The expression of type III hyperlipoproteinemia: involvement of lipolysis genes

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper- and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG) patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and type III HLP. The frequency of the rare allele of APOC3 3238 G>C and APOA5 −1131 T>C (in linkage disequilibrium) was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs 5.8%, respectively, (P<0.05). Furthermore, the frequencies of the APOA5 c.56 G>C polymorphism and LPL c.27 G>A mutation were higher in type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 −1131 T>C, c.56 G>C and/or LPL c.27 G>A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7, 95% confidence interval=1.8–7.5, P<0.0001). The HTG patients showed similar allele frequencies of the APOA5, APOC3 and LPL polymorphisms, whereas the NDCP showed similar allele frequencies as the normolipidemic APOE2/2. Patients with the APOC3 3238 G>C/APOA5 −1131 T>C polymorphism showed a more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type III HLP in APOE2/2.     

Contemporary approach to the problem of depression and disturbances of mental health in mentally disabled people

The approach towards the issues of depression and mental health problems of mentally disabled persons is discussed in the paper. The author discussed the various susceptibilities, resistances and typical mental health disturbances of mentally disabled persons as well as their diagnostic criteria and methods of measuring them. A longer part of the paper concerns the approach towards depressive disorders in the population with developmental disabilities.     

Influence of HLA disparity, immunosuppressive regimen used, and type of kidney allograft on production of anti-HLA class-I antibodies after transplant and occurrence of rejection

We studied the effects of HLA disparity, immunosuppressive regimen used, and the type of kidney allograft on production of anti-HLA antibodies after transplant and the occurrence of rejection episodes. Five living-unrelated donors and 4 living-related donors kidney recipients received quadruple therapy (including sirolimus and mycophenolate mofetil). Fifteen living-unrelated donors and 19 living-related donors received triple therapy (excluding sirolimus). A single bolus of 4 to 6 mg/kg rabbit anti-human T-lymphocyte immune serum was included with both regimens. Recipients were studied over a 3-year period. Human leukocyte antigen profiles were determined by DNA (SSP) typing, and anti-HLA class-I antibodies were determined by the complement-dependent microcytotoxicity assay and an enzyme-linked immunosorbent assay. The degree of HLA disparity did not appear to affect anti-HLA antibody production or the occurrences of rejection episodes. None of the patients who received quadruple therapy developed anti-HLA class-I antibodies. Two living-unrelated donors and 2 living-related donors recipients who received triple therapy developed anti-HLA class-I antibodies. One of the 2 living-unrelated donors antibody-positive patients rejected the kidney and returned to dialysis, and the other patient has normal graft function 3 years after the transplant. The 2 living-related donors patients with normal graft function were antibody-positive 1 year after the transplant but were antibody-negative at 2 and 3 years after transplant. Sirolimus appeared to inhibit production of antibodies after transplant. Moreover, use of present day immunosuppressive agents diminishes the role of HLA matching in relation to the occurrence of rejection episodes.     

Spinal cord transection modifies ileal fluid and electrolyte transport in rats

Spinal cord injury (SCI) is associated with severe autonomic changes, including inhibition of gastrointestinal (GI) motility. GI motility changes are known to affect electrolytes transport and these changes have not been adequately studied after SCI. We studied the ileal permeability to fluid and electrolytes in rats submitted to experimental spinal cord transection (SCT), between T4 and T5, throughout the first week after SCT. SCT increased ileal secretion of Na+ (P<0.05) and decreased the Cl(-) absorption during the first week post SCI (P<0.05). Water transport was also significantly altered, leading to increased water secretion following the Na+ gradient. Ileal secretion of K+ was significantly increased 1 and 7 days after spinal cord injury. To our knowledge, the present findings are the first direct evidence that SCT alters ileal electrolyte transport in rats. Further studies are necessary to evaluate the mechanisms involved in this phenomenon.     

Docosahexaenoic acid and butyrate synergistically induce colonocyte apoptosis by enhancing mitochondrial Ca2+ accumulation

We have previously shown that butyrate, a short-chain fatty acid fiber fermentation product, induces colonocyte apoptosis via a nonmitochondrial, Fas-mediated, extrinsic pathway. Interestingly, fermentable fiber when combined with fish oil containing docosahexaenoic acid (DHA, 22:6n-3) exhibits an enhanced ability to induce apoptosis and protect against colon tumorigenesis. To determine the molecular mechanism of action, the effect of DHA and butyrate cotreatment on intracellular Ca2+ homeostasis was examined. Mouse colonocytes were treated with 50 micromol/L DHA or linoleic acid (LA) for 72 h +/- butyrate (0-10 mmol/L) for the final 24 h. Cytosolic and mitochondrial Ca2+ levels were measured using Fluo-4 and Rhod-2. DHA did not alter basal Ca2+ or the intracellular inositol trisphosphate (IP3) pool after 6 h butyrate cotreatment. In contrast, at 12 and 24 h, DHA- and butyrate-treated cultures exhibited a 25% and 38% decrease in cytosolic Ca2+ compared with LA and butyrate. Chelation of extracellular Ca2+ abolished the effect of thapsigargin on the IP3-releasable Ca2+ pool. DHA and butyrate cotreatment compared with untreated cells increased the mitochondrial-to-cytosolic Ca2+ ratio at 6, 12, and 24 h by 73%, 18%, and 37%, respectively. The accumulation of mitochondrial Ca2+ preceded the onset of apoptosis. RU-360, a mitochondrial-uniporter inhibitor, abrogated mitochondrial Ca2+ accumulation and also partially blocked apoptosis in DHA and butyrate cotreated cells. Collectively, these data show that the combination of DHA and butyrate, compared with butyrate alone, further enhances apoptosis by additionally recruiting a Ca2+ -mediated intrinsic mitochondrial pathway.     

A clinical study of patients with novel CDHR1 genotypes associated with late-onset macular dystrophy

PurposeTo describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 alleles, and compare the associated phenotypes with previous reports.MethodsThe clinical records of patients with macular dystrophy and biallelic variants in CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG).ResultsSeven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of CDHR1: p.(Gly188Ser), p.(Met1?), or p.(Val458Asp); one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5–6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases.ConclusionsThis report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin.Subject terms: Hereditary eye disease, Disease genetics     

Acute hypervolaemia increases gastroduodenal resistance to the flow of liquid in the rat.

The effect of volume expansion of extracellular fluid on gastroduodenal resistance to the flow of isotonic saline was assessed in three groups of rats using intravenous infusions of isotonic, isotonic-isoncotic, and isotonic-isoncotic-isohaemic solutions. The gastroduodenal segment of 29 male Wistar rats was barostatically perfused at a constant pressure gradient of 4 cm H2O and changes in flow (ml/minute) were taken as a reflection of changes in gastroduodenal resistance. Isotonic expansion led to a 33% drop in gastroduodenal flow compared with the normovolaemic period in the same animals (p less than 0.01). Extracellular fluid expansion with isotonic-isoncotic and isotonic-isoncotic-isohaemic solutions was associated with reductions in gastroduodenal flow of 29% (p less than 0.05) and 31% (p less than 0.01) respectively. The increase in gastroduodenal resistance is due to hypervolaemia per se and not to haemodilution, decreases in plasma oncotic pressure, or electrolyte imbalance. The effect of hypervolaemia on gastroduodenal resistance, which was reversed by small haemorrhages (0.5-1.0 ml per 100 g body weight), may be due to changes in tonus or phasic motor activity, or both, and may be part of the homeostatic processes that help the organism minimise liquid volume excess.