rephosphorylation, and less mucin was produced. We conclude that NCI-H292 cells but not NHBE cells produce CCL20 in response to EGFR activation, which leads to a second phase of EGFR-P and subsequent exaggerated mucin production. These findings have potentially important therapeutic implications in obstructive airway diseases. | Gold Standard | disease mechanism | 2 |
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