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Summary: Helicobacter pylori (H. pylori) infection is a known cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the underlying mechanisms by which H. pylori infection triggers these disorders are still not clearly understood. Gastric cancer is a slow progressing disease, which makes it difficult to study. We have developed an accelerated disease progression mouse model, which leverages mice deficient in the myeloid differentiation primary response 88 gene (Myd88−/−) infected with Helicobacter felis (H. felis). Using this model and gastric biopsy samples from patients, we report that activation of the Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-β (TRIF)-type I interferon (IFN-I) signaling pathway promotes Helicobacter-induced disease progression toward severe gastric pathology and gastric cancer development. Further, results implicated downstream targets of this pathway in disease pathogenesis. These findings may facilitate stratification of Helicobacter-infected patients and thus enable treatment prioritization of patients.

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 μg PBR was 1.70 (±0.56); the mean 50 μg PBR was 2.64 (±0.97); the mean 100 μg PBR was 3.32 (±1.33); and the mean 150 μg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 μg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy.

Designing machine learning hardware on flexible substrates is promising for several applications. Here, the authors propose an integrated smart system built with low-cost flexible electronics components for classifying human malodour, and demonstrates that the proposed system scores malodour as good as expert human assessors.

Gastric cancer is the third leading cause of cancer-related deaths, with more than one million new cases and approximately 841,000 deaths annually worldwide. We report a case of a young patient (25 years old) with an aggressive form of gastric cancer. The patient had previously been treated for Helicobacter pylori (H. pylori), which is a main risk factor for developing gastric cancer. Genetic testing showed an E-cadherin (CDH1) germline mutation of unknown significance. After eight cycles of chemotherapy, a positron emission tomography (PET) scan showed disease progression with an enlarging hypermetabolic right adnexal mass suspicious for metastatic disease. Tumor pathology demonstrated invasive and poorly differentiated gastric carcinoma. The analysis of the tumor biopsy indicated the very high expression of a chemokine, C-X-C motif chemokine 5 (CXCL5). The combination of H. pylori infection with an existence of a rare CDH1 mutation could have contributed to this aggressive gastric cancer.

Abstract Background Caesarean section (CS) rates are increasing and there are wide variations in rates internationally and nationally. There is evidence that women who attend their obstetrician privately have a higher incidence of CS than those who attend publicly. The purpose of this observational study was to further investigate why CS rates may be higher in women who chose to attend their obstetrician privately. Methods This study analysed data collected as part of the clinical records by midwives at the woman’s first antenatal appointment in a large European maternity hospital. All women who delivered between the years 2009 and 2017 were included. Data were analysed both cross-sectionally and longitudinally. Results Overall, 73,266 women had a singleton pregnancy and 1830 had a multiple pregnancy. Of the packages of maternity care, 75.2% chose public, 10.8% chose semiprivate and 14.0% chose private. During the study, 11,991 women attended the hospital for their first and second pregnancies. Overall, women who attended privately were older and had higher proportions of infertility treatment and history of miscarriage (all p

Abstract Objective In 2010, national guidelines were published in Ireland recommending more sensitive criteria for the diagnosis of Gestational Diabetes Mellitus (GDM). The criteria were based on the 2008 Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study and were endorsed subsequently by the World Health Organization (WHO). Screening nationally is selective based on risk factors. We examined the impact of the new criteria on hospital trends nationally for GDM over the 10 years 2008–17. Research design and methods Data from three national databases, the Hospital Inpatient Enquiry System (HIPE), National Perinatal Reporting System (NPRS) and the Irish Maternity Indicator System (IMIS), were analyzed using descriptive statistics, analysis of variance, and Poisson loglinear modelling. Results The overall incidence of GDM nationally increased almost five-fold from 3.1% in 2008 to 14.8% in 2017 (p ≤ 0.001). The incidence varied widely across maternity units. In 2008, the incidence varied from 0.4 to 5.9% and in 2017 it varied from 1.9 to 29.4%. There were increased obstetric interventions among women with GDM over the decade, specifically women with GDM having increased cesarean sections (CS) and induction of labor (IOL) (p ≤ 0.001). These trends were significant in large and mid-sized maternity hospitals (p ≤ 0.001). The increase in GDM diagnosis could not be explained by an increase in maternal age nationally over the decade. The data did not include information on other risk factors such as obesity. The increased incidence in GDM diagnosis was accompanied by a decrease in high birthweight ≥ 4.5 kg nationally. Conclusions We found adoption of the new criteria for diagnosis of GDM resulted in a major increase in the incidence of GDM rates. Inter-hospital variations increased over the decade, which may be explained by variations in the implementation of the new national guidelines in different maternity units. It is likely to escalate further as compliance with national guidelines improves at all maternity hospitals, with implications for provision and configuration of maternity services. We observed trends that may indicate improvements for women and their offspring, but more research is required to understand patterns of guideline implementation across hospitals and to demonstrate how increased GDM diagnosis will improve clinical outcomes.

Lung cancer maintains a relatively small survival rate (~19%) over a 5-year period and up to 80–85% of all lung cancer diagnoses are Non-Small Cell Lung Cancer (NSCLC). To determine whether metformin reduces non-small cell lung cancer (NSCLC) LL/2 cell growth, cells were grown in vitro and treated with metformin for 48 h. qPCR was used to assess genes related to cell cycle regulation and pro-apoptotic markers, namely Cyclin D, CDK4, p27, p21, and HES1. Treatment with 10 mM metformin significantly reduced HES1 expression (p = 0.011). Furthermore, 10 mM metformin treatment significantly decreased REDD1 (p = 0.0082) and increased p-mTOR Ser2448 (p = 0.003) protein expression. Control cells showed significant reductions in phosphorylated p53 protein expression (p = 0.0367), whereas metformin treated cells exhibited reduced total p53 protein expression (p = 0.0078). There were no significant reductions in AMPK, PKB/AKT, or STAT3. In addition, NSCLC cells were treated for 48 h. with 10 mM metformin, 4 µM gamma-secretase inhibitor (GSI), or the combination of metformin (10 mM) and GSI (4 µM) to determine the contribution of respective signaling pathways. Metformin treatment significantly reduced total nucleus expression of the proliferation maker Ki-67 with an above 65% reduction in Ki-67 expression between control and metformin-treated cells (p = 0.0021). GSI (4 µM) treatment significantly reduced Ki-67 expression by ~20% over 48 h (p = 0.0028). Combination treatment (10 mM metformin and 4 µM GSI) significantly reduced Ki-67 expression by more than 50% over 48 h (p = 0.0245). As such, direct administration of metformin (10 mM for 48 h) proved to be an effective pharmaceutical agent in reducing the proliferation of cultured non-small cell cancer cells. These intriguing in vitro results, therefore, support the further study of metformin in appropriate in vivo models as an anti-oncogenic agent and/or an adjunctive therapy.

Tumor-specific targeting with fluorescent probes can enhance contrast for identification of cancer during surgical resection and visualize otherwise invisible tumor margins. Nanobodies are the smallest naturally-occurring antigen-binding molecules with rapid pharmacokinetics. The present work demonstrates the efficacy of a fluorescent anti-CEA nanobody conjugated to an IR800 dye to target and label patient derived pancreatic cancer xenografts. After intravenous administration, the probe rapidly localized to the pancreatic cancer tumors within an hour and had a tumor-to-background ratio of 2.0 by 3 h. The fluorescence signal was durable over a prolonged period of time. With the rapid kinetics afforded by fluorescent nanobodies, both targeting and imaging can be performed on the same day as surgery.

Abstract Organic semiconductors (OSCs) promise to deliver next‐generation electronic and energy devices that are flexible, scalable and printable. Unfortunately, realizing this opportunity is hampered by increasing concerns about the use of volatile organic compounds (VOCs), particularly toxic halogenated solvents that are detrimental to the environment and human health. Here, a cradle‐to‐grave process is reported to achieve high performance p‐ and n‐type OSC devices based on indacenodithiophene and diketopyrrolopyrrole semiconducting polymers that utilizes aqueous‐processes, fewer steps, lower reaction temperatures, a significant reduction in VOCs (>99%) and avoids all halogenated solvents. The process involves an aqueous mini‐emulsion polymerization that generates a surfactant‐stabilized aqueous dispersion of OSC nanoparticles at sufficient concentration to permit direct aqueous processing into thin films for use in organic field‐effect transistors. Promisingly, the performance of these devices is comparable to those prepared using conventional synthesis and processing procedures optimized for large amounts of VOCs and halogenated solvents. Ultimately, the holistic approach reported addresses the environmental issues and enables a viable guideline for the delivery of future OSC devices using only aqueous media for synthesis, purification and thin‐film processing.

Colorectal cancer (CRC) is a common cause of cancer and cancer-related death. Surgery is the only curative modality. Fluorescence-enhanced visualization of CRC with targeted fluorescent probes that can delineate boundaries and target tumor-specific biomarkers can increase rates of curative resection. Approaches to enhancing visualization of the tumor-to-normal tissue interface are active areas of investigation. Nonspecific dyes are the most-used approach, but tumor-specific targeting agents are progressing in clinical trials. The present narrative review describes the principles of fluorescence targeting of CRC for diagnosis and fluorescence-guided surgery with molecular biomarkers for preclinical or clinical evaluation.

Abstract Background Susceptibility of tsetse flies (Glossina spp.) to trypanosomes of both humans and animals has been associated with the presence of the endosymbiont Sodalis glossinidius. However, intrinsic biological characteristics of the flies and environmental factors can influence the presence of both S. glossinidius and the parasites. It thus remains unclear whether it is the S. glossinidius or other attributes of the flies that explains the apparent association. The objective of this study was to test whether the presence of Trypanosoma vivax, T. congolense and T. brucei are related to the presence of S. glossinidius in tsetse flies when other factors are accounted for: geographic location, species of Glossina, sex or age of the host flies. Results Flies (n = 1090) were trapped from four sites in the Shimba Hills and Nguruman regions in Kenya. Sex and species of tsetse (G. austeni, G. brevipalpis, G. longipennis and G. pallidipes) were determined based on external morphological characters and age was estimated by a wing fray score method. The presence of trypanosomes and S. glossinidius was detected using PCR targeting the internal transcribed spacer region 1 and the haemolysin gene, respectively. Sequencing was used to confirm species identification. Generalised Linear Models (GLMs) and Multiple Correspondence Analysis (MCA) were applied to investigate multivariable associations. The overall prevalence of trypanosomes was 42.1%, but GLMs revealed complex patterns of associations: the presence of S. glossinidius was associated with trypanosome presence but only in interactions with other factors and only in some species of trypanosomes. The strongest association was found for T. congolense, and no association was found for T. vivax. The MCA also suggested only a weak association between the presence of trypanosomes and S. glossinidius. Trypanosome-positive status showed strong associations with sex and age while S. glossinidius-positive status showed a strong association with geographic location and species of fly. Conclusions We suggest that previous conclusions about the presence of endosymbionts increasing probability of trypanosome presence in tsetse flies may have been confounded by other factors, such as community composition of the tsetse flies and the specific trypanosomes found in different regions.

Abstract Background Much interest has been focussed on both maternal obesity and gestational weight gain (GWG), particularly on their role in influencing birth weight (BW). Several large reviews have reported that excessive GWG is associated with an increase in BW. However recent large, well-designed, randomized controlled trials studying interventions aimed at reducing GWG have all consistently failed to show a reduction in BW despite achieving a reduction in GWG. The aim of this longitudinal prospective study was to examine the relationship between GWG and birth weight in women where GWG and Body Mass Index (BMI) were measured accurately in a strictly standardized way. Methods Women were enrolled at their convenience before 18 weeks gestation. Height and weight were measured accurately at the first antenatal visit and BMI calculated. Maternal weight was measured again after 37 weeks gestation. The weight of the baby was measured at birth. Relationships were tested using linear regression analysis, chi-squared tests and t-tests as appropriate. Results Of the 522 women studied, the mean BMI was 25.3 kg/m2 and 15.7% were obese. The mean BW at term was 3576 g (2160–5120) and 2.7% (n = 14) weighed ≥4500 g. The mean GWG overall was 12.3 kg (4.6 to 28.4) and GWG decreased as BMI increased. The mean GWG was less in obese women, at 8.7 kg (− 4.6 to 23.4), compared to non-obese,13.0 kg (0.6–28.4) (p

Hirshfeld atom refinement (HAR) is a novel X-ray structure refinement technique that employs aspherical atomic scattering factors obtained from stockholder partitioning of a theoretically determined tailor-made static electron density. HAR overcomes many of the known limitations of independent atom modelling (IAM), such as too short element–hydrogen distances, r(X—H), or too large atomic displacement parameters (ADPs). This study probes the accuracy and precision of anisotropic hydrogen and non-hydrogen ADPs and of r(X—H) values obtained from HAR. These quantities are compared and found to agree with those obtained from (i) accurate neutron diffraction data measured at the same temperatures as the X-ray data and (ii) multipole modelling (MM), an established alternative method for interpreting X-ray diffraction data with the help of aspherical atomic scattering factors. Results are presented for three chemically different systems: the aromatic hydrocarbon rubrene (orthorhombic 5,6,11,12-tetraphenyltetracene), a co-crystal of zwitterionic betaine, imidazolium cations and picrate anions (BIPa), and the salt potassium hydrogen oxalate (KHOx). The non-hydrogen HAR-ADPs are as accurate and precise as the MM-ADPs. Both show excellent agreement with the neutron-based values and are superior to IAM-ADPs. The anisotropic hydrogen HAR-ADPs show a somewhat larger deviation from neutron-based values than the hydrogen SHADE-ADPs used in MM. Element–hydrogen bond lengths from HAR are in excellent agreement with those obtained from neutron diffraction experiments, although they are somewhat less precise. The residual density contour maps after HAR show fewer features than those after MM. Calculating the static electron density with the def2-TZVP basis set instead of the simpler def2-SVP one does not improve the refinement results significantly. All HARs were performed within the recently introduced HARt option implemented in the Olex2 program. They are easily launched inside its graphical user interface following a conventional IAM.

A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its resection. Several cancer types express carcinoembryonic antigen (CEA) including colorectal, pancreatic and gastric cancer. Antibodies to CEA have been developed and tagged with near-infrared fluorescent dyes. This review article surveyed the use of CEA antibodies conjugated to fluorescent probes for in vivo studies since 1990. PubMed and Google Scholar databases were queried, and 900 titles and abstracts were screened. Fifty-nine entries were identified as possibly meeting inclusion/exclusion criteria and were reviewed in full. Forty articles were included in the review and their citations were screened for additional entries. A total of 44 articles were included in the final review. The use of fluorescent anti-CEA antibodies has been shown to improve detection and resection of tumors in both murine models and clinically. The cumulative results indicate that fluorescent-conjugated anti-CEA antibodies have important potential to improve cancer diagnosis and surgery. In an emerging technology, anti-CEA fluorescent antibodies have also been successfully used for photoimmunotherapy treatment for cancer.

Non-small-cell lung cancer (NSCLC) makes up 80–85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining skeletal muscle health, C57BL/6J mice were injected with Lewis lung cancer (LL/2), containing a bioluminescent reporter for in vivo tracking, into the left lung. Control and metformin (250 mg/kg) groups received treatments twice weekly. Skeletal muscle was analyzed for changes in genes and proteins related to inflammation, muscle mass, and metabolism. The LL/2 model effectively mimics lung cancer growth and tumor burden. The in vivo data indicate that metformin as administered was not associated with significant improvement in tumor burden in this immunocompetent NSCLC model. Additionally, metformin was not associated with significant changes in key tumor cell division and inflammation markers, or improved skeletal muscle health. Metformin treatment, while exhibiting anti-neoplastic characteristics in many cancers, appears not to be an appropriate monotherapy for NSCLC tumor growth in vivo. Future studies should pursue co-treatment modalities, with metformin as a potentially supportive drug rather than a monotherapy to mitigate cancer progression.

The role of Notch signaling is widely studied in skeletal muscle regeneration but little is known about its influences on muscle protein synthesis (MPS). The purpose of this study was to investigate whether Notch signaling is involved in the regulation of MPS. C2C12 cells were treated with a γ-secretase inhibitor (GSI), to determine the effect of reduced Notch signaling on MPS and anabolic signaling markers. GSI treatment increased myotube hypertrophy by increasing myonuclear accretion (nuclei/myotube: p = 0.01) and myonuclear domain (myotube area per fusing nuclei: p < 0.001) in differentiating C2C12 cells. GSI treatment also elevated myotube hypertrophy in differentiated C2C12s (area/myotube; p = 0.01). In concert, GSI treatment augmented pmTOR Ser2448 (p = 0.01) and protein synthesis (using SUnSET method) in myotubes (p < 0.001). Examining protein expression upstream of mTOR revealed reductions in PTEN (p = 0.04), with subsequent elevations in pAKT Thr308 (p < 0.001) and pAKT Ser473 (p = 0.05). These findings reveal that GSI treatment elevates myotube hypertrophy through both augmentation of fusion and MPS. This study sheds light on the potential multifaceted roles of Notch within skeletal muscle. Furthermore, we have demonstrated that Notch may modulate the PTEN/AKT/mTOR pathway.

Missing values are known to be problematic for the analysis of gas chromatography-mass spectrometry (GC-MS) metabolomics data. Typically these values cover about 10%–20% of all data and can originate from various backgrounds, including analytical, computational, as well as biological. Currently, the most well known substitute for missing values is a mean imputation. In fact, some researchers consider this aspect of data analysis in their metabolomics pipeline as so routine that they do not even mention using this replacement approach. However, this may have a significant influence on the data analysis output(s) and might be highly sensitive to the distribution of samples between different classes. Therefore, in this study we have analysed different substitutes of missing values namely: zero, mean, median, k-nearest neighbours (kNN) and random forest (RF) imputation, in terms of their influence on unsupervised and supervised learning and, thus, their impact on the final output(s) in terms of biological interpretation. These comparisons have been demonstrated both visually and computationally (classification rate) to support our findings. The results show that the selection of the replacement methods to impute missing values may have a considerable effect on the classification accuracy, if performed incorrectly this may negatively influence the biomarkers selected for an early disease diagnosis or identification of cancer related metabolites. In the case of GC-MS metabolomics data studied here our findings recommend that RF should be favored as an imputation of missing value over the other tested methods. This approach displayed excellent results in terms of classification rate for both supervised methods namely: principal components-linear discriminant analysis (PC-LDA) (98.02%) and partial least squares-discriminant analysis (PLS-DA) (97.96%) outperforming other imputation methods.

Low-voltage, solution-processed organic thin-film transistors (OTFTs) have tremendous potential to be key components in low-cost, flexible and large-area electronics. However, for these devices to operate at low voltage, robust and high capacitance gate dielectrics are urgently needed. Herein, the fabrication of OTFTs that operate at 1 V is reported. These devices comprise a solution-processed, self-assembled monolayer (SAM) modified tantalum pentoxide (Ta2O5) as the gate dielectric. The morphology and dielectric properties of the anodized Ta2O5 films with and without n-octadecyltrichlorosilane (OTS) SAM treatment have been studied. The thickness of the Ta2O5 film was optimized by varying the anodization voltage. The results show that organic TFTs gated with OTS-modified tantalum pentoxide anodized at 3 V (d ~7 nm) exhibit the best performance. The devices operate at 1 V with a saturation field-effect mobility larger than 0.2 cm2 V−1 s−1, threshold voltage −0.55 V, subthreshold swing 120 mV/dec, and current on/off ratio in excess of 5 × 103. As a result, the demonstrated OTFTs display a promising performance for applications in low-voltage, portable electronics.

Obesity is a chronic inflammatory state characterized by infiltration of adipose tissue by immune cell populations, including T lymphocytes. Natural killer T (NKT) cells, a specialized lymphocyte subset recognizing lipid antigens, can be pro- or anti-inflammatory. Their role in adipose inflammation continues to be inconclusive and contradictory. In obesity, the infiltration of tissues by invariant NKT (iNKT) cells is decreased. We therefore hypothesized that an excess iNKT cell complement might improve metabolic abnormalities in obesity. Vα14 transgenic (Vα14tg) mice, with increased iNKT cell numbers, on a LDL receptor-deficient (Ldlr-/-) background and control Ldlr-/- mice were placed on an obesogenic diet for 16 weeks. Vα14tg.Ldlr-/- mice gained 25% more weight and had increased adiposity than littermate controls. Transgenic mice also developed greater dyslipidemia, hyperinsulinemia, insulin resistance, and hepatic triglyceride accumulation. Increased macrophage Mac2 immunostaining and proinflammatory macrophage gene expression suggested worsened adipose inflammation. Concurrently, these mice had increased atherosclerotic lesion area and aortic inflammation. Thus, increasing the complement of iNKT cells surprisingly exacerbated the metabolic, inflammatory, and atherosclerotic features of obesity. These findings suggest that the reduction of iNKT cells normally observed in obesity may represent a physiological attempt to compensate for this inflammatory condition.

Objective: The purpose of this nested cohort study was to compare the rate of pre-pregnancy supplementation in obese women with that of women with a normal BMI. Methods: Pregnant women were enrolled at their convenience in a large university hospital. Weight and height were measured in the first trimester and BMI categorised. Results: Of the 288 women, 35.1% were in the normal, 29.5% in the overweight and 35.4% in the obese BMI categories. Only 45.1% (n = 46) of the obese women took pre-pregnancy folic acid compared with 60.4% (n = 61) of women with a normal BMI (p Conclusions: Obese women should take folate supplements whether they are planning to conceive or not.

OBJECTIVE:Internationally, caesarean section (CS) rates are rising. However, mean rates of CS across providers obscure extremes of CS provision. We aimed to quantify variation between all maternity units in Ireland. METHODS:Two national databases, the National Perinatal Reporting System and the Hospital Inpatient Enquiry Scheme, were used to analyse data for all women delivering singleton births weighing ≥500g. We used multilevel models to examine variation between hospitals in Ireland for elective and emergency CS, adjusted for individual level sociodemographic, clinical and organisational variables. Analyses were subsequently stratified for nullipara and multipara with and without prior CS. RESULTS:The national CS rate was 25.6% (range 18.2% ─ 35.1%). This was highest in multipara with prior CS at 86.1% (range 6.9% ─ 100%). The proportion of variation in CS that was attributable to the hospital of birth was 11.1% (95% CI, 6.0 ─ 19.4) for elective CS and 2.9% (95% CI, 1.4 ─ 5.6) for emergency CS, after adjustment. Stratifying across parity group, variation between hospitals was greatest for multipara with prior CS. Both types of CS were predicted by increasing age, prior history of miscarriage or stillbirth, prior CS, antenatal complications and private model of care. CONCLUSION:The proportion of variation attributable to the hospital was higher for elective CS than emergency CS suggesting that variation is more likely influenced by antenatal decision making than intrapartum decision making. Multipara with prior CS were particularly subject to variability, highlighting a need for consensus on appropriate care in this group.

The aim of this paper was to determine if weekly physical activity levels were greater in an independent-living older adult population that was regularly participating in structured fitness activities. Also, lifetime exercise history and sex differences were investigated in an effort to understand how they relate to current weekly step activity. Total weekly step counts, measured with a pedometer, were assessed in two older adult groups; the first consisted of members of a local senior center who regularly used the fitness facility (74.5±6.0 yrs; mean ± SD) while the second group consisted of members who did not use the fitness facility (74.8±6.0 yrs). Participants also completed the Lifetime Physical Activity Questionnaire (LPAQ). No significant difference was found in the total number of weekly steps between groups (p=0.88) or sexes (p=0.27). The LPAQ suggested a significant decline in activity with aging (p=0.01) but no difference between groups (p=0.54) or sexes (p=0.80). A relationship was observed between current step activity and MET expenditure over the past year (p=0.008, r2=0.153) and from ages 35 to 50 years (p=0.037, r2=0.097). The lack of difference in weekly physical activity level between our groups suggests that independent-living older adults will seek out and perform their desired activity, in either a scheduled exercise program or other leisure-time activities. Also, the best predictor of current physical activity level in independent-living older adults was the activity performed over the past year.

Spatial impulse response analysis techniques are commonly used in the field of acoustics, as they help to characterise the interaction of sound with an enclosed environment. This paper presents a novel approach for spatial analyses of binaural impulse responses, using a binaural model fronted neural network. The proposed method uses binaural cues utilised by the human auditory system, which are mapped by the neural network to the azimuth direction of arrival classes. A cascade-correlation neural network was trained using a multi-conditional training dataset of head-related impulse responses with added noise. The neural network is tested using a set of binaural impulse responses captured using two dummy head microphones in an anechoic chamber, with a reflective boundary positioned to produce a reflection with a known direction of arrival. Results showed that the neural network was generalisable for the direct sound of the binaural room impulse responses for both dummy head microphones. However, it was found to be less accurate at predicting the direction of arrival of the reflections. The work indicates the potential of using such an algorithm for the spatial analysis of binaural impulse responses, while indicating where the method applied needs to be made more robust for more general application.

African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda) and Southern (Malawi) Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics.

Trypanosoma brucei is the causative agent of African Sleeping Sickness in humans and contributes to the related veterinary disease, Nagana. T. brucei is segregated into three subspecies based on host specificity, geography and pathology. T. b. brucei is limited to animals (excluding some primates) throughout sub-Saharan Africa and is non-infective to humans due to trypanolytic factors found in human serum. T. b. gambiense and T. b. rhodesiense are human infective sub-species. T. b. gambiense is the more prevalent human, causing over 97% of human cases. Study of T. b. gambiense is complicated in that there are two distinct groups delineated by genetics and phenotype. The relationships between the two groups and local T. b. brucei are unclear and may have a bearing on the evolution of the human infectivity traits.A collection of sympatric T. brucei isolates from Côte d'Ivoire, consisting of T. b. brucei and both groups of T. b. gambiense have previously been categorized by isoenzymes, RFLPs and Blood Incubation Infectivity Tests. These samples were further characterized using the group 1 specific marker, TgSGP, and seven microsatellites. The relationships between the T. b. brucei and T. b. gambiense isolates were determined using principal components analysis, neighbor-joining phylogenetics, STRUCTURE, FST, Hardy-Weinberg equilibrium and linkage disequilibrium.Group 1 T. b. gambiense form a clonal genetic group, distinct from group 2 and T. b. brucei, whereas group 2 T. b. gambiense are genetically indistinguishable from local T. b. brucei. There is strong evidence for mating within and between group 2 T. b. gambiense and T. b. brucei. We found no evidence to support the hypothesis that group 2 T. b. gambiense are hybrids of group 1 and T. b. brucei, suggesting that human infectivity has evolved independently in groups 1 and 2 T. b. gambiense.

Adipose tissue inflammation and specifically, pro-inflammatory macrophages are believed to contribute to insulin resistance (IR) in obesity in humans and animal models. Recent studies have invoked T cells in the recruitment of pro-inflammatory macrophages and the development of IR. To test the role of the T cell response in adipose tissue of mice fed an obesogenic diet, we used two agents (CTLA-4 Ig and anti-CD40L antibody) that block co-stimulation, which is essential for full T cell activation. C57BL/6 mice were fed an obesogenic diet for 16 weeks, and concomitantly either treated with CTLA-4 Ig, anti-CD40L antibody or an IgG control (300 µg/week). The treatments altered the immune cell composition of adipose tissue in obese mice. Treated mice demonstrated a marked reduction in pro-inflammatory adipose tissue macrophages and activated CD8+ T cells. Mice treated with anti-CD40L exhibited reduced weight gain, which was accompanied by a trend toward improved IR. CTLA-4 Ig treatment, however, was not associated with improved IR. These data suggest that the presence of pro-inflammatory T cells and macrophages can be altered with co-stimulatory inhibitors, but may not be a significant contributor to the whole body IR phenotype.

The three sub-species of Trypanosoma brucei are important pathogens of sub-Saharan Africa. T. b. brucei is unable to infect humans due to sensitivity to trypanosome lytic factors (TLF) 1 and 2 found in human serum. T. b. rhodesiense and T. b. gambiense are able to resist lysis by TLF. There are two distinct sub-groups of T. b. gambiense that differ genetically and by human serum resistance phenotypes. Group 1 T. b. gambiense have an invariant phenotype whereas group 2 show variable resistance. Previous data indicated that group 1 T. b. gambiense are resistant to TLF-1 due in-part to reduced uptake of TLF-1 mediated by reduced expression of the TLF-1 receptor (the haptoglobin-hemoglobin receptor (HpHbR)) gene. Here we investigate if this is also true in group 2 parasites.Isogenic resistant and sensitive group 2 T. b. gambiense were derived and compared to other T. brucei parasites. Both resistant and sensitive lines express the HpHbR gene at similar levels and internalized fluorescently labeled TLF-1 similar fashion to T. b. brucei. Both resistant and sensitive group 2, as well as group 1 T. b. gambiense, internalize recombinant APOL1, but only sensitive group 2 parasites are lysed.Our data indicate that, despite group 1 T. b. gambiense avoiding TLF-1, it is resistant to the main lytic component, APOL1. Similarly group 2 T. b. gambiense is innately resistant to APOL1, which could be based on the same mechanism. However, group 2 T. b. gambiense variably displays this phenotype and expression does not appear to correlate with a change in expression site or expression of HpHbR. Thus there are differences in the mechanism of human serum resistance between T. b. gambiense groups 1 and 2.

Peripartum cardiomyopathy is a serious, potentially life-threatening heart disease of uncertain aetiology in previously healthy women. We report a morbidly obese woman who presented with peripartum shortness of breath. We discuss the differential diagnosis of dyspnoea in pregnancy and highlight the complexity of care of the morbidly obese woman.

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named TbOrg1). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (TbOrg2). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits.

The protozoan parasite, Trypanosoma congolense, is one of the most economically important pathogens of livestock in Africa and, through its impact on cattle health and productivity, has a significant effect on human health and well being. Despite the importance of this parasite our knowledge of some of the fundamental biological processes is limited. For example, it is unknown whether mating takes place. In this paper we have taken a population genetics based approach to address this question. The availability of genome sequence of the parasite allowed us to identify polymorphic microsatellite markers, which were used to genotype T. congolense isolates from livestock in a discrete geographical area of The Gambia. The data showed a high level of diversity with a large number of distinct genotypes, but a deficit in heterozygotes. Further analysis identified cryptic genetic subdivision into four sub-populations. In one of these, parasite genotypic diversity could only be explained by the occurrence of frequent mating in T. congolense. These data are completely inconsistent with previous suggestions that the parasite expands asexually in the absence of mating. The discovery of mating in this species of trypanosome has significant consequences for the spread of critical traits, such as drug resistance, as well as for fundamental aspects of the biology and epidemiology of this neglected but economically important pathogen.