Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor.

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 µM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ's inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.

Safety and efficacy of eliglustat combined to enzyme replacement therapy for lymphadenopathy in patients with Gaucher disease type 3.

Patients with Gaucher disease type 3 (GD3), especially those with GBA p.L444P homozygous mutation, often suffer from complications including lymphadenopathy even under regular enzyme replacement therapy (ERT). In order to improve their outcome, we administrated eliglustat, a substrate reduction therapy (SRT), in combination with ERT to four patients, age ranged 9-18 years, for two years. The results revealed that patients' plasma glucosylsphingosine (lyso-GL1) level and chitotriosidase activity both decreased after adding eliglustat. In three patients who completed follow-up MRI scanning, sizes of lymph nodes all decreased. No severe adverse events were attributed to eliglustat. Therefore, our data suggest that a combined SRT and ERT treatment may improve the ERT-resistant symptoms in patients with GD3.

RNA-seq of peripheral blood mononuclear cells of congenital generalized lipodystrophy type 2 patients.

Illumina RNA-seq analysis was used to characterize the whole transcriptomes of peripheral blood mononuclear cells (PBMCs) from patients with congenital generalized lipodystrophy. RNA-seq information for seven patients with type 2 congenital generalized lipodystrophy (CGL2; Berardinelli-Seip congenital lipodystrophy, BSCL2) was obtained and compared with similar information for seven age- and sex-matched healthy control subjects. All seven CGL2 patients carried biallelic pathogenic mutations affecting the BSCL2 gene and had clinical symptoms of varying severity. The findings provide the whole-transcriptome signatures of PBMCs of CGL2 patients, allowing further exploration of gene expression patterns/signatures associated with the various clinical symptoms of patients with this disease.

Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences.

OBJECTIVE: Enzyme replacement therapy (ERT), the only approved therapy for infantile-onset Pompe disease (IOPD), had heterogeneous clinical effects due to factors such as severity, age at first treatment, dosage, and dosing regimens. We report the clinical and biochemical outcomes of a cohort of IOPD patients identified through newborn screening, and evaluating the dosage effect. STUDY DESIGN: A retrospective observational study was designed to describe the long-term clinical and biochemical outcomes of a uniform cohort of IOPD patients who have been treated with high-dosage of ERT. RESULTS: Twenty-eight patients received alglucosidase alpha at either the labeled dosage followed by a high dosage (n = 23) or a high dosage exclusively (n = 5). At a median age of 8.3 years (0.8-17.3), 15 patients were walkers, 8 were weak walkers, and 5 were nonwalkers. The three groups exhibited a significant difference in the age of gross motor decline (p < .001). In patients with classical IOPD diagnosed through newborn screening, those late in ERT initiation (p = .006) or late in high-dosage ERT initiation (p = .044) had a higher risk of motor decline. At the latest assessment, both serum creatine kinase (CK) and urinary glucose tetrasaccharide (uGlc4) levels were lowest in the walkers. During follow up, the biomarker levels, once rose, never returned to normal. CONCLUSION: Low CK and uGlc4 levels were correlated with favorable response to ERT in IOPD patients, although CK may be more fluctuated than uGlc4. High-dose ERT instituted immediately at newborn screening seems to give the best outcome, and a dosage increase is necessary upon - or, even better, before - a rise in biomarker levels.

Congenital generalized lipodystrophy in Taiwan.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by scarce adipose tissue. This disease is distributed worldwide, but little is known about these patients in the Chinese population. Here, we delineate the phenotype and prognosis of CGL in our cohort. METHODS: Patients diagnosed with CGL from 8 medical centers were reviewed. The initial presentation, laboratory findings, and molecular testing were retrospectively analyzed. RESULTS: A total of 16 patients were analyzed, and the current median age was 3.5 years (range, 9 months-17.5 years). In all patients, molecular results confirmed BSCL2 mutation. c.782dupG (p.Ile262Hisfs*12) was the most common genotype identified. All patients had triangular faces and muscular hypertrophy. In addition, 75% presented with hepatomegaly, 19% had cardiomegaly, and 44% exhibited acanthosis nigricans. Developmental delay was noted in 5 out of 9 patients (56%) with a median developmental quotient (DQ)/intelligence quotient (IQ) of 61. Thirteen patients (81.3%) had high triglyceride levels. Eight patients received leptin analysis, and 7 of them (88%) had low leptin levels. One patient exclusively received a lipid-lowering drug, 4 patients were exclusively placed on a fat-restricted diet, 5 patients were administered combination therapy, and 5 patients received no treatment. Three patients (19%) who developed diabetes mellitus received both oral hypoglycemic agents and insulin. Three patients (19%) experienced loss of ambulation and died prematurely. CONCLUSION: Our findings highlight the uniqueness of the genotype and phenotype in our cohort. Further long-term surveillance for comorbidities is necessary for early detection and management of these patients.

Psychometric testing of the short-form Chinese version of the self-management for adolescents with type 1 diabetes scale.

Self-management among adolescents with type 1 diabetes (T1D) is poorer than in other age groups during childhood. A valid and reliable short-form scale to measure self-management in adolescents with T1D is prudent for enhancing their self-management in clinical settings. We used a cross-sectional design to develop a short-form Chinese version of the Self-Management of Type 1 Diabetes for Adolescents Scale (C-SMOD-A) and test its psychometric characteristics. Two hundred adolescents with T1D were recruited from four hospitals in Taiwan through convenience sampling. Content validity, exploratory factor analysis, and corrected item-total correlations were used to shorten the 52-item C-SMOD-A. Confirmatory factor analysis, criterion-related validity, and reliability testing were used to examine the psychometric characteristics of the short-form C-SMOD-A. Finally, the 23-item C-SMOD-A (C-SMOD-A-23) with five inter-correlated factors was developed. Glycated hemoglobin levels were significantly associated with each subscale of the C-SMOD-A-23 with correlation coefficients ranging from -0.18 to -0.31. The composite reliability and test-retest reliability of the five subscales ranged from 0.70 to 0.88 and from 0.78 to 0.93 respectively. Accordingly, the C-SMOD-A-23 has acceptable validity and reliability to measure five specific domains of self-management for adolescents with T1D. Health-care providers could use the C-SMOD-A-23 as a clinical reference to assess specific domains of self-management and provide interventions to enhance self-management for adolescents with T1D.

Are doctors assessing patients with hypertension appropriately at their initial presentation?

INTRODUCTION: The aim of this study was to determine the extent to which primary care doctors assessed patients newly diagnosed with hypertension for the risk factors of cardiovascular disease (CVD) during the patients' first clinic visit for hypertension. The study also aimed to examine the trend of assessment for CVD risk factors over a 15-year period. METHODS: This retrospective study was conducted between January and May 2012. Data was extracted from the paper-based medical records of patients with hypertension using a 1:4 systematic random sampling method. Data collected included CVD risk factors and a history of target organ damage (TOD), which were identified during the patient's first visit to the primary care doctor for hypertension, as well as the results of the physical examinations and investigations performed during the same visit. RESULTS: A total of 1,060 medical records were reviewed. We found that assessment of CVD risk factors during the first clinic visit for hypertension was poor (5.4%-40.8%). Assessments for a history of TOD were found in only 5.8%-11.8% of the records, and documented physical examinations and investigations for the assessment of TOD and secondary hypertension ranged from 0.1%-63.3%. Over time, there was a decreasing trend in the percentage of documented physical examinations performed, but an increasing trend in the percentage of investigations ordered. CONCLUSION: There was poor assessment of the patients' CVD risk factors, secondary causes of hypertension and TOD at their first clinic visit for hypertension. The trends observed in the assessment suggest an over-reliance on investigations over clinical examinations.

Distal 10q trisomy with copy number gain in chromosome region 10q23.1-10q25.1: the Wnt signaling pathway is the most pertinent to the gene content in the region of copy number gain: a case report.

BACKGROUND: Complete or partial trisomy 10q involves a duplication of 10q, or the long arm of chromosome 10. Distal 10q trisomy is a well-recognized and defined but rare genetic syndrome in which duplication of distal segments of 10q results in a pattern of malformations. Although abnormal chromosome phenotypes are commonly detected by visualization of chromosomes by traditional cytogenetic techniques, this approach is marginal in both diagnostic sensitivity and potential for biological interpretation, thus making implementation of advanced techniques and analysis methods an important consideration in a health service. CASE PRESENTATION: The present study describes the case of a Taiwanese boy from healthy parents with mental, growth, and psychomotor retardations. Additional clinical features included facial dysmorphism, microcephaly, brain atrophy, camptodactyly, and-as the first reported case-bilateral renal atrophy with chronic kidney disease stage 2 and the presence of a renal cyst in one kidney. A novel 21.8 Mb copy number variation region in chromosome region 10q23.1-10q25.1 was verified by array-comparative genomic hybridization in combination with quantitative real-time polymerase chain reaction. Subsequently, 200 protein-coding genes were identified in this copy number variation region and analyzed for their biological meaning using the database for annotation, visualization and integrated discovery. CONCLUSION: According to the result of gene functional enrichment analysis using database for annotation, visualization and integrated discovery, the Wnt signaling pathway is the most pertinent to the gene content in the copy number variation region. A change in the expression levels of some Wnt signaling pathway components and of NFKB2 and PTEN genes due to a gain in their gene copy number may be associated with the patient's clinical outcomes including brain atrophy, bilateral renal atrophy with chronic kidney disease stage 2, a renal cyst in one kidney, and growth retardation.

Outcome of early-treated type III Gaucher disease patients.

Recombinant human acid ß-glucosidase GBA (rhGBA) infusion is an effective therapy for non-neuropathic (type I) Gaucher disease (GD), but its effect on subacute neuropathic (type III) GD is still controversial. The most common genotype for type III GD is homozygous c.1448T>C (p.L444P) mutation, and in this study, we treated seven such patients starting from an early age (median 2.1 years; range 1-2.9 years). Before the start of treatment, all patients presented hepatosplenomegaly, anemia, and thrombocytopenia, but with no neurological signs. Normalization of hemoglobin levels and platelet numbers was achieved in all patients in one year. However, after a median treatment period of 7.6 years (2.2-12.0 years), two patients developed horizontal gaze palsy, one had seizures, four demonstrated mental retardation, and five showed kyphosis. Moreover, lymphadenopathy in the neck, thorax, or abdomen was observed in four patients. Therefore, the progression of neurological symptoms in these patients probably reflected the neurologic natural history of type III GD. Residual somatic symptoms, including kyphosis and lymphadenopathy, may be more common than what we thought. An additional treatment will be necessary to improve the outcome of type III GD.

Seventeen alpha-hydroxylase deficiency.

Seventeen alpha-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia in which defects in the biosynthesis of cortisol and sex steroid result in mineralocorticoid excess, hypokalemic hypertension and sexual abnormalities such as pseudohermaphroditism in males, and sexual infantilism in females. The disease is inherited in an autosomal recessive pattern, and is caused by mutations in the gene encoding cytochrome P450c17 (CYP17), which is the single polypeptide that mediates both 17alpha-hydroxylase and 17,20-lyase activities. We report the case of a 15-year-old patient with 17OHD who had a female phenotype but male karyotype (46,XY). The diagnosis was made based on classical clinical features, biochemical data and molecular genetic study. Two mutations were identified by polymerase chain reaction amplification and sequencing, including a S106P point mutation in exon 2 and a 9-bp (GACTCTTTC) deletion from nucleotide position 1519 in exon 8 of CYP17. The first of these mutations was found in the father and the second in the mother, and both have been previously reported in Asia. The patient's hypertension and hypokalemia resolved after glucocorticoid replacement and treatment with potassium-sparing diuretics. Sex hormone replacement was prescribed for induction of sexual development and reduction of the final height. Prophylactic gonadectomy was scheduled. In summary, 17OHD should be suspected in patients with hypokalemic hypertension and lack of secondary sexual development so that appropriate therapy can be implemented.