Role of Acinetobacter baumannii UmuD Homologs in Antibiotic Resistance Acquired through DNA Damage-Induced Mutagenesis

The role of Acinetobacter baumannii ATCC 17978 UmuDC homologs A1S_0636-A1S_0637, A1S_1174-A1S_1173, and A1S_1389 (UmuD_Ab) in antibiotic resistance acquired through UV-induced mutagenesis was evaluated. Neither the growth rate nor the UV-related survival of any of the three mutants was significantly different from that of the wild-type parental strain. However, all mutants, and especially the umuD_Ab mutant, were less able to acquire resistance to rifampin and streptomycin through the activities of their error-prone DNA polymerases. Furthermore, in the A. baumannii mutant defective in the umuD_Ab gene, the spectrum of mutations included a dramatic reduction in the frequency of transition mutations, the mutagenic signature of the DNA polymerase V encoded by umuDC.     

Short and longer-term psychological consequences of Operation Cast Lead: documentation from a mental health program in the Gaza Strip

Background

There is growing recognition of the psychological impact of adversity associated with armed conflict on exposed civilian populations. Yet there is a paucity of evidence on the value of mental health programs in these contexts, and of the chronology of psychological sequelae, especially in prolonged conflicts with repeated cycles of extreme violence. Here, we describe changes in the psychological profile of new patients in a mental health program after the military offensive Cast Lead, in the context of the prolonged armed conflict involving the Gaza Strip.

Methods

This study analyses routinely collected program data from a Médecins Sans Frontières mental health program in the Gaza Strip spanning 2007?C2011. Data consist of socio-demographic as well as clinical baseline and follow-up data on new patients entering the program. Comparisons were made through Chi square and Fisher??s exact tests, univariate and multivariate logistic and linear regression.

Results

PTSD, depression and other anxiety disorders were the most frequent psychopathologies, with 21% having multiple diagnoses. With a median of nine sessions, clinical improvement was recorded for 83% (1122/1357), and more common for those with separation anxiety, acute and posttraumatic disorders as principal diagnosis (855/1005), compared to depression (141/183, p<0.01). Noted changes proximal to Operation Cast Lead were: a doubling in patient case load with a broader socio-economic background, shorter interval from an identified traumatic event to seeking care, and a rise in diagnoses of acute and posttraumatic stress disorders. Sustained changes included: high case load, more distal triggering events, and increase in diagnoses of other anxiety disorders (especially for children 15 years and younger) and depression (especially for patients 16 years and older).

Conclusion

Evolving changes in patient volume, diagnoses and recall period to triggering events suggest a lengthy and durable effect of an intensified exposure to violence in a context of prolonged conflict. Our findings suggest that mental health related humanitarian relief in protracted conflicts might need to prepare for an increase in patients with changing profiles over an extended period following an acute flare-up in violence.     

Multiparity causes uncoordinated activity of pelvic- and perineal-striated muscles and urodynamic changes in rabbits

Temporal and coordinated activation of pelvic- (pubococcygeous) and perineal- (bulbospongiosus and ischiocavernosus) striated muscles occurs during micturition in female rabbits. We have hypothesized that the coordinated activation of pelvic and perineal muscles is modified during the micturition of young multiparous rabbits. Young virgin and multiparous female chinchilla rabbits were used to simultaneously record cystometrograms and electromyograms of the pubococcygeous, ischocavernosus, and bulbospongiosus muscles. Bladder function was assessed using standard urodynamic variables. The temporal coordination of pelvic- and perineal-striated muscle activity was changed in multiparous rabbits. The cystometrogram recordings were different than those obtained from virgin rabbits, as seen in alterations of the threshold volume, the residual volume, the voiding duration, and the maximum pressure. In rabbits, we find that multiparity causes uncoordinated activity of pubococcygeous, ischiocavernosus, and bulbospongiosus muscles and modifies the urodynamics.     

Endocranial morphology of the piciformes (Aves,Coraciimorphae): Functional and ecological implications

We used three-dimensional digital models to investigate the brain and endosseous labyrinth morphology of selected Neotropical Piciformes (Picidae, Ramphastidae, Galbulidae and Bucconidae). Remarkably, the brain morphology of Galbulidae clearly separates from species of other families. The eminentiae sagittales of Galbulidae and Bucconidae (insectivorous with high aerial maneuverability abilities) are smaller than those of the toucans (scansorial frugivores). Galbula showed the proportionally largest cerebellum, and Ramphastidae showed the least foliated one. Optic lobes ratio relative to the telencephalic hemispheres showed a strong phylogenetic signal. Three hypotheses were tested: (a) insectivorous taxa that need precise and fast movements to catch their prey, have well developed eminentiae sagittales compared to fruit eaters, (b) species that require high beak control would show larger cerebellum compared to other brain regions and higher number of visible folia and (c) there are marked differences between the brain shape of the four families studied here that bring valuable information of this interesting bird group. Hypotheses H1 and H2 are rejected, meanwhile H3 is accepted.     

Pharmacological activation of insulin-degrading enzyme improves insulin secretion and glucose tolerance in diet-induced obese mice

Aim

To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes.

Materials and Methods

We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for 25 days. Glucose tolerance, circulating insulin and C-peptide levels, and GSIS were assessed. In addition, β-cells (Min-6) were used to test the effects of sPIF on GSIS and insulin-degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets.

Results

GSIS was enhanced 2-fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored β-cell function. Finally, genetic (shRNA-IDE) or pharmacological (6bK) inactivation of IDE in Min-6 abolished sPIF-mediated effects on GSIS, showing that both the protein and its protease activity are required for its action.

Conclusions

We conclude that sPIF is a promising secretagogue for the treatment of T2D.     

Evolocumab has no effects on heart failure with reduced ejection fraction injury biomarkers: The EVO-HF trial

Aim

Patients with heart failure with reduced ejection fraction (HFrEF) have not been shown to benefit from statins. We hypothesized that, by limiting disease progression in stable HFrEF of ischaemic etiology, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab could reduce circulating troponin levels, a surrogate biomarker of myocyte injury and atherosclerosis progression.

Methods and results

The EVO-HF multicentre prospective randomized trial compared evolocumab (420 mg/month administered subcutaneously) plus guideline-directed medical therapy (GDMT; n = 17) versus GDMT alone (n = 22) for 1 year in patients with stable coronary artery disease and left ventricular ejection fraction (LVEF) <40%, ischaemic aetiology, New York Heart Association class II, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥400 pg/ml, high-sensitivity troponin T (hs-TnT) >10 pg/ml, low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl. The primary endpoint was change in hs-TnT concentration. Secondary endpoints included NT-proBNP, interleukin-1 receptor-like 1 (ST2), high-sensitivity C-reactive protein (hs-CRP), LDL, low-density lipoprotein receptor (LDLR), high-density lipoprotein cholesterol (HDL-C), and PCSK9 levels at 1 year. Patients were mainly Caucasian (71.8%), male (79.5%), relatively young (mean age 68.1 ± 9.4 years), with a mean LVEF of 30.4 ± 6.5%, and managed with contemporary treatments. No significant changes in hs-TnT levels were observed in any group at 1 year. NT-proBNP and ST2 levels decreased in the GDMT plus evolocumab group (p = 0.045 and p = 0.008, respectively), without changes in hs-CRP, HDL-C, or LDLR. Total and LDL-C decreased in both groups, significantly higher in the intervention group (p = 0.003), and PCSK9 levels increased in the intervention group.

Conclusions

This prospective randomized pilot trial, although with the limitation of the small sample size, does not support the benefit of evolocumab in reducing troponin levels in patients with elevated LDL-C levels, history of coronary artery disease, and stable HFrEF.     

DNA polymorphisms associated with lactase persistence,self-perceived symptoms of lactose intolerance,milk and dairy consumption,and ancestry,in the Uruguayan population

Uruguay has one of the highest per capita milk intakes worldwide, even with a limited supply of lactose-free products; furthermore, the admixed nature of its population is well known, and various frequencies of lactase persistence (LP) are observed in the source populations. We aimed to contribute to the understanding of the relation between allelic variants associated with LP, milk consumption, digestive symptoms, and genetic ancestry in the Uruguayan population. Samples of saliva or peripheral blood were collected from 190 unrelated individuals from two regions of Uruguay, genotypes for polymorphic sites in a fragment within the LCT enhancer were determined and allelic frequencies calculated in all of them. Data were collected on frequency of milk and dairy consumption and self-reported symptoms in a subsample of 153 individuals. Biparental and maternal ancestry was determined by analyzing individual ancestry markers and mitochondrial DNA. Twenty-nine percentage of individuals reported symptoms attributed to the ingestion of fresh milk, with abdominal pain, bloating and flatulence being the most frequent. European LP-associated allele T-13910 showed a frequency of 33%, while other LP-associated alleles like G-13915 and T-14011 were observed in very low frequencies. Associations between self-reported symptoms, fresh milk intake, and C/T-13910 genotype were statistically significant. No evidence of association between genetic ancestry and C/T-13910 was found, although individuals carrying one T-13910 allele appeared to have more European ancestry. In conclusion, the main polymorphism capable of predicting lactose intolerance in Uruguayans is C/T-13910, although more studies are required to unravel the relation between genotype and lactase activity, especially in heterozygotes.