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Abstract Background Neural circuit function is highly sensitive to energetic limitations. Much like mammals, brain activity in American bullfrogs quickly fails in hypoxia. However, after emergence from overwintering, circuits transform to function for approximately 30-fold longer without oxygen using only anaerobic glycolysis for fuel, a unique trait among vertebrates considering the high cost of network activity. Here, we assessed neuronal functions that normally limit network output and identified components that undergo energetic plasticity to increase robustness in hypoxia. Results In control animals, oxygen deprivation depressed excitatory synaptic drive within native circuits, which decreased postsynaptic firing to cause network failure within minutes. Assessments of evoked and spontaneous synaptic transmission showed that hypoxia impairs synaptic communication at pre- and postsynaptic loci. However, control neurons maintained membrane potentials and a capacity for firing during hypoxia, indicating that those processes do not limit network activity. After overwintering, synaptic transmission persisted in hypoxia to sustain motor function for at least 2 h. Conclusions Alterations that allow anaerobic metabolism to fuel synapses are critical for transforming a circuit to function without oxygen. Data from many vertebrate species indicate that anaerobic glycolysis cannot fuel active synapses due to the low ATP yield of this pathway. Thus, our results point to a unique strategy whereby synapses switch from oxidative to exclusively anaerobic glycolytic metabolism to preserve circuit function during prolonged energy limitations.

Este estudo objetivou refletir sobre a importância da bitcoin como um novo formato das transações financeiras. Além de tudo, buscou entender sobre as características e funcionamento do dinheiro virtual, analisando comparativamente entre as transações com a moeda convencional e criptomoeda. Para construção do artigo foi realizado um levantamento bibliográfico e documental, no qual se verificou que em relação à moeda tradicional a bitcoin possui inúmeras vantagens e desvantagens e que cada uma conta com seus atributos. Diante do exposto conclui-se que a utilização do (dinheiro) virtual denominada bitcoin é vantajosa nas realizações de transações financeiras, possibilitando benefícios aos seus donos e sem intervenção de instituições bancárias, ou seja, o usuário faz a administração do seu próprio montante. Além disso, a bitcoin oportuniza custos menores em cada transferência.

Neurons tightly regulate firing rate and a failure to do so leads to multiple neurological disorders. Therefore, a fundamental question in neuroscience is how neurons produce reliable activity patterns for decades to generate behavior. Neurons have built-in feedback mechanisms that allow them to monitor their output and rapidly stabilize firing rate. Most work emphasizes the role of a dominant feedback system within a neuronal population for the control of moment-to-moment firing. In contrast, we find that respiratory motoneurons use 2 activity-dependent controllers in unique combinations across cells, dynamic activation of an Na+ pump subtype, and rapid potentiation of Kv7 channels. Both systems constrain firing rate by reducing excitability for up to a minute after a burst of action potentials but are recruited by different cellular signals associated with activity, increased intracellular Na+ (the Na+ pump), and membrane depolarization (Kv7 channels). Individual neurons do not simply contain equal amounts of each system. Rather, neurons under strong control of the Na+ pump are weakly regulated by Kv7 enhancement and vice versa along a continuum. Thus, each motoneuron maintains its characteristic firing rate through a unique combination of the Na+ pump and Kv7 channels, which are dynamically regulated by distinct feedback signals. These results reveal a new organizing strategy for stable circuit output involving multiple fast activity sensors scaled inversely across a neuronal population.

Transient receptor potential vanilloid 4 (TRPV4) channels are sensitive to warm ambient temperatures (Tas), triggering heat loss responses in adult rats in a Tas range of ∼26–30°C. In birds, however, the thermoregulatory role of TRPV4 has never been shown. Here, we hypothesized that stimulation of TRPV4 induces thermolytic responses for body temperature (Tb) maintenance in birds, and that this function is already present in early life, when the Ta range for TRPV4 activation does not represent a warm condition for these animals. We first demonstrated the presence of TRPV4 in the dorsal and ventral skin of chickens (Gallus gallus domesticus) by immunohistochemistry. Then, we evaluated the effects of the TRPV4 agonist, RN1747, and the TRPV4 antagonists, HC067047 and GSK2193874, on Tb and thermoeffectors at different Tas in 5-day-old chicks and 60-day-old adult chickens. For the chicks, RN1747 transiently reduced Tb both in thermoneutrality (31°C) and in a cold Ta for this phase (26°C), which relied on huddling behavior inhibition. The TRPV4 antagonists alone did not affect Tb or thermoeffectors but blocked the Tb decrease and huddling inhibition promoted by RN1747. For the adults, TRPV4 antagonism increased Tb when animals were exposed to 28°C (suprathermoneutral condition for adults), but not to 19°C. In contrast, RN1747 decreased Tb by reducing metabolic rate and activating thermal tachypnea at 19°C, a Ta below the activation range of TRPV4. Our results indicate that peripheral TRPV4 receptors are functional in early life, but may be inhibited at that time when the range of activation (∼26–30°C) represents cold Ta for chicks, and become physiologically relevant for Tb maintenance when the activation Ta range for TRPV4 becomes suprathermoneutral for adult chickens.

Abelhas são insetos extremamente importantes para a manutenção da vida no planeta, e oferecem inúmeras possibilidades didáticas no Ensino de Ciências. Ao levar em conta a importância ecológica e educacional desta temática, o objetivo deste estudo é analisar como o conteúdo relacionado às abelhas vem sendo abordado em livros didáticos da disciplina de Ciências do Ensino Fundamental II, disponíveis online , no âmbito do Programa Nacional do Livro e do Material Didático (PNLD 2020). A metodologia caracteriza se como uma pesquisa qualitativa que apresenta elementos da pesquisa descritiva documental. A coleta de dados foi realizada por meio de extratos textuais e imagens de livros didáticos selecionados, submetidos à análise de conteúdo e avaliados com critérios estabelecidos previamente. Após análise dos dados, observamos que a temática foi pouco explorada pelos livros. Quando exploradas, uma relação utilitarista e antropocêntrica foi predominante. Aspectos medicinais dos produtos apícolas, culturais e históricos sequer foram mencionados. Em sí ntese, vários aspectos ambientais e funções ecológicas importantes deixaram de ser apresentadas nos livros didáticos avaliados, o que pode trazer prejuízos à aprendizagem, especialmente em que pese o desenvolvimento da Educação Ambiental e da aprendizagem no Ensino de Ciências.

This study analyzes whether the rigor of environmental regulations encourages industrial companies in developed and emerging countries to invest in Green Innovation (GI), and what is the impact on financial performance. The sample was composed of 159 industrial companies, listed in the Financial Times’ 500 largest companies by market value in 2015. For the analysis, Structural Equation Modeling was used to verify the relationship between the variables. The main results were that the strictness of the countries’ environmental regulations, and the size of the companies had a statistically significant positive impact only on construct GI2, composed of the variables Global Compact and environmental investments. Countries competitiveness did not positively influence companies’ GI efforts, and the degree of internationalization of companies had no significant effect on any of the GI constructs. Furthermore, the efforts of companies in GI do not reflect positively on their financial performance.

Awareness of health benefits of goji berries coming from their bioactive compounds, mostly antioxidants like ascorbic acid, has grown. Recently, an ascorbic acid analogue from goji berries, the 2-O-?-D-glucopyranosyl-L-ascorbic acid has been reported. In rats, the analogue is absorbed intact and in the form of free vitamin C and consequently has been proposed as a provitamin C. Synthesis of the analogue is demanding and laborious and therefore reliable natural sources are searched. Knowledge concerning the analogue's occurrence in other parts of goji plant is lacking. The aim of this study was to evaluate the contents of 2-O-?-D-glucopyranosyl-L-ascorbic acid in rhizomes, stems and leaves from Lycium barbarum. Rhizomes, stems and leaveswere extracted and the content of 2-O-?-D-glucopyranosyl-L-ascorbic acid and non glucosylated, free ascorbic acid was determined by HPLC-DAD. 2-O-?-D-glucopyranosyl-L-ascorbic acid was found in all goji plant tissues investigated. Based on dry weight, 3.34 mg/100 g were found in the leaves, 4.05 mg/100 g in the stems and up to 12.6 mg/100 g in the rhizomes. Nevertheless, the analogue content in goji berries is much higher (40 to 280 mg/100 g dry weight). The present study confirmed the presence of 2-O-?-D-glucopyranosyl-L-ascorbic acid in rhizomes, stems and leaves of Lycium barbarum. However, their content compared to goji berries is considerably lower.

Introduction: Severe inflammation may induce body temperature (Tb) reduction instead of fever. In this situation, morbidity and mortality is generally higher. In mammals, based on experimental models of rats injected with endotoxin (LPS), a biphasic thermal response is suggested to be a regulated process. The initial Tb reduction, which avoids tissue hypoxia and damage because of reduction in O2 demands, is followed by fever, which is considered to be a beneficial response when the LPS concentrations become lower throughout the time. In fact, different humoral pathways are involved in each thermal response, as for example, cyclooxygenase (COX)-1 in the Tb reduction and COX-2 during fever. The demonstration of such phenomenon in other species is important for supporting the adaptive nature of thermal responses to systemic inflammation. In this context, birds are the other endothermic vertebrate group besides mammals, which deserve investigation. Objective: To use a precocious bird as animal model for investigating: 1) the effect of COX-2 and COX-1 inhibition on Tb changes induced by LPS; 2) the metabolic response to LPS under other two challenging conditions for O2 demand such as food deprivation and cold. Material and Methods: Five-day old chicks (Gallus gallus; ~100 g) injected with LPS (100 μg/kg, IM) decreased (-1.0±0.0oC) and increased Tb (+0.9±0.2oC) 1h and 4h after injection, respectively. Results: The selective COX-2 inhibitor (SC-236, 1.25 mg/kg) caused no change in the initial Tb fall but attenuated the subsequent fever. In contrast, SC560 (selective COX-1 inhibitor; 1, 2.5, 5 mg/kg) did not affect the Tb reduction, but the lower doses induced a faster increase of Tb after 2h of LPS injection. Regardless the feed (food deprived or not) and thermal (cold-25oC or neutral-30oC) conditions, O2 consumption was reduced 40-60 min after LPS injection, coinciding with Tb falling. The febrile response, however, was affected by cold and fasting as Tb increase was inhibited despite of no change in O2 consumption. Conclusions: Thus, our preliminary results suggest that, similarly to rats, the febrile response to LPS is affected by other O2 demands and may be modulated by COX-2 dependent pathways. In contrast, the initial thermal and metabolic decreases of Tb seem not to be affected by competing O2 demands and is independent of COX-2 activity. Keywords: Thermal, Metabolic Biphasic Response, inflammation, chikens, rats, Temperature, febrile response

Weather at different locations in the Hungarian lowland in different seasons (winter, summer) and times of day (morning, noon) is investigated from the human biometeorological point of view. Human thermal load characteristics of weather are described in terms of clothing resistance and operative temperature. Individual human thermal load–thermal sensation relationships have been estimated to study weather variation in the cities of Sopron (cooler part of Hungary) and Szeged (warmer part of Hungary). In the clothing resistance model, the humans are walking at a speed of 1.1 ms−1 in outdoor conditions without sweating. The main findings are as follows. (1) In the early summer mornings, the weather is sensed as “neutral” or “cool”, in these cases the inter-person variation effect is very small. (2) At noon in summer, heat stresses (clothing resistance parameter values less than −2 clo) are registered. In these cases, high temperature and irradiation, as well as low or moderate wind, characterized the atmospheric environment. Then, the inter-person variation effect is clearly visible. (3) The strength of summer heat excess at noon seems to be larger than the strength of winter heat deficit in the early morning. (4) Clothing resistance differences caused by inter-person variations and by weather variations between the cities of Sopron and Szeged are comparable in the majority of cases. When they are not comparable, the site variation effect is much larger than the inter-person variation effect. The clothing resistance model is constructed for individual use and it can be equally applied on both weather and climate data.

BACKGROUND: Non cephalic presentation in childbirth involves various risks to both the mother and the foetus. The incidence in Spain is 3.8% of all full-term pregnancies. The most common technique used to end the gestation in cases of non cephalic presentation is that of caesarian section, and although it provokes a lower rate of morbi-mortality than does vaginal delivery in such situations, there remains the possibility of traumatic injury to the foetal head and neck, while maternal morbidity is also increased. The application of heat (moxibustion) to an acupuncture point, in order to correct non cephalic presentation, has been practised in China since ancient times, but as yet there is insufficient evidence of its real effectiveness. METHODS/DESIGN: The experimental design consists of a multi-centre randomised controlled trial with three parallel arms, used to compare real moxibustion, sham moxibustion and the natural course of events, among pregnant women with a non cephalic presentation and a gestational duration of 33-35 weeks (estimated by echography). The participants in the trial will be blinded to both interventions. The results obtained will be analyzed by professionals, blinded with respect to the allocation to the different types of intervention. In addition, we intend to carry out a economic analysis. DISCUSSION: This trial will contribute to the development of evidence concerning moxibustion in the correction of non cephalic presentations. The primary outcome variable is the proportion of cephalic presentations at term. As secondary outcomes, we will evaluate the proportion of cephalic presentations at week 38 of gestation, determined by echography, together with the safety of the technique, the specificity of moxibustion and the control of the blinding process.This study has been funded by the Health Ministry of the Andalusian Regional Government. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10634508. [ABSTRACT FROM AUTHOR]

Background: Vestibular schwannomas (VS) are complex and heterogeneous human tumors arising from the Schwann cell compartment of the vestibulocochlear nerve. VS cause significant neurological deficit such as hearing loss and vestibular impairment, and in some cases death due to brainstem compression. There is an urgent need to find pharmacotherapies for VS since surgical removal and stereotactic radiosurgery are the only effective treatments. Cancer therapy based in the combination of drug-induced senescence and senolytics may provide an innovative pharmacological alternative for VS management., Methods: Senescence-associated β-galactosidase (SA-β-GAL) activity detection assay, real-time polymerase chain reaction (RT-PCR), western blotting and immunofluorescence, together with viability assays were used to analyze the response to different chemotherapy drugs of the human VS HEI-193 cell line. Human VS tumor paraffin sections were also studied for SA-β-GAL-stained cells., Results: We found that chemotherapy compounds induced genotoxic stress and cellular senescence in HEI-193 VS cells, as characterized by increased SA-β-GAL activity, growth arrest, increased levels of the cyclin-dependent kinase inhibitor p21 and the accumulation of DNA damage. These cellular senescence markers were also accompanied by an increase of senescence-associated secretory phenotype (SASP): IL6, IL8, IL1B and MMP1. Induction of senescence by chemotherapy rendered HEI-193 VS cells as druggable targets for senolytic compounds, as navitoclax. Thus, treatment with navitoclax selectively eliminated bleomycin-induced senescent HEI-193 VS cells by activating the extrinsic and intrinsic apoptosis pathways. Our data also show the presence of senescent cells, SA-β-GAL-positive stain, in human VS tumors, which are not present in healthy great auricular nerve sections., Conclusions: These findings suggest that a one-two punch strategy of pro-senescence therapy induced by chemotherapy treatment followed by senolytic therapy represents a new paradigm for the pharmacological treatment of VS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest concerning this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Sepsis, mainly caused by bacterial infections, is the leading cause of in-patient hospitalizations. After discharge, most sepsis survivors suffer from long-term medical complications, particularly chronic skeletal muscle weakness. To investigate this medical condition in detail, we previously developed a murine severe sepsis-survival model that exhibits long-term post-sepsis skeletal muscle weakness. While mitochondrial abnormalities were present in the skeletal muscle of the sepsis surviving mice, the relationship between abnormal mitochondria and muscle weakness remained unclear. Herein, we aimed to investigate whether mitochondrial abnormalities have a causal role in chronic post-sepsis muscle weakness and could thereby serve as a therapeutic target., Methods: Experimental polymicrobial abdominal sepsis was induced in 16-18 months old male and female mice using cecal slurry injection with subsequent antibiotic and fluid resuscitation. To evaluate the pathological roles of mitochondrial abnormalities in post-sepsis skeletal muscle weakness, we utilized a transgenic mouse strain overexpressing the mitochondria-specific antioxidant enzyme manganese superoxide dismutase (MnSOD). Following sepsis development in C57BL/6 mice, we evaluated the effect of the mitochondria-targeting synthetic tetrapeptide SS-31 in protecting mitochondria from sepsis-induced damage and preventing skeletal muscle weakness development. In vivo and in vitro techniques were leveraged to assess muscle function at multiple timepoints throughout sepsis development and resolution. Histological and biochemical analyses including bulk mRNA sequencing were used to detect molecular changes in the muscle during and after sepsis RESULTS: Our time course study revealed that post sepsis skeletal muscle weakness develops progressively after the resolution of acute sepsis and in parallel with the accumulation of mitochondrial abnormalities and changes in the mitochondria-related gene expression profile. Transgenic mice overexpressing MnSOD were protected from mitochondrial abnormalities and muscle weakness following sepsis. Further, pharmacological protection of mitochondria utilizing SS-31 during sepsis effectively prevented the later development of muscle weakness., Conclusions: Our study revealed that the accumulation of mitochondrial abnormalities is the major cause of post-sepsis skeletal muscle weakness. Pharmacological protection of mitochondria during acute sepsis is a potential clinical treatment strategy to prevent post-sepsis muscle weakness., Competing Interests: Declarations Ethics approval and consent to participate All animal experiments were conducted according to procedures described in our Animal Use Protocol #2009-0541 which is approved by the Institutional Animal Care and Use Committee at the University of Kentucky. Consent for publication Not Applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Rotator cuff tears are potentially a career-ending injury for athletes. The surgeon must identify which patients will benefit from surgical repair. The factors to consider are age, type of sport, time since injury, athlete's level, and the patient's expectations. An essential and independent fact determining the surgical treatment is whether the damage is due to overuse or from a traumatic/collision injury. Some sports are more demanding than others resulting in different return-to-participation (RTP) rates. This RTP return rate can present a real challenge and more so by a desire to reach the pre-injury level of play. The incidence of rotator cuff tearing varies from one sport to another. In football players this can be 12% whereas for tennis players this incidence is 4% to 17%. The RTP rate must be considered when making treatment decisions and is influenced by the level of the athlete: for professional athletes, the rate is 61%, and for recreational 73%. When the surgeon and the patient decide on the surgical treatment, the surgeon must consider whether to perform a double-row or a single-row rotator cuff tendon repair. The decision-making and the surgical technique will be addressed., Competing Interests: Disclosure: The authors declare no conflict of interest, (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Umbilical cord blood (UCB) serves as a source of hematopoietic stem and progenitor cells (HSPCs) utilized in the regeneration of hematopoietic and immune systems, forming a crucial part of the treatment for various benign and malignant hematological diseases. UCB has been utilized as an alternative HSPC source to bone marrow (BM). Although the use of UCB has extended transplantation access to many individuals, it still encounters significant challenges in selecting a histocompatible UCB unit with an adequate cell dose for a substantial proportion of adults with malignant hematological diseases. Consequently, recent research has focused on developing ex vivo expansion strategies for UCB HSPCs. Our results demonstrate that co-cultures with the investigated mesenchymal stromal cells (MSCs) enable a 10- to 15-fold increase in the cellular dose of UCB HSPCs while partially regulating the proliferation capacity when compared to HSPCs expanded with early acting cytokines. Furthermore, the secretory profile of UCB-derived MSCs closely resembles that of BM-derived MSCs. Moreover, both co-cultures exhibit alterations in cytokine secretion, which could potentially impact HSPC proliferation during the expansion process. This study underscores the fact that UCB-derived MSCs possess a remarkably similar supportive capacity to BM-derived MSCs, implying their potential use as feeder layers in the ex vivo expansion process of HSPCs.

Diversity is widely recognized as a driver of excellence and innovation. In recent years, women have become an increasingly significant part of the rheumatology workforce. We aimed to assess the gender representation of the leading rheumatology journals' editors and to explore whether editors' gender correlates with the gender of the first and last authors of published articles. We conducted a cross-sectional study and extracted editorial members of rheumatology journals in quartiles 1 to 3 (Clarivate Analytics) from each journal's website. We categorized editorial positions according to the level of influence in manuscript acceptance decision-making (levels I to III). The gender of editors and of the first and last authors in all 2019 original articles published in a sample of 15 rheumatology journals was assigned using a combination of digital gallery and manual searches. There were 2242 editors' names retrieved from 43 journals, 24 (26%) of the 94 editors at level I, 139 (36%) of 385 editors at level II, and 469 (27%) of 1763 at level III were female. The imbalance between journals was heterogeneous. Females were the first authors in 1342 (48%) and the last authors in 969 (35%) of the 2797 published articles. However, we found no significant correlation between editors' and authors' gender. Our data showed uneven gender representation on the editorial boards of most rheumatology journals, but we did not find any apparent vertical segregation or influence on publishing by gender. Our findings suggest that a generational transition may be occurring among authors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: The primary aim of this study was to evaluate the presence of diversity and inclusion promotion among US physical medicine and rehabilitation residency program Websites. A list of physical medicine and rehabilitation residency programs was obtained from the Fellowship and Residency Electronic Interactive Database. The program Website links were obtained from the Fellowship and Residency Electronic Interactive Database or Google. Two reviewers evaluated the presence of 11 predetermined diversity and inclusion metrics. The presence of individual resident and faculty photos and biographies was also evaluated. Cross-sectional and descriptive analyses were performed. A total of 90 physical medicine and rehabilitation residency program Websites were reviewed. Only 15 (17%) Websites met at least 1 of the 11 predetermined criteria. Nine (10%) Websites mentioned diversity in their program mission statement, whereas 7 (8%) included a separate diversity statement. Eight (9%) Websites had a dedicated diversity page/section. Of Websites that included information on their residents and faculty, 62 (85%) had completed 100% of resident photos and 41 (47%) Websites had completed 100% of faculty photos. A total of 30 (41%) Websites had completed 100% of resident biographies, and 15 (17%) Websites had completed 100% of faculty biographies. Less than 20% of all residency program Websites promoted diversity and inclusion. Residency Websites lack key information that prospective applicants use to evaluate diversity., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction  There is consensus on the need for early microsurgical reconstruction in birth palsies involving three or more roots, that is, extensive partial palsies and total palsies. The fundamental principles of these operations are complete exploration and judicious use of the ruptured stumps by nerve grafting to suitable distal targets. The frequent observation of root avulsions in such cases makes it imperative to look for extraplexual nerve donors for some functions. Intercostal nerves are readily available in such patients. Materials and Methods  This is a study of 50 patients of extensive partial and total birth palsies operated upon by the senior author between 1995 and 2010. These included 33 patients with total palsies, 16 patients with near total palsies, and one patient with C56 deficit (operated upon more than 20 years ago). These children were all operated upon between 3 and 6 months of age, except for two patients in whom surgery was delayed till a year due to the phrenic nerve deficit noted at birth. Four intercostal nerves were transferred to the musculocutaneous nerve (MCN) by direct approximation with fibrin glue. Results  No respiratory complication was noted from the intercostal harvest. The follow-up ranged from 8 to 20 years (mean 10 years). As many as 48 of the 50 patients regained fully independent elbow flexion. In two cases, the procedure failed completely and had to be salvaged with a free functioning muscle transfer and reuse of the intercostal nerves. Conclusion  Intercostal nerve transfers can be relied upon for restoration of elbow flexion in birth palsies. The ruptured roots can then be utilized for augmenting shoulder function in partial palsies or for hand function in total palsies., Competing Interests: Conflicts of Interest None declared.

Purpose of Review: Advances in personal genomics have made predictive genetic testing increasingly popular. The purpose of this review is to examine and summarize recent literature regarding the ethical concerns and considerations surrounding genetic testing for Alzheimer's disease., Recent Findings: Four basic bioethical principles can be applied in the context of genetic testing: autonomy, nonmaleficence, beneficence and justice. The concepts of clinical validity, clinical utility and personal utility are also necessary for the ethical deliberation of genetic testing for Alzheimer's disease. Ethical considerations can differ among three distinct settings present in the literature: research, clinical and direct-to-consumer services. Studies have found that the negative psychosocial impact of genetic test results on the individual is limited, but emphasize the importance of pre/posttesting genetic counselling., Summary: The literature should ideally inform policy-making around genetic testing. There exists an urgent need for regulation, particularly in the direct-to-consumer (DTC) market, since interest for testing in this context is rapidly growing. Standardized protocols for disclosure should be developed, and there is a need to find ways to meet the growing need for genetic counselling. Importantly, comprehensive, evidence-based regulation requires that research be conducted in different contexts with more diverse participants.

The microbiome of the female reproductive tract has implications for women's reproductive health. We examined the vaginal microbiome in two cohorts of women who experienced normal term births: a cross-sectionally sampled cohort of 613 pregnant and 1,969 non-pregnant women, focusing on 300 pregnant and 300 non-pregnant women of African, Hispanic or European ancestry case-matched for race, gestational age and household income; and a longitudinally sampled cohort of 90 pregnant women of African or non-African ancestry. In these women, the vaginal microbiome shifted during pregnancy toward Lactobacillus-dominated profiles at the expense of taxa often associated with vaginal dysbiosis. The shifts occurred early in pregnancy, followed predictable patterns, were associated with simplification of the metabolic capacity of the microbiome and were significant only in women of African or Hispanic ancestry. Both genomic and environmental factors are likely contributors to these trends, with socioeconomic status as a likely environmental influence.

The incidence of preterm birth exceeds 10% worldwide. There are significant disparities in the frequency of preterm birth among populations within countries, and women of African ancestry disproportionately bear the burden of risk in the United States. In the present study, we report a community resource that includes 'omics' data from approximately 12,000 samples as part of the integrative Human Microbiome Project. Longitudinal analyses of 16S ribosomal RNA, metagenomic, metatranscriptomic and cytokine profiles from 45 preterm and 90 term birth controls identified harbingers of preterm birth in this cohort of women predominantly of African ancestry. Women who delivered preterm exhibited significantly lower vaginal levels of Lactobacillus crispatus and higher levels of BVAB1, Sneathia amnii, TM7-H1, a group of Prevotella species and nine additional taxa. The first representative genomes of BVAB1 and TM7-H1 are described. Preterm-birth-associated taxa were correlated with proinflammatory cytokines in vaginal fluid. These findings highlight new opportunities for assessment of the risk of preterm birth.

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

We screened the genomes of a broad panel of kinetoplastid protists for genes encoding proteins associated with the RNA interference (RNAi) system using probes from the Argonaute (AGO1), Dicer1 (DCL1), and Dicer2 (DCL2) genes of Leishmania brasiliensis and Crithidia fasciculata. We identified homologs for all the three of these genes in the genomes of a subset of these organisms. However, several of these organisms lacked evidence for any of these genes, while others lacked only DCL2. The open reading frames encoding these putative proteins were structurally analyzed in silico. The alignments indicated that the genes are homologous with a high degree of confidence, and three-dimensional structural models strongly supported a functional relationship to previously characterized AGO1, DCL1, and DCL2 proteins. Phylogenetic analysis of these putative proteins showed that these genes, when present, evolved in parallel with other nuclear genes, arguing that the RNAi system genes share a common progenitor, likely across all Kinetoplastea. In addition, the genome segments bearing these genes are highly conserved and syntenic, even among those taxa in which they are absent. However, taxa in which these genes are apparently absent represent several widely divergent branches of kinetoplastids, arguing that these genes were independently lost at least six times in the evolutionary history of these organisms. The mechanisms responsible for the apparent coordinate loss of these RNAi system genes independently in several lineages of kinetoplastids, while being maintained in other related lineages, are currently unknown.

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children.

Schwann cell migration is essential during the regenerative response to nerve injury, however, the factors that regulate this phenomenon are not yet clear. Here we describe that retinoic acid (RA), whose production and signaling activity are greatly enhanced during nerve regeneration, increases Schwann cell migration. This is accompanied by the up-regulation of NEDD9, a member of the CAS family of scaffold proteins previously implicated in migratory and invasive behavior in gliomas, melanomas and the neural crest cells from which Schwann cells derive. This RA-induced NEDD9 accumulation is due to augmented mRNA levels, as well as an increase of NEDD9 protein stability. Although all NEDD9 phospho-isoforms present in Schwann cells are induced by the retinoid, the hormone also changes its phosphorylation status, thus altering the ratio between the different isoforms. Silencing NEDD9 in Schwann cells had no effect on basal migratory ability, but completely abrogated RA-induced enhanced migration. Collectively, our results indicate that RA could be a major regulator of Schwann cell migration after nerve injury, thus offering a new insight into peripheral nerve repair., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We describe herein a Toll-like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic-polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK-BR-3 breast carcinoma cells. Our results show that poly(I:C)-conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA-TLR3 interaction. Such interaction also triggered apoptotic pathways in SK-BR-3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles' mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the English National Health Service (NHS), patients are now expected to choose the time and place of treatment and even choose the actual treatment. However, the theory on which patient choice is based and the implementation of patient choice are controversial. There is evidence to indicate that attitudes and abilities to make choices are relatively sophisticated and not as straightforward as policy developments suggest. In addition, and surprisingly, there is little research on whether making individual choices about care is regarded as a priority by the largest NHS patient group and the single largest group for most GPs-older people. This conceptual paper examines the theory of patient choice concerning accessing and engaging with healthcare provision and reviews existing evidence on older people and patient choice in primary care.

Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic-polycytidylic acid (poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-β (IFNβ), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.

Aims: The aims of this review are to identify and evaluate studies exploring the cost-effectiveness of primary angioplasty (PPCI) vs. thrombolysis (TL) for treating acute myocardial infarction (AMI)., Methods and Results: A comprehensive free-text searching identified economic evaluation studies that were reviewed with respect to their effectiveness data, identification, measurement and valuation of resource data, measurement and valuation of health outcomes (clinical and QALYs) and uncertainty analysis. A total of 14 studies were included in the review: seven were economic evaluations alongside RCTs, two community-based studies or registries and five decision-analytical models. PPCI was found to be cost-effective when compared with TL in eight studies, cost-saving in three, cost-neutral in one, and not significantly different in terms of both cost and benefits in two studies., Conclusions: The cost-effective evidence available is mainly derived from RCTs with stringent inclusion criteria using established catheter laboratories for providing PPCI treatment; these two components might restrict the generalisability of their "for managing patients with STEMI in hospital" settings. In order to aid policy makers on the real costs and benefits of the PPCI and TL, it is necessary to conduct more analyses with data from the real world in which there are more strategies evaluated for delivering PPCI than merely those in established catheter laboratories.

Herein, we report the biochemical and functional characterization of a novel Ca(2+)-activated nucleoside diphosphatase (apyrase), CApy, of the intracellular gut pathogen Cryptosporidium. The purified recombinant CApy protein displayed activity, substrate specificity and calcium dependency strikingly similar to the previously described human apyrase, SCAN-1 (soluble calcium-activated nucleotidase 1). CApy was found to be expressed in both Cryptosporidium parvum oocysts and sporozoites, and displayed a polar localization in the latter, suggesting a possible co-localization with the apical complex of the parasite. In vitro binding experiments revealed that CApy interacts with the host cell in a dose-dependent fashion, implying the presence of an interacting partner on the surface of the host cell. Antibodies directed against CApy block Cryptosporidium parvum sporozoite invasion of HCT-8 cells, suggesting that CApy may play an active role during the early stages of parasite invasion. Sequence analyses revealed that the capy gene shares a high degree of homology with apyrases identified in other organisms, including parasites, insects and humans. Phylogenetic analysis argues that the capy gene is most likely an ancestral feature that has been lost from most apicomplexan genomes except Cryptosporidium, Neospora and Toxoplasma.

Antiretroviral therapy (ART) improves the quality of life of people living with HIV/AIDS. However, adherence remains a challenge. A total of eight focus group discussions (FGD) were conducted with participants from a randomised controlled trial that monitored strategies for managing ART in African adults: Development of Antiretroviral Therapy. All FGD participants had received ART for at least one year. Perceived benefits of ART were key motivators for adherence. These benefits included improved physical health, restored self-esteem, acceptance in the community and hope for a longer and healthier life and reduced fear of HIV/AIDS-related death. Barriers to adherence included a high pill burden, ART side effects and socio-economic constraints, including lack of food and safe water for taking the pills. Visible ART side effects and involvement in an exclusively HIV/AIDS clinic could expose their HIV status, thus exacerbating stigma. Gender and socio-economic differences were found in the variety of strategies employed to ensure adherence. ART was perceived as improving the overall quality of life of recipients; however, it is crucial for ART programmes to be gender and socio-economic cognizant in order to enhance adherence to a lifelong therapy.

Cryptosporidiosis is a ubiquitous infectious disease, caused by the protozoan parasites Cryptosporidium hominis and Cryptosporidium parvum, leading to acute, persistent, and chronic diarrhea with life-threatening consequences in immunocompromised individuals. In developing countries, cryptosporidiosis in early childhood has been associated with subsequent significant impairment in growth, physical fitness, and intellectual abilities. Currently, vaccines are unavailable and chemotherapeutics are toxic and impractical, and agents for immunoprophylaxis or treatment of cryptosporidiosis are a high priority. Availability of the genome sequences for C. hominis and C. parvum provides new opportunities to procure and examine novel vaccine candidates. Using the novel approach of "reverse vaccinology," we identified several new potential vaccine candidates. Three of these antigens--Cp15, profilin, and a Cryptosporidium apyrase--were delivered in heterologous prime-boost regimens as fusions with cytolysin A (ClyA) in a Salmonella live vaccine vector and as purified recombinant antigens, and they were found to induce specific and potent humoral and cellular immune responses, suggesting their potential as new vaccinogens against Cryptosporidium infection.

It has been known for decades that some insect-infecting trypanosomatids can survive in culture without heme supplementation while others cannot, and that this capability is associated with the presence of a betaproteobacterial endosymbiont in the flagellate's cytoplasm. However, the specific mechanisms involved in this process remained obscure. In this work, we sequence and phylogenetically analyze the heme pathway genes from the symbionts and from their hosts, as well as from a number of heme synthesis-deficient Kinetoplastida. Our results show that the enzymes responsible for synthesis of heme are encoded on the symbiont genomes and produced in close cooperation with the flagellate host. Our evidence suggests that this synergistic relationship is the end result of a history of extensive gene loss and multiple lateral gene transfer events in different branches of the phylogeny of the Trypanosomatidae.

Background: Cryptosporidiosis is a ubiquitous infectious disease, caused by the protozoan parasites Cryptosporidium hominis and C. parvum, leading to acute, persistent and chronic diarrhea worldwide. Although the complications of this disease can be serious, even fatal, in immunocompromised patients of any age, they have also been found to lead to long term effects, including growth inhibition and impaired cognitive development, in infected immunocompetent children. The Cryptosporidium life cycle alternates between a dormant stage, the oocyst, and a highly replicative phase that includes both asexual vegetative stages as well as sexual stages, implying fine genetic regulatory mechanisms. The parasite is extremely difficult to study because it cannot be cultured in vitro and animal models are equally challenging. The recent publication of the genome sequence of C. hominis and C. parvum has, however, significantly advanced our understanding of the biology and pathogenesis of this parasite., Methodology/principal Findings: Herein, our goal was to identify cis-regulatory elements associated with heat shock response in Cryptosporidium using a combination of in silico and real time RT-PCR strategies. Analysis with Gibbs-Sampling algorithms of upstream non-translated regions of twelve genes annotated as heat shock proteins in the Cryptosporidium genome identified a highly conserved over-represented sequence motif in eleven of them. RT-PCR analyses, described herein and also by others, show that these eleven genes bearing the putative element are induced concurrent with excystation of parasite oocysts via heat shock., Conclusions/significance: Our analyses suggest that occurrences of a motif identified in the upstream regions of the Cryptosporidium heat shock genes represent parts of the transcriptional apparatus and function as stress response elements that activate expression of these genes during excystation, and possibly at other stages in the life cycle of the parasite. Since heat shock and excystation represent a critical step in the development of the infectious sporozoite form of Cryptosporidium, these results provide important insight into the pathogenicity of the parasite.

Background: Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers., Results: Using different breast cancer cell models, we show here that depending on the cellular context retinoids can signal either towards cell death or cell survival. Indeed, retinoids can induce the expression of pro-apoptotic (i.e. TRAIL, TNF-Related Apoptosis-Inducing Ligand, Apo2L/TNFSF10) and anti-apoptotic (i.e. cIAP2, inhibitor of apoptosis protein-2) genes. Promoter mapping, gel retardation and chromatin immunoprecipitation assays revealed that retinoids induce the expression of this gene mainly through crosstalk with NF-kappaB. Supporting this crosstalk, the activation of NF-kappaB by retinoids in T47D cells antagonizes the apoptosis triggered by the chemotherapeutic drugs etoposide, camptothecin or doxorubicin. Notably apoptosis induced by death ligands (i.e. TRAIL or antiFAS) is not antagonized by retinoids. That knockdown of cIAP2 expression by small interfering RNA does not alter the inhibition of etoposide-induced apoptosis by retinoids in T47D cells reveals that stimulation of cIAP2 expression is not the cause of their anti-apoptotic action. However, ectopic overexpression of a NF-kappaB repressor increases apoptosis by retinoids moderately and abrogates almost completely the retinoid-dependent inhibition of etoposide-induced apoptosis. Our data exclude cIAP2 and suggest that retinoids target other regulator(s) of the NF-kappaB signaling pathway to induce resistance to etoposide on certain breast cancer cells., Conclusions: This study shows an important role for the NF-kappaB pathway in retinoic acid signaling and retinoic acid-mediated resistance to cancer therapy-mediated apoptosis in breast cancer cells, independently of cIAP2. Our data support the use of NF-kappaB pathway activation as a marker for screening that will help to develop novel retinoids, or retinoid-based combination therapies with improved efficacy.

Background: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa., Methods: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779., Findings: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases)., Interpretation: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment., Funding: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A systematic study of the effect of design and operation conditions of an electrochemical reactor on the treatment time for arsenic (As) electro-removal from underground water (GW) was carried out to analyse the energy and electrode consumption. The effects of four factors--current density, interelectrode distance, electrode area-volume ratio, and liquid motion driving mode--were evaluated. The response variables were the energy and the electrode consumption and the treatment time to reduce the GW residual As concentration to 10 microg L(-1), which is the maximum contaminant level (MCL) established by the World Health Organization (WHO) in drinking water. The results obtained in this study showed that the factor that had the greatest effect on most of the response variables was the liquid motion driving mode. The best residence time was 20s, which favoured low energy consumption (58.78 Wh m(-3)) and low electrode material loss (9.59 g m(-3)).

Informal sources of care may lead to ineffective use of antimalarial drugs. A survey conducted in Malawi estimated the frequency of use of informal and formal services, medications, and household costs. A total of 508 household interviews were conducted. Treatment with an antimalarial was reported in 24% of young children accessing the informal sector and in 91% accessing formal services. Informal care was associated with shorter travel and waiting times, a lower proportion of carers or feverish adults missing work or studies and losing earnings, and a lower proportion of older children missing studies or work. Total out of pocket costs of fever episodes constitutes between 9% and 14% in young children and 18% in adults of their total available resources. Patients may perceive informal services to be associated with opportunity cost advantages; however, these may be associated with health risks of inadequate prescribing, particularly in young children.

The transcription factor T-bet (T-box, expressed in T cells), promotes type I immunity to pathogens through effects involving T cells and dendritic cells. In CD8(+) T cells, many of the functions of T-bet are redundant with those of eomesodermin (Eomes), a paralogue of T-bet. We therefore investigated the role of T-bet in immunity to Trypanosoma cruzi, an intracellular pathogen that causes Chagas disease, and which requires CD8(+) T cells for resistance. T-bet-deficient mice (tbx21(-/-)) were highly susceptible to T. cruzi infection, marked by severe liver pathology. CD8(+) T cells from infected tbx21(-/-) mice expressed typical markers of activation, including CD44 and CD25. In striking contrast, there was a 10-fold reduction in the number of antigen-specific CD8(+) T cells in tbx21(-/-) mice. This reduction was not a consequence of increased apoptosis or altered tissue-specific migration. Further, antigen-presenting cell (APC) functions in tbx21(-/-) mice were normal as we observed comparable levels of B7-1, B7-2 and CD40 expression as well as normal antigen-driven proliferation of wild-type CD8(+) T cells in infected tbx21(-/-) mice. However, adoptive transfer of naïve T cells from tbx21(-/-) donors into infected Rag-2-deficient mice (tbx21(+/+)) demonstrated a similar quantitative defect in CD8(+) T-cell expansion. These data demonstrate that T-bet facilitates immunity to T. cruzi by promoting the expansion of T. cruzi-specific CD8(+) T cells in a T cell-intrinsic manner. They also serve to further illustrate the multifaceted functions of T-box proteins in regulating quantitative aspects of T-cell immunity, in addition to qualitative components such as cytokine production.

HIV/AIDS has had a devastating impact at individual, household and community levels. This qualitative research investigates the role of HIV voluntary counselling and testing (VCT) and treatment in enabling HIV-positive Ugandans to cope with this disease. Twelve predetermined focus group discussions (FGDs) were conducted; six with men and six with women. Half of the men and women's groups were receiving antiretroviral therapy (ART) and half were not. An FGD was held with the health care providers administering ART. Testing for HIV was perceived as soliciting a death warrant. Participants affirmed that the incentive for testing was the possibility of accessing free ART. They described experiencing gender-variant stigma and depression on confirming their HIV status and commended the role of counselling in supporting them to adopt positive living. For those receiving ART, counselling reinforced treatment adherence. The findings also revealed gender differences in treatment adherence strategies. ART was described to reduce disease symptoms and restore physical health allowing them to resume their daily activities. Additionally, ART was preferred over traditional herbal treatment because it had clear dosages, expiry dates and was scientifically manufactured. Those that were not receiving ART bore myths and misconceptions about the effectiveness and side effects of ART, delaying the decision to seek treatment. Stigma and the attached concern of HIV/AIDS-related swift death, is a major barrier for VCT. Based on this study's findings, ensuring the provision of quality assured and gender conscious VCT and ART delivery services will enhance positive living and enforce compliance to ART programmes.

Background: Trypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host. Constraint-based modeling has emerged in the last decade as a useful approach to integrating genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of research and published in the literature., Results: We present a validated, constraint-based model of the core metabolism of Trypanosoma cruzi strain CL Brener. The model includes four compartments (extracellular space, cytosol, mitochondrion, glycosome), 51 transport reactions, and 93 metabolic reactions covering carbohydrate, amino acid, and energy metabolism. In addition, we make use of several replicate high-throughput proteomic data sets to specifically examine metabolism of the morphological form of T. cruzi in the insect gut (epimastigote stage)., Conclusion: This work demonstrates the utility of constraint-based models for integrating various sources of data (e.g., genomics, primary biochemical literature, proteomics) to generate testable hypotheses. This model represents an approach for the systematic study of T. cruzi metabolism under a wide range of conditions and perturbations, and should eventually aid in the identification of urgently needed novel chemotherapeutic targets.

Arsenic (As) was removed electrochemically from underground water (GW) by electrocoagulation (EC) process employing a bipolar cell configuration with continuous flow using iron electrodes. A kinetic model derived from the Lagergren equation was applied to specify the kinetics of the arsenic removal reaction. Elucidation of the effect of the liquid flow rate on the treatment time and on the simulation results of the model was achieved. The results showed that treatment times decreased from 10.50 min to 0.75 min as the flow rate decreased from 3.500 to 0.875 L min(-1) and the current density varied from 15 to 45 A m(-2) respectively. The used sorption kinetic model successfully describes the arsenic removal by this process. The coefficients of determination were found to be very high in all cases (R(2)>0.99) indicating a good fit of the experimental data to Lagergren model.

Objective: To assess the psychometric performance of using standard gamble (SG), time trade-off (TTO) and visual analogue scale (VAS) in the evaluation of three predetermined HIV/AIDS health states in HIV-infected Ugandans, for use in cost-effectiveness analyses., Methods: We recruited participants with CD4 cells <200/microl from the Development of AntiRetroviral Therapy in Africa (DART) trial cohort [randomized trial evaluating antiretroviral therapy (ART) management strategies] in Uganda, before they initiated ART (n = 276). A comparison group of ART-naive HIV-infected individuals was recruited from the Entebbe Cohort study (n = 159). Participants were interviewed and asked to rate his/her own health state using VAS; rank and evaluate HIV/AIDS predetermined health states using TTO and SG relative to an improved health state. Tools were tested for psychometrical properties., Results: Women constituted 64% and 76% of the DART and Entebbe Cohorts. Mean age was 36.5 and 36.7 years, respectively. Participants could discriminate between predetermined HIV/AIDS health states. Deterioration in health status was associated with a reduction in rating scores (VAS), increased willingness to give up time (TTO) and acceptance of increased risk (SG) to achieve a better health state, independent of the participant's actual health state, as measured by CD4 cell counts., Conclusion: VAS, TTO and SG have good psychometric properties, making them good candidates for use in resource-constrained settings. Further research in a wider population is necessary to generate an evidence base with which to inform resource allocation decisions.

Background: Despite policies advocating centralised transfusion services based on voluntary donors, the hospital-based replacement donor system is widespread in sub-Saharan Africa., Aims: To evaluate the cost of all laboratory resources needed to provide a unit of safe blood in rural Malawi using the family replacement donor system, Methods: Full economic costs of all laboratory tests used to screen potential donors and to perform cross-matching were documented in a prospective, observational study in Ntcheu district hospital laboratory., Results: 1729 potential donors were screened and 11,008 tests were performed to ensure that 1104 units of safe blood were available for transfusion. The annual cost of all transfusion-related tests (in 2005 USdollars) was USdollars 17,976, equivalent to USdollars 16.28 per unit of transfusion-ready blood. Transfusion-related tests used 53% of the laboratory's total annual expenditure of USdollars 33,608., Conclusions: This is the first study to provide prospective economic costs of all laboratory tests associated with the family replacement donor system in a district hospital in Africa. Results show that despite potential economies of scale, a unit of blood from the centralised system costs about three times as much as one from the hospital-based "replacement" system. Factors affecting these relative costs are complex but are in part due to the cost of donor recruitment in centralised systems. In the replacement system the cost of donor recruitment is entirely borne by families of patients needing a blood transfusion.

Colorectal cancer is a disease that originates from the neoplastic transformation of epithelial cells of the colon and rectum, as a result of the accumulation of genetic and epigenetic aberrations. At least four sequential genetic changes, affecting one oncogene (KRAS) and three tumor suppressor genes (APC, SMAD4 and TP53), are required for the development of colorectal cancer. Abundant experimental studies and epidemiological data, as well as several human clinical trials suggest a protective effect of Vitamin D against colon carcinogenesis. Hypercalcemia, a side effect of natural Vitamin D, has currently restricted its therapeutic use; however, the development of new synthetic analogs with reduced hypercalcemic activity is promising for cancer therapy and prevention. Extensive research to elucidate the mechanisms underlying the anti-cancer action of Vitamin D is being undertaken. Understanding the complex molecular and cellular networks induced by Vitamin D or its analogs will improve the use of these compounds for the prevention and treatment of colorectal cancer.

Although the main role of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is to regulate calcium homeostasis, the valuable therapeutic applications of this compound have led to the search of new 1,25-(OH)(2)D(3)-vitamin D receptor (VDR) ligands with less side effects. In this work we have characterized seven 1,25-(OH)(2)D(3) derivatives (ZK136607, ZK161422, ZK157202, ZK159222, ZK168492, ZK191732, and ZK168289). ZK157202 is an agonist that gives a pattern similar to that of 1,25-(OH)(2)D(3) or ZK161422 in limited trypsin digestion assays, is able to recruit p160 and VDR-interacting protein 205 coactivators, is as potent as 1,25-(OH)(2)D(3) to stimulate vitamin D response element-dependent transcription in HeLa cells, and acts as a superagonist in human embryonic kidney 293T cells. This compound is also more potent than the natural ligand to transrepress the activation of the retinoic acid receptor beta2 promoter by retinoic acid and the response of the collagenase promoter to 4alpha-12-O-tetradecanoylphorbol 13-acetate. ZK136607, ZK168492, ZK191732, and ZK168289 have a profile similar to that of the partial antagonist ZK159222. They induce an antagonistic-type proteolytic pattern, do not recruit classical coactivators, and have little transactivation potency. However, they act in a cell context-dependent manner because they lack activity in HeLa cells while presenting some agonistic activity in human embryonic kidney 293T cells, or vice versa. Furthermore, some of these compounds have a dissociated activity: they cannot transactivate but they are as potent as 1,25-(OH)(2)D(3) in transrepression assays. Together our results demonstrate the existence of novel VDR ligands with variable biological functions and dissociated activity. They should represent useful tools for studying VDR function and could have therapeutic utility.

Retinoic acid (RA) cures more than 75% of patients with acute promyelocytic leukemia (APL). Here, we review the various anti-cancer activities of retinoids and rexinoids, alone and in combination with other drugs, with emphasis on the RA-dependent induction of a cancer-cell-selective apoptosis signaling pathway to which multiple anti-cancer signals converge. These findings identify the TRAIL (tumor-necrosis-factor-related apoptosis-inducing ligand) pathway as a central cell-autonomous anti-cancer weapon that can act independently of the immune system.