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Background: The presence of infections is one of the main factors that leads to delays in healing or non-closure of cutaneous wounds. Although the goal of antibiotic use is to treat or prevent infection, there is currently no agreement on the effectiveness of these products. Aim: The aim of this study was to evaluate the efficacy of antibiotic use during the healing process of skin wounds in animal models not intentionally infected, as well as to analyze the advances and limitations of the studies carried out in this field. Main methods: This systematic review was performed according to the PRISMA guidelines, using a structured search on the MedLine (PubMed) and Scopus platforms to retrieve studies published until August 29, 2018, 13:35p.m. The studies included were limited to those that used excision or incision wound models and that were not intentionally infected. The data for the animal models, antibiotic used, and the main results of the studies were extracted, and compared where possible. Bias analysis and methodological quality assessments were examined through the SYRCLE's Risk of Bias tool. Key findings: Twenty-seven studies were selected. Overall, the effects of the antibiotic on the wound decreased inflammatory cell infiltration and promoted an increased number of fibroblasts, extracellular matrix constituents, re-epithelialization and tissue strength. A great deal of important information about the methodology was not presented, such as: the statistical analysis used, the animal model (sex and age), antibiotic dosage, blinding and randomization of the animals chosen. Significance: Based on the results found, we believe that antibiotic therapy can be considered a viable alternative for the treatment of cutaneous wounds. However, current evidence obtained from the methodological quality analysis points towards a high risk of bias. This is due to the incomplete characterization of the experimental design and treatment protocol, which compromises the reproducibility of the studies. [ABSTRACT FROM AUTHOR]

Blood stream infections rank among the top seven causes of death of the general population. The aim of our study was to better understand the epidemiology of BSI in order to improve diagnostics and patient outcome. We used retrospective aggregated laboratory data of blood samples received from all public hospitals in Tyrol, Austria between 2006 and 2015. Microorganisms were categorized into obligatory, facultative, unusual pathogens and contaminants. The distribution, the cumulative incidence and antimicrobial susceptibility patterns were compared between the tertiary (TH) and regional peripheral hospitals (PH). Among 256,364 blood samples, 76.1% were from the TH The incidence of obligatory pathogens was 1.7 fold, and up to 3 times higher for facultative, unusual pathogens and contaminants in the TH and increased mainly due to an increase of E.coli, which was the most common isolated pathogen (n = 2,869), followed by Staphylococcus aureus (n = 1,439), Enterococcus sp. (n = 953) and Klebsiella sp. (n = 816). The distribution of obligatory pathogens differed between the hospital settings: In the TH Enterococcus sp. accounted for 40.8% and E.coli for 70.4%, respectively, whereas in the PH for 25.4% (p<0.0001) and 57.8%, respectively (p<0.0001) Antibiotic resistance of Gram negative bacteria and Staphylococcus aureus did not change during the observation period. Carbapenem resistance of Klebsiella sp. and vancomycin and linezolid resistance of Enterococcus faecium showed a non-significant increase since 2010 in the TH setting. We concluded that the incidence of BSI in TH was higher compared to PH. We observed higher contamination rates in the TH. We could not interpret the data of coagulase negative staphylococci due to lack of clinical data. We strongly recommend enhancement of training on blood culture sampling to decrease the rate of contamination. Due to differences in pathogen distribution and antimicrobial resistance between different hospital settings we recommend separate treatment guidelines for BSI by hospital setting. [ABSTRACT FROM AUTHOR]

We examined the influence of linear perspective cues and texture gradients in the perceptual rescaling of stimuli over a highly-salient Ponzo illusion of a corridor. We performed two experiments using the Method of Constant Stimuli where participants judged the size of one of two rings. In experiment 1, one ring was presented in the upper visual-field at the end of the corridor and the other in the lower visual-field at the front of the corridor. The perceived size of the top and bottom rings changed as a function of the availability of linear perspective and textures. In experiment 2, only one ring was presented either at the top or the bottom of the image. The perceived size of the top but not the bottom ring changed as a function of the availability of linear perspective and textures. In both experiments, the effects of the cues were additive. Perceptual rescaling was also stronger for the top compared to the bottom ring. Additional eye-tracking revealed that participants tended to gaze more in the upper than the lower visual-field. These findings indicate that top-down mechanisms provide an important contribution to the Ponzo illusion. Nonetheless, additional maximum likelihood estimation analyses revealed that linear perspective fulfilled a greater contribution in experiment 2, which is suggestive of a bottom-up mechanism. We conclude that both top-down and bottom-up mechanisms play important roles. However, the former seems to fulfil a more prominent role when both stimuli are presented in the image. [ABSTRACT FROM AUTHOR]

Introduction: While extracorporeal membrane oxygenation (ECMO) is effective in preventing further hypoxemia and maintains blood flow in endotoxin-induced shock, ECMO alone does not reverse the hypotension. In this study, we tested whether concurrent vasopressor use with ECMO would provide increased circulatory support and blood flow, and characterized regional blood flow distribution to vital organs. Methods: Endotoxic shock was induced in piglets to achieve a 30% decrease in mean arterial pressure (MAP). Measurements of untreated pigs were compared to pigs treated with ECMO alone or ECMO and vasopressors. Results: ECMO provided cardiac support during vasodilatory endotoxic shock and improved oxygen delivery, but vasopressor therapy was required to return MAP to normotensive levels. Increased blood pressure with vasopressors did not alter oxygen consumption or extraction compared to ECMO alone. Regional microcirculatory blood flow (RBF) to the brain, kidney, and liver were maintained or increased during ECMO with and without vasopressors. Conclusion: ECMO support and concurrent vasopressor use improve regional blood flow and oxygen delivery even in the absence of full blood pressure restoration. Vasopressor-induced selective distribution of blood flow to vital organs is retained when vasopressors are administered with ECMO. [ABSTRACT FROM AUTHOR]

In the pig, intrauterine competition (IUC) greatly affects postnatal traits, such as birth weight, but also locomotor capacities. In a previous study, our group discovered a lower motor performance in piglets with a low birth weight and low vitality (L piglets), compared to piglets with a normal birth weight and normal vitality (N piglets). In order to explain the force deficit causing this reduced motor performance, in a subsequent study, we investigated whether this deficit in L piglets was caused by a lower force generating capacity (FGC) of the extensors of the hind limb and/or a lower number of type II (fast-twitch) fibers in m. vastus lateralis. L piglets had a lower absolute FGC, but surprisingly, a higher relative FGC (to birth weight) in the hind limb, compared to N piglets. In addition, we found no differences in fiber composition of m. vastus lateralis. In the present study, we assessed whether this higher relative FGC is a common feature for front and hind limb locomotor muscles of L piglets. To that end, the physiological cross-sectional area of the main extensor muscles of the front limb was calculated from their volume and fiber length, in order to calculate both the absolute and the relative FGC. By immunohistochemical staining of m. triceps brachii caput longum, the percentage of type II (fast-contracting) fibers could be determined. Similar to the results of the hind limb, we found a smaller absolute FGC, but a larger relative FGC in the front limb of L piglets, compared to N piglets. In addition, m. triceps brachii caput longum did not have a different muscle fiber composition in L and N piglets. As such, we can conclude that IUC affects the locomotor muscles in the front and hind limb in a similar way and that the observed force deficit in L piglets cannot be explained by a different force generating capacity or a lower percentage of type II muscle fibers. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed "non-odonto") (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL "c.1559delT" mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP. [ABSTRACT FROM AUTHOR]

Background: Examining body mass index (BMI) change over life course is crucial for cardiovascular health promotion and prevention. So far, there is very few evidence on the long-term change of BMI from childhood to late life. This study aimed to examine the life-course trajectory patterns of BMI and then to link the trajectory patterns to cardiovascular risk factors in adulthood. Methods: Based on longitudinal data from the China Health and Nutrition Survey, 5276 participants (aged 6–60) at baseline (in 1989) with up to 7 measurements of BMI during 1989–2009 were selected in this study. Cardiovascular risk factors including high blood pressure, high blood glucose and high blood lipids were assessed in 2411 participants in 2009. Latent growth curve modelling was used to analyse the BMI trajectories, and logistic regression was used to examine the associations between trajectory patterns and cardiovascular risk factors. Results: Four trajectories patterns of BMI over life course (age 6–80) were identified: Normal-Stable (22.4% of the total participants), Low normal-Normal-Stable (44.1%), Low normal-Normal-Overweight (27.2%), and Overweight-Obese (4.3%). Compared to those with Normal-Stable pattern, those with Low normal-Normal-Stable pattern, Low normal-Normal-Overweight pattern and Overweight-Obese pattern had higher risk of high blood pressure (odds ratio range = 1.6–6.6), high blood glucose (1.7–9.1), dyslipidemia (2.6–5.9) and having at least two of the three cardiovascular risk factors (3.9–30.9). Conclusions: Having a stable BMI within normal range over life course is associated with the lowest cardiovascular risk, whereas remaining overweight and obese over life course is associated with the highest cardiovascular risk. [ABSTRACT FROM AUTHOR]

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact. [ABSTRACT FROM AUTHOR]

Background: The function of the pelvic bones is to transfer load generated by body weight. Proper function of the pelvic bones can be disturbed by alignment changes that occur during pregnancy. Further, misalignment of the pelvic bones can lead to pain, urinary incontinence, and other complications. An understanding of the timing and nature of pelvic alignment changes during pregnancy may aid in preventing and treating these complications. Objective: To investigate the changes in pelvic alignment during pregnancy and one month after childbirth. Methods: This is a prospective, longitudinal cohort study. Pelvic measurements were obtained for 201 women at 12, 24, 30, and 36 weeks of pregnancy, and 1 month after childbirth. The anterior and posterior width of the pelvis (the distance between the bilateral anterior superior iliac spines and the bilateral posterior superior iliac spines), the anterior pelvic tilt, and pelvic asymmetry (the mean left and right pelvic tilt degrees and the bilateral difference of the anterior pelvic tilt) were measured. For the change in pelvic alignment, a Friedman test was conducted to determine any significant difference in the measurements over time. Results: The anterior and posterior width of the pelvis became significantly wider with pregnancy progress and the anterior width of the pelvis at 1 month after childbirth remained wider than that at 12 weeks of pregnancy (p < 0.001). The anterior pelvic tilt increased during pregnancy and decreased after childbirth (p < 0.05). Conclusion: Some changes in pelvic alignment occur continuously during the perinatal period. Changes in the anterior width of the pelvis are not recovered at one month post-childbirth. Understanding these perinatal changes may help clinicians avert complications due to pelvic misalignment. [ABSTRACT FROM AUTHOR]

Cells damaged by mechanical or infectious injury release proinflammatory mitochondrial DNA (mtDNA) fragments into the circulation. We evaluated the relation between plasma levels of mtDNA fragments in obese type 2 diabetes mellitus (T2DM) patients and measures of chronic inflammation and insulin resistance. In 10 obese T2DM patients and 12 healthy control (HC) subjects, we measured levels of plasma cell-free mtDNA with quantitative real-time polymerase chain reaction, and mtDNA damage in skeletal muscle with quantitative alkaline Southern blot. Also, markers of systemic inflammation and oxidative stress in skeletal muscle were measured. Plasma levels of mtDNA fragments, mtDNA damage in skeletal muscle and plasma tumor necrosis factor α levels were greater in obese T2DM patients than HC subjects. Also, the abundance of plasma mtDNA fragments in obese T2DM patients levels positively correlated with insulin resistance. To the best of our knowledge, this is the first published evidence that elevated level of plasma mtDNA fragments is associated with mtDNA damage and oxidative stress in skeletal muscle and correlates with insulin resistance in obese T2DM patients. Plasma mtDNA may be a useful biomarker for predicting and monitoring insulin resistance in obese patients. [ABSTRACT FROM AUTHOR]

Plantar fasciitis is a frequently occurring overuse injury of the foot. Shoes with a stiff rocker profile are a commonly prescribed treatment modality used to alleviate complaints associated with plantar fasciitis. In rocker shoes the apex position was moved proximally as compared to normal shoes, limiting the progression of the ground reaction forces (GRF) and peak plantarflexion moments during gait. A stiff sole minimizes dorsiflexion of the toes. The aim of this study was to investigate whether the biomechanical effects of rocker shoes lead to minimization of plantar aponeurosis (PA) strain during gait in patients with plantar fasciitis and in healthy young adults. 8 patients with plantar fasciitis (1 male, 7 females; mean age 55.0 ± 8.4 years) and 8 healthy young adults (8 females; mean age 24.1 ± 1.6 years) participated in the study. Each participant walked for 1 minute on an instrumented treadmill while wearing consecutively in random order shoes with a normal apex position (61.2 ± 2.8% apex) with flexible insole (FN), normal apex position with stiff insole (SN), proximal apex position (56.1 ± 2.6% apex) with flexible insole (FR) and proximal apex position with stiff insole (SR). Marker position data of the foot and lower leg and GRF were recorded. An OpenSim foot model was used to compute the change in PA length based on changes in foot segment positions during gait. The changes in PA length due to increases in Achilles tendon forces were computed based on previous data of a cadaver study. PA strain computed from both methods was not statistically different between shoe conditions. Peak Achilles tendon force, peak first metatarsophalangeal (MTP1) joint angle and peak plantarflexion moment were significantly lower when walking with the rocker shoe with a proximal apex position and a stiff insole for all subjects (p<.05). Changes in Achilles tendon forces during gait accounted for 65 ± 2% of the total PA strain. Rocker shoes with a stiff insole reduce peak dorsiflexion angles of the toes and plantar flexion moments, but not PA strain because the effects of a proximal apex position and stiff insole do not occur at the same time, but independently affect PA strain at 80–90% and 90–100% of the stance phase. Rocker shoes with an apex position of ~56% are insufficient to significantly reduce peak PA strain values in patients with plantar fasciitis and healthy young adults. [ABSTRACT FROM AUTHOR]

Background: Dietary management is highly important for the maintenance of renal function in patients with chronic kidney disease (CKD). Cerebral oxygen saturation (rSO2) was reportedly associated with the estimated glomerular filtration rate (eGFR) and cognitive function. However, data concerning the association between cerebral rSO2 and dietary intake of CKD patients is limited. Methods: This was a single-center observational study. We recruited 67 CKD patients not undergoing dialysis. Cerebral rSO2 was monitored using the INVOS 5100c oxygen saturation monitor. Energy intake was evaluated by dietitians based on 3-day meal records. Daily protein and salt intakes were calculated from 24-h urine collection. Results: Multivariable regression analysis showed that cerebral rSO2 was independently associated with energy intake (standardized coefficient: 0.370) and serum albumin concentration (standardized coefficient: 0.236) in Model 1 using parameters with p < 0.10 in simple linear regression analysis (body mass index, Hb level, serum albumin concentration, salt and energy intake) and confounding factors (eGFR, serum sodium concentration, protein intake), and the energy/salt index (standardized coefficient: 0.343) and Hb level (standardized coefficient: 0.284) in Model 2 using energy/protein index as indicated by energy intake/protein intake and energy/salt index by energy intake/salt intake in place of salt, protein and energy intake. Conclusions: Cerebral rSO2 is affected by energy intake, energy/salt index, serum albumin concentration and Hb level. Sufficient energy intake and adequate salt restriction is important to prevent deterioration of cerebral oxygenation, which might contribute to the maintenance of cognitive function in addition to the prevention of renal dysfunction in CKD patients. [ABSTRACT FROM AUTHOR]

Background: In patients with left heart failure, micro-RNAs (miRNAs) have been shown to be of diagnostic and prognostic value. The present study aims to identify those miRNAs in patients with univentricular heart (UVH) disease that may be associated with overt heart failure. Methods: A large panel of human miRNA arrays were used to determine miRNA expression profiles in the blood of 48 UVH patients and 32 healthy controls. For further selection, the most abundantly expressed miRNA arrays were related to clinical measures of heart failure and selected miRNAs validated by polymerase chain reaction were used for the prediction of overt heart failure and all-cause mortality. Results: According to microarray analysis, 50 miRNAs were found to be significantly abundant in UVH patients of which miR-150-5p was best related to heart failure parameters. According to ROC analysis, NT-proBNP levels (AUC 0.940, 95% CI 0.873–1.000; p = 0.001), miR-150-5p (AUC 0.905, 95% CI 0.779–1.000; p = 0.001) and a higher NYHA class ≥ III (AUC 0.893, 95% CI 0.713–1.000; p = 0.002) were the 3 most significant predictors of overt heart failure. Using a combined biomarker model, AUC increased to 0.980 indicating an additive value of miR-150-5p. Moreover, in the multivariate analysis, a higher NYHA class ≥ III (p = 0.005) and miR-150-5p (p = 0.006) turned out to be independent predictors of overt heart failure. Conclusion: In patients with UVH, miR-150-5p is an independent predictor of overt heart failure and thus may be used in the risk assessment of these patients. [ABSTRACT FROM AUTHOR]

Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer presents well-defined risk factors: myometrial invasion, histological subtype, tumor grade, lymphovascular space invasion (LVSI). Some low and intermediate-risk endometrioid endometrial cancer patients exhibited unexpected outcomes. This study aimed to investigate other clinical-pathological factors that might influence the recurrence rates of patients diagnosed with low and intermediate-risk endometrioid endometrial cancer. Methods: A case-control study from a cohort retrospective of 196 patients diagnosed with low and intermediate-risk endometrioid endometrial cancer at a single institution from 2009 to 2014 was conducted. Medical records were reviewed to compare clinical (race, smoking, menopause age, body mass index) and pathological (endometrioid vs endometrioid with squamous differentiation, tumor differentiation grade, tumor location, endocervical invasion, LVSI) features of patients with recurrence (case) and without recurrence (control) of disease. Three controls for each case were matched for age and staging. Results: Twenty-one patients with recurrence were found (10.7%), of which 14 were stage IA, and 7 were stage IB. In accordance, 63 patients without recurrence were selected as controls. There were no significant differences in any clinical characteristics between cases and controls. Among pathological variables, presence of squamous differentiation (28.6% vs. 4.8%, p = 0.007), tumor differentiation grade 2 or 3 (57.1% vs. 30.2%, p = 0.037) and presence of endocervical invasion (28.6% vs. 12.7%, p = 0.103) were associated with disease recurrence on a univariate analysis. On multivariable analysis, only squamous differentiation was a significant risk factor for recurrence (p = 0.031). Conclusion: Our data suggest that squamous differentiation may be an adverse prognostic factor in patients with low and intermediate-risk endometrioid endometrial cancer, that showed a 5.6-fold increased risk for recurrence. [ABSTRACT FROM AUTHOR]

The objectives of this study were: 1) to classify animals into groups of high and low feed efficiency using two feed efficiency indexes (Residual feed intake (RFI) and residual feed intake and body weight gain (RIG)), and 2) to evaluate if pre-weaning heifer calves divergent for feed efficiency indexes exhibit differences in performance, body measurements, digestibility, energy partitioning, and nitrogen partitioning. A total of 32 Gyr heifer calves were enrolled in a 63-d trial and classified into two feed efficiency (FE) groups based on RFI and RIG (mean ± 0.5 SD). The groups were classified as high efficiency (HE) RFI (HE RFI, n = 9; HE RIG, n = 10), and low efficiency (LE) RFI (LE RFI, n = 10; LE RIG, n = 11). The remaining animals were classified as intermediate (n = 13 (RFI) and n = 11 (RIG)). HE and LE calves had RFI values of—0.052 and 0.049 kg/d (P < 0.05), respectively. The HE RFI group consumed 8.9% less solid diet than the LE RFI group. HE RFI animals exhibited an increased digestibility of crude protein and ether extract and tended to have greater total dry and organic matter digestibility. LE RFI animals had greater gross energy and nitrogen intake, though greater fecal losses resulted in a tendency to reduce energy and nitrogen use efficiency. HE and LE calves had RIG values of 0.080 and -0.077kg/d (P ≤ 0.01), respectively. HE RIG animals exhibited greater average daily gain (9.4%), body weight (BW), and heart girth, though HE RIG group exhibited narrower hip width. HE RIG animals tended to have greater ether extract digestibility but greater methane losses (% of gross energy). HE RFI in pre-weaning heifers seems to be related to differences in digestibility. Divergent animals for RIG during the assessed phase appear to differ in body measurements, which may be related to differences in the composition of the gain. [ABSTRACT FROM AUTHOR]

In the present study, antibiotic residues were detected in milk samples collected from the dairy herds located in Karnataka, India, by microbiological assay. Subsequently, the detected antibiotics were identified as azithromycin and tetracycline, by high-performance liquid chromatography, further both the antibiotics detected in the cow milk samples were found to be at high concentration (9708.7 and 5460 μg kg-1, respectively). We then investigated the effects of temperature and pH on the stabilities of azithromycin and tetracycline to determine the degradation rate constant k using first-order kinetic equation. Results indicated that significant reduction in stability and antibacterial activity of azithromycin solution when subjected to 70 and 100°C for 24 h. While stability of tetracycline was significantly reduced when subjected to 70 and 100°C for 24 h. However no significant reduction in antibacterial activity of tetracycline was observed at respective temperatures when compared with that of control. In addition, the stabilities of azithromycin and tetracycline were found to be decreased in acidic pH 4–5. The results of the present study revealed the high risk of contamination of milk sample with veterinary antibiotics and also demonstrated the effect of temperature and pH on stability of antibiotics. Therefore the study suggest that the qualitative and quantitative screening of milk for the presence of antibiotics need to be strictly performed to ensure safe drinking milk for consumers. [ABSTRACT FROM AUTHOR]

Several models for the long-term development of T2DM already exist, focusing on the dynamics of the interaction between glycemia, insulinemia and β-cell mass. Current models consider representative (fasting or daily average) glycemia and insulinemia as characterizing the compensation state of the subject at some instant in slow time. This implies that only these representative levels can be followed through time and that the role of fast glycemic oscillations is neglected. An improved model (DPM15) for the long-term progression of T2DM is proposed, introducing separate peripheral and hepatic (liver and kidney) insulin actions. The DPM15 model no longer uses near-equilibrium approximation to separate fast and slow time scales, but rather describes, at each step in slow time, a complete day in the life of the virtual subject in fast time. The model can thus represent both fasting and postprandial glycemic levels and describe the effect of interventions acting on insulin-enhanced tissue glucose disposal or on insulin-inhibited hepatic glucose output, as well as on insulin secretion and β-cell replicating ability. The model can simulate long-term variations of commonly used clinical indices (HOMA-B, HOMA-IR, insulinogenic index) as well as of Oral Glucose Tolerance or Euglycemic Hyperinsulinemic Clamp test results. The model has been calibrated against observational data from the Diabetes Prevention Program study: it shows good adaptation to observations as a function of very plausible values of the parameters describing the effect of such interventions as Placebo, Intensive LifeStyle and Metformin administration. [ABSTRACT FROM AUTHOR]

Background: Physical inactivity is high within the Qatari population, particularly within females, and school-based environments, contributing to increased morbidity and mortality. School-based physical activity (PA) outcomes may be mediated by physical self-concept. Low physical self-concept may negatively impact PA engagement, compromising childhood and adolescent physical fitness, which may translate into adulthood. Normative physical fitness data for the Qatari population is unavailable. Stratifying normative physical fitness appears prudent, to not only allow comparisons to be made worldwide, but enable informed decisions for public health policy and future interventions in the Qatari population. Purpose: To establish the physical fitness of young adults in Qatar, and examine differences between males and females for physical self-concept, and engagement in school-based and extra-curricular PA. Method: 186 (females n = 85) healthy participants [median (minimum—maximum) age: males = 21 (18–26), females = 21 (18–24) y; height: males = 1.74 (1.57–1.99), females = 1.61 (1.46–1.76) m; body mass: males = 71.9 (49.3–145.0), females = 56.8 (35.7–96.4) kg] completed the ALPHA-FIT test battery for adults (one leg stand, figure of eight run, handgrip strength, jump and reach, modified push-up, dynamic sit-up and 2 km walk), physical self-description questionnaire (measuring physical self-concept), and were asked to answer 'yes' or 'no' to whether they participated in school-based and extra-curricular PA. Results: Data is reported as effect size; ±90% confidence limit. Males compared to females most likely performed better for dynamic sit-up (2.2; ±0.76), very likely better for the figure of eight run (0.86; ±0.42) and likely better for handgrip strength (2.1; ±0.75). Males likely had higher physical self-concept for coordination (0.78; ±0.37) and endurance (0.66; ±0.27) compared to females. There were no differences for school-based PA (p ≥ 0.78) or for extra-curricular PA for males (p ≥ 0.26) or females (p ≥ 0.21). Conclusion: The data suggests that the young Qatari adult population has variable, yet generally low, physical fitness traits compared to individuals worldwide, likely due to their low PA. The precise aetiology for this is not well documented, yet such data may be prudent to evidence-inform strategies to improve physical fitness through increased PA (synergistic relationship), given the strong association between physical activity/fitness and morbidity/mortality. [ABSTRACT FROM AUTHOR]

The problem of handling non-ignorable non-response has been typically addressed under the design-based approach using the well-known sub-sampling technique introduced by Hansen and Hurwitz [1946, Journal of the American Statistical Association, Vol 41(236), Page 517- 529]. Alternatively, the model-based paradigm emphasizes on utilizing the underlying model relationship between the outcome variable and one or more covariate(s) whose population values are known prior to the survey. This article utilizes the model relationship between the study variable and covariate(s) for handling non-ignorable non-response and obtaining an unbiased estimator for the population total under the sub-sampling technique. The main idea is to combine the estimates obtained from the sample on first call and the sub-sample from second call using separate model relationships. The contribution of this paper helps us in providing unbiased estimates with an improved efficiency under model-based paradigm in presence of non-ignorable non-response. The provided method is more economical than the available estimators under callback methods as we are working sub-sampling and also increase response rate as a stronger mode of interview is employed for data collection. A numerical study using Monte Carlo is presented to illustrate the behavior of the proposed and the efficiency comparison. [ABSTRACT FROM AUTHOR]

The prefrontal cortex is central to higher order cognitive function. However, the cerebellum, generally thought to be involved in motor control and learning, has also been implicated in higher order cognition. Recent work using transcranial direct current stimulation (tDCS) provides some support for right cerebellar involvement in higher order cognition, though the results are mixed, and often contradictory. Here, we used cathodal high definition tDCS (HD-tDCS) over the right cerebellum to assess the impact of HD-tDCS on modulating cognitive performance. We predicted that stimulation would result in performance decreases, which would suggest that optimal cerebellar function is necessary for cognitive performance, much like the prefrontal cortex. That is, it is not simply a structure that lends support to complete difficult tasks. While the expected cognitive behavioral effects were present, we did not find effects of stimulation. This has broad implications for cerebellar tDCS research, particularly for those who are interested in using HD-tDCS as a way of examining cerebellar function. Further implications, limitations, and future directions are discussed with particular emphasis on why null findings might be critical in developing a clear picture of the effects of tDCS on the cerebellum. [ABSTRACT FROM AUTHOR]

Hypoxia and angiogenesis are critical components in the progression of solid cancer, including gastric cancers (GCs). miR-382 has been identified as a hypoxia-induced miR (hypoxamiR), but the clinical significance in GCs has not been identified yet. To explore the clinical and prognostic importance of miR-382 in GCs, the surgical specimens of 398 patients with GCs in KNU hospital in Korea, the total of 183 patients was randomly selected using simple sampling methods and big data with 446 GCs and 45 normal tissues from the data portal () were analysed. Expression of miR-382 as well as miR-210, as a positive control hypoxamiR by qRT-PCR in histologically malignant region of GCs showed significantly positive correlation (R = 0.516, p<0.001). High miR-210 and miR-382 expression was significantly correlated with unfavorable prognosis including advanced GCs (AGC), higher T category, N category, pathologic TNM stage, lymphovascular invasion, venous invasion, and perinueral invasion, respectively (all p<0.05). In univariate analysis, high miR-210 expression was significantly associated with worse overall survival (OS) (p = 0.036) but not high miR-382. In paired 60 gastric normal and cancer tissues, miR-382 expression in cancer tissues was significantly higher than normal counterpart (p = 0.003), but not miR-210 expression. However, by increasing the patient number from the big data analysis, miR-210 as well as miR-382 expression in tumor tissues was significantly higher than the normal tissues. Our results suggest that miR-382, as novel hypoxamiR, can be a prognostic marker for advanced GCs and might be correlated with metastatic potential. miR-382 might play important roles in the aggressiveness, progression and prognosis of GCs. In addition, miR-382 give a predictive marker for progression of GCs compared to the normal or preneoplastic lesion. [ABSTRACT FROM AUTHOR]

Streptococcus suis is an important porcine bacterial pathogen and a zoonotic agent responsible for sudden death, septic shock and meningitis, of which serotype 2 is the most widespread, with serotype 14 also causing infections in humans in South-East Asia. Knowledge of its pathogenesis and virulence are almost exclusively based on these two serotypes. Though serotype 9 is responsible for the greatest number of porcine cases in Spain, the Netherlands and Germany, very little information is currently available regarding this serotype. Of the different virulence factors, the capsular polysaccharide (CPS) is required for S. suis virulence as it promotes resistance to phagocytosis and killing and masks surface components responsible for host cell activation. However, these roles have been described for serotypes 2 and 14, whose CPSs are structurally and compositionally similar, both containing sialic acid. Consequently, we evaluated herein the interactions of serotype 9 with host cells and the role of its CPS, which greatly differs from those of serotypes 2 and 14. Results demonstrated that serotype 9 adhesion to but not invasion of respiratory epithelial cells was greater than that of serotypes 2 and 14. Furthermore serotype 9 was more internalized by macrophages but equally resistant to whole blood killing. Though recognition of serotypes 2, 9 and 14 by DCs required MyD88-dependent signaling, in vitro pro-inflammatory mediator production induced by serotype 9 was much lower. In vivo, however, serotype 9 causes an exacerbated inflammatory response, which combined with persistent bacterial presence, is probably responsible for host death during the systemic infection. Though presence of the serotype 9 CPS masks surface components less efficiently than those of serotypes 2 and 14, the serotype 9 CPS remains critical for virulence as it is required for survival in blood and development of clinical disease, and this regardless of its unique composition and structure. [ABSTRACT FROM AUTHOR]

Cell-free DNA (cfDNA) in the human blood circulation has been under investigation since its initial observation in 1948. Plasma cfDNA is known to be significantly elevated in diseased people. Due to possible variation in the population, evaluating cfDNA as a non-invasive biomarker at disease onset alone may not be sensitive enough to accurately diagnose diseases, particularly early stage cancers on a personal level. To understand the factors that define the cfDNA levels on the personal level and for better use as a non-invasive biomarker, we isolated cfDNA from the plasma of healthy individuals with varying degrees of genetic and/or environmental similarities (monozygotic twins, dizygotic twins, sibling pairs, and unrelated individuals) as well as from patients with varying stages of breast and ovarian cancer undergoing treatment. Cell-free DNA levels were quantified by a fluorometer (ng/ml) and/or real-time PCR (copies/ml). The associations between individuals with various degrees of genetic and/or environmental similarities and their plasma cfDNA levels were evaluated. The ACE model (A = additive genetic, C = common environment, and E = specific environmental factors) was used to determine the proportion of each factor on the cfDNA levels. We found a high correlation (r = 0.77; p < 0.0001) in plasma cfDNA levels between monozygotic twins (n = 39). However, the correlation was gradually reduced to moderate (r = 0.47; p = 0.016) between dizygotic twins (n = 13) and low correlation (r = 0.28; p = 0.043) between sibling pairs (n = 26). The ACE model analysis showed that the plasma cfDNA level of a given healthy individual is influenced both by genetic and the environmental components in similar proportions (53% and 47%, respectively; A = 53%, C = 22.5%, E = 24.5%). Moreover, while age had no effect, gender significantly influenced the individual's plasma cfDNA level. As expected, cfDNA levels were significantly higher in both breast (n = 26) (p<0.0001) and ovarian (n = 64) (p<0.0001) cancer patients compared to the healthy individuals. Our study demonstrated that both genome and environmental factors modulate the individual's cfDNA level suggesting that its diagnostic sensitivity may be improved only if the person's cfDNA level is known prior to disease presentation. [ABSTRACT FROM AUTHOR]

Activated platelets release adenosine trisphosphate (ATP) and bioluminescence analysis of ATP release is usually used to monitor activation of platelets induced by various stimulants. However, bioluminescence analysis of ATP possesses poor linearity, the signal is quickly attenuated, and the accuracy of ATP release from platelets is hard to determine accurately enough to be used in a high throughput screening of platelet inhibitors. The present study was designed to optimize bioluminescence analysis of ATP released by platelets and expand its application in high throughput screening of platelet inhibitors. The results showed that accuracy of ATP analysis was significantly improved by adding coenzyme A (CoA) and signal attenuation of ATP analysis was greatly postponed by adding bovine serum albumin (BSA) both in Hank's balanced salt solution (HBSS) and Tyrode's buffer. Furthermore, ATP release of activated platelets and inhibitory effects of Ly294002 and Staurosporine on platelet activation were accurately determined by our optimized bioluminescence analysis of ATP. Thus, we have successfully constructed an optimized bioluminescence analysis of ATP which can be used in high throughput screening of platelet inhibitors. [ABSTRACT FROM AUTHOR]

Peripheral Blood gene expression is widely used in the discovery of biomarkers and development of therapeutics. Recently, a spate of commercial blood collection and preservation systems have been introduced with proprietary variations that may differentially impact the transcriptomic profiles. Comparative analysis of these collection platforms will help optimize protocols to detect, identify, and reproducibly validate true biological variance among subjects. In the current study, we tested two recently introduced whole blood collection methods, RNAgard® and PAXgene® RNA, in addition to the traditional method of peripheral blood mononuclear cells (PBMCs) separated from whole blood and preserved in Trizol reagent. Study results revealed striking differences in the transcriptomic profiles from the three different methods that imply ex vivo changes in gene expression occurred during the blood collection, preservation, and mRNA extraction processes. When comparing the ability of the three preservation methods to accurately capture individuals' expression differences, RNAgard® outperformed PAXgene® RNA, and both showed better individual separation of transcriptomic profiles than PBMCs. Hence, our study recommends using a single blood collection platform, and strongly cautions against combining methods during the course of a defined study. [ABSTRACT FROM AUTHOR]

Malignant gliomas remain incurable with a poor prognosis despite of aggressive treatment. We have been studying the development of brain tumors in a glioma rat model, where rats develop brain tumors after prenatal exposure to ethylnitrosourea (ENU), and there is a sizable interval between when the first pathological changes are noted and tumors become detectable with MRI. Our aim to define a molecular timeline through proteomic profiling of the cerebrospinal fluid (CSF) such that brain tumor commitment can be revealed earlier than at the presymptomatic stage. A comparative proteomic approach was applied to profile CSF collected serially either before, at and after the time MRI becomes positive. Elastic net (EN) based models were developed to infer the timeline of normal or tumor development respectively, mirroring a chronology of precisely timed, "clocked", adaptations. These CSF changes were later quantified by longitudinal entropy analyses of the EN predictive metric. False discovery rates (FDR) were computed to control the expected proportion of the EN models that are due to multiple hypothesis testing. Our ENU rat brain tumor dating EN model indicated that protein content in CSF is programmed even before tumor MRI detection. The findings of the precisely timed CSF tumor microenvironment changes at presymptomatic stages, deviation from the normal development timeline, may provide the groundwork for the understanding of adaptation of the brain environment in tumorigenesis to devise effective brain tumor management strategies. [ABSTRACT FROM AUTHOR]

Breastfeeding has a wide range of benefits for both infants and mothers. The identification of factors associated with exclusive breastfeeding (EBF) are important to increase the prevalence of EBF. The study aimed to determine the prevalence of EBF within the first six months and its associated factors in Kaiyuan, Yunnan Province, Southwest China. This cross-sectional study was conducted in Kaiyuan, a middle-sized city of Yunnan Province, Southwest China. Mothers of infants under twelve months were randomly selected for a face to face interview in four towns (two in urban areas and two in rural areas) in Kaiyuan. A structured questionnaire was applied for collection of sociodemographic information, mothers’ and infants’ health, and breastfeeding information. A 24-hour food recall survey was used to collect infant feeding information. A logistic regression analysis was performed to identify the factors independently associated with exclusive breastfeeding for infants up to six months of age. The number of 417 mothers with infants under six months was interviewed. The prevalence of EBF at six months was 27.34%. Logistic regression indicated that EBF within six months was more likely to be practiced by mothers who had higher average household income per year (OR = 2.09, 95% CI: 1.05–4.17 p = 0.037; OR = 1.85, 95% CI: 1.04–3.28 p = 0.037), and mothers who received breastfeeding information (OR = 2.46, (95%CI: 1.45–4.18, p = 0.0009). The prevalence of EBF in Kaiyuan, Southwest China is considerably lower than national and international recommendations. Yearly household income, and mothers who received breastfeeding information are associated with higher EBF prevalence. Breastfeeding information should be given to mothers in order to increase the prevalence of EBF. [ABSTRACT FROM AUTHOR]

Objectives: Aging is associated with low muscle mass and has been linked to adverse health outcomes. The objectives of this cross-sectional study were: (1) to describe anthropometry, body composition, appendicular skeletal muscle mass index (ASMI; appendicular skeletal muscle mass/height2), and prevalence of low ASMI in older people with normal nutritional status (Malnutrition Universal Screening Tool score = 0); (2) to determine factors associated with ASMI, and odds ratios of having low ASMI. Methods: SHIELD is a study of community-dwelling older people aged 65 years and above in Singapore. ASMI was determined using bioelectrical impedance analysis and low ASMI was defined as <7.0 kg/m2 for males and <5.7 kg/m2 for females (Asian Working Group for Sarcopenia, 2014). Results: A total of 400 older people (183 males and 217 females) took part in this study. The overall prevalence of low ASMI was 20.6% (15.5% in males and 24.9% in females). Females had significantly lower ASMI than males (P < 0.0001), age was inversely associated with ASMI (P = 0.0024) while BMI and calf circumference were positively associated with ASMI (both P < 0.0001) in the total cohort. In addition, ASMI was positively associated with bone mass in both genders (both P < 0.0001). After adjusting for covariates, the odds ratios of having low ASMI with every 1 year and 10 years increase in age were 1.13 (95% CI: 1.06, 1.20) and 3.36 (95% CI: 1.82, 6.21) respectively. Conclusions: The high prevalence of low ASMI in community-dwelling older people with normal nutritional status highlights the need for early screening. There was a strong inverse association between age and ASMI while BMI, calf circumference and bone mass were positively associated with ASMI. These findings will give further weight to the importance and development of public health strategies in maintaining and improving muscle health in this population group. [ABSTRACT FROM AUTHOR]

Sepsis can be caused by malaria infection, but little is known about the utility of the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) and SOFA score in malaria. We conducted a prospective observational study from March 2013 to February 2017 to examine adults admitted with community-acquired infection in a tertiary-care hospital in Ubon Ratchathani, Northeast Thailand (Ubon-sepsis). Subjects were classified as having sepsis if they had a modified SOFA score ≥2 within 24 hours of admission. Serum was stored and later tested for malaria parasites using a nested PCR assay. Presence of severe malaria was defined using modified World Health Organization criteria. Of 4,989 patients enrolled, 153 patients (3%) were PCR positive for either Plasmodium falciparum (74 [48%]), P. vivax (69 [45%]), or both organisms (10 [7%]). Of 153 malaria patients, 80 were severe malaria patients presenting with sepsis, 70 were non-severe malaria patients presenting with sepsis, and three were non-severe malaria patients presenting without sepsis. The modified SOFA score (median 5; IQR 4–6; range 1–18) was strongly correlated with malaria severity determined by the number of World Health Organization severity criteria satisfied by the patient (Spearman’s rho = 0.61, p<0.001). Of 80 severe malaria patients, 2 (2.5%), 11 (14%), 62 (77.5%) and 5 (6%), presented with qSOFA scores of 0, 1, 2 and 3, respectively. Twenty eight-day mortality was 1.3% (2/153). In conclusion, qSOFA and SOFA can serve as markers of disease severity in adults with malarial sepsis. Patients presenting with a qSOFA score of 1 may also require careful evaluation for sepsis; including diagnosis of cause of infection, initiation of medical intervention, and consideration for referral as appropriate. [ABSTRACT FROM AUTHOR]

Background: Postural orthostatic tachycardia syndrome is a disorder of the autonomic nervous system. Approximately 30% of patients experience orthostatic headaches. Orthostatic headaches also are a hallmark symptom in spontaneous intracranial hypotension. While the cause of orthostatic headaches in spontaneous intracranial hypotension can be linked to the cerebrospinal fluid loss at the spinal level and consecutively reduced intracranial pressure in the upright position, the cause of orthostatic headaches in postural orthostatic tachycardia syndrome still remains unknown. The present study examined orthostatic changes of intracranial pressure using dynamic ultrasound of the optic nerve and optic nerve sheath diameter in postural orthostatic tachycardia syndrome, spontaneous intracranial hypotension and healthy subjects. Methods: Data was obtained from postural orthostatic tachycardia syndrome patients with (n = 7) and without orthostatic headaches (n = 7), spontaneous intracranial hypotension patients (n = 5) and healthy subjects (n = 8). All participants underwent high-resolution transorbital ultrasound in the supine and upright position to assess optic nerve and optic nerve sheath diameter. Results: Group differences were found in percentage deviations when changing position of optic nerve sheath diameter (p < 0.01), but not regarding the optic nerve diameter. Pairwise comparisons indicated differences in optic nerve sheath diameter only between spontaneous intracranial hypotension and the other groups. No differences were found between postural orthostatic tachycardia syndrome patients with and without orthostatic headaches. Conclusion: This study shows that the size of the optic nerve sheath diameter dynamically decreases during orthostatic stress in spontaneous intracranial hypotension, but not in postural orthostatic tachycardia syndrome with or without orthostatic headaches, which indicates different underlying causes. [ABSTRACT FROM AUTHOR]

Background: Understanding the cardiorespiratory factors related to the increase in oxygen consumption () during exercise is essential for improving cardiorespiratory fitness in individuals with stroke. However, cardiorespiratory factors related to the increase in during exercise in these individuals have not been examined using multivariate analysis. This study aimed to identify cardiorespiratory factors related to the increase in during a graded exercise in terms of respiratory function, cardiac function, and the ability of skeletal muscles to extract oxygen. Methods: Eighteen individuals with stroke (aged 60.1 ± 9.4 years, 67.1 ± 30.8 days poststroke) underwent a graded exercise test for the assessment of cardiorespiratory response to exercise. The increases in from rest to first threshold and that from rest to peak exercise were measured as a dependent variable. The increases in respiratory rate, tidal volume, minute ventilation, heart rate, stroke volume, cardiac output, and arterial-venous oxygen difference from rest to first threshold and those from rest to peak exercise were measured as the independent variables. Results: From rest to first threshold, the increases in arterial-venous oxygen difference (β = 0.711) and cardiac output (β = 0.572) were significant independent variables for the increase in (adjusted R2 = 0.877 p < 0.001). Similarly, from rest to peak exercise, the increases in arterial-venous oxygen difference (β = 0.665) and cardiac output (β = 0.636) were significant factors related to the increase in (adjusted R2 = 0.923, p < 0.001). Conclusion: Our results suggest that the ability of skeletal muscle to extract oxygen is a major cardiorespiratory factor related to the increase in during exercise testing in individuals with stroke. For improved cardiorespiratory fitness in individuals with stroke, the amount of functional muscle mass during exercise may need to be increased. [ABSTRACT FROM AUTHOR]

Gastric emptying (GE) can be either delayed or accelerated in diabetes mellitus (DM). However, most research has focused on delayed GE mediated by a chronic hyperglycemic condition in DM. As such, the function of GE in the early stages of DM is not well understood. Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract. In the present study, we investigated changes in GE and ICC networks in the early stages of DM using a streptozotocin-induced type 1 diabetic mouse model. The changes in GE were measured by the 13C-octanoic acid breath test. ICC networks were immunohistochemically detected by an antibody for c-Kit, a specific marker for ICC. Our results showed that GE in type 1 DM was significantly accelerated in the early stages of DM (2–4 weeks after onset). In addition, acute normalization of blood glucose levels by a single administration of insulin did not recover normal GE. ICC networks of the gastric antrum were significantly increased in DM and were not affected by the acute normalization of blood glucose. In conclusion, our results suggest that GE is accelerated in the early stages of DM, and it is associated with increased ICC networks. This mechanism may help to clarify a link between the onset of DM and GE disorders. [ABSTRACT FROM AUTHOR]

Purpose: To investigate if there are differences in macular capillaries between black and white subjects using optical coherence tomography angiography (OCTA) and identify potential factors underlying the epidemiologically-based higher vulnerability of black populations to diabetic retinopathy (DR). Methods: This prospective, observational cross-sectional study included 93 eyes of 47 healthy subjects with no medical history and ocular history who self-identified as black or white and were matched for age, sex, refractive error, and image quality. Subjects underwent OCTA imaging (RTVue-XR Avanti) of the superficial (SCP) and deep (DCP) capillary plexuses and choriocapillaris. AngioAnalytics was used to analyze vessel density (VD) and choriocapillaris % blood flow area (BFA) in the 1mm-diameter fovea, parafovea, and 3mm-diameter circular area including the fovea and parafovea (3x3mm image). Foveal avascular zone (FAZ) was also analyzed. Linear mixed models were used to evaluate for differences between the study groups. Results: Compared to the white subjects in this study, black subjects were found to have: lower foveal VD in the SCP (p<0.05); lower VD in the parafovea and in the 3x3mm image in the DCP (p<0.05); larger FAZ in SCP and DCP (p<0.05); and decreased choriocapillary BFA in the area underlying the fovea, parafovea, and 3x3mm image (p<0.05). Conclusion: In our study, our black subjects had decreased macular capillary vasculature compared to matched white subjects, even in early adulthood and the absence of any systemic or ocular conditions. To our knowledge, this is the first report showing that retinal and choriocapillary vascular differences may contribute to racial disparities in vulnerability to DR. [ABSTRACT FROM AUTHOR]

Reversal reactions (RRs) in leprosy are characterized by a reduction in the number of bacilli in lesions associated with an increase in cell-mediated immunity against the intracellular bacterium Mycobacterium leprae, the causative pathogen of leprosy. To identify the mechanisms that contribute to cell-mediated immunity in leprosy, we measured changes in the whole blood-derived transcriptome of patients with leprosy before, during and after RR. We identified an 'RR signature' of 1017 genes that were upregulated at the time of the clinical diagnosis of RR. Using weighted gene correlated network analysis (WGCNA), we detected a module of 794 genes, bisque4, that was significantly correlated with RR, of which 434 genes were part of the RR signature. An enrichment for both IFN-γ and IFN-β downstream gene pathways was present in the RR signature as well as the RR upregulated genes in the bisque4 module, including those encoding proteins of the guanylate binding protein (GBP) family that contributes to antimicrobial responses against mycobacteria. Specifically, GBP1, GBP2, GBP3 and GBP5 mRNAs were upregulated in the RR peripheral blood transcriptome, with GBP1, GBP2 and GBP5 mRNAs also upregulated in the RR disease lesion transcriptome. These data indicate that RRs involve a systemic upregulation of IFN-γ downstream genes including GBP family members as part of the host antimicrobial response against mycobacteria. [ABSTRACT FROM AUTHOR]

Background: Triatoma brasiliensis, a triatomine-bug vector of Chagas disease, evolved in the semiarid Caatinga, where it occupies rocky outcrops, shrubby cacti, and human dwellings. Dwellings and rocks are considered high-quality microhabitats for this saxicolous species, whereas cacti probably represent secondary, lower-quality microhabitats. This 'microhabitat-quality hierarchy' hypothesis predicts that T. brasiliensis populations occupying dwellings or rocks should endure harsh environmental conditions better than their cactus-living relatives. Methods/Findings: We tested this prediction by comparing T. brasiliensis infestation (proportion of microhabitats with bugs), density (bugs per microhabitat), and crowding (bugs per infested microhabitat) in dwellings, rocks, and cacti sampled before and during the extreme drought that ravaged the Caatinga in 2012–2016. We used random-intercepts generalized linear mixed models to account for microhabitat spatial clustering and for variations in bug-catch effort; we assessed model performance and computed model-averaged effect estimates using Akaike's information criterion. Pre-drought infestation was similar across microhabitat types; during the drought, infestation remained stable in dwellings and rocks but dropped in cacti. Pre-drought bug density declined from dwellings to rocks to cacti; an additional decline associated with the drought was largely comparable across microhabitats, albeit perhaps somewhat larger in cacti. Finally, pre-drought bug crowding was higher in dwellings than in rocks or cacti and changed little during the drought–possibly with a downward trend in dwellings and an upward trend in cacti. Conclusions: Triatoma brasiliensis populations fared better in dwellings and rocks than in cacti during extreme drought. Estimates of microhabitat and drought effects on infestation, density, and crowding suggest that only a few cacti (versus many rocks and dwellings) represent good-quality habitat under such extremely harsh conditions. Our findings provide empirical support to the microhabitat-quality hierarchy hypothesis, and imply that T. brasiliensis can endure extreme climate by exploiting high-quality microhabitats, whether wild or man-made, in the semiarid Caatinga. [ABSTRACT FROM AUTHOR]

The study of protein N-glycosylation is essential in biological and biopharmaceutical research as N-glycans have been reported to regulate a wide range of physiological and pathological processes. Monitoring glycosylation in diagnosis, prognosis, as well as biopharmaceutical development and quality control are important research areas. A number of techniques for the analysis of protein N-glycosylation are currently available. Here we examine three methodologies routinely used for the release of N-glycans, in the effort to establish and standardize glycoproteomics technologies for quantitative glycan analysis from cultured cell lines. N-glycans from human gamma immunoglobulins (IgG), plasma and a pool of four cancer cell lines were released following three approaches and the performance of each method was evaluated. [ABSTRACT FROM AUTHOR]

Two novel and related pathogenic variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene were structurally and functionally characterized. These alterations have not been previously described in literature. Two patients with diagnosis of Cystic Fibrosis (CF) based on the presence of one mutated allele, p.Phe508del, pathological sweat test and clinical symptoms were studied. To complete the genotypes of both patients, an extensive genetic and functional analysis of the CFTR gene was performed. Extensive genetic characterization confirmed the presence of p.Phe508del pathogenic variant and revealed, in both patients, the presence of an insertion of part of intron 10 in intron 9 of the CFTR gene, within the (TG)m repeat, with a variable poly-T stretch. The molecular lesions resulted to be very similar in both patients, with only a difference in the number of T in the poly-T stretch. The functional characterization at RNA level revealed a complete anomalous splicing, without exon 10, from the allele with the insertion of both patients. Consequently, the alleles with the insertions are expected not to contribute to the formation of a functional CFTR protein. Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene. This also allowed the completion of the genetic characterization of both patients. [ABSTRACT FROM AUTHOR]

Purpose: Decreasing the risk of catheter related bloodstream infections (CRBSIs) remains a key focus for improving outcomes and reducing cost of care for hemodialysis (HD) patients. Recent studies demonstrate CRBSI rates can be improved by managing bacterial colonization at the catheter exit site. Herein we present the results of a study documenting the clinical performance of the NexSite HD catheter, a new tunneled central venous catheter which incorporates Exit Site Management (ESM) technology. Methods: We conducted an observational study using a prospective, multi-center registry of HD patients implanted with the NexSite HD catheter. The primary endpoint for the study was CRBSI rate for a period up to 180-days following catheter placement. Secondary endpoints included device placement success rate, exit site healing, development of an exit site or tunnel infection, and early or late non-infectious catheter-related complications. All reasons for early non-elective catheter removal were recorded. Results: A total of 115 HD patients at 6 sites were included in the final analysis. Cumulative catheter use was 10,924 days with a mean duration of 95 days. Seven patients experienced CRBSIs during the study period resulting in a CRBSI rate of 0.64 per 1,000 catheter-days. Seventy-four patients (64.3%) had either elective catheter removal (n = 56) or utilized the catheter for the entire 180-day observation period (n = 18). Thirty-five patients (30%) underwent non-elective device removal either due to CRBSI (n = 5), low flow (n = 16), exit site issues (n = 7), or for other causes (n = 7). Six patients died during the observation period with 1 death due to CRBSI-associated complications and the remaining 5 deaths attributed to non-device related causes. Conclusion: Our findings demonstrate that the NexSite HD catheter equipped with ESM technology can achieve a CRBSI rate in compliance with the NKF KDOQI (National Kidney Foundation Kidney Disease Outcome Quality Initiatives) Clinical Performance Guidelines stated goal of less than 1.0/1,000 catheter-days when used in hemodialysis patients using current standard of care nursing protocols. [ABSTRACT FROM AUTHOR]

To understand the effect of attention on neuronal dynamics, we propose a multi-module network, with each module consisting of fully interconnected groups of excitatory and inhibitory neurons. This network shows transitive dynamics among quasi-attractors as its typical dynamics. When the release of acetylcholine onto the network is simulated by attention, the transitive dynamics change into stable dynamics in which the system converges to an attractor. We found that this network can reproduce three experimentally observed properties of attention-dependent response modulation, namely an increase in the firing rate, a decrease in the Fano factor of the firing rate, and a decrease in the correlation coefficients between the firing rates of pairs of neurons. Moreover, we also showed theoretically that the release of acetylcholine increases the sensitivity to bottom-up inputs by changing the response function. [ABSTRACT FROM AUTHOR]

Extrusion of xenobiotics is essential for allowing animals to remove toxic substances present in their diet or generated as a biproduct of their metabolism. By transporting a wide range of potentially noxious substrates, active transporters of the ABC transporter family play an important role in xenobiotic extrusion. One such class of transporters are the multidrug resistance P-glycoprotein transporters. Here, we investigated P-glycoprotein transport in the Malpighian tubules of the desert locust (Schistocerca gregaria), a species whose diet includes plants that contain toxic secondary metabolites. To this end, we studied transporter physiology using a modified Ramsay assay in which ex vivo Malpighian tubules are incubated in different solutions containing the P-glycoprotein substrate dye rhodamine B in combination with different concentrations of the P-glycoprotein inhibitor verapamil. To determine the quantity of the P-glycoprotein substrate extruded we developed a simple and cheap method as an alternative to liquid chromatography–mass spectrometry, radiolabelled alkaloids or confocal microscopy. Our evidence shows that: (i) the Malpighian tubules contain a P-glycoprotein; (ii) tubule surface area is positively correlated with the tubule fluid secretion rate; and (iii) as the fluid secretion rate increases so too does the net extrusion of rhodamine B. We were able to quantify precisely the relationships between the fluid secretion, surface area, and net extrusion. We interpret these results in the context of the life history and foraging ecology of desert locusts. We argue that P-glycoproteins contribute to the removal of xenobiotic substances from the haemolymph, thereby enabling gregarious desert locusts to maintain toxicity through the ingestion of toxic plants without suffering the deleterious effects themselves. [ABSTRACT FROM AUTHOR]

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart’s electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction. [ABSTRACT FROM AUTHOR]

The bipartite transcription factor β-catenin (β-cat)/T cell factor (TCF), formed by free β-cat and a given TCF family member, serves as the effector of the developmental Wnt signaling cascade. β-cat/TCFs also serve as effectors of certain peptide hormones or growth factors during adulthood. We reported that liver-specific expression of dominant-negative Transcription factor 7 like 2 (TCF7L2DN) led to impaired glucose disposal. Here we show that, in this LTCFDN transgenic mouse model, serum and hepatic lipid contents were elevated in male but not in female mice. In hepatocytes, TCF7L2DN adenovirus infection led to stimulated expression of genes that encode lipogenic transcription factors and lipogenic enzymes, while estradiol (E2) treatment attenuated the stimulation, associated with Wnt-target gene activation. Mechanistically, this E2-mediated activation can be attributed to elevated β-cat Ser675 phosphorylation and TCF expression. In wild-type female mice, ovariectomy (OVX) plus high-fat diet (HFD) challenge impaired glucose disposal and insulin tolerance, associated with increased hepatic lipogenic transcription factor sterol regulatory element-binding protein 1-c (SREBP-1c) expression. In wild-type mice with OVX, E2 reconstitution attenuated HFD-induced metabolic defects. Some of the attenuation effects, including insulin intolerance, elevated liver-weight gain, and hepatic SREBP-1c expression, were not affected by E2 reconstitution in HFD-fed LTCFDN mice with OVX. Finally, the effects of E2 in hepatocytes on β-cat/TCF activation can be attenuated by the G-protein-coupled estrogen receptor (GPER) antagonist G15. Our study thus expanded the scope of functions of the Wnt pathway effector β-cat/TCF, as it can also mediate hepatic functions of E2 during adulthood. This study also enriches our mechanistic understanding of gender differences in the risk and pathophysiology of metabolic diseases. [ABSTRACT FROM AUTHOR]

The case-fatality rate of yellow fever virus (YFV) is one of the highest among arthropod-borne viruses (arboviruses). Although historically, the Asia-Pacific region has remained free of YFV, the risk of introduction has never been higher due to the increasing influx of people from endemic regions and the recent outbreaks in Africa and South America. Singapore is a global hub for trade and tourism and therefore at high risk for YFV introduction. Effective control of the main domestic mosquito vector Aedes aegypti in Singapore has failed to prevent re-emergence of dengue, chikungunya and Zika viruses in the last two decades, raising suspicions that peridomestic mosquito species untargeted by domestic vector control measures may contribute to arbovirus transmission. Here, we provide empirical evidence that the peridomestic mosquito Aedes malayensis found in Singapore can transmit YFV. Our laboratory mosquito colony recently derived from wild Ae. malayensis in Singapore was experimentally competent for YFV to a similar level as Ae. aegypti controls. In addition, we captured Ae. malayensis females in one human-baited trap during three days of collection, providing preliminary evidence that host-vector contact may occur in field conditions. Finally, we detected Ae. malayensis eggs in traps deployed in high-rise building areas of Singapore. We conclude that Ae. malayensis is a competent vector of YFV and re-emphasize that vector control methods should be extended to target peridomestic vector species. [ABSTRACT FROM AUTHOR]

Deficits in the ankle plantarflexor muscles, such as weakness and contracture, occur commonly in conditions such as cerebral palsy, stroke, muscular dystrophy, Charcot-Marie-Tooth disease, and sarcopenia. While these deficits likely contribute to observed gait pathologies, determining cause-effect relationships is difficult due to the often co-occurring biomechanical and neural deficits. To elucidate the effects of weakness and contracture, we systematically introduced isolated deficits into a musculoskeletal model and generated simulations of walking to predict gait adaptations due to these deficits. We trained a planar model containing 9 degrees of freedom and 18 musculotendon actuators to walk using a custom optimization framework through which we imposed simple objectives, such as minimizing cost of transport while avoiding falling and injury, and maintaining head stability. We first generated gaits at prescribed speeds between 0.50 m/s and 2.00 m/s that reproduced experimentally observed kinematic, kinetic, and metabolic trends for walking. We then generated a gait at self-selected walking speed; quantitative comparisons between our simulation and experimental data for joint angles, joint moments, and ground reaction forces showed root-mean-squared errors of less than 1.6 standard deviations and normalized cross-correlations above 0.8 except for knee joint moment trajectories. Finally, we applied mild, moderate, and severe levels of muscle weakness or contracture to either the soleus (SOL) or gastrocnemius (GAS) or both of these major plantarflexors (PF) and retrained the model to walk at a self-selected speed. The model was robust to all deficits, finding a stable gait in all cases. Severe PF weakness caused the model to adopt a slower, "heel-walking" gait. Severe contracture of only SOL or both PF yielded similar results: the model adopted a "toe-walking" gait with excessive hip and knee flexion during stance. These results highlight how plantarflexor weakness and contracture may contribute to observed gait patterns. [ABSTRACT FROM AUTHOR]

Message passing between components of a distributed physical system is non-instantaneous and contributes to determine the time scales of the emerging collective dynamics. In biological neuron networks this is due in part to local synaptic filtering of exchanged spikes, and in part to the distribution of the axonal transmission delays. How differently these two kinds of communication protocols affect the network dynamics is still an open issue due to the difficulties in dealing with the non-Markovian nature of synaptic transmission. Here, we develop a mean-field dimensional reduction yielding to an effective Markovian dynamics of the population density of the neuronal membrane potential, valid under the hypothesis of small fluctuations of the synaptic current. Within this limit, the resulting theory allows us to prove the formal equivalence between the two transmission mechanisms, holding for any synaptic time scale, integrate-and-fire neuron model, spike emission regimes and for different network states even when the neuron number is finite. The equivalence holds even for larger fluctuations of the synaptic input, if white noise currents are incorporated to model other possible biological features such as ionic channel stochasticity. [ABSTRACT FROM AUTHOR]

Background: This study investigated the incidence and predictors of retreatment after discontinuation of either entecavir (ETV) or tenofovir disoproxil fumarate (TDF) treatment in Taiwan. Methods: A total of 535 non-cirrhotic chronic hepatitis B (CHB) patients undergoing either ETV (n = 358) or TDF (n = 177) treatment were enrolled. Patients were followed for at least 12 months after stopping ETV or TDF treatment. Most patients (86.3%) fulfilled the retreatment criteria of Taiwan's National Health Plan. Results: The 5-year cumulative rates of clinical relapse and retreatment were 52.1% and 47%, respectively, in 160 hepatitis B e antigen (HBeAg)-positive patients, and were 62% and 54.8%, respectively, in 375 HBeAg-negative patients. The median duration from the end of treatment until clinical relapse and retreatment was 40 and 57 weeks, respectively, for all patients. Multivariate Cox regression analysis revealed that discontinuing TDF treatment, old age, male gender, and higher baseline HBsAg levels were independent factors of retreatment in HBeAg-positive patients; old age, HBV genotype B, and higher baseline and end-of-treatment HBsAg levels were independent factors in HBeAg-negative patients. A total of 18.8% of retreated patients satisfied the retreatment criteria of hepatic decompensation according to Taiwan's National Health Plan. Of the 64 patients who had clinical relapse without retreatment, 17 achieved sustained virological remission and 26 did not experience clinical relapse until their last visit after clinical relapse. Four patients developed HBsAg loss. Conclusions: The 5-year retreatment rate was about 50% in HBeAg-positive and HBeAg-negative patients. Discontinuing TDF treatment was an independent factor of retreatment in HBeAg-positive patients. [ABSTRACT FROM AUTHOR]

Spleen stromal lines which support in vitro hematopoiesis are investigated for their lineage origin and hematopoietic support function in vivo. Marker expression and gene profiling identify a lineage relationship with mesenchymal stem cells and perivascular reticular cells described recently in bone marrow. Stromal lines commonly express Cxcl12, Pdgfra and Pdgfr typical of bone marrow derived perivascular reticular cells but reflect a unique cell type in terms of other gene and marker expression. Their classification as osteoprogenitors is confirmed through ability to undergo osteogenic, but not adipogenic or chondrogenic differentiation. Some stromal lines were shown to form ectopic niches for HSCs following engraftment under the kidney capsule of NOD/SCID mice. The presence of myeloid cells and a higher representation of a specific dendritic-like cell type over other myeloid cells within grafts was consistent with previous in vitro evidence of hematopoietic support capacity. These studies reinforce the role of perivascular/perisinusoidal reticular cells in hematopoiesis and implicate such cells as niches for hematopoiesis in spleen. [ABSTRACT FROM AUTHOR]

Background: Host-vector contact is a key factor in vectorial capacity assessment and thus the transmission of mosquito-borne viruses such as Rift Valley Fever (RVF), an emerging zoonotic disease of interest in West Africa. The knowledge of the host-feeding patterns of vector species constitutes a key element in the assessment of their epidemiological importance in a given environment. The aim of this work was to identify the blood meal origins of the mosquito Aedes vexans arabiensis, the main vector of RVF virus in the Ferlo pastoral ecosystem of Senegal. Methodology/principal findings: Engorged female mosquitoes were collected in Younouféré in the pastoral ecosystem in the Ferlo region during the 2014 rainy season. CO2-baited CDC light traps were set at six points for two consecutive nights every month from July to November. Domestic animals present around traps were identified and counted for each trapping session. Blood meal sources of engorged mosquitoes were identified using a vertebrate-specific multiplexed primer set based on cytochrome b. Blood meal sources were successfully identified for 319 out of 416 blood-fed females (76.68%), of which 163 (51.1%) were single meals, 146 (45.77%) mixed meals from two different hosts and 10 (3.13%) mixed meals from three different hosts. Aedes vexans arabiensis fed preferentially on mammals especially on horse compared to other hosts (FR = 46.83). Proportions of single and mixed meals showed significant temporal and spatial variations according to the availability of the hosts. Conclusion: Aedes vexans arabiensis shows an opportunistic feeding behavior depending on the host availability. This species fed preferentially on mammals especially on horses (primary hosts) and ruminants (secondary hosts). [ABSTRACT FROM AUTHOR]

Background: Evidence indicates that human circadian rhythm is affected by the intestinal microbiota, and establishment of the circadian rhythm begins during fetal development. However, the relationship between maternal fermented food intake and infant sleep duration has not been previously investigated. In this study, we examined whether dietary consumption of fermented food during pregnancy is associated with infant sleep duration at 1 year of age. Methods: This birth cohort study used data from a nationwide government-funded study called The Japan Environment and Children’s Study (JECS). After exclusions from a dataset comprising 104,065 JECS records, we evaluated 72,624 mother-child pairs where the child was 1 year old. We investigated the association between dietary intake of fermented foods during pregnancy and infant sleep duration of less than 11 h at 1 year of age. Results: Multivariable logistic regression showed that maternal intake of fermented food, especially miso, during the pregnancy was independently associated with reduced risk of infant sleep duration of less than 11 h. Conclusions: Further research, including interventional studies, is warranted to confirm the association between consumption of fermented foods during pregnancy and sufficient infant sleep duration. Trial registration: . [ABSTRACT FROM AUTHOR]