Leptin signaling in adipose tissue: role in lipid accumulation and weight gain

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.     

Spontaneous cerebellar hemorrhage associated with a novel Notch3 mutation

A 55-year-old woman with no significant medical history presented with an acute onset severe headache. A non-enhanced CT scan of the head revealed a right cerebellar hemorrhage. Investigation for etiology of the hemorrhage included an MRI showing extensive subcortical ischemic disease and also several previous microbleeds. The MRI appearance and absence of any other etiology for hemorrhage prompted work up for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). She was found to have a guanosine to thymidine transversion at nucleotide position 1336, codon position 420, resulting in a glycine > cysteine substitution interpreted as “predicted CADASIL-associated mutation”. To our knowledge, this mutation has not yet been reported in association with CADASIL.     

Bioactivity guided fractionation of methanolic extract of Terminalia arjuna for its CYP3A and CYP2D inhibition in rat liver microsomes

Terminalia arjuna (T. arjuna) is an Indian medicinal plant belonging to the family Combretaceae and possesses numerous therapeutic activities including its immense cardioprotective activity. In the present work, a methanolic bark extract of T. arjuna was evaluated for CYP3A and CYP2D inhibition potential in rat liver microsomes (RLM). Further, the methanolic bark extract was fractionated successively using increasing polarity solvents starting with petroleum ether, chloroform, ethyl acetate and n‐butanol. The fractions so obtained were also evaluated for their CYP3A and CYP2D inhibition potential. Probe substrates testosterone and dextromethorphan were used for CYP3A and CYP2D respectively. The IC₅₀ values for the methanolic extract and the fractions were found to be less than 50 μg/ml in RLM for both CYP3A and CYP2D isoenzymes. The most potent n‐butanol fraction was further fractionated with column chromatography to isolate the highest active constituent responsible for the activity. Fraction 4 of the n‐butanol extract was the most potent fraction with IC₅₀ values of 5.64 ± 0.735 μg/ml and 16.63 ± 0.879 μg/ml for CYP3A and CYP2D in RLM, respectively. Therefore, in vitro data indicated that the Terminalia arjuna extract contains constituents that can potentially inhibit the CYP3A and CYP2D isoenzymes which may in turn lead to pharmacokinetic drug–herb interaction.     

Molecular characterization of the variable domains of an alphaIIbbeta3-specific immunoglobulin M kappa platelet cold agglutinin in a follicular lymphoma patient with treatment refractory autoimmune thrombocytopenia: idiotypic overlap between alphaIIbbeta3 integrin antibodies

BACKGROUND: Cold hemagglutinins are generally immunoglobulin M (IgM) kappa antibodies reactive at temperatures below 37 degrees C and if of high titer may cause hemolysis. Platelet (PLT) cold agglutinins (CAs) are rare and poorly characterized. A detailed molecular characterization of the variable domains of a pathologic, PLT-reactive, CA is presented. CASE REPORT: A 70-year-old woman was admitted with rectal bleeding accompanied by widespread petechiae, bruising, tongue and buccal mucosa bleeding, and epistaxes and proved refractory to HLA- and HPA-matched PLTs. Detailed investigation showed monoclonal heavy-chain gene rearrangement with an IgM paraprotein of 3.3 g per L and a trace of kappa Bence Jones protein in the urine, compatible with a diagnosis of secretory B-cell non-Hodgkin's lymphoma (B-NHL). PLT antibody (PAIg) investigations revealed a potent IgM kappa PLT CA. Sequencing of the rearranged variable domain genes of the malignant clone together with idiotype-specific antibodies obtained by DNA-based immunization of rabbits and matrix-assisted laser desorption/ionization-time-of-flight analysis of the PAIgM provided a irrefutable link between the thrombocytopenia, the IgM paraprotein, and the PAIgM against alphaIIbbeta3. The thrombocytopenia and bleeding were refractory to standard treatment and PLT transfusion, but treatment with rituximab resulted in a recovery of the PLT count and a complete remission of B-NHL. CONCLUSION: The IgM kappa paraprotein derived from the malignant B-cell clone was a potent and clinically significant CA against alphaIIbbeta3. The testing for PLT CAs in patients with a paraprotein and refractory to matched PLTs may aid the selection of appropriate treatment.     

Vitamin D Supplementation in Young White and African American Women

There is limited information on the effects of vitamin D on serum 25 hydroxyvitamin D (25OHD) in young people and none on African Americans. The main objective of this trial was to measure the effect of different doses of vitamin D3 on serum 25OHD and serum parathyroid hormone (PTH) in young women with vitamin D insufficiency (serum 25OHD ≤ 20 ng/mL (50 nmol/L). A randomized double‐blind placebo‐controlled trial of vitamin D3 was conducted in young white and African American women, age 25 to 45 years. A total of 198 healthy white (60%) and African American (40%) women were randomly assigned to placebo, or to 400, 800, 1600, or 2400 IU of vitamin D3 daily. Calcium supplements were added to maintain a total calcium intake of 1000 to 1200 mg daily. The primary outcomes of the study were the final serum 25OHD and PTH levels at 12 months. The absolute increase in serum 25OHD with 400, 800, 1600, and 2400 IU of vitamin D daily was slightly greater in African American women than in white women. On the highest dose of 2400 IU/d, the mixed model predicted that mean 25OHD increased from baseline 12.4 ng/mL (95% confidence interval [CI], 9.2–15.7) to 43.2 ng/mL (95% CI, 38.2–48.1) in African American women and from 15.0 ng/mL (95% CI, 12.3–17.6) to 39.1 ng/mL (95% CI, 36.2–42.0) in white women. There was no significant effect of vitamin D dose on serum PTH in either race but there was a significant inverse relationship between final serum PTH and serum 25OHD. Serum 25OHD exceeded 20 ng/mL in 97.5% of whites on the 400 IU/d dose and between 800 and 1600 IU/d for African Americans. The recommended dietary allowance (RDA) suggested by the Institute of Medicine for young people is 600 IU daily. The increase in serum 25OHD after vitamin D supplementation was similar in young and old, and in white and African American women. © 2014 American Society for Bone and Mineral Research.     

Strain measurement by cardiovascular magnetic resonance in pediatric cancer survivors: validation of feature tracking against harmonic phase imaging

Background

Left ventricular strain may be a more sensitive marker of left ventricular dysfunction than ejection fraction in pediatric cancer survivors after anthracycline therapy, but there is limited validation of strain measurement by feature tracking on cardiovascular magnetic resonance (MR) images.

Objective

To compare left ventricular circumferential and radial strain by feature tracking vs. harmonic phase imaging analysis (HARP) in pediatric cancer survivors.

Materials and methods

Twenty-six patients (20.2?±?5.6 years old) underwent cardiovascular MR at least 5 years after completing anthracycline therapy. Circumferential and radial strain were measured at the base, midventricle and apex from short-axis myocardial tagged images by HARP, and from steady-state free precession images by feature tracking.

Results

Left ventricular ejection fraction more closely correlated with global circumferential strain by feature tracking (r?=??0.63, P?=?0.0005) than by HARP (r?=??0.39, P?=?0.05). Midventricular circumferential strain did not significantly differ by feature tracking or HARP (?20.8?±?3.4 vs. ?19.5?±?2.5, P?=?0.07), with acceptable limits of agreement. Midventricular circumferential strain by feature tracking strongly correlated with global circumferential strain by feature tracking (r?=?0.87, P?HARP, particularly at higher values of radial strain. Intraobserver and interobserver reproducibility was excellent for feature tracking circumferential strain, but reproducibility was poor for feature tracking radial strain.

Conclusion

Midventricular circumferential strain by feature tracking is a reliable and reproducible measure of myocardial deformation in patients status post anthracycline therapy, while radial strain measurements are unreliable. Further studies are necessary to evaluate potential relation to long-term outcomes.     

Interface enriched highly interlaced layered MoS2/NiS2 nanocomposites for the photocatalytic degradation of rhodamine B dye

In the past few decades, air and water pollution by organic dyes has become a serious concern due to their high toxicity. Removal of these organic dyes from polluted water bodies is a serious environmental concern and the development of new advanced photocatalytic materials for decomposing organic dyes can be a good solution. In this work, layered molybdenum disulfide/nickel disulfide (MoS₂/NiS₂) nanocomposites with various NiS₂ content was synthesized by a one-step hydrothermal method using citric acid as a reducing agent. The X-ray diffraction pattern shows the hexagonal and cubical crystal structure of MoS₂ and NiS₂, respectively. Morphological analysis confirms the formation of MoS₂/NiS₂ nanosheets. The elemental composition of the samples was carried out by XPS, which shows a significant interaction between NiS₂ and MoS₂. The photocatalytic performance of MoS₂/NiS₂ nanocomposites was studied by the degradation of rhodamine B (RhB). Ni-4 sample shows higher photocatalytic activity with a maximum degradation of 90.61% under visible light irradiation for 32 min.

The photocatalytic performance of MoS₂/NiS₂ nanocomposites was studied by the degradation of rhodamine B (RhB). Ni-4 sample shows higher photocatalytic activity with a maximum degradation of 90.61% under visible light irradiation for 32 min.