Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats

Visceral hypersensitivity has been implicated as an important pathophysiological mechanism in functional gastrointestinal disorders. In this study, we investigated whether the sustained visceral hyperalgesia induced by repeated psychological stress in rats involves the activation of CRF(1) signaling system using two different antagonists. Male Wistar rats were exposed to 10 consecutive days of water avoidance stress (WAS) or sham stress for 1 h/day, and the visceromotor response to phasic colorectal distension (CRD) was assessed before and after the stress period. Animals were injected subcutaneously with the brain penetrant CRF(1) antagonist, CP-154,526, acutely (30 min before the final CRD) or chronically (via osmotic minipump implanted subcutaneously, during stress) or with the peripherally restricted, nonselective CRF(1) and CRF(2) antagonist, astressin, chronically (15 min before each stress session). Repeated WAS induced visceral hypersensitivity to CRD at 40 and 60 mmHg. CP-154,526 injected acutely significantly reduced stress-induced visceral hyperalgesia at 40 mmHg but not at 60 mmHg. Chronic subcutaneous delivery of astressin reduced the stress-induced visceral hyperalgesia to baseline at all distension pressures. Interestingly, chronically administered CP-154,526 eliminated hyperalgesia and produced responses below baseline at 40 mmHg and 60 mmHg, indicating a hypoalgesic effect of the compound. These data support a major role for CRF(1) in both the development and maintenance of visceral hyperalgesia induced by repeated stress and indicate a possible role of peripheral CRF receptors in such mechanisms.     

Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents

Objectives: Obestatin has been initially characterized as a new peptide derived from the ghrelin precursor, which suppresses food intake and inhibits the orexigenic and prokinetic actions of ghrelin when injected peripherally or centrally in lean mice. However, reproducing these data remains controversial. Reasons for the disparity may be the use of different doses, routes, and animal models. We aimed to investigate the effects of peripheral and intracisternal (IC) injection of obestatin on feeding, gastric motility, and blood glucose in rats as well as in diet‐induced obese (DIO) mice. Research Methods and Procedures: Food intake and gastric emptying of a semi‐liquid caloric meal were measured after intraperitoneal (IP) injection of obestatin in rats and DIO mice. Gastric phasic motility and blood glucose were monitored in urethane‐anesthetized rats after IC or intravenous (IV) injection of obestatin. Results: Obestatin injected intraperitoneally at doses ranging from 0.1 to 3 mg/kg influenced neither acute food intake nor gastric emptying in rats. Obestatin injected intravenously at 0.3 or 3 mg/kg and IC at 7.5 or 30 µg/rat modified neither fasted gastric phasic motility nor blood glucose levels, while ghrelin (30 µg/kg, IV) increased and vagotomy suppressed gastric motility, and an oligosomatostatin analog (3 µg/rat, IC) decreased blood glucose. Obestatin, injected intraperitoneally (0.3 mg/kg) in DIO mice, did not alter feeding response to a fast, while urocortin 1 (10 µg/kg, IP) induced a 73.3% inhibition at 2 hours. Discussion: Our data demonstrate that peripheral administration of obestatin did not modify food intake in rats or obese mice or gastric motor function in rats.     

Multidrug-resistant tuberculosis treatment outcomes in Karakalpakstan, Uzbekistan: treatment complexity and XDR-TB among treatment failures

Background

A pilot programme to treat multidrug-resistant TB (MDR-TB) was implemented in Karakalpakstan, Uzbekistan in 2003. This region has particularly high levels of MDR-TB, with 13% and 40% among new and previously treated cases, respectively.

Methodology

This study describes the treatment process and outcomes for the first cohort of patients enrolled in the programme, between October 2003 and January 2005. Confirmed MDR-TB cases were treated with an individualised, second-line drug regimen based on drug susceptibility test results, while suspected MDR-TB cases were treated with a standardised regimen pending susceptibility results.

Principal Findings

Of 108 MDR-TB patients, 87 were started on treatment during the study period. Of these, 33 (38%) were infected with strains resistant to at least one second-line drug at baseline, but none had initial ofloxacin resistance. Treatment was successful for 54 (62%) patients, with 13 (15%) dying during treatment, 12 (14%) defaulting and 8 (8%) failing treatment. Poor clinical condition and baseline second-line resistance contributed to treatment failure or death. Treatment regimens were changed in 71 (82%) patients due to severe adverse events or drug resistance. Adverse events were most commonly attributed to cycloserine, ethionamide and p-aminosalicylic acid. Extensively drug resistant TB (XDR-TB) was found among 4 of the 6 patients who failed treatment and were still alive in November 2006.

Conclusions

While acceptable treatment success was achieved, the complexity of treatment and the development of XDR-TB among treatment failures are important issues to be addressed when considering scaling up MDR-TB treatment.     

Multilocus Sequence Analysis of Xanthomonads Causing Bacterial Spot of Tomato and Pepper Plants Reveals Strains Generated by Recombination among Species and Recent Global Spread of Xanthomonas gardneri

Four Xanthomonas species are known to cause bacterial spot of tomato and pepper, but the global distribution and genetic diversity of these species are not well understood. A collection of bacterial spot-causing strains from the Americas, Africa, Southeast Asia, and New Zealand were characterized for genetic diversity and phylogenetic relationships using multilocus sequence analysis of six housekeeping genes. By examining strains from different continents, we found unexpected phylogeographic patterns, including the global distribution of a single multilocus haplotype of X. gardneri, possible regional differentiation in X. vesicatoria, and high species diversity on tomato in Africa. In addition, we found evidence of multiple recombination events between X. euvesicatoria and X. perforans. Our results indicate that there have been shifts in the species composition of bacterial spot pathogen populations due to the global spread of dominant genotypes and that recombination between species has generated genetic diversity in these populations.     

Shrinking the Lymphatic Filariasis Map of Ethiopia: Reassessing the Population at Risk through Nationwide Mapping

Background

Mapping of lymphatic filariasis (LF) is essential for the delineation of endemic implementation units and determining the population at risk that will be targeted for mass drug administration (MDA). Prior to the current study, only 116 of the 832 woredas (districts) in Ethiopia had been mapped for LF. The aim of this study was to perform a nationwide mapping exercise to determine the number of people that should be targeted for MDA in 2016 when national coverage was anticipated.

Methodology/Principal Finding

A two-stage cluster purposive sampling was used to conduct a community-based cross-sectional survey for an integrated mapping of LF and podoconiosis, in seven regional states and two city administrations. Two communities in each woreda were purposely selected using the World Health Organization (WHO) mapping strategy for LF based on sampling 100 individuals per community and two purposely selected communities per woreda. Overall, 130 166 people were examined in 1315 communities in 658 woredas. In total, 140 people were found to be positive for circulating LF antigen by immunochromatographic card test (ICT) in 89 communities. Based on WHO guidelines, 75 of the 658 woredas surveyed in the nine regions were found to be endemic for LF with a 2016 projected population of 9 267 410 residing in areas of active disease transmission. Combining these results with other data it is estimated that 11 580 010 people in 112 woredas will be exposed to infection in 2016.

Conclusions

We have conducted nationwide mapping of LF in Ethiopia and demonstrated that the number of people living in LF endemic areas is 60% lower than current estimates. We also showed that integrated mapping of multiple NTDs is feasible and cost effective and if properly planned, can be quickly achieved at national scale.     

Efficacy of Handwashing with Soap and Nail Clipping on Intestinal Parasitic Infections in School-Aged Children: A Factorial Cluster Randomized Controlled Trial

Background

Intestinal parasitic infections are highly endemic among school-aged children in resource-limited settings. To lower their impact, preventive measures should be implemented that are sustainable with available resources. The aim of this study was to assess the impact of handwashing with soap and nail clipping on the prevention of intestinal parasite reinfections.

Methods and Findings

In this trial, 367 parasite-negative school-aged children (aged 6–15 y) were randomly assigned to receive both, one or the other, or neither of the interventions in a 2 × 2 factorial design. Assignment sequence was concealed. After 6 mo of follow-up, stool samples were examined using direct, concentration, and Kato-Katz methods. Hemoglobin levels were determined using a HemoCue spectrometer. The primary study outcomes were prevalence of intestinal parasite reinfection and infection intensity. The secondary outcome was anemia prevalence. Analysis was by intention to treat. Main effects were adjusted for sex, age, drinking water source, latrine use, pre-treatment parasites, handwashing with soap and nail clipping at baseline, and the other factor in the additive model. Fourteen percent (95% CI: 9% to 19%) of the children in the handwashing with soap intervention group were reinfected versus 29% (95% CI: 22% to 36%) in the groups with no handwashing with soap (adjusted odds ratio [AOR] 0.32, 95% CI: 0.17 to 0.62). Similarly, 17% (95% CI: 12% to 22%) of the children in the nail clipping intervention group were reinfected versus 26% (95% CI: 20% to 32%) in the groups with no nail clipping (AOR 0.51, 95% CI: 0.27 to 0.95). Likewise, following the intervention, 13% (95% CI: 8% to 18%) of the children in the handwashing group were anemic versus 23% (95% CI: 17% to 29%) in the groups with no handwashing with soap (AOR 0.39, 95% CI: 0.20 to 0.78). The prevalence of anemia did not differ significantly between children in the nail clipping group and those in the groups with no nail clipping (AOR 0.53, 95% CI: 0.27 to 1.04). The intensive follow-up and monitoring during this study made it such that the assessment of the observed intervention benefits was under rather ideal circumstances, and hence the study could possibly overestimate the effects when compared to usual conditions.

Conclusions

Handwashing with soap at key times and weekly nail clipping significantly decreased intestinal parasite reinfection rates. Furthermore, the handwashing intervention significantly reduced anemia prevalence in children. The next essential step should be implementing pragmatic studies and developing more effective approaches to promote and implement handwashing with soap and nail clipping at larger scales.     

Enhancement of Thermoelectric Performance of n‐Type PbSe by Cr Doping with Optimized Carrier Concentration

Ti, V, Cr, Nb, and Mo are found to be effective at increasing the Seebeck coefficient and power factor of n‐type PbSe at temperatures below 600 K. It is found that the higher Seebeck coefficients and power factors are due to higher Hall mobility ≈1000 cm² V^?1s^?1 at lower carrier concentration. A larger average ZT value (relevant for applications) can be obtained by an optimization of carrier concentration to ≈10¹⁸–10¹⁹ cm^?3. Even though the highest room temperature power factor ≈3.3 × 10^?3 W m^?1 K^?2 is found in 1 at% Mo‐doped PbSe, the highest ZT is achieved in Cr‐doped PbSe. Combined with the lower thermal conductivity, ZT is improved to ≈0.4 at room temperature and peak ZTs of ≈1.0 are observed at ≈573 K for Pb_0.9925Cr_0.0075Se and ≈673 K for Pb_0.995Cr_0.005Se. The calculated device efficiency of Pb_0.995Cr_0.005Se is as high as ≈12.5% with cold side 300 K and hot side 873 K, higher than those of all the n‐type PbSe materials reported in the literature.     

Integrated Environmental and Genomic Analysis Reveals the Drivers of Local Adaptation in African Indigenous Chickens

Breeding for climate resilience is currently an important goal for sustainable livestock production. Local adaptations exhibited by indigenous livestock allow investigating the genetic control of this resilience. Ecological niche modeling (ENM) provides a powerful avenue to identify the main environmental drivers of selection. Here, we applied an integrative approach combining ENM with genome-wide selection signature analyses (XPEHH and Fst) and genotype−environment association (redundancy analysis), with the aim of identifying the genomic signatures of adaptation in African village chickens. By dissecting 34 agro-climatic variables from the ecosystems of 25 Ethiopian village chicken populations, ENM identified six key drivers of environmental challenges: One temperature variable—strongly correlated with elevation, three precipitation variables as proxies for water availability, and two soil/land cover variables as proxies of food availability for foraging chickens. Genome analyses based on whole-genome sequencing (n = 245), identified a few strongly supported genomic regions under selection for environmental challenges related to altitude, temperature, water scarcity, and food availability. These regions harbor several gene clusters including regulatory genes, suggesting a predominantly oligogenic control of environmental adaptation. Few candidate genes detected in relation to heat-stress, indicates likely epigenetic regulation of thermo-tolerance for a domestic species originating from a tropical Asian wild ancestor. These results provide possible explanations for the rapid past adaptation of chickens to diverse African agro-ecologies, while also representing new landmarks for sustainable breeding improvement for climate resilience. We show that the pre-identification of key environmental drivers, followed by genomic investigation, provides a powerful new approach for elucidating adaptation in domestic animals.     

Urocortins and the regulation of gastrointestinal motor function and visceral pain

Urocortin (Ucn) 1, 2 and 3 are corticotropin-releasing factor (CRF)-related peptides recently characterized in mammals. Urocortin 1 binds with high affinity to CRF type 1 (CRF1) and type 2 (CRF2) receptors while Ucn 2 and Ucn 3 are selective CRF2 ligands. They also have a distinct pattern of distribution, both in the brain and the gastrointestinal tract, compatible with a role mediating, with CRF, the response to stress. In rats and mice, Ucn 1 injected centrally or peripherally inhibited gastric emptying and stimulated colonic propulsive motor function, mimicking the effects of stress or exogenous CRF. Centrally administered Ucn 2 inhibited gastric emptying with similar potency as CRF, while Ucn 1 and Ucn 3 were less potent. However, after peripheral administration, Ucn 1 and Ucn 2 were more potent than CRF. In mice, centrally administered Ucn 1 and 2 stimulated colonic motility with lower potency than CRF, and Ucn 3 was inactive. Studies with selective CRF1 and CRF2 antagonists demonstrated that the gastric-inhibitory and colonic-stimulatory effects of exogenously administered Ucns are mediated through CRF2 and CRF1 receptors, respectively. In addition, Ucn 2 showed visceral anti-nociceptive activity associated with the selective activation of CRF2 receptors. These observations suggest that, acting centrally and peripherally, Ucns might play a significant role in the modulation of gastrointestinal motor and pain responses during stress and stress-related pathophysiological conditions.     

Assessment of potential antagonists for anthracnose (Colletotrichum gloeosporioides) disease of mango (Mangifera indica L.) in North Western Ethiopia (Pawe)

Mango (Mangifera indica L.) is considered as one of the most popular fruits among millions of people in the tropical area and increasingly in the developed countries. Anthracnose, caused by the fungus Colletotrichum gloeosporioides, is the most important pre- and post-harvest disease of mango. The objective of this research was to evaluate the prevalence of different promising antagonistic Trichoderma and Bacillus spp. on phyloplane of mango in Ethiopia and to evaluate their antagonistic potential against the pathogen. A total of 19 mango fields were surveyed and anthracnose affected all fields. Culture studies on potato dextrose agar for evaluation of antibiosis activity of Trichoderma spp. and Bacillus spp. revealed that they have inhibitory and lytic effect on C. gloeosporioides, which is an indication of their potential biocontrol agent for management of mango anthracnose as an alternative to chemical control. Significant differences (p?<?0.05) were observed among Bacillus isolates in causing lysis of pathogen mycelium, when inoculated on actively growing colony of C. gloeosporioides. Maximum reduction in growth rate of pathogen was observed with Bacillus spp. (B50), which restricted the growth to 2.7?mm compared to 8.3?mm in the control with 67.5% efficacies. There were similar effects (p?<?0.05) among Trichoderma spp. in formation of inhibition zones and lysis by varying degrees up to 59.7% efficacies in reducing linear growth of the pathogen in dual culture.