Incretin Response to a Standard Test Meal in a Rat Model of Sleeve Gastrectomy with Diet-Induced Obesity

Background

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects.

Methods

Male Sprague–Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham).

Results

After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response.

Conclusions

A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.     

Intracranial infectious aneurysms: a comprehensive review

Intracranial infectious aneurysms, or mycotic aneurysms, are rare infectious cerebrovascular lesions which arise through microbial infection of the cerebral arterial wall. Due to the rarity of these lesions, the variability in their clinical presentations, and the lack of population-based epidemiological data, there is no widely accepted management methodology. We undertook a comprehensive literature search using the OVID gateway of the MEDLINE database (1950–2009) using the following keywords (singly and in combination): “infectious,” “mycotic,” “cerebral aneurysm,” and “intracranial aneurysm.” We identified 27 published clinical series describing a total of 287 patients in the English literature that presented demographic and clinical data regarding presentation, treatment, and outcome of patients with mycotic aneurysms. We then synthesized the available data into a combined cohort to more closely estimate the true demographic and clinical characteristics of this disease. We follow by presenting a comprehensive review of mycotic aneurysms, highlighting current treatment paradigms. The literature supports the administration of antibiotics in conjunction with surgical or endovascular intervention depending on the character and location of the aneurysm, as well as the clinical status of the patient. Mycotic aneurysms comprise an important subtype of potentially life-threatening cerebrovascular lesions, and further prospective studies are warranted to define outcome following both conservative and surgical or endovascular treatment.     

Acromegaly as a cause of 1,25-dihydroxyvitamin D-dependent hypercalcemia: case reports and review of the literature

Growth hormone excess has been associated with hypercalciuria and nephrolithiasis. Hypercalcemia in acromegaly is rare and usually due to coexistent primary hyperparathyroidism. To report two cases of 1,25-dihydroxyvitamin D (1,25 (OH)₂ D)-dependent hypercalcemia in cromegaly. A 50 year-old female with 2 years history of hypercalcemia presented with features of acromegaly. Serum calcium (Ca) was 10.9 mg/dl (8.6–10.2), parathyroid hormone (PTH) 20 pg/ml (10–65), PTH-related peptide undetectable, and 1,25 (OH)₂ D 119 pg/ml (15–75). Insulin-like growth factor 1 (IGF1) was 911 ng/ml (49–292) and growth hormone (GH) 14.5 ng/ml (0.03–10). MRI showed a 1.7 cm pituitary tumor. Transsphenoidal adenectomy (TSA) resulted in normalization of IGF1, GH, Ca, and 1,25 (OH)₂ D (50 pg/ml) and complete tumor resection. A 52-year-old female was diagnosed with visual field deficits on routine exam. MRI showed a 3 cm invasive pituitary macroadenoma. IGF1 was 416 ng/ml (87–238) and GH 75.8 (0–6.0) ng/ml. Incidentally, she was found with high Ca of 10.8 mg/dl (8.9–10.3) associated with PTH 19 pg/ml and 1,25 (OH)₂ D66 pg/ml. Postoperatively, IGF1 and GH remained abnormal (440 and 12.8 ng/ml, respectively), while MRI showed parasellar tumor residue. Ca remained high (10.1–11.1 mg/dl), along with elevated 1,25 (OH)₂ D level (81.3 pg/ml). In both cases, other causes of hypercalcemia were ruled out. We present 2 cases of 1,25 (OH)₂ D-dependent hypercalcemia associated with growth hormone excess. Complete resection of tumor produced biochemical remission of acromegaly and normalization of calcium and 1,25 (OH)₂ D levels, while incomplete resection was associated with persistent 1,25 (OH)₂ D-dependent hypercalcemia. Acromegaly should be considered a cause of 1,25 (OH)₂ D-dependent hypercalcemia.

     

Design and characterization of polytope construct with multiple B and TH epitopes of Japanese encephalitis virus

Japanese encephalitis (JE) remains a major public health threat with vaccination as the only measure for its prevention. Epitope-based vaccination is a promising approach for achieving protective immunity and avoid immunopathology in Japanese encephalitis virus (JEV) infection due to flavivirus cross-reactivity. We have mapped B-cell epitopes from JEV envelope protein, responsible for elicitation of neutralizing antibodies. Incorporation of T helper (T(H)) epitopes, along with these, imparted protective immunity to the host. In the present study, based on in silico epitope selection we optimized and proposed a polytope DNA construct (P-JEV) consisting B-cell and T(H) epitopes from the JEV envelope (E) protein as well as non-structural protein-1 (NS1). The immunogenicity and protective efficacy of P-JEV was assessed by in vitro and in vivo experiments. The expressed P-JEV showed reactivity in in vitro assays with JEV monoclonal antibodies. Protective efficacy of P-JEV was assessed in BALB/c mice. Our findings indicate that P-JEV may be a candidate vaccine for the prevention of JEV infection.     

Falcipain-1, a Plasmodium falciparum cysteine protease with vaccine potential

Cysteine proteases (falcipains) of Plasmodium falciparum are potential targets for antimalarial chemotherapy, since they have been shown to be involved in important cellular functions such as hemoglobin degradation and invasion/rupture of red blood cells during parasite life cycle. The role of falcipain-1 at the asexual blood stages of the parasite still remains uncertain. This is mainly due to a lack of methods to prepare this protein in an active form. In order to obtain biologically active falcipain-1, a number of falcipain-1 constructs were designed and a systematic assessment of the refolding conditions was done. We describe here the expression, purification, and characterization of a falcipain-1 construct encoding mature falcipain-1 and 35 amino acids from the C-terminal of the pro domain. Recombinant falcipain-1 was overexpressed in the form of inclusion bodies, solubilized, and purified by Ni²⁺-nitrilotriacetic acid affinity chromatography under denaturing conditions. A systemic approach was then followed to optimize refolding parameters. An optimum refolding condition was obtained, and the yield of the purified refolded falcipain-1 was ~1 mg/liter. Activity of the protein was analyzed by fluorometric and gelatin degradation assays. Immunolocalization studies using anti-falcipain-1 sera revealed a distinct staining at the apical end of the P. falciparum merozoites. Previous studies using falcipain-1-specific inhibitors have suggested a role of falcipain-1 in merozoite invasion. Based on its localization and its role in invasion, we analyzed the immunogenicity of falcipain-1 in mice, followed by heterologous challenge with Plasmodium yoelii sporozoites. Our results suggest a possible role of falcipain-1 in merozoite invasion.     

Linkage to care following a home-based HIV counselling and testing intervention in rural South Africa

Introduction

Efforts to increase awareness of HIV status have led to growing interest in community-based models of HIV testing. Maximizing the benefits of such programmes requires timely linkage to care and treatment. Thus, an understanding of linkage and its potential barriers is imperative for scale-up.

Methods

This study was conducted in rural South Africa. HIV-positive clients (n=492) identified through home-based HIV counselling and testing (HBHCT) were followed up to assess linkage to care, defined as obtaining a CD4 count. Among 359 eligible clients, we calculated the proportion that linked to care within three months. For 226 clients with available data, we calculated the median CD4. To determine factors associated with the rate of linkage, Cox regression was performed on a subsample of 196 clients with additional data on socio-demographic factors and personal characteristics.

Results

We found that 62.1% (95% CI: 55.7 to 68.5%) of clients from the primary sample (n=359) linked to care within three months of HBHCT. Among those who linked, the median CD4 count was 341 cells/mm³ (interquartile range [IQR] 224 to 542 cells/mm³). In the subsample of 196 clients, factors predictive of increased linkage included the following: believing that drugs/supplies were available at the health facility (adjusted hazard ratio [aHR] 1.78; 95% CI: 1.07 to 2.96); experiencing three or more depression symptoms (aHR 2.09; 95% CI: 1.24 to 3.53); being a caregiver for four or more people (aHR 1.93; 95% CI: 1.07 to 3.47); and knowing someone who died of HIV/AIDS (aHR 1.68; 95% CI: 1.13 to 2.49). Factors predictive of decreased linkage included the following: younger age – 15 to 24 years (aHR 0.50; 95% CI: 0.28 to 0.91); living with two or more adults (aHR 0.52; 95% CI: 0.35 to 0.77); not believing or being unsure about the test results (aHR 0.48; 95% CI: 0.30 to 0.77); difficulty finding time to seek health care (aHR 0.40; 95% CI: 0.24 to 0.67); believing that antiretroviral treatment can make you sick (aHR 0.56; 95% CI: 0.35 to 0.89); and drinking alcohol (aHR 0.52; 95% CI: 0.34 to 0.80).

Conclusions

The findings highlight barriers to linkage following an increasingly popular model of HIV testing. Further, they draw attention to ways in which practical interventions and health education strategies could be used to improve linkage to care.