Segmental volvulus of the ileum without malrotation in an infant: A case report

AbstractIntestinal volvulus usually occur secondary to malrotation, and primary segmental volvulus has rarely been reported. A 12-month-old female infant presented with a 3-day history of excessive vomiting. An ultrasonography revealed a “whirlpool sign” in the right upper abdomen, suggesting small bowel volvulus with obstruction. Laparotomy revealed a twisted, viable loop of small bowel in the right upper abdomen, and abnormal adhesions were noted between the distal and mid ileum, with resulting mesenteric narrowing. Attempted mesenteric widening by dissection of the peritoneum overlying the adhesions failed, because of abnormal, taut mesenteric vessels. Subsequent resection of the involved segment cured the patient. Recurrent obstructive symptoms in an infant can be an atypical presentation of segmental volvulus, and segmental volvulus should be included in the differential diagnosis of such cases

Adeno-associated virus LPL(S447X) gene therapy in LDL receptor knockout mice

BACKGROUND: Overexpression of lipoprotein lipase (LPL) protects against atherosclerosis in genetically engineered mice. We tested whether a gene therapy vector that delivers human (h) LPL(S447X) cDNA to skeletal muscle could induce similar effects. METHODS: LDL receptor knockout (LDLr-/-) mice were injected intramuscular (i.m.) with adeno-associated virus serotype 1 (AAV1) LPL(S447X) or PBS. Four weeks later they were started on an atherogenic diet for 12 weeks. After termination, atherosclerosis was assessed and homogenates of muscle and liver tissue were analyzed. RESULTS: AAV1-treated mice showed hLPL concentrations of 768+/-293 ng/mL in post-heparin plasma associated with 48% reductions of fasting triglycerides (TG) levels (p <0.0001). In the absence of an effect on total cholesterol (TC) levels, no effects on atherosclerosis were found. An increase in lipid content of injected muscles was accompanied by a significant decrease of TG (-20%, p <0.0001) and free cholesterol (FC) content (-24%, p <0.0001) in liver homogenates. CONCLUSIONS: The data show that transgenic hLPL(S447X) on top of endogenous murine LPL reduces fasting TG levels in plasma but has no effect on atherosclerosis in LDLr-/- mice. While lipid accumulation in the injected muscle was anticipated, this coincided with an interesting decrease of both TG and FC in liver homogenate

AAV gene therapy as a means to increase apolipoprotein (Apo) A-I and high-density lipoprotein-cholesterol levels:correction of murine ApoA-I deficiency

BACKGROUND: Inherited apolipoprotein (Apo) A-I deficiency is an orphan disorder characterized by high-density lipoprotein (HDL)-cholesterol deficiency and premature atherosclerosis. Constitutive over-expression of ApoA-I might provide a means to treat this disease. The present study provides a comprehensive evaluation of adeno-associated virus (AAV)-mediated ApoA-I gene delivery to express human (h)ApoA-I and correct the low HDL-cholesterol phenotype associated with ApoA-I deficiency. METHODS: In an effort to maximize AAV-mediated gene expression, we performed head-to-head comparisons of recombinant AAVs with pseudotype capsids 1, 2, 6 and 8 administered by different routes with the use of five different liver-specific promoters in addition to cytomegalovirus as single-stranded or as self-complementary (sc) AAV vectors. RESULTS: Intravenous administration of 1 x 10(13) gc/kg scAAV8, in combination with the liver-specific promoter LP1, in female ApoA-I(-/-) mice resulted in hApoA-I expression levels of 634 +/- 69 mg/l, which persisted for the duration of the study (15 weeks). This treatment resulted in full recovery of HDL-cholesterol levels with correction of HDL particle size and apolipoprotein composition. In addition, we observed increased adrenal cholesterol content and a significant increase in bodyweight in treated mice. CONCLUSIONS: The present study demonstrates that systemic delivery of a scAAV8 vector provides a means for efficient liver expression of hApoA-I, thereby correcting the lipid abnormalities associated with murine ApoA-I deficiency. Importantly, the study demonstrates that AAV-based gene therapy can be used to express therapeutic proteins at a high level for a prolonged period of time and, as such, provides a basis for further development of this strategy to treat hApoA-I deficiency

Chylomicronemia with low Postheparin Lipoprotein Lipase levels in the setting of GPIHBP1 defects

Background-Recent studies in mice have established that an endothelial cell protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), is essential for the lipolytic processing of triglyceride-rich lipoproteins. Methods and Results-We report the discovery of a homozygous missense mutation in GPIHBP1 in a young boy with severe chylomicronemia. The mutation, p.C65Y, replaces a conserved cysteine in the GPIHBP1 lymphocyte antigen 6 domain with a tyrosine and is predicted to perturb protein structure by interfering with the formation of a disulfide bond. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1-C65Y reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL). When the GPIHBP1-C65Y homozygote was given an intravenous bolus of heparin, only trace amounts of LPL entered the plasma. We also observed very low levels of LPL in the postheparin plasma of a subject with chylomicronemia who was homozygous for a different GPIHBP1 mutation (p.Q115P). When the GPIHBP1-Q115P homozygote was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1780 to 120 mg/dL. Conclusions-We identified a novel GPIHBP1 missense mutation (p.C65Y) associated with defective LPL binding in a young boy with severe chylomicronemia. We also show that homozygosity for the C65Y or Q115P mutations is associated with low levels of LPL in the postheparin plasma, demonstrating that GPIHBP1 is important for plasma triglyceride metabolism in humans. ( Circ Cardiovasc Genet. 2010; 3: 169-178.

Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.

The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes. Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed. Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I. The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.Funding agencies: EUs Sixth Framework Program [037631]; European Union [FP7-603091-2]; CardioVascular Research Initiative [CVON2011-16]; Research Council of South East Sweden [FORSS-3755]; County Council of Ostergotland (C-ALF); Faculty of Health Sciences in Linkoping; Ven</p

Determining efficacy of Monosodium Glutamate for salt reduction inPlain and spiced ‘Poories’ through sensory responses

Palatability is considered as a major determinant of food selection and intake. Umami foods are being employed widely in savory food formulation for its greater potential for enhancing savory taste. In the present investigation, the role of monosodium glutamate (MSG) in salt reduction along with spices was investigated to understand the flavor potentiating effect and synergistic action of MSG. Deep fried unleavened wheat based traditional Indian bread (Poories) was chosen to study the acceptability. Control product was prepared with 2.0% salt. For experimental products, two levels of MSG viz, 75 and 100 mg/100 g and three levels of salt, namely, 1.5, 1.75 and 2.0% were selected. Spices, namely, chili (Capsicum annum L.) cumin (Cuminum cyminum)), pepper (Piper nigrum L) and omum (Trachyspermum ammi)) were incorporated into the product, either as single spice or in combination. The results revealed that the MSG added products were given a higher score for umami flavour in comparison to the control product. In general, MSG added products scored better for flavor in salt reduced products. Results of low sodium poories with single spices and different level of salt indicated that all products prepared with spices were equally liked for the selected sensory characteristics. The products prepared with 1.75% salt obtained highest scores. This is indicative of the flavour enhancing property of MSG. Similarly for products with mixture of spices; salt reduced products were also accepted well. PCA plot revealed the flavor potentiating effect of MSG in salt reduction. Thus it could be said that using MSG and spices combination would be a better option for achieving salt reduction in savory products

Gene therapy for lipoprotein lipase deficiency: Working toward clinical application

Lipoprotein lipase (LPL) deficiency causes hypertriglyceridemia and recurrent, potentially life- threatening pancreatitis. There currently is no adequate treatment for this disease. Previously, we showed that intramuscular administration of an adeno- associated virus serotype 1 (AAV1) vector encoding the human LPLS447X variant cDNA (AAV1-LPLS447X) normalized the dyslipidemia of LPL-/- mice for more than 1 year. In preparation for a clinical trial, we evaluated the safety and biodistribution of AAV1-LPLS447X in wild- type mice and fully characterized six LPL-deficient patients. Toxicological analysis in mice showed that intramuscular administration was well tolerated. Acute inflammatory response markers were transiently increased, and anti-AAV1 antibodies were generated. Histological analyses indicated a dose- dependent reversible spleen hyperplasia, and myositis at the injection sites. Biodistribution data showed short- term vector leakage from injection sites into the circulation, followed by liver- mediated clearance. Persistence of vector DNA was limited to the injected muscle and draining lymph nodes, and spread to reproductive organs was limited. Characterization of LPL- deficient patients showed that all patients presented with hypertriglyceridemia and recurrent pancreatitis. LPL catalytic activity was absent, but LPL protein levels were 20 - 100% of normal. Myoblasts derived from skeletal muscle biopsies of these patients were efficiently transduced by AAV1- LPLS447X and secreted active LPL. These data support the initiation of a clinical trial in LPL- deficient patients, for which regulatory approval has been grante

Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man.

Item does not contain fulltextGenome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene