Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in ...part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.
Nephrotic syndrome (NS) is a renal disease characterized by heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. Its presentation within the first 3 months of life or in multiple family ...members suggests an underlying inherited cause. To determine the frequency of inherited NS, 62 cases (representing 49 families with NS) from Saudi Arabia were screened for mutations in NPHS1, NPHS2, LAMB2, PLCE1, CD2AP, MYO1E, WT1, PTPRO and Nei endonuclease VIII-like 1 (NEIL1). We detected likely causative mutations in 25 out of 49 families studied (51%). We found that the most common genetic cause of NS in our cohort was a homozygous mutation in the NPHS2 gene, found in 11 of the 49 families (22%). Mutations in the NPHS1 and PLCE1 genes allowed a molecular genetic diagnosis in 12% and 8% of families, respectively. We detected novel MYO1E mutations in three families (6%). No mutations were found in WT1, PTPRO or NEIL1. The pathogenicity of novel variants was analyzed by in silico tests and by genetic screening of ethnically matched control populations. This is the first report describing the molecular genetics of NS in the Arabian Peninsula.
To identify risk factors for Clostridium difficile-associated disease (CDAD) in nursing home patients.
Retrospective chart reviews.
Long-term care facility with 347 beds and an additional 180 ...sub-acute care beds, adjacent to an academic tertiary care hospital center.
Twenty-five patients had documented diagnosis of CDAD. Eighty-four percent were female, 76% white, 16% black, 4% Asian, and 4% Hispanic. Age ranged between 60 and 97 years (mean: 82.2 years). The control group had 28 patients, 68% were female, 89% white, and 11% black. Age ranged between 61 and 101 years (mean: 82.3 years).
Length of stay at the facility, initial presenting symptoms, white blood cell count at the time of diagnosis, serum albumin level prior to the start of antibiotics, body mass index calculated from weight and height, presence or absence of dementia, history of diabetes mellitus and colonic disease, activity of daily living data include mobility, toileting and eating, use of percutaneous enterogastrostomy feeding, antibiotic administration, namely, type and duration, use of enema and laxatives, and use of proton pump inhibitors.
Episodes of CDAD occurred mainly within the first year of admission to our facility, with a mean of 6 months, whereas the mean length of stay was 25 months in the control group (t = 3.452; df = 51; P < .01). Albumin level was another major risk factor for CDAD, with an overwhelming 68% of CDAD patients having albumin levels below 3 g/dL (mean 2.68 g/dL) compared with a mean of 3.22 g/dL in the control group (t = 4.210; df = 51; P < .001). The third significant risk factor was the use of proton pump inhibitors, 60% versus 32%, respectively (chi(2) = 4.137; df = 1; P < .05). Levofloxacin was the most frequently prescribed antibiotic (37%). Surprisingly, factors not associated with CDAD included dementia, diabetes mellitus, colonic disease, use of enema, use of laxatives, weight and body metabolic index, duration of previous antibiotic therapy for unrelated infection, mobility, toileting, and method of eating.
A low albumin level, a recent admission to a nursing facility, and the use of proton pump inhibitors should be considered as probable risk factors for CDAD when assessing institutionalized patients with diarrhea. These findings may facilitate the timely and efficient management of CDAD in nursing home patients.
Idiopathic nephrotic syndrome (INS) is a common pediatric disease. Minimal change disease (MCD) is the most common histopathological subtype and usually has good prognosis. However, in less common ...presentations, INS may have an unusual course that makes renal biopsy a necessity to identify its etiology. Immunoglobulin M (IgM) occasionally deposits in the mesangium and can be seen under immunofluorescence (IF). The role of IgM is controversial in MCD. It is likely associated with less favorable outcomes for MCD. This study aims to investigate the clinical significance of mesangial IgM deposits on the outcome of MCD in a pediatric population.
In this retrospective cohort study, we obtained native kidney biopsy samples from 192 children who were diagnosed with MCD from 2003 to 2014. The samples were divided into groups according to the histopathological deposition of IgM in biopsies under IF. The group for which biopsies showed IgM was labeled as IgM + IF (n = 77), and the group for which biopsies were without IgM was labeled as IgM-IF (n = 115). We reviewed hypertension, hematuria, and estimated glomerular filtration rate (eGFR) at the time of presentation to our institute; response to steroid therapy (remission, dependence, frequent relapses, and resistance) and response after adjuvant immunosuppressive therapy (complete remission, partial remission, frequent relapses, and no response) when indicated; development of chronic kidney disease (CKD) and end-stage renal disease during the course of the disease (ESRD).
Our results showed that mesangial IgM deposition in MCD showed significant statistical association with hypertension at the time of presentation (P = .05). There was statistically significant association between the presence of IgM deposition and the development of steroid dependence (P = .05) and CKD during the course of the disease (P = .05).
Our study showed that IgM deposition in MCD showed statistical association with hypertension by the time the patient presented to our institute, development of steroid dependence, and CKD. IgM may play a role in MCD. However, we recommend a prospective study to verify the role of IgM in MCD outcomes.
Summary
Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent ...randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin‐stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP‐1 from intestinal L‐cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin‐treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin‐based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.
Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab ...families.
Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions.
We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion.
Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing.
We report a consanguineous family from Saudi Arabia with three affected children presenting with infantile nephrotic syndrome. In order to provide a molecular diagnosis, a genome-wide SNP analysis of ...the affected patients was performed. We identified a region of homozygosity on chromosome 1, containing the NPHS2 gene. Direct sequencing, by exon PCR, of NPHS2 identified a homozygous nucleotide change 385C > T within exon 3 in the three affected children, leading to a premature stop codon (Q129X). This homozygous truncating mutation in NPHS2 is novel and was associated with a severe clinical phenotype. Additional mutations in related genes NPHS1, PLCE1 and NEPH1 were not identified, excluding tri-allelism within these genes in this family.
Objective: To assess the effect of vildagliptin relative to sulfonylurea (SU) on hypoglycemic events, in Muslim patients from the Middle East with type 2 diabetes who fast during Ramadan. The primary ...endpoint was the proportion of patients with at least one hypoglycemic event (HE) during the fasting period. Secondary endpoints included change in weight, HbA1c levels, treatment adherence and overall safety.
Design and methods: This multicenter, prospective, observational cohort study enrolled Muslim adult T2DM patients from Middle Eastern countries who received treatment with vildagliptin or SU as add on to metformin or monotherapy. During a ∼16 week observation period, data was collected up to 6 weeks before and 6 weeks after Ramadan fasting.
Results: A total of 584 patients from the Middle East enrolled in the study; 308 patients received vildagliptin and 265 received SU. Significantly fewer vildagliptin patients reported at least one HE (3.7% vildagliptin vs. 25.5% SU; p < .001). No grade 2 HEs were reported in vildagliptin patients versus two in SU patients (p = .128). Mean change in HbA1c at the end of study showed −0.18% between treatment difference in favor of vildagliptin, p = .001. Mean body weight change at the end of study showed −0.68 kg between treatment difference in favor of vildagliptin, p < .001. Treatment exposure and adherence were high and similar in both cohorts. There were 4.3% adverse events reported in vildagliptin compared to 25.3% in the SU cohort, with hypoglycemia being the most experienced event in both cohorts.
Limitations: Being observational and not mandating HE confirmation with blood glucose measurement (though it was done in a large number of patients) were key limitations.
Conclusion: Anti-hyperglycemic treatment with vildagliptin led to significantly fewer hypoglycemia events compared to sulfonylurea treatment among Muslim diabetic patients who fast during Ramadan. Good glycemic control, weight control and safety results supported this outcome.
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