Repeated dose toxicity evaluation of a cold chain-free,live, attenuated oral cholera vaccine in Sprague Dawley rats

The repeated dose toxicity of a prototype cold chain-free, live, attenuated oral cholera vaccine containing 5?×?10⁶?CFU/mL of the VCUSM14P strain was evaluated in Sprague Dawley (SD) rats (single dose administered daily for 30?days) to ascertain its safety for clinical use. Repeated dose toxicity studies for cholera vaccines in the literature have administered 2 or 3 fixed doses at 7, 14, 21 or 69?day intervals. The present study reports an evaluation of 30 repeated doses of cholera vaccine administered at three different concentrations (Group II (1.25?×?10⁶?CFU), Group III (2.5?×?10⁶?CFU) and Group IV (5?×?10⁶?CFU)) in SD rats. The liquid vaccine was administered orally to the rats with the respective dose every day, and normal saline was administered to the control group (Group I). No significant difference (P?>?0.05) was observed in the body weights and biochemical parameters of the rats after 15 and 30 repeated doses compared to those of the control group. However, compared to those of Group I, a significant increase (P?<?0.05) in the organ to body weight ratios of the lungs, ureter, liver, kidney, heart and spleen was found in G-II, G-III and G-IV. In the haematological analysis, a significant increase in the WBC was observed in G-II and G-IV compared to that in G-I. The histopathological findings indicated mild to moderate degeneration in the liver, kidney, heart and spleen in the treated rats. Mild to moderate lymphocytic infiltration in the lungs was observed in the G-II and G-III rats, and severe infiltration was observed in the G-IV rats. These histopathological findings may be attributed to the 30 doses of vaccine given in daily succession without an interval. In the acute toxicity study, a single dose of vaccine up to 10?×?10⁶?CFU did not cause any adverse effects and lethality in SD rats.     

Assessments of Process Parameters on Cutting Force and Surface Roughness during Drilling of AA7075/TiB2 In Situ Composite

Reinforced aluminum composites are the basic class of materials for aviation and transport industries. The machinability of these composites is still an issue due to the presence of hard fillers. The current research is aimed to investigate the drilling topographies of AA7075/TiB₂ composites. The samples were prepared with 0, 3, 6, 9 and 12 wt.% of fillers and experiments were conducted by varying the cutting speed, feed, depth of cut and tool nose radius. The machining forces and surface topographies, the structure of the cutting tool and chip patterns were examined. The maximum cutting force was recorded upon increase in cutting speed because of thermal softening, loss of strength discontinuity and reduction of the built-up-edge. The increased plastic deformation with higher cutting speed resulted in the excess metal chip. In addition, the increase in cutting speed improved the surface roughness due to decrease in material movement. The cutting force was decreased upon high loading of TiB₂ due to the deterioration of chips caused by fillers. Further introduction of TiB₂ particles above 12 wt.% weakened the composite; however, due to the impact of the microcutting action of the fillers, the surface roughness was improved.     

Synthesis and antibacterial evaluation of 3,3′-diindolylmethane derivatives

Various 3,3′-diindolylmethane (DIM) derivatives were synthesized and the antibacterial activity of these compounds were tested against ten bacterial strains and their minimum inhibitory concentration (MIC) values were determined. The MIC values of derivatives 3a–d and 5a–e were ranging from 125 to 500 μg/mL. Among these derivatives, 2-(di(1H-indol-3-yl)methyl)phenol (5a) and 3-((1H-indol-3-yl)(pyridin-3-yl)methyl)-1H-indole (5d) exhibited potent activity, showing MIC values 6.5–62.5 μg/mL against Gram positive and Gram negative bacteria. Hemolytic assay of these active DIM derivatives did not show considerable toxic effect on the normal human erythrocytes.     

Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation

Thrombotic microangiopathy (TMA) in renal transplant recipients is commonly associated with calcineurin inhibitors (CNIs), though several factors such as vascular rejection, viral infections and other drugs may play a contributory role. We report a series of 29 patients with TMA, all of whom were on CNIs. Though plasma exchange (PEx) is widely used to treat TMA, therapeutic guidelines are not well defined. All our patients were treated with PEx and discontinuation of CNIs. Thrombotic microangiopathy was diagnosed at a median of 7 days post-transplant. The mean decrease in Hgb and platelets during TMA was 66% and 64%, respectively, and peak serum creatinine during TMA was 7.4 ± 2.9 mg%. Mean duration of PEx therapy was 8.5 (range 5–23) days. Recovery of platelet count to 150K/mcL and Hgb to 8–10 g/dL were used as endpoints for PEx. Twenty-three/29 (80%) patients recovered graft function after PEx. Twenty/23 (87%) patients who recovered were placed back on CNl. Nineteen/20 (95%) patients tolerated reinstitution of CNl without recurrence of TMA. In post-transplant TMA, PEx was associated with a graft salvage rate of 80%, reversal of hematological changes can be used as the endpoint for PEx therapy and CNl can be reintroduced without risk of recurrence in the majority of patients .     

Sustained attention following mild closed-head injury

The sustained-attention performance of patients with mild closed-head injury (CHI) was examined within one month of injury using a high-event rate, digit-discrimination vigilance task with two levels of stimulus degradation (undegraded, highly degraded). Under undegraded stimulus conditions, vigilance performance for mild CHI subjects, uninjured case-matched control subjects, and college students was highly accurate and remained so across the entire task period. When stimuli were presented in degraded fashion, however, all three groups showed a similar decline over time (i.e., vigilance decrement) in hit rates and d' scores. Although mild CHI did not lead to a greater rate of deterioration in vigilance performance in the degraded stimulus condition, it did produce lower overall levels of sensitivity (d') in target detection. These results suggest that, during the first month after mild CHI, vigilance performance is unimpaired under normal task conditions, but may fall short under task conditions that require sustained effortful processing. These findings join a growing body of evidence showing that mild CHI can lead to measurable deficits in cognitive functioning.     

Disuccinyl Betulin Triggers Metacaspase-Dependent Endonuclease G-Mediated Cell Death in Unicellular Protozoan Parasite Leishmania donovani

The unicellular organism Leishmania undergoes apoptosis-like cell death in response to external stress or exposure to antileishmanial agents. Here, we showed that 3-O,28-O-disuccinyl betulin (DiSB), a potent topoisomerase type IB inhibitor, induced parasitic cell death by generating oxidative stress. The characteristic feature of the death process resembled the programmed cell death (PCD) seen in higher eukaryotes. In the current study, the generation of reactive oxygen species (ROS), followed by the depolarization of mitochondrial membrane potential (ΔΨ_m), caused a loss in ATP production in Leishmania parasites. This further gave positive feedback to produce a large amount of ROS, which in turn caused oxidative DNA lesions and genomic DNA fragmentation. The treatment of promastigotes with DiSB induced high expression levels of metacaspase protein that led to cell death in this unicellular organism. The PCD was insensitive to benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), suggesting that the death process was not associated with the activation of caspases. DiSB treatment translocated Leishmania donovani endonuclease G (LdEndoG) from mitochondria to the nucleus, which was responsible for the DNA degradation process. Conditional antisense knockdown of L. donovani metacaspase (LdMC), as well as EndoG, -subverted death of the parasite and rescued cell cycle arrest in G₁ phase. The present study on the effector molecules associated with the PCD pathway of the parasite should help to manifest the mechanisms of PCD and also might be exploited in antileishmanial chemotherapy.     

Early interaction between perceptual load and involuntary attention: An event-related potential study

Whether selective attention affects C1, the first (earliest) visual cortical component of the event-related potential (ERP), remains controversial. We used a cued, involuntary attention task requiring discrimination of targets under low and high levels of perceptual load to examine early attentional modulation in visual cortex. Potential confounds due to physical stimulus differences between load conditions and cue–target sensory interaction were minimized. An interaction between perceptual load and involuntary attention was observed for the P1m component (peak latency between 100 and 140 ms). Furthermore, the parieto-central C1 component (peak latency 80 ms) was modulated by attention, but only under the high-load condition. Thus, whereas attention typically modulates the later P1 component, attentional modulation of C1 is possible under optimal conditions. Specifically, a high perceptual load is necessary for eliciting this earliest attentional effect on cortical processing.