Limits of stimulation of proliferation and differentiation of bone marrow cells of mice treated with swainsonine

The limits of stimulation of the immunomodulatory alkaloid swainsonine (8alphabeta-indolizidine-1alpha,2alpha,8beta-triol) were studied in inbred C57BL/6 mice for potential support of intense high dose cancer chemotherapy and/or radiation because of its attractive pharmacologic profile on the hematopoietic system. Specifically, the effects of swainsonine on bone marrow cellularity and on in vitro progenitor cell proliferation to total colony forming units (CFU) and differentiation to different lineages were studied as a function of number of days post drug administration. The lineages evaluated were colony forming units-granulocyte-macrophage (CFU-GM), erythroid-burst forming units (BFU-e) and CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM or CFU-Mix). Groups of mice were treated with swainsonine or plain vehicle, phosphate buffered saline for 10 consecutive days. The effects of these agents on the hematopoietic system were studied up to 60 days following their discontinuation. The magnitude of the effects of swainsonine on bone marrow system gradually declined with increasing duration of days following its discontinuation. Nevertheless, its residual stimulatory effects on bone marrow cellularity, total CFU, CFU-GM, BFU-e and CFU-Mix continued to be significant (P<0.0001) up to 45, 50, 50, 55 and 50 days, respectively, compared to those of diluent buffer or untreated controls. Since cancer chemotherapeutic agents or radiation are normally given in schedules and/or cycles, these results strongly suggest that swainsonine effects are sustained long enough to potentially support and facilitate hematopoietic recovery during anti-cancer cytotoxic treatment.     

−NMDA R/+VDR pharmacological phenotype as a novel therapeutic target in relieving motor–cognitive impairments in Parkinsonism

Background: Parkinsonism describes Parkinson’s disease and other associated degenerative changes in the brain resulting in movement disorders. The motor cortex, extrapyramidal tracts and nigrostriatal tract are brain regions forming part of the motor neural system and are primary targets for drug or chemotoxins induced Parkinsonism. The cause of Parkinsonism has been described as wide and elusive, however, environmental toxins and drugs accounts for large percentage of spontaneous cases in humans. A common mechanism in the cause and progression of drug/chemotoxin induced Parkinsonism involves calcium signalling in; oxidative stress, autophagy, cytoskeletal instability and excitotoxicity

.Aim: This study sets to investigate the effect of targeting calcium controlling receptors, specifically activation of Vitamin D₃ receptor (VDR) and inhibition of N-Methyl-D-Aspartate Receptor (NMDAR) in the motor cortex of mice model of drug induced Parkinsonism. Also we demonstrated how these interventions improved neural activity, cytoskeleton, glia/neuron count and motor–cognitive functions in vivo.

Methods: Adult mice were separated into six groups of n?=?5 animals each. Body weight (5?mg/kg) of haloperidol was administered intraperitoneally for 7 days to block dopaminergic D₂ receptors and induce degeneration in the motor cortex following which an intervention of VDR agonist (VDRA), and (or) NMDAR inhibitor was administered for 7 days. A set of control animals received normal saline while a separate group of control animals received the combined intervention of VDRA and NMDAR inhibitor without prior treatment with haloperidol. Behavioral tests for motor and cognitive functions were carried out at the end of the treatment and intervention periods. Subsequently, neural activity in the motor cortex was recorded in vivo using unilateral wire electrodes. We also employed immunohistochemistry to demonstrate neuron, glia, neurofilament and proliferation in the motor cortex after haloperidol treatment and the intervention.

Result/Discussion: We observed a decline in motor function and memory index in the haloperidol treatment group when compared with the control. Similarly, there was a decline in neural activity in the motor cortex (a reduced depolarization peak frequency). General cell loss (neuron and glia) and depletion of neurofilament were characteristic anatomical changes seen in the motor cortex of this group. However, Vitamin D₃ intervention facilitated an improvement in motor–cognitive function, neural activity, glia/neuron survival and neurofilament expression. NMDAR inhibition and the combined intervention improved motor–cognitive functions but not as significant as values observed in VDRA intervention. Interestingly, animals treated with the combined intervention without prior haloperidol treatment showed a decline in motor function and neural activity.

Conclusion: Our findings suggest that calcium mediated toxicity is primary to the cause and progression of Parkinsonism and targeting receptors that primarily modulates calcium reduces the morphological and behavioral deficits in drug induced Parkinsonism. VDR activation was more effective than NMDAR inhibition and a combined intervention. We conclude that targeting VDR is key for controlling calcium toxicity in drug/chemotoxin induced Parkinsonism.     

Standardization of NIRR-1 irradiation and counting facilities for instrumental neutron activation analysis.

The first nuclear reactor in Nigeria, the Nigeria Research Reactor-1 (NIRR-1), is a Miniature Neutron Source Reactor (MNSR). It was specifically acquired for elemental analysis by the neutron activation analysis (NAA) technique. In this work, routine experimental schemes for the determination of over 30 elements of interest in different sample matrices have been developed. In order to validate the experimental procedures the following standard reference materials, IAEA-359 (Cabbage), IAEA-336 (Lichen), GSR-5 and GSD-11 (Chinese Geochemical Rock Standards), as well as IAEA-SL-3 and IAEA-405 (Sediments) were analyzed. Validated results are presented for the following elements Al, As, Au, Ba, Br, Ca, Ce, Cl, Co, Cr, Cs, Cu, Dy, Eu, Fe, Ga, Hf, In, K, La, Lu, Mg, Mn, Na, Rb, Sb, Sc, Sm, Ta, Tb, Th, Ti, U, V, Yb and Zn. To further assess analytical capabilities of the facilities, the detection limits are presented.     

Functional Properties,Nutritional and Sensory Qualities of Maize-Based Snack (Kokoro) Supplemented with Protein Hydrolysate Prepared from Pigeon Pea (Cajanus Cajan) Seed

Kokoro is a popular maize-based snack in Nigeria, which is consumed by adults and children but characterized by low protein content. The snacks were produced from blends of maize flour supplemented with protein hydrolysate from pigeon pea at 100:0 (control), 95:5, 90:10, 85:15, and 80:20. Flour blends were evaluated for functional and pasting properties, while snacks were analyzed for proximate composition and sensory qualities. Proximate analysis results showed significant (p < 0.05) increase in protein (9.64–11.12%), fat (13.40–20.17%), ash (1.83–2.38%) content, and energy value (431.84–468.97 kcal/100 g), while fiber (1.19–0.96%) and carbohydrate (68.17–60.74%) content decreased with inclusion of protein hydrolysate. No significant difference (p < 0.05) occurred in the sensory qualities of products from 100% maize and 80:20 flour blend. Hence, acceptable Kokoro snacks from an 80:20 (maize: protein hydrolysate) blend have been formulated, which could enhance the nutritional wellness of the target consumers.     

Post-traumatic stress disorder (PTSD) after stigma related events in HIV infected individuals in Nigeria

Background  

One of the most distressing concerns of many people living with HIV in sub-Saharan Africa is the stigma. Intense stigma may be traumatic. This study aimed to investigate the probability and correlates of Posttraumatic stress disorder (PTSD) following intense stigmatizing events and situations in HIV infected individuals in Nigeria.     

Protein Energy Malnutrition Is Associated with Worse Outcomes in Sepsis—A Nationwide Analysis

BackgroundProtein-energy malnutrition (PEM), resulting from depleted energy and nutrient stores, compromises the body’s defense systems and may exacerbate sepsis and its impact. However, population-based studies examining the association of PEM on the prevalence and health-care burden of sepsis are lacking.ObjectiveTo investigate the relationship between PEM and sepsis, influence of PEM on clinical outcomes of sepsis, and impact of PEM on trends in sepsis mortality.DesignThe primary study is a retrospective cohort analysis of the 2012-2014 National Inpatient Sample (NIS) patient discharge records. Secondary analyses are cross-sectional study on the 2014 NIS and trend analysis on 2007-2014 NIS.Participants/settingThe primary study included adult inpatient hospitalizations for sepsis in the United States.Main outcome measuresMortality, complicated sepsis, and 10 other metrics of clinical outcomes and health care utilization.Statistical analysisFirst, patients with sepsis (2014 NIS) were stratified into two groups: uncomplicated (without shock) and complicated (with shock). The adjusted odds ratio of having sepsis (total, uncomplicated, and complicated) was estimated with PEM as predictor using logistic regressions (binomial and multinomial). Second, among patients with sepsis (2012-2014 NIS), PEM cases were matched to cases without PEM (no-PEM) using a greedy-algorithm based propensity-matching methodology (1:1), and the outcomes were measured with conditional regression models. Finally, the trend in mortality from sepsis was calculated, stratified by PEM status, as an effect modifier, using Poisson models (2007-2014 NIS). All models accounted for the complex sampling methodology (SAS 9.4).ResultsIn 2014, PEM was associated with higher odds for sepsis (3.97 [3.89 to 4.05], P<0.0001) and complicated vs uncomplicated sepsis (1.74 [1.67 to 1.81], P<0.0001). From 2012-2014, about 18% (167,133 of 908,552) of hospitalizations for sepsis had coexisting PEM. After propensity matching, PEM was associated with higher mortality (adjusted odds ratio: 1.35 [1.32 to 1.37], P<0.0001), cost ($160,724 [159,517 to 161,940] vs $86,650 [85,931 to 87,375], P<0.0001), length of stay (14.8 [14.9 to 14.8] vs 8.5 [8.5 to 8.6] days, P<0.0001), adverse events, and resource utilization. Although mortality in sepsis has been trending down from 2007-2014 (?1.19% per year, P trend<0.0001), the decrease was less pronounced among those with PEM vs no-PEM (?0.86% per year vs ?1.29% per year, P<0.0001).ConclusionsPEM is a risk factor for sepsis and associated with poorer outcomes among patients with sepsis. A concerted effort involving all health care workers in the prevention, identification, and treatment of PEM in community-dwelling people before hospitalization might mitigate against these devastating outcomes.     

White Matter Tract Integrity of Anterior Limb of Internal Capsule in Major Depression and Type 2 Diabetes

A number of studies have shown an association between diabetes and depression. However, the underlying mechanisms are still unclear. Previous findings indicate a role for the prefrontal cortex and subcortical gray matter regions in type 2 diabetes and major depressive disorder (MDD). The purpose of this study was to examine the white matter integrity in the fibers that are part of the anterior limb of internal capsule (ALIC) in MDD and diabetic subjects using diffusion tensor imaging tractography. We studied 4 groups of subjects including 1) 42 healthy controls (HC), 2) 28 MDD subjects (MD), 3) 24 patients diagnosed with type 2 diabetes without depression (DC), and 4) 22 patients diagnosed with diabetes and depression (DD). Results revealed significantly decreased fractional anisotropy (FA; P=.021) and a trend towards significant increase in radial diffusivity (RD; P=.078) of the right ALIC in depressed subjects (MD+DD) compared to non-depressed subjects (HC+DC). While there were no significant diabetes effects or interactions between depression and diabetes, subjects with high depression ratings and high hemoglobin A1c levels had the lowest mean FA values in the right ALIC. In addition, we found a significant negative correlation between FA of the left ALIC with hemoglobin A1c in diabetic subjects (DC+DD; P=.016). Our study demonstrated novel findings of white matter abnormalities of the ALIC in depression and diabetes. These findings have implications for clinical manifestations of depression and diabetes as well as their pathophysiology.     

Measuring embeddedness: Hierarchical scale‐dependent information exchange efficiency of the human brain connectome

This article presents a novel approach for understanding information exchange efficiency and its decay across hierarchies of modularity, from local to global, of the structural human brain connectome. Magnetic resonance imaging techniques have allowed us to study the human brain connectivity as a graph, which can then be analyzed using a graph‐theoretical approach. Collectively termed brain connectomics, these sophisticated mathematical techniques have revealed that the brain connectome, like many networks, is highly modular and brain regions can thus be organized into communities or modules. Here, using tractography‐informed structural connectomes from 46 normal healthy human subjects, we constructed the hierarchical modularity of the structural connectome using bifurcating dendrograms. Moving from fine to coarse (i.e., local to global) up the connectome's hierarchy, we computed the rate of decay of a new metric that hierarchically preferentially weighs the information exchange between two nodes in the same module. By computing “embeddedness”‐the ratio between nodal efficiency and this decay rate, one could thus probe the relative scale‐invariant information exchange efficiency of the human brain. Results suggest that regions that exhibit high embeddedness are those that comprise the limbic system, the default mode network, and the subcortical nuclei. This supports the presence of near‐decomposability overall yet relative embeddedness in select areas of the brain. The areas we identified as highly embedded are varied in function but are arguably linked in the evolutionary role they play in memory, emotion and behavior. Hum Brain Mapp 36:3653–3665, 2015. © 2015 Wiley Periodicals, Inc.