Genetic stratification reveals COL4A variants and spontaneous remission in Egyptian children with proteinuria in the first 2 years of life.

AIM: The earlier the onset of proteinuria, the higher the incidence of genetic forms. Therefore, we aimed to analyse the spectrum of monogenic proteinuria in Egyptian children presenting at age <2 years. METHODS: The results of 27-gene panel or whole-exome sequencing were correlated with phenotype and treatment outcomes in 54 patients from 45 families. RESULTS: Disease-causing variants were identified in 29/45 (64.4%) families. Mutations often occurred in three podocytopathy genes: NPHS1, NPHS2 and PLCE1 (19 families). Some showed extrarenal manifestations. Additionally, mutations were detected in 10 other genes, including novel variants of OSGEP, SGPL1 and SYNPO2. COL4A variants phenocopied isolated steroid-resistant nephrotic syndrome (2/29 families, 6.9%). NPHS2 M1L was the single most common genetic finding beyond the age of 3 months (4/18 families, 22.2%). Biopsy results did not correlate with genotypes (n = 30). On renin-angiotensin-aldosterone system antagonists alone, partial and complete remission occurred in 3/24 (12.5%) patients with monogenic proteinuria each, whereas 6.3% (1/16) achieved complete remission on immunosuppression. CONCLUSION: Genotyping is mandatory to avoid biopsies and immunosuppression when proteinuria presents at age <2 years. Even with such a presentation, COL4A genes should be included. NPHS2 M1L was prevalent in Egyptian children (4 months-2 years) with proteinuria, demonstrating precision diagnostic utility.

Impact of maternal iron deficiency on the auditory functions in the young and adult guinea pig.

OBJECTIVES: The aim of this study was to evaluate the hearing function in the guinea pig offspring at post-natal day (PNd) 24 and PNd84 born from dams suffering from iron deficiency during pregnancy and lactation by using the auditory brainstem response (ABR). METHOD: Female guinea pigs (n = 24 per dietary group) were fed an iron sufficient (IS) diet (114 mg/kg) or an iron deficient (ID) diet (11.7 mg/kg) during the gestation and lactation periods. Pups in both groups were weaned at PNd9 and given the IS diet. The hematocrit level was measured at every trimester of pregnancy and at the day of sacrifice in dams and at PNd24 and PNd84 in pups. The animal body weight was measured on every second day until the day of sacrifice. The ABR was used in pups to measure the hearing threshold using a broad range of stimulus intensities and latency at 100 and 80 dB in response to 2, 4, 8, 16, and 32 kHz tone pips at PNd24 and 84. RESULTS AND DISCUSSION: No significant difference between dietary groups was measured in hearing threshold and absolute latencies in pups at PNd24 and PNd84. Although the ID offspring (n = 16) did not differ in brainstem transmission times (BTTs) at 80 dB compare to the IS siblings (n = 25) at PNd24, they showed significant delayed inter-peak latency (IPL) I-IV at 100 dB suggesting a delayed BTT. At PNd84, the latency of all peaks including IPL I-IV at 80 and 100 dB significantly decreased and was also similar in pups from both dietary groups suggesting a better brain maturation. This is the first study investigating the long-term impact of maternal iron deficiency on the auditory functions in the guinea pig offspring during early development to adulthood.

Increase serum cortisol in young guinea pig offspring in response to maternal iron deficiency.

Iron deficiency (ID) has been reported as a risk factor in the pathology of attention-deficit/hyperactivity disorder, although the mechanisms seem unclear. Previous results from our research group showed that guinea pig offspring born from ID dams were significantly more active in the Open Field Test than the controls. This behavior could potentially be associated to stress. We therefore hypothesized that maternal iron deficiency (MID) elevates the offspring serum cortisol, a biomarker of stress, during childhood and possibly at mature age. Twenty-four female guinea pigs were fed an iron-sufficient (IS) diet (114 mg/kg) or ID diet (11.7 mg/kg) during the gestation and lactation. Pups in both groups were weaned at postnatal day (PNd) 9 and given an IS diet. Hematocrit and serum cortisol levels were measured in dams at every trimester of gestation and in pups at PNd24 and 84. We found no impact of MID on dam's cortisol values. However, our findings indicate that MID increased cortisol secretion in the offspring during childhood, cortisol values being significantly elevated in ID than IS pups at PNd24 (P < .05). During adulthood (PNd84), both groups showed comparable cortisol levels. The elevated cortisol secretion observed in the offspring born from ID mothers during childhood may indicate increased stress reactivity which may have contributed to the higher level of activity when tested in a novel open environment. These findings suggest that MID can potentially act as internal stressor affecting the early development conceivably leading to increased stress levels in the children.

Insulin-degrading enzyme deficiency in bone marrow cells increases atherosclerosis in LDL receptor-deficient mice.

BACKGROUND: Insulin-degrading enzyme (IDE), a protease implicated in several chronic diseases, associates with the cytoplasmic domain of the macrophage Type A scavenger receptor (SR-A). Our goal was to investigate the effect of IDE deficiency (Ide(-/-)) on diet-induced atherosclerosis in low density lipoprotein-deficient (Ldlr(-/-)) mice and on SR-A function. METHODS: Irradiated Ldlr(-/-) or Ide(-/-)Ldlr(-/-) mice were reconstituted with wild-type or Ide(-/-) bone marrow and, 6 weeks later, were placed on a high-fat diet for 8 weeks. RESULTS: After 8 weeks on a high-fat diet, male Ldlr(-/-) recipients of Ide(-/-) bone marrow had more atherosclerosis, higher serum cholesterol and increased lesion-associated ß-amyloid, an IDE substrate, and receptor for advanced glycation end products (RAGE), a proinflammatory receptor for ß-amyloid, compared to male Ldlr(-/-) recipients of wild-type bone marrow. IDE deficiency in male Ldlr(-/-) recipient mice did not affect atherosclerosis or cholesterol levels and moderated the effects of IDE deficiency of bone marrow-derived cells. No differences were seen between Ldlr(-/-) and Ide(-/-)Ldlr(-/-) female mice reconstituted with Ide(-/-) or wild-type bone marrow. IDE deficiency in macrophages did not alter SR-A levels, cell surface SR-A, or foam cell formation. CONCLUSION: IDE deficiency in bone marrow-derived cells results in larger atherosclerotic lesions, increased lesion-associated Aß and RAGE, and higher serum cholesterol in male, Ldlr(-/-) mice.

Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice.

BACKGROUND: Caspase-1 is a cysteine protease that contributes to mammalian immunity through proteolytic activation of the proinflammatory cytokines, interleukin (IL)-1ß and IL-18. METHODS: To determine if caspase-1 deficiency can protect apolipoprotein E-null (Apoe(-/-)) mice from atherosclerosis, gender-matched, paired-littermate Apoe(-/-) mice with (Casp1(+/+)Apoe(-/-)) or without (Casp1(-/-)Apoe(-/-)) a functional caspase-1 (Casp1) gene were fed either a low fat diet for 26 weeks, or a saturated fat and cholesterol-enriched diet for 8 weeks. Plasma lipids and lipoproteins were determined and atherosclerosis was quantified in the aortic sinus and aortic arch. RESULTS: On either diet, caspase-1 deficiency did not affect total serum cholesterol concentrations and lipoprotein-cholesterol distributions. However, caspase-1 deficiency significantly decreased atherosclerosis in the ascending aorta by 35%-45% in both sexes of mice fed either diet. We further examined atherosclerotic lesions for 2 indices of immune cell activation: Major Histocompatibility Complex (MHC) class II and interferon (IFN)-γ expression. There was a 40%-50% reduction in the number of lesion-associated cells expressing MHC class II from both sexes of Casp1(-/-)Apoe(-/-) mice compared with Casp1(+/+)Apoe(-/-) mice and, a significant reduction in lesion-associated IFN-γ in female Casp1(-/-)Apoe(-/-) compared with their Casp1(+/+)Apoe(-/-) counterparts. CONCLUSIONS: We conclude that caspase-1 promotes atherosclerosis by enhancing the inflammatory status of the lesion through a mechanism likely involving activation of lesion-associated immune cells and IFN-γ expression.

Specific loss of toll-like receptor 2 on bone marrow derived cells decreases atherosclerosis in LDL receptor null mice.

Innate immunity and, notably, Toll-like receptors (TLR), have an important role in atherogenesis. We have tested the hypothesis that the selective loss of TLR-2 by cells of bone marrow (BM) origin will protect low-density receptor-deficient (Ldlr (-/-)) mice from both early- and late-stage atherosclerosis. BM cells from Tlr2(+/+) and Tlr2(-/-) littermates were used to reconstitute lethally irradiated Ldlr(-/-) mice. Following a recovery period, mice were placed either on a diet containing 21% saturated fat - 0.15% cholesterol for 8 weeks to study early-stage atherosclerosis, or on a diet richer in cholesterol (1.5%) for 16 weeks to study late-stage atherosclerosis. Donor cell Tlr2 genotype did not alter serum cholesterol levels or lipoprotein profiles in recipient animals. After 8 weeks on the 0.15% cholesterol diet, deficiency of TLR-2 expression on cells of BM origin reduced atherosclerosis in the aortic root and the aortic arch in both genders of mice. In contrast, the BM recipients who received the 1.5% cholesterol diet for 16 weeks showed much larger lesions in the aortic root, and TLR-2 deficiency in BM cells failed to provide protection. Thus, TLR-2 expression in BM-derived cells contributes primarily to early stage atherosclerosis.

PADI4 polymorphism predisposes male smokers to rheumatoid arthritis.

OBJECTIVE: To elucidate the differential role of peptidyl arginine deiminase 4 (PADI4) polymorphism in rheumatoid arthritis (RA) between Asian and European populations, possible gene-environmental interactions among the PADI4 polymorphism, sex and smoking status were analysed. METHODS: Three independent sets of case-control samples were genotyped for single-nucleotide polymorphisms in PADI4; Japanese samples (first set, 1019 RA patients, 907 controls; second set, 999 RA patients, 1128 controls) using TaqMan assays and Dutch samples (635 RA patients, 391 controls) using Sequenom MassARRAY platform. The association of PADI4 with RA susceptibility was evaluated by smoking status and sex in contingency tables and logistic regression models. RESULTS: In the first set of Japanese samples, PADI4 polymorphism (rs1748033) showed a greater risk in men (OR(allele) 1.39; 95% CI 1.10 to 1.76; p(trend)=0.0054) than in women and in ever-smokers (OR(allele) 1.25; 95% CI 1.02 to 1.53; p(trend)=0.032) than in never-smokers. Moreover, the highest risk was seen in male ever-smokers (OR(allele) 1.46; 95% CI 1.12 to 1.90; p(trend)=0.0047). Similar trends were observed in the second set of Japanese samples as well as in Dutch samples. CONCLUSION: PADI4 polymorphism highly predisposes male smokers to RA, and the genetic heterogeneity observed between Asian and European populations may be partly explained by differences in smoking prevalence among men.

Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis.

Wyeth Research was developing apratastat (TMI-005), one in a series of dual TNFalpha-converting enzyme and matrix metalloprotease-13 inhibitors, for the potential treatment of inflammation, especially rheumatoid arthritis. By January 2005, apratastat had entered a phase II clinical trial; however, in October 2006, Wyeth reported that it had terminated development of the drug because of lack of efficacy in this trial.