Postrenal transplant Plasmodium vivax malaria: neglected and not benign

Plasmodium vivax is causing increasingly more cases of severe malaria worldwide. We reported a case of postrenal transplantation acute kidney injury (AKI) associated with P. vivax, a neglected human malaria parasite. The diagnosis of P. vivax monoinfection was confirmed by direct visualization of the parasite in blood smear and rapid diagnostic test. On admission, serum creatinine (SCr.) increased from 1.45 to 3.7 mg/dl. The other etiologies of fever and AKI were ruled out. He responded to prompt therapy with antimalarial drugs. There was no change in tacrolimus trough level before and after antimalarial drugs. Two weeks after discharge, his SCr. was 1.43 mg/dl. Our patient lived in an endemic malarial area and the transplant took place in December 2010. The patient subsequently presented with clinical malaria in June 2012, so we thought that posttransplantation transmission by the mosquito was a possibility and very less likely that other dormant form of the parasite had been the source of the clinical infection. P. vivax can lead to as AKI in renal transplant recipient. P. vivax should be considered in the differential diagnosis of fever in transplant recipients who had received organs or blood products from malaria-endemic area to facilitate a prompt diagnosis and adequate treatment.     

Outcome of renal transplantation from older living donors compared to younger living donor in developing country

Objectives: To evaluate whether the outcomes of renal grafts from living related donors older than 60 years are acceptable, in terms of renal function and patient/graft survival. Material and methods: One hundred and forty-seven patients who received kidneys from donor age ≥60 years constituted the study group (group 1). The control group (group 2) consisted of 1310 patients who received renal transplants from donor age <60 years. Outcome measures included graft, patient survival, acute rejection rate and serum creatinine (SCr) in patients/donors. Graft and patient survivals were compared using the Kaplan–Meier method. Results: The mean age of donors was 62.7?±?3.39 years in group 1 and 43.45?±?9.65 years in group 2. Patient survival at 1, 3 and 5 years was 95.7%, 89.4% and 82.6% in group 1 and 93.8%, 89.1% and 83.1% in group 2 (p?=?0.785), respectively. Death-censored graft survival at 1, 3 and 5 years was 98.5%, 94.8% and 94.8% in group 1 and 96.1%, 92.9% and 89% in group 2 (p?=?0.166), respectively. Biopsy-proven acute rejections were 21% and 16.8% (p?=?0.206) and chronic rejections 5% and 3.4% in group 1 and 2, respectively (p?=?0.542). Recipient SCr (mg/dL) was 1.8?±?0.31 in group 1 and 1.58?±?0.37 in group 2. The donor SCr levels at the last follow-up were 1?mg/dL and 0.9?mg/dL in group 1 and 2, respectively. Conclusions: Donor age did not affect patient and graft survival in the 5-year follow-up in our study. Age alone seems not to be an exclusion criterion to living kidney donation.     

Formulation and Evaluation of Chitosan-Based Buccal Bioadhesive Films of Zolmitriptan

Purpose

Therapeutic efficacy of zolmitriptan in oral therapy is primarily limited by the biopharmaceutical issues. The objective of this study is to design and optimize chitosan-based buccal bioadhesive system for the effective delivery of zolmitriptan in the treatment of migraine.

Methods

Factorial design (3²) is constructed and conducted in a fully randomized manner to study all nine possible experimental runs. The films were prepared by solvent casting method by varying the content of chitosan (X₁) and polyvinyl alcohol (X₂). The effect of these two independent variables on swelling index (Y1), percent drug release in 15 min (Y2) and 5 h (Y3), and mucoadhesive strength (Y4) of prepared films was evaluated.

Results

The physical and chemical characteristics displayed by the prepared films (F1–F9) were found to be optimal. It was observed that the factor X₁ has positive and X₂ has negative effect on response Y1. In contrast, factor X₁ showed negative effects on drug release at both time intervals (15 min and 5 h) while X₂ displayed positive responses for these variables (Y2 and Y3). However, the mucoadhesion increased with an increase in factor X₁ and decreased when the factor X₂ was increased. Indeed, the desirable characteristics exhibited by the film F7 are ideal for buccal application. Greater flux (63.93?±?12.51 μg/cm²/h) demonstrated in ex vivo studies substantiated the potential of optimized film to effectively deliver zolmitriptan across the buccal membrane.

Conclusions

This study concludes that the chitosan-based buccal film (F7) could be used in both prophylaxis and acute treatment of migraine, although need to be proved in vivo.

     

The polarity of myxobacterial gliding is regulated by direct interactions between the gliding motors and the Ras homolog MglA

Gliding motility in Myxococcus xanthus is powered by flagella stator homologs that move in helical trajectories using proton motive force. The Frz chemosensory pathway regulates the cell polarity axis through MglA, a Ras family GTPase; however, little is known about how MglA establishes the polarity of gliding, because the gliding motors move simultaneously in opposite directions. Here we examined the localization and dynamics of MglA and gliding motors in high spatial and time resolution. We determined that MglA localizes not only at the cell poles, but also along the cell bodies, forming a decreasing concentration gradient toward the lagging cell pole. MglA directly interacts with the motor protein AglR, and the spatial distribution of AglR reversals is positively correlated with the MglA gradient. Thus, the motors moving toward lagging cell poles are less likely to reverse, generating stronger forward propulsion. MglB, the GTPase-activating protein of MglA, regulates motor reversal by maintaining the MglA gradient. Our results suggest a mechanism whereby bacteria use Ras family proteins to modulate cellular polarity.Generating and maintaining polarity is fundamental to the proper functioning of cells. Eukaryotic cells generate polarity for migration and the accurate positioning of macromolecules and organelles (1, 2). For bacteria, polarity is important for motility, division, signal transduction, and pathogenesis (3, 4). The Gram-negative soil bacterium Myxococcus xanthus is a model organism for use in the study of cell polarity for its directed surface motilities.M. xanthus cells move on solid surfaces using two distinct mechanisms. The first mechanism, social motility (S-motility), is powered by the extension and retraction of type IV pili from the leading cell poles (5, 6). In contrast, the second mechanism, gliding motility (adventurous or A-motility), uses proton motive force to power the movement of motor complexes containing flagella stator homologs (7–11). Gliding M. xanthus cells on 1.5% agar plates typically reverse their polarity approximately every 8–12 min (12). The Frz chemosensory pathway regulates the reversal frequency and thus the direction of cell movements of both motility systems (12–16). MglA, a Ras family GTPase, has been identified as the central regulator of cell polarity and the principal responder to Frz pathway signaling (13–15). It has been reported that MglA is connected to the Frz pathway by the response regulator RomR (17–19). Importantly, MglA switches between an active GTP-bound form and an inactive GDP-bound form, which is regulated by MglB, the cognate GTPase-activating protein (GAP) of MglA, providing another layer of regulation (13, 14).The importance of cell polarity in S-motility is obvious, because the S-motility motors localize to cell poles in an MglA-dependent manner (5, 20). In contrast, cell polarity for gliding motility is enigmatic, because the gliding motor complexes, as represented by the MotA homolog AglR and motor-associated proteins, such as AgmU (GltD), localize in blurry patches that move simultaneously in opposite directions along a helical track (7, 8, 10, 11).The gliding complexes consist of the motor proteins AglR, AglQ, and AglS, along with numerous motor-associated proteins that localize in the cytoplasm, inner membrane, and periplasm (21). Genomic analysis has shown that the M. xanthus motor complexes, unlike the MotAB complexes of enteric bacteria, lack peptidoglycan-binding domains and thus are free to move within the membrane (7). Consistent with this idea, the motor protein AglR and the motor-associated protein AgmU (GltD) have been observed to decorate a helical macrostructure that rotates as cells move forward (7, 8). In addition, tracking the movements of single AglR molecules using single-particle photoactivatable localization microscopy (sptPALM) (22) revealed that the gliding motors containing AglR molecules move in helical trajectories. A subpopulation of motors slow down and accumulate into evenly distributed “traffic jam” clusters at the ventral sides of cells, where they contact surfaces. The traffic jam clusters appear to be stationary in relation to the substratum when cells move forward (7). These clusters were originally called “focal adhesion sites” because of some similarities with eukaryotic motility complexes (9, 23).Based on the results of our high-resolution experiments, we proposed a revised model of bacterial gliding (the helical rotor model) that envisions the distance between two adjacent traffic jam sites as corresponding to the period of the helical track (11). According to this model, motors at these sites push against the gliding surface, deform the cell membrane, and exert force against the surface slime (Fig. 1A) (7). This model explains evenly distributed traffic jam sites in gliding cells, without invoking that force is transmitted to the surface by breaching the peptidoglycan barrier (21, 23); however, how the bidirectional motion of gliding motors generates unidirectional cell movements remains unknown.Open in a separate windowFig. 1.Single molecules of AglR-pamCherry reverse their moving directions along cell bodies. (A) The helical rotor model predicts that the gliding motors move simultaneously toward opposite directions along helical tracks. (B) Kymograph of AglR-pamCherry fluorescence in a moving cell. AglR molecules move simultaneously toward the leading and lagging cell poles. Yellow arrows point to the reversal events of AglR. A significant population of AglR molecules also appear stationary (blue dots), which we attribute to the molecules that slow down at traffic jam sites owing to the resistance of the underlying gliding surfaces. The yellow lines mark the positions of the cell poles in the kymograph. An example of the cells is shown in Movie S2.In the present study, we found that MglA directly interacts with AglR. Using a combination of sptPALM and conventional fluorescence microscopy, we showed that MglA localizes not only at the cell poles, but also along the cell bodies, forming a gradient toward the lagging cell poles. We investigated the role of MglA in regulating gliding motility by tracking the movements of motors in various genetic backgrounds. We found that the probability of AglR reversal is positively correlated with the local MglA gradient. Our observations suggest that the MglA gradient dictates the polarity of gliding by triggering the reversal of gliding motors asymmetrically.     

A Study of the Impact of Cannabis on Doses of Discharge Antipsychotic Medication in Individuals with Schizophrenia or Schizoaffective Disorder

Patients with schizophrenia or schizoaffective disorder have a high prevalence of comorbid cannabis use disorder (CUD). CUD has been associated with poorer outcomes in patients. We compared doses of antipsychotic medications at the time of discharge from hospital among inpatients with schizophrenia or schizoaffective disorder with or without concurrent cannabis use. We reviewed the medical records of patients (N = 8157) with schizophrenia or schizoaffective disorder discharged from the hospital between 2008 and 2012. The patients were divided into two groups; those with urine drug tests positive for cannabis and those negative for cannabis. Doses of antipsychotic medications were converted to chlorpromazine equivalents. Bivariate analyses were done with Student’s t test for continuous variables and χ ² test for categorical variables. Linear regression was carried out to adjust for potential confounders. Unadjusted analysis revealed that the cannabis positive group was discharged on lower doses of antipsychotic medication compared with the cannabis negative group (geometric mean chlorpromazine equivalent doses 431.22 ± 2.20 vs 485.18 ± 2.21; P < 0.001). However, the difference in geometric mean chlorpromazine equivalent doses between the two groups was no longer significant after adjusting for sex, age, race, and length of stay (geometric mean difference 0.99; 95 % CI 0.92–1.10). Though limited by lack of information on duration, amount and severity of cannabis use, as well as inability to control for other non-antipsychotic medications, our study suggests that cannabis use did not significantly impact on doses of antipsychotics required during the periods of acute exacerbation in patients with schizophrenia or schizoaffective disorder.     

Evaluation of a practice‐based research design using an asthma care model

Objective — To evaluate a quasi‐experimental research design using a practice‐based model in community pharmacy by comparing baseline characteristics of the control and intervention samples used. Methods — An asthma care model was chosen to trial the use of a quasi‐experimental design. Two geographically separate areas were selected as intervention and control areas. Pharmacists from the intervention area were trained and provided with resources to set up asthma specialty practices and recruit intervention patients. Control area pharmacists were not offered training but were requested to recruit patients with asthma to act as a control sample to data being collected from the intervention population. The research design aimed to establish equivalence between the two groups. In both cases, data were gathered using an “asthma file,” which consisted of a patient demographics and asthma information form and a series of previously validated questionnaires to examine humanistic outcomes. Setting — Community pharmacies in two non‐urban areas of New South Wales, Australia. Key findings — Nine of 15 intervention pharmacies recruited 52 patients into the study and 11 of 20 control pharmacies recruited 50 patients. No apparent differences existed between the two samples with respect to the humanistic parameters of asthma‐related quality of life, asthma general knowledge and perceived control of asthma. In terms of asthma severity and disease‐specific parameters, such as asthma‐related hospitalisations, no statistically significant differences were found. Control and intervention groups were thus found to be equivalent for the purposes of the study. Conclusion — The data support the use of the quasi‐experimental research method employed in the study.     

Synthesis and antimicrobial evaluation of new pyrano[4,3-b]pyran and Pyrano[3,2-c]chromene derivatives bearing a 2-thiophenoxyquinoline nucleus

A new series of pyrano[4,3-b]pyran 4a-i and pyrano[3,2-c]chromene 6a-r derivatives bearing a 2-thiophenoxyquinoline nucleus were synthesized by reaction of 2-(4-(un)-substituted thiophenoxy)quinoline-3-carbaldehydes 2a-i with 6-methyl-4-hydroxypyran-2-one 3 and 4-hydroxy-6-(un)-substituted-2H-chromen-2-one 5a-b respectively and malononitrile at room temperature in the presence of KOH as a basic catalyst. All the compounds were screened against three Gram-positive bacteria (Streptococcus pneumoniae, Bacillus subtilis, Clostridium tetani), three Gram-negative bacteria (Salmonella typhi, Escherichia coli, Vibrio cholerae) and two fungi (Candida albicans, Aspergillus fumigatus) using the broth microdilution MIC (minimum inhibitory concentration) method. Upon antimicrobial screening, it was observed that the majority of the compounds were found to be active against Bacillus subtilis, Clostridium tetani and Candida albicans as compared to standard drugs.     

Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder

Patients with Bipolar Disorder (BD) perform poorly on tasks of selective attention and inhibitory control. Although similar behavioural deficits have been noted in their relatives, it is yet unclear whether they reflect dysfunction in the same neural circuits. We used functional magnetic resonance imaging and the Stroop Colour Word Task to compare task related neural activity between 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with Major Depressive Disorder) and 48 healthy controls. Compared to controls, all individuals with familial predisposition to BD, irrespective of diagnosis, showed similar reductions in neural responsiveness in regions involved in selective attention within the posterior and inferior parietal lobules. In contrast, hypoactivation within fronto-striatal regions, implicated in inhibitory control, was observed only in BD patients and MDD relatives. Although striatal deficits were comparable between BD patients and their MDD relatives, right ventrolateral prefrontal dysfunction was uniquely associated with BD. Our findings suggest that while reduced parietal engagement relates to genetic risk, fronto-striatal dysfunction reflects processes underpinning disease expression for mood disorders.     

Computerized left ventricular regional ejection fraction analysis for detection of ischemic coronary artery disease with multidetector CT angiography

Regional ejection fraction (REF) provides important functional information of the left ventricular regional myocardium. We aimed to test the diagnostic accuracy of computerized REF analysis for detecting the ischemia and significant stenosis with multidetector CT angiography (MDCT). This is a retrospective study including 155 patients who underwent MDCT scans for evaluation of coronary artery disease. Among them, 83 patients also underwent SPECT imaging and invasive coronary angiography (ICA). Two groups of patients were defined: Control group with 0 coronary artery calcium and normal global and regional ventricular function, and comparison group. REF measurement was performed on all patients using computerized software. Control group REF measurements will be used as reference standard (mean-2SD REF/mean global ejection fraction) to define abnormal REF. The sensitivity, specificity, positive and negative predictive value of REF in detecting perfusion defects (fixed and reversible) was 73, 80, 75 and 79 % respectively, in a patient based analysis of comparison group. The diagnostic accuracy of REF in predicting significant stenosis (>50 %) on ICA compared with SPECT was 72 versus 61 % and 85 versus 79 % in patient and vessel based analysis of comparison group, respectively. ROC curve analysis showed REF to be a better predictor of perfusion defects on SPECT compared with significant stenosis (>50 %) alone or stenosis combined with REF (P < 0.05). The computerized assessment of REF analysis is comparable to SPECT in predicting ischemia and a better predictor of significant stenosis than SPECT. This study also provides reference standard to define abnormal values.