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resistance - Top 30 Publications

Evaluation of the rapid carbapenem inactivation method (rCIM): a phenotypic screening test for carbapenemase-producing Enterobacteriaceae.

Fast and accurate diagnostic tests to identify carbapenemase-producing Enterobacteriaceae (CPE) are mandatory for proper antimicrobial therapy and implementing infection control measures. Here, we have developed a rapid Carbapenem Inactivation Method (rCIM) for CPE detection.

Antimicrobial peptide resistance mechanism contributes to Staphylococcus aureus infection.

Antimicrobial peptides (AMPs) constitute an important part of innate host defense. Possibly limiting the therapeutic potential of AMPs is the fact that bacteria have developed AMP resistance mechanisms during their co-evolution with humans. However, there is no direct evidence that AMP resistance per se is important during an infection. Here we show that the Staphylococcus aureus Pmt ABC transporter defends the bacteria from killing by important human AMPs and elimination by human neutrophils. By showing that Pmt contributes to virulence during skin infection in an AMP-dependent manner, we provide evidence that AMP resistance plays a key role in bacterial infection.

Heat exposure induces oxidative stress and DNA damage in the male germ line.

The reproductive consequences of global warming are not currently understood. In order to address this issue we have examined the reproductive consequences of exposing male mice to a mild heat stress. For this purpose, adult male mice were exposed to an elevated ambient temperature of 35°C under two exposure models. The first involved acute exposure for 24 hours, followed by recovery periods of between 1 day and 6 weeks. The alternative heating regimen involved a daily exposure of 8 hours for periods of 1 or 2 weeks. In our acute model, we identified elevated sperm mitochondrial ROS generation (p < 0.05), increased sperm membrane fluidity (p < 0.05), DNA damage in the form of single strand breaks (p < 0.001) and oxidative DNA damage (p < 0.05); characteristic of an oxidative stress cascade. This DNA damage was detected in pachytene spermatocytes (p < 0.001) and round spermatids (p < 0.001) isolated from testes after 1 day heat recovery. Despite these lesions, the spermatozoa of heat-treated mice exhibited no differences in their ability to achieve hallmarks of capacitation or to fertilize the oocyte and support development of embryos to the blastocyst stage (all p > 0.05). Collectively, our acute heat stress model supports the existence of heat susceptible stages of germ cell development, with the round spermatids being most perturbed and spermatogonial stem cells exhibiting resistance to this insult. Such findings were complemented by our chronic heat stress model, which further supported the vulnerability of the round spermatid population.

Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer.

Steatosis in South African women: How much and why?

Globally, steatosis is the commonest type of liver pathology and is closely associated with obesity and the metabolic syndrome. Obesity is common in urban African females but no data is available on hepatic fat content in this population group when compared to other ethnic groups. The aim of this study was therefore to compare hepatic fat content in woman from different ethnic groups in South Africa and to characterise the principle determinants of liver fat.

Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia.

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized fifteen healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet and activity controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently-sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia , and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

Insulin signaling displayed a differential tissue specific response to low dose DHT in female mice.

Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low dose dihydrotestosterone (DHT), a PCOS model, on insulin signaling in metabolic and re-productive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and WAT from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared to controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin signaling genes were not lowered in DHT mice compared to control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice. DHT mice were hyperinsulinemic (HI). However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepato-cytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage versus reproductive tissues independent of hyperinsulinemia.

Regulation of glucose metabolism in non-diabetic, metabolically-obese normal-weight Asians.

Type 2 diabetes in Asia occurs largely in the absence of obesity. The metabolically-obese normal-weight (MONW) phenotype refers to lean subjects with metabolic dysfunction that is typically observed in people with obesity, and is associated with increased risk for diabetes. Previous studies evaluated MONW subjects who had greater BMI or total body fat than respective control groups, making interpretation of the results difficult. We evaluated insulin sensitivity (hyperinsulinemic-euglycemic clamp), insulin secretion (mixed meal with oral minimal modeling), intra-abdominal, muscle, and liver fat contents (magnetic resonance), and fasting and postprandial glucose and insulin concentrations in 18 MONW subjects and 18 metabolically-healthy controls matched for age (43{plus minus}3 and 40{plus minus}3 y; P=0.52), BMI (both 22{plus minus}1 kg/m2; P=0.69), total body fat (17{plus minus}1 and 16{plus minus}1 kg; P=0.33), and sex (9 men and 9 women in each group). Compared with controls, MONW subjects had ~2-fold greater visceral adipose tissue volume and ~4-fold greater intrahepatic fat content (but similar muscle fat), 20%-30% lower glucose disposal rates and insulin sensitivity, and 30%-40% greater insulin secretion rates (all P<0.05). The disposition index, fasting glucose and HbA1c concentrations were not different between groups, whereas postprandial glucose and insulin concentrations were ~15% and ~65% greater, respectively, in MONW than control subjects (both P<0.05). We conclude that the MONW phenotype is associated with accumulation of fat in the intra-abdominal area and the liver, profound insulin resistance, but also a robust β-cell insulin secretion response which compensates for insulin resistance and helps maintain glucose homeostasis.

Mechanistically different effects of fat and sugar on insulin resistance, hypertension and gut microbiota in rats.

Insulin resistance (IR) and impaired glucose tolerance (IGT) are the first manifestations of diet-induced metabolic alterations leading to type-2 diabetes, while hypertension is the deadliest risk factor of cardiovascular disease. The roles of dietary fat and fructose in the development of IR, IGT and hypertension are controversial. We tested the long-term effects of an excess of fat or sucrose (fructose/glucose) on healthy male Wistar Kyoto (WKY) rats. Fat affects IR and IGT earlier than fructose through low-grade systemic inflammation evidenced by liver inflammatory infiltration, increased levels of plasma interleukin-6, prostaglandin E2 and reduced levels of protective short-chain fatty acids without triggering hypertension. Increased populations of gut Enterobacteriales and Escherichia coli may contribute to systemic inflammation through the generation of lipopolysaccharides. Unlike fat, fructose induces increased levels of diacylglycerols (lipid mediators of IR) in the liver, urine F2-isoprostanes (markers of systemic oxidative stress) and uric acid, and triggers hypertension. Elevated populations of Enterobacteriales and E. coli were only detected in rats given an excess of fructose at the end of the study. Dietary fat and fructose trigger IR and IGT in clearly differentiated ways in WKY rats: early low-grade inflammation and late direct lipid toxicity, respectively; gut microbiota plays a role mainly in fat-induced IR; and hypertension is independent of inflammation-mediated IR. The results provide evidence which suggests that the combination of fat and sugar is potentially more harmful than fat or sugar alone when taken in excess.

Telomerase reverse transcriptase protects against Angiotensin II induced microvascular endothelial dysfunction.

A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO's vasodilator and anti-inflammatory effects. Although primarily studied in the larger conduit arteries, excess ROS release and a corresponding loss of NO also occurs in the smaller resistance arteries of the microcirculation, but underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [max dilation (%): Vehicle 52.0{plus minus}6.1, L-NAME: 60.4{plus minus}12.9, Peg-CAT: 32.2{plus minus}12.2*; N = 9-19; *P<0.05] but not TERC [max dilation (%): Vehicle 79{plus minus}5; L-NAME 10.7{plus minus}9.8*; Peg-CAT 86.4{plus minus}8.4; N = 4-7; *P<0.05] promotes flow-induced ROS formation. Moreover, TERT KO exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [max dilation (%): vehicle: 88.22{plus minus}4.6 vs. ANG II (1000ng/kg/min) 74.0{plus minus}7.3; N = 4; P=NS]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies.

Macrophage-dependent impairment of α2-adrenergic autoreceptor function in sympathetic neurons from DOCA-salt but not high fat diet-induced hypertensive rats.

DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional α2-adrenergic receptors (α2ARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca2+ channels. Increased neuronal norepinephrine release in DOCA-salt and obesity-related hypertension occurs through impaired α2AR signaling, however, the mechanisms involved are unclear. Mesenteric arteries are resistance arteries that receive sympathetic innervation from the superior mesenteric and celiac ganglia (SMCG). We tested the hypothesis that macrophages impair α2AR-mediated inhibition of Ca2+ channels in SMCG neurons obtained from DOCA-salt and high fat diet (HFD)-induced hypertensive rats. Whole cell patch clamp methods were used to record Ca2+ currents from SMCG neurons maintained in primary culture. We found that DOCA-salt but not HFD-induced hypertension caused macrophage accumulation in mesenteric arteries, increased SMCG mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α, and impaired α2AR-mediated inhibition of Ca2+ currents in SMCG neurons. α2AR dysfunction did not involve changes in α2AR receptor expression, desensitization, or downstream signaling factors. Oxidative stress impaired α2AR-mediated inhibition of Ca2+ currents in SMCG neurons and resulted in receptor internalization in HEK-293T cells. Systemic clodronate-induced macrophage depletion preserved α2AR function and lowered blood pressure in DOCA-salt rats. A HFD caused hypertension without obesity in Sprague-Dawley rats and hypertension with obesity in DahlS rats. HFD-induced hypertension is not associated with inflammation in SMCG and mesenteric arteries or α2AR dysfunction in SMCG neurons. These results suggest that macrophage-mediated α2AR dysfunction may only be relevant to mineralocorticoid-salt excess.

Cardiac Vanilloid Receptor-1 Afferent Depletion Enhances Stellate Ganglion Neuronal Activity and Efferent Sympathetic Response to Cardiac Stress.

Afferent fibers expressing the vanilloid receptor 1 (VR1) channel are implicated in cardiac nociception, however, their role in modulating reflex responses to cardiac stress is not well-understood. We evaluated this role in Yorkshire pigs by percutaneous epicardial application of resiniferatoxin (RTX), a toxic activator of the VR1 channel, resulting in depletion of cardiac VR1-expressing afferents. Hemodynamics, epicardial activation recovery intervals (ARIs), and in vivo activity of stellate ganglion (SG) neurons (SGNs) were recorded in control and RTX-treated animals. Stressors included inferior vena cava (IVC occ) or aortic occlusion (Ao occ), and rapid right ventricular pacing (RVP) to induce dyssynchrony and ischemia. In epicardium, SG, and dorsal root ganglia, immunostaining for the VR1 channel, calcitonin gene-related peptide, and substance P was significantly diminished by RTX. RTX-treated animals exhibited higher basal systolic blood pressures and contractility than controls. Reflex responses to epicardial bradykinin and capsaicin were mitigated by RTX. Cardiovascular reflex function, as assessed by IVC occ or Ao occ, was similar in RTX-treated vs. control animals. RTX-treated animals exhibited resistance to hemodynamic collapse induced by RVP. ARI shortening during RVP, a marker of cardiac sympathetic outflow, was greater in RTX-treated animals, and exhibited significant delay returning to baseline values after cessation of RVP. Basal firing rate of SGNs and firing rates in response to RVP were also greater in RTX-treated subjects, as was the SGN network activity in response to cardiac stressors. These data suggest that elimination of cardiac nociceptive afferents reorganizes central-peripheral nervous system interaction to enhance cardiac sympathetic outflow.


Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signalling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signalling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of pro-opiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high fat diet (HFD). Compared to control mice (PTP1Bflox/flox), male and female mice deficient in POMC neuronal PTP1B (PTP1Bflox/flox/POMC-Cre) had attenuated body weight gain (Male: -18%; Fem ale: -16%) and fat mass (Male: -33%; Female: -29%) in response to HFD. Glucose tolerance was improved by 40% and liver lipid accumulation was reduced by 40% in PTP1Bflox/flox/POMC-Cre males but not in females. Compared to control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (Male: 112{plus minus}1 vs. 112{plus minus}1 mmHg in controls; Female: 106{plus minus}3 vs. 109{plus minus}3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in male or female compared to control mice (Male: Δ32{plus minus}0 vs. Δ29{plus minus}4 mmHg; Female: Δ22{plus minus}2 vs. Δ27{plus minus}4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice, attenuated weight gain in males and females, but did not enhance the MAP and HR responses to a HFD or to acute stress.

Source of dietary sucrose influences development of leptin resistance in male and female rats.

Male rats offered 30% sucrose solution in addition to chow develop leptin resistance without increasing energy intake or body fat. Here we tested whether the leptin resistance was dependent upon the physical form of the sucrose. Sprague Dawley rats were offered a sucrose-free diet (NS), a 66.6% energy as sucrose diet (HS), or NS diet and 30% sucrose solution (LS). Sucrose intake of LS rats equaled that of HS rats, but total carbohydrate intake exceeded that of HS rats. After 33 days male and female LS rats were resistant to the inhibitory effect of peripherally administered leptin on food intake. LS rats drank small, frequent meals of sucrose during light and dark periods whereas HS rats consumed more meals during the dark than the light period and remained leptin responsive. Diet did not affect daily energy intake or insulin sensitivity. There was a small increase in female body fat. Leptin sensitivity was restored within 5 days of withdrawing sucrose in male LS rats. This rapid reversal suggested that leptin resistance was associated with the metabolic impact of drinking sucrose. We tested whether hexosamine biosynthetic pathway activity and glycation of leptin signaling proteins were increased in LS rats, but obtained equivocal results. A final experiment determined that female LS rats were leptin resistant within 18 days of access to sucrose solution and that the small, but significant increase in body fat was associated with increased adipocyte glucose utilization and insulin responsiveness that may have been secondary to adipocyte leptin resistance.

Acute and chronic resistance training downregulates select LINE-1 retrotransposon activity markers in human skeletal muscle.

Herein, we examined if acute or chronic resistance exercise affected markers of skeletal muscle LINE-1 retrotransposon activity. In study 1, 10 resistance-trained college-aged males performed three consecutive daily back squat sessions, and vastus lateralis biopsies were taken prior to (Pre), 2 h following session 1 (Post1), and 3 days following session 3 (Post2). In study 2, 13 untrained college-aged males performed a full-body resistance training program (3 d/wk), and vastus lateralis biopsies were taken prior to (week 0) and ~72 h following training cessation (week 12). In study 1, LINE-1 mRNA decreased 42-48% at Post1&2 (p<0.05), and reverse transcriptase (RT) activity trended downward at Post2 (-37%, p=0.067). In study 2, LINE-1 mRNA trended downward at week 12 (-17%, p=0.056) while LINE-1 promoter methylation increased (+142%, p=0.041). ORF2p protein expression (-24%, p=0.059) and RT activity (-26%, p=0.063) also trended downward by week 12. Additionally, changes in RT activity versus satellite cell number were inversely associated (r= -0.725, p=0.008). Follow-up in vitro experiments demonstrate 48 h treatments with lower doses (1 μM and 10 μM) of efavirenz and nevirapine (non-nucleoside RT inhibitors) increased myoblast proliferation (p<0.05). However, we observed a paradoxical decrease in myoblast proliferation with higher doses (50 μM) of efavirenz and delavirdine. This is the first report suggesting resistance exercise downregulates markers of skeletal muscle LINE-1 activity. Given our discordant in vitro findings, future research is needed to thoroughly assess is LINE-1-mediated RT activity enhances or blunts myoblast, or primary satellite cell, proliferative capacity.

Muscular Performance and Body Composition Changes Following Multi- versus Combined Multi- and Single-Joint Exercises in Aging Adults.

The aim of the present study was to compare muscular performance and body composition changes following low volume resistance training programs consisting of multi-joint (MJ) exercises (cable chest press and seated row)versus a combination of multi- and single-joint (MJ+SJ) exercises (cable chest press, seated row, biceps curl, and triceps extension). Thirty untrained healthy aging adults were randomly assigned to three groups: MJ (n=11), MJ+SJ (n=11), and Control (n=8). Twelve-repetition maximums (12-RM) for the cable chest press and seated row; localized muscular endurance for the elbow flexors handgrip strength; and body composition were assessed before and after the 8-week training program. All comparisons were analyzed via a mixed model analysis with repeated measures (group x time) and the Bonferroni post-hoc test (p<0.05). The MJ and MJ+SJ groups increased performance in the cable chest press 12-RM (MJ=61.5±24.6% and MJ+SJ=71.1±25.6%), seated row 12-RM (MJ=46.4±26.3% and MJ+SJ=51.5±21.0%), localized muscular endurance (MJ= 24.7±16.7% and MJ+SJ= 37.0±11.4%), and handgrip strength (MJ= 9.3±10.4% and MJ+SJ= 16.6±25.3%) after the intervention. Body composition (i.e., trunk and upper limb fat and lean mass) did not change for any groups. No significant differences were observed between the MJ versus the MJ+SJ after the intervention for any variables. In conclusion, for aging adults, either MJ or MJ+SJ low volume resistance training resulted in similar increases in 12-RM, localized muscular endurance, and handgrip strength, without changes in body composition after 8 weeks of training.

Synergistic effect of azole antimycotics (clotrimazole and fluconazole) and natural substances.

Nowadays the treatment of fungal infections is difficult due to increasing resistance of fungal pathogens to antimycotics. The efficacy of antimycotics can be increased by a proper combination of commercial drugs and natural substances. The 100% antimycotic activity was found using susceptibility testing of Candida albicans yeasts on clotrimazole alone and in combination with tea tree oil, or with a multicomponent preparation containing cannabis oil and various essential oils and in combination with propolis tincture. Combination of natural substances with fluconazole seems to be also prospective. Fluconazole alone achieved an antifungal activity of 80.95% but natural active substances increased its efficacy by 9.55-14.25%.Key words: Candida albicans fluconazole clotrimazole natural active substances synergism.

Stockouts of HIV commodities in public health facilities in Kinshasa: Barriers to end HIV.

Stockouts of HIV commodities increase the risk of treatment interruption, antiretroviral resistance, treatment failure, morbidity and mortality. The study objective was to assess the magnitude and duration of stockouts of HIV medicines and diagnostic tests in public facilities in Kinshasa, Democratic Republic of the Congo. This was a cross-sectional survey involving visits to facilities and warehouses in April and May 2015. All zonal warehouses, all public facilities with more than 200 patients on antiretroviral treatment (ART) (high-burden facilities) and a purposive sample of facilities with 200 or fewer patients (low-burden facilities) in Kinshasa were selected. We focused on three adult ART formulations, cotrimoxazole tablets, and HIV diagnostic tests. Availability of items was determined by physical check, while stockout duration until the day of the survey visit was verified with stock cards. In case of ART stockouts, we asked the pharmacist in charge what the facility coping strategy was for patients needing those medicines. The study included 28 high-burden facilities and 64 low-burden facilities, together serving around 22000 ART patients. During the study period, a national shortage of the newly introduced first-line regimen Tenofovir-Lamivudine-Efavirenz resulted in stockouts of this regimen in 56% of high-burden and 43% of low-burden facilities, lasting a median of 36 (interquartile range 29-90) and 44 days (interquartile range 24-90) until the day of the survey visit, respectively. Each of the other investigated commodities were found out of stock in at least two low-burden and two high-burden facilities. In 30/41 (73%) of stockout cases, the commodity was absent at the facility but present at the upstream warehouse. In 30/57 (54%) of ART stockout cases, patients did not receive any medicines. In some cases, patients were switched to different ART formulations or regimens. Stockouts of HIV commodities were common in the visited facilities. Introduction of new ART regimens needs additional planning.

Fatty Acid Based Microemulsions to Combat Ophthalmia Neonatorum Caused by Neisseria gonorrhoeae and Staphylococcus aureus.

The bacterial species Neisseria gonorrhoeae (N. gonorrhoeae) and Staphylococcus aureus (S. aureus) are amongst the main microorganisms that cause ophthalmia neonatorum. The current treatment involves the use of various antibiotics such as ciprofloxacin, cephalosporin, ceftriaxone and cefotaxime. However, this treatment strategy is becoming more ineffective due to the antibiotic resistance in N. gonorrhoeae. The current study explores the potential use of fatty acid based microemulsions (ME) to prevent N. gonorrhoeae and S. aureus infections in new-borns' eyes without harmful side effects such as corneal or conjunctiva irritation. Pseudo-ternary phase diagrams were constructed to evaluate microemulsion regions and six different α-linolenic acid based microemulsions were prepared. The prepared formulations were characterized for α-linolenic acid content, size, transparency, zeta potential, Polarized light Microscopy, antimicrobial activity and ex vivo ocular toxicity. The mean droplet size of the ME formulations was in the range of 190.4 to 350.5 nm and polydispersity index (PDI) values were in the range of 0.102 to 0.561. All formulations were found stable upon storage for at least 8 weeks. In addition, self-diffusion coefficients determined by nuclear magnetic resonance (NMR) reflected that the diffusability of water increased at higher than 30% w/w water, while that of fatty acids and surfactants was in reverse. The antimicrobial efficacy of microemulsions was determined against N. gonorrhoeae and S. aureus. It was concluded that all microemulsions have strong antimicrobial effects against N. gonorrhoeae and S. aureus. Finally, bovine corneal opacity permeability (BCOP) and hen's egg chorioallantoic (HET-CAM) tests results showed that all microemulsion formulations were not strong ocular irritants.

A Comprehensive Study of a Micro-Channel Heat Sink Using Integrated Thin-Film Temperature Sensors.

A micro-channel heat sink is a promising cooling method for high power integrated circuits (IC). However, the understanding of such a micro-channel device is not sufficient, because the tools for studying it are very limited. The details inside the micro-channels are not readily available. In this letter, a micro-channel heat sink is comprehensively studied using the integrated temperature sensors. The highly sensitive thin film temperature sensors can accurately monitor the temperature change in the micro-channel in real time. The outstanding heat dissipation performance of the micro-channel heat sink is proven in terms of maximum temperature, cooling speed and heat resistance. The temperature profile along the micro-channel is extracted, and even small temperature perturbations can be detected. The heat source formed temperature peak shifts towards the flow direction with the increasing flow rate. However, the temperature non-uniformity is independent of flow rate, but solely dependent on the heating power. Specific designs for minimizing the temperature non-uniformity are necessary. In addition, the experimental results from the integrated temperature sensors match the simulation results well. This can be used to directly verify the modeling results, helping to build a convincing simulation model. The integrated sensor could be a powerful tool for studying the micro-channel based heat sink.

Machine Learning and Infrared Thermography for Fiber Orientation Assessment on Randomly-Oriented Strands Parts.

The use of fiber reinforced materials such as randomly-oriented strands has grown in recent years, especially for manufacturing of aerospace composite structures. This growth is mainly due to their advantageous properties: they are lighter and more resistant to corrosion when compared to metals and are more easily shaped than continuous fiber composites. The resistance and stiffness of these materials are directly related to their fiber orientation. Thus, efficient approaches to assess their fiber orientation are in demand. In this paper, a non-destructive evaluation method is applied to assess the fiber orientation on laminates reinforced with randomly-oriented strands. More specifically, a method called pulsed thermal ellipsometry combined with an artificial neural network, a machine learning technique, is used in order to estimate the fiber orientation on the surface of inspected parts. Results showed that the method can be potentially used to inspect large areas with good accuracy and speed.

Trends in Resistance to Extended-Spectrum Cephalosporins and Carbapenems among Escherichia coli and Klebsiella spp. Isolates in a District in Western India during 2004-2014.

Surveillance data on the level of resistant bacteria is needed to inform strategies to reduce the development and spread of antibiotic resistance. The aim of this study was to determine the non-susceptibility trends to extended-spectrum cephalosporins and carbapenems among Escherichia coli and Klebsiella spp. isolates from the district of Nashik in Western India during the period 2004-2014. Antibacterial susceptibility testing of clinical isolates was performed using Kirby-Bauer disc diffusion method to determine inhibitory zone diameters. The change in proportions of non-susceptible bacteria over calendar time was investigated with spline transformations in a logistic regression model. For the extended-spectrum cephalosporins, the proportions of non-susceptible E. coli and Klebsiella spp. isolates were above 78.4% and 84.9% throughout the study period, respectively. E. coli and Klebsiella spp. isolates exhibited carbapenem non-susceptibility levels as high as 76.9% and 84.1% respectively. The proportions of extended-spectrum betalactamase (ESBL)-producing isolates ranged from 38.3-85.9% in E. coli and from 45.1-93.1% in Klebsiella spp. Significantly higher proportions of non-susceptible and ESBL-producing isolates were found among isolates from inpatients compared to isolates from outpatients for both E. coli and Klebsiella spp. (p < 0.050). The high proportions of non-susceptible isolates observed show that there is great need to focus on optimal use of antibiotics to reduce the development of antibiotic resistance.

Mechanical Structural Design of a MEMS-Based Piezoresistive Accelerometer for Head Injuries Monitoring: A Computational Analysis by Increments of the Sensor Mass Moment of Inertia.

This work focuses on the proof-mass mechanical structural design improvement of a tri-axial piezoresistive accelerometer specifically designed for head injuries monitoring where medium-G impacts are common; for example, in sports such as racing cars or American Football. The device requires the highest sensitivity achievable with a single proof-mass approach, and a very low error (<1%) as the accuracy for these types of applications is paramount. The optimization method differs from previous work as it is based on the progressive increment of the sensor proof-mass mass moment of inertia (MMI) in all three axes. Three different designs are presented in this study, where at each step of design evolution, the MMI of the sensor proof-mass gradually increases in all axes. The work numerically demonstrates that an increment of MMI determines an increment of device sensitivity with a simultaneous reduction of cross-axis sensitivity in the particular axis under study. This is due to the linkage between the external applied stress and the distribution of mass (of the proof-mass), and therefore of its mass moment of inertia. Progressively concentrating the mass on the axes where the piezoresistors are located (i.e., x- and y-axis) by increasing the MMI in the x- and y-axis, will undoubtedly increase the longitudinal stresses applied in that areas for a given external acceleration, therefore increasing the piezoresistors fractional resistance change and eventually positively affecting the sensor sensitivity. The final device shows a sensitivity increase of about 80% in the z-axis and a reduction of cross-axis sensitivity of 18% respect to state-of-art sensors available in the literature from a previous work of the authors. Sensor design, modelling, and optimization are presented, concluding the work with results, discussion, and conclusion.

A High Sensitivity Electric Field Microsensor Based on Torsional Resonance.

This paper proposes a high sensitivity electric field microsensor (EFM) based on torsional resonance. The proposed microsensor adopts torsional shutter, which is composed of shielding electrodes and torsional beams. The movable shielding electrodes and the fixed sensing electrodes are fabricated on the same plane and interdigitally arranged. Push-pull electrostatic actuation method is employed to excite the torsional shutter. Simulation results proved that the torsional shutter has higher efficiency of charge induction. The optimization of structure parameters was conducted to improve its efficiency of charge induction further. A micromachining fabrication process was developed to fabricate the EFM. Experiments were conducted to characterize the EFM. A good linearity of 0.15% was achieved within an electrostatic field range of 0-50 kV/m, and the uncertainty was below 0.38% in the three roundtrip measurements. A high sensitivity of 4.82 mV/(kV/m) was achieved with the trans-resistance of 100 MΩ, which is improved by at least one order of magnitude compared with previously reported EFMs. The efficiency of charge induction for this microsensor reached 48.19 pA/(kV/m).

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.

Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo.

Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low resistance. In this review, we discuss the diversity, history and the various mechanisms of action of AMPs. Although many AMPs have reached clinical trials, to date not many have been approved by the US Food and Drug Administration (FDA) due to issues with toxicity, protease cleavage and short half-life. Some of the recent strategies developed to improve the activity and biocompatibility of AMPs, such as chemical modifications and the use of delivery systems, are also reviewed in this article.

The Role of Cadaverine Synthesis on Pneumococcal Capsule and Protein Expression.

Invasive infections caused by Streptococcus pneumoniae, a commensal in the nasopharynx, pose significant risk to human health. Limited serotype coverage by the available polysaccharide-based conjugate vaccines coupled with increasing incidence of antibiotic resistance complicates therapeutic strategies. Bacterial physiology and metabolism that allows pathogens to adapt to the host are a promising avenue for the discovery of novel therapeutics. Intracellular polyamine concentrations are tightly regulated by biosynthesis, transport and degradation. We previously reported that deletion of cadA, a gene that encodes for lysine decarboxylase, an enzyme that catalyzes cadaverine synthesis results in an attenuated phenotype. Here, we report the impact of cadA deletion on pneumococcal capsule and protein expression. Our data show that genes for polyamine biosynthesis and transport are downregulated in ∆cadA. Immunoblot assays show reduced capsule in ∆cadA. Reduced capsule synthesis could be due to reduced transcription and availability of precursors for synthesis. The capsule is the predominant virulence factor in pneumococci and is critical for evading opsonophagocytosis and its loss in ∆cadA could explain the reported attenuation in vivo. Results from this study show that capsule synthesis in pneumococci is regulated by polyamine metabolism, which can be targeted for developing novel therapies.

High Proportions of Multidrug-Resistant Acinetobacter spp. Isolates in a District in Western India: A Four-Year Antibiotic Susceptibility Study of Clinical Isolates.

The purpose of the study was to determine the proportions of multidrug-resistant (MDR) Acinetobacter spp. isolates from the district of Nashik in Western India during the period from 2011-2014. Antibacterial susceptibility testing of isolates from inpatients and outpatients was performed using Kirby-Bauer disc diffusion method to determine inhibitory zone diameters. Proportions of non-susceptible isolates were calculated from the antibacterial susceptibility data. MDR was defined as an isolate being non-susceptible to at least one antibacterial agent in at least three antibacterial categories. The change in proportions of MDR isolates; extended-spectrum β-lactamase (ESBL)-producing isolates; and non-susceptible isolates to specific antibacterial categories over calendar time was investigated by logistic regression. The proportions of MDR and ESBL-producing isolates ranged from 89.4% to 95.9% and from 87.9% to 94.0%; respectively. The proportions of non-susceptible isolates to aminoglycosides; carbapenems; antipseudomonal penicillins/β-lactamase inhibitors; cephalosporins; folate pathway inhibitors; or penicillins/β-lactamase inhibitors exceeded 77.5%. Proportions of fluoroquinolone and tetracycline non-susceptible isolates ranged from 65.3% to 83.3% and from 71.3% to 75.9%; respectively. No changes in trends were observed over time; except for a decreasing trend in fluoroquinolone non-susceptible isolates (OR = 0.75 (95% CI, 0.62-0.91)). Significantly higher proportions of non-susceptible; MDR and ESBL-producing isolates were found among isolates from the respiratory system compared to isolates from all other specimen types (p < 0.05). High proportions of MDR Acinetobacter spp. isolates were observed in the period from 2011-2014. Antimicrobial stewardship programmes are needed to prevent the emergence and spread of antibiotic resistance.

The management of partial zone II intrasynovial flexor tendon lacerations: A literature review of biomechanics, clinical outcomes and complications.

Penetrating trauma or lacerations within zone II of the flexor sheath may result in partial tendon injury. The proper management of this injury is controversial; the literature contains differing indications for surgical treatment and post-operative rehabilitation.

Comparison of the Force-, Velocity- and Power-Time Curves Between the Concentric-Only and Eccentric-Concentric Bench Press Exercises.

The aim of this study was to compare the temporal and mechanical variables between the concentric-only and eccentric-concentric bench press (BP) variants. Twenty-one men (age: 22.0±4.2 years, body mass: 73.4±7.7 kg, height: 177.2±8.0 cm; one-repetition maximum [1RM]: 1.12±0.12 kg⋅kg) were evaluated during the concentric-only and eccentric-concentric BP variants using 80% 1RM. Temporal (concentric phase duration, propulsive phase duration, and time to reach the maximum values of force, velocity, and power) and mechanical variables (force, velocity, and power), determined using a linear velocity transducer, were compared between both BP variants. All temporal variables were significantly lower during the eccentric-concentric BP compared to the concentric-only BP (P < 0.05; effect size [ES] range: 0.80-2.52). Maximum force as well as the mean values of velocity and power were significantly higher for the eccentric-concentric BP compared to the concentric-only BP (all P < 0.001; ES range: 2.87-3.58). However, trivial to small differences between both BP variants were observed for mean force (ES: 0.00-0.36) as well as for maximum velocity (ES: 0.40) and power (ES: 0.41). The stretch-shortening cycle (i.e., eccentric-concentric BP) mainly enhanced force production at the early portion of the concentric phase, but this potentiation effect gradually reduced over the latter part of the movement. Finally, force was higher for the concentric-only BP during 49% of the concentric phase duration. These results suggest that both BP variants should be included during resistance training programs in order to optimize force output at different points of the concentric phase.