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Background: The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified., Methods: Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques., Results: TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients., Conclusion: The findings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Persistent inflammation is a major contributor to healing impairment in diabetic chronic wounds. Paradoxically, diabetic wound environment during the acute phase of healing is completely different because it exhibits a reduced macrophage response owing to inadequate expression of CCL2 proinflammatory cytokine. What causes a reduction in CCL2 expression in diabetic wounds early after injury remains unknown. In this study, we report that in contrast to prolonged exposure to high glucose, which makes monocytes proinflammatory, short-term exposure to high glucose causes a rapid monocyte reprogramming, manifested by increased expression and secretion of IL-10, which in an autocrine/paracrine fashion reduces glucose uptake and transforms monocytes into an anti-inflammatory phenotype by dampening signaling through toll-like receptors. We show that IL-10 expression is significantly increased in diabetic wounds during the acute phase of healing, causing significant reductions in toll-like receptor signaling and proinflammatory cytokine production, delaying macrophage and leukocyte responses, and underlying healing impairment in diabetic wounds. Importantly, blocking IL-10 signaling during the acute phase of healing improves toll-like receptor signaling, increases proinflammatory cytokine production, enhances macrophage and leukocyte responses, and stimulates healing in diabetic wounds. We posit that anti-IL-10 strategies have therapeutic potential if added topically after surgical debridement, which resets chronic wounds into acute fresh wounds., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Infection is a major co-morbidity that contributes to impaired healing in diabetic wounds. Although impairments in diabetic neutrophils have been blamed for this co-morbidity, what causes these impairments and whether they can be overcome, remain largely unclear. Diabetic neutrophils, isolated from diabetic individuals, exhibit chemotaxis impairment but this peculiar functional impairment has been largely ignored because it appears to contradict the clinical findings which blame excessive neutrophil influx as a major impediment to healing in chronic diabetic ulcers. Here, we report that exposure to glucose in diabetic range results in impaired chemotaxis signaling through the formyl peptide receptor (FPR) in neutrophils, culminating in reduced chemotaxis and delayed neutrophil trafficking in the wound of Lepr db (db/db) type two diabetic mice, rendering diabetic wound vulnerable to infection. We further show that at least some auxiliary receptors remain functional under diabetic conditions and their engagement by the pro-inflammatory cytokine CCL3, overrides the requirement for FPR signaling and substantially improves infection control by jumpstarting the neutrophil trafficking toward infection, and stimulates healing in diabetic wound. We posit that CCL3 may have therapeutic potential for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process which is intended to reset chronic ulcers into acute fresh wounds., Competing Interests: RR, JZ, SS, KD, SW, MM, DF, YA, TP, RE, EG, TK, AZ, JR No competing interests declared, SS Rush University Medical Center has filed a patent (International Application Number: PCT/US19/41112). Dr. Sasha Shafikhani is the listed inventor on this application, (© 2022, Roy et al.)

Disparities in SARS-CoV-2 genomic surveillance have limited our understanding of the viral population dynamics and may delay identification of globally important variants. Despite being the most populated country in Africa, Nigeria has remained critically under sampled. Here, we report sequences from 378 SARS-CoV-2 isolates collected in Oyo State, Nigeria between July 2020 and August 2021. In early 2021, most isolates belonged to the Alpha "variant of concern" (VOC) or the Eta lineage. Eta outcompeted Alpha in Nigeria and across West Africa, persisting in the region even after expansion of an otherwise rare Delta sub-lineage. Spike protein from the Eta variant conferred increased infectivity and decreased neutralization by convalescent sera in vitro. Phylodynamic reconstructions suggest that Eta originated in West Africa before spreading globally and represented a VOC in early 2021. These results demonstrate a distinct distribution of SARS-CoV-2 lineages in Nigeria, and emphasize the need for improved genomic surveillance worldwide., (© 2022. The Author(s).)

Introduction: Dermatologic complaints are a common reason for emergency department visits., Methods: Retrospective chart review from 1 January 2015 to 31 December 2019. Patients in the Mayo Clinic Emergency Department receiving dermatology consultation were included., Results: Dermatitis (24.7%, n  = 113), infection (20.4%, n  = 93), and drug reaction (10.3%, n  = 47) accounted for the majority of diagnoses. Emergency department providers often provide no diagnosis (38%) or a differential diagnosis (22%), and dermatology consultation frequently alters diagnosis (46%) and treatment (83%). Patients receiving in-person consultations are admitted more frequently than those receiving teledermatology consultations (40% vs. 16%, p  < 0.001). Primary diagnostic concordance with subsequent dermatology evaluation is high for in-person (94%) and teledermatology (88%) consultations., Discussion: This is the largest study of emergency department dermatology consultations in the United States and the first to compare in-person and teledermatology emergency department consultation utilization in clinical practice. These modalities are utilized in a complementary fashion at our institution, with severe dermatologic diagnoses seen in-person. The valuable role of emergency department dermatologists is highlighted by frequent changes to diagnosis and treatment plans that result from dermatology consultation. Furthermore, our data suggest that teledermatology is an effective modality with the potential to expand access to dermatologic expertise in the emergency department setting.

Purpose: Integrative therapies such as yoga are potential treatments for many psychological and physical symptoms that occur during and/or after treatment for cancer. The purpose of the current study was to evaluate the patient-perceived benefit of yoga for symptoms commonly experienced by breast cancer survivors., Methods: 1,049 breast cancer survivors who had self-reported use of yoga on a follow up survey, in an ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR), received an additional mailed yoga-focused survey asking about the impact of yoga on a variety of symptoms. Differences between pre- and post- scores were assessed using Wilcoxon Signed Rank Test., Results: 802/1,049 (76%) of women who were approached to participate, consented and returned the survey. 507/802 (63%) reported use of yoga during and/or after their cancer diagnosis. The vast majority of respondents (89.4%) reported some symptomatic benefit from yoga. The most common symptoms that prompted the use of yoga were breast/chest wall pain, lymphedema, and anxiety. Only 9% of patients reported that they had been referred to yoga by a medical professional. While the greatest symptom improvement was reported with breast/chest wall pain and anxiety, significant improvement was also perceived in joint pain, muscle pain, fatigue, headache, quality of life, hot flashes, nausea/vomiting, depression, insomnia, lymphedema, and peripheral neuropathy, (all p-values <0.004)., Conclusion: Data supporting the use of yoga for symptom management after cancer are limited and typically focus on mental health. In this study, users of yoga often reported physical benefits as well as mental health benefits. Further prospective studies investigating the efficacy of yoga in survivorship are warranted., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Fergus Couch is on Ambry Genetics and Qiagen’s Speakers' Bureau, consults for AstraZeneca, receives travel grants from GRAIL and Qiagen, and receives research funding from GRAIL. Dr. Charles Loprinzi consults for PledPharmaCompany, Metys Pharmaceuticals, Asahi Kasei, Disarm Therapeutics, OnQuality Pharmaceuticals, NKMax, and Mitsubishi Tanabe Pharma, has intellectual property with Janssen, and receives research funding from Bristol-Myers Squibb., (© The Author(s) 2021.)

Purpose: The purpose of this study was to evaluate acupuncture use among breast cancer survivors, including perceived symptom improvements and referral patterns., Methods: Breast cancer survivors who had used acupuncture for cancer- or treatment-related symptoms were identified using an ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR). Additionally, Mayo Clinic electronic health records (MCEHR) were queried to identify eligible participants. All received a mailed consent form and survey including acupuncture-related questions about acupuncture referrals, delivery, and costs. Respondents were also asked to recall symptom severity before and after acupuncture treatment and time to benefit on Likert scales., Results: Acupuncture use was reported among 415 participants (12.3%) of the MCBDR. Among MCBDR and MCEHR eligible participants, 241 women returned surveys. A total of 193 (82.1%) participants reported a symptomatic benefit from acupuncture, and 57 (24.1% of participants) reported a "substantial benefit" or "totally resolved my symptoms" (corresponding to 4 and 5 on the 5-point Likert scale). The mean symptom severity decreased by at least 1 point of the 5-point scale for each symptom; the percentage of patients who reported an improvement in symptoms ranged from 56% (lymphedema) to 79% (headache). The majority of patients reported time to benefit as "immediate" (34%) or "after a few treatments" (40.4%). Over half of the participants self-referred for treatment; 24.1% were referred by their oncologist. Acupuncture delivery was more frequent in private offices (61.0%) than in hospital or medical settings (42.3%). Twelve participants (5.1%) reported negative side effects, such as discomfort., Conclusions: Acupuncture is commonly utilized by patients for a variety of breast cancer-related symptoms. However, patients frequently self-refer for acupuncture treatments, and most acupuncture care is completed at private offices, rather than medical clinic or hospital settings.

People with disabilities experience health disparities arising from social, environmental, and system-level factors. Evidence from a range of settings suggests women with disabilities have reduced access to health information and experience barriers to screening, prevention, and care services. This results in greater unmet health needs, particularly in relation to sexual and reproductive health. Women with disabilities are also more likely to experience physical and sexual violence than women without disabilities, further undermining their health. Community-based participatory research (CBPR) can generate knowledge and underpin action to address such health disparities and promote health equity. However, the potential and challenges of disability inclusion in CBPR, particularly in contexts of poverty and structural inequality such as those found in low- and middle-income countries, are not well documented. In this paper, we reflect on our experience of implementing and evaluating W-DARE, a three-year program of disability-inclusive CBPR aiming to increase access to sexual and reproductive health and violence-response services for women with disabilities in the Philippines. We discuss strategies for increasing disability inclusion in research and use a framework of reflexive solidarity to consider the uneven distribution of the benefits, costs, and responsibilities for action arising from the W-DARE program., (© 2020 The Authors. American Journal of Community Psychology published by Wiley Periodicals LLC on behalf of Society for Community Research and Action.)

Breast cancer is the most common invasive cancer in women worldwide. Functional follow-up of breast cancer genome-wide association studies has led to the discovery of genes that regulate endocrine therapy response in a SNP- and drug-dependent manner. Here, we will present four examples in which functional genomic studies from breast cancer clinical trials led to novel pharmacogenomic insights and molecular mechanisms of selective estrogen receptor modulators and aromatase inhibitors. The approach utilized for studying genetic variability described in this review offers substantial potential for meaningful discoveries that move the field toward precision medicine for patients.

Triple-negative breast cancer (TNBC) accounts for 15-20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.

Purpose: In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion., Methods: The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500., Results: Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM., Conclusions: We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.

Women with disabilities experience a range of violations of their sexual and reproductive rights. The Philippines ratified the United Nations Convention on the Rights of Persons with Disabilities and have laws in place to promote the rights to sexual and reproductive health and protection from violence. However, limited resourcing, and opposition to such laws undermine access to these rights for all women. Inadequate disability inclusion within policy and programming, and limited disability awareness of services, further impedes women with disabilities from attaining these rights. The W-DARE project (Women with Disability taking Action on REproductive and sexual health) was a three-year participatory action research program designed to (1) understand the sexual and reproductive health experiences and needs of women with disabilities; and (2) improve access to quality sexual and reproductive health, including violence response services, for women with disabilities in the Philippines. In response to the highlighted need for more information about sexual and reproductive health and greater access to services, the W-DARE team developed and implemented a pilot intervention focused on peer-facilitated Participatory Action Groups (PAGs) for women with disabilities. This paper focuses on the qualitative findings from the evaluation of this PAG intervention.

The Akt pathway is a central regulator that promotes cell survival in response to extracellular signals. Depletion of SIRT7, an NAD + -dependent deacetylase that is the least-studied sirtuin, is known to significantly increase Akt activity in mice through unknown mechanisms. In this study, we demonstrate that SIRT7 depletion in breast cancer cells results in Akt hyper-phosphorylation and increases cell survival following genotoxic stress. Mechanistically, SIRT7 specifically interacts with and deacetylates FKBP51 at residue lysines 28 and 155 (K28 and K155), resulting in enhanced interactions among FKBP51, Akt, and PHLPP, as well as Akt dephosphorylation. Mutating both lysines to arginines abolishes the effect of SIRT7 on Akt activity through FKBP51 deacetylation. Finally, energy stress strengthens SIRT7-mediated effects on Akt dephosphorylation through FKBP51 and thus sensitizes cancer cells to cytotoxic agents. These results reveal a direct role of SIRT7 in Akt regulation and raise the possibility of using the glucose analog 2-deoxy-D-glucose (2DG) as a chemo-sensitizing agent., Competing Interests: None., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

The most commonly reported data after natural disasters are the number of deceased and displaced and the structural and economic damage, whereas disability data are often lacking. Our study assessed disability among the survivors of the Haiyan/Yolanda typhoon that struck Philippines in 2013 and is aimed to identify which context-level variables are associated with higher disability. We used a cross-sectional design and administered a household questionnaire, an individual sociodemographic questionnaire, and the WHODAS 2.0 to 1982 adults. Logistic regression analysis was carried out to address the degree to which demographic variables, effects of the typhoon, individual health state, and rural or urban residence were associated with higher disability. Those aged above 65, employed individuals, students, those not living in their households, and those with one or more health condition or rating their own as health moderate or very poor had higher likelihood of having severe disability. Survivors living in rural contexts and those who received tools/materials to repair their houses were less likely to have higher disability. This study outlines that disability can and should be used as an indicator in surveys after emergencies to identify the most vulnerable groups, thus guiding policies, reconstruction strategies, and health and social interventions.

Background: International recognition that people with disabilities were excluded from the Millennium Development Goals has led to better inclusion of people with disabilities in the recently agreed Global Goals for Sustainable Development (SDGs) 2015-2030. Given the current global agenda for disability inclusion, it is crucial to increase the understanding of the situation of people with disabilities in the Philippines. The aim of this study was to estimate the prevalence of disability and compare the well-being and access to the community between people with and without disabilities., Methods: A population-based survey was undertaken in District 2 of Quezon City and in Ligao City. 60 clusters of 50 people aged 18 years and older were selected with probability proportion to size sampling from both locations. The Rapid Assessment of Disability (RAD) survey was used to identify people with disabilities based on their responses to activity limitations. The levels of well-being and access to the community for people with disabilities were compared with controls matched by age, gender, and cluster. Information on barriers to accessing the community was also collected., Results: The prevalence of disability was 6.8 (95 % CI: 5.9, 7.9) and 13.6 % (95 % CI: 11.4, 16.2) in Quezon City and Ligao City respectively. Psychological distress was the most commonly reported condition in both locations, although it was often reported with a co-morbid condition related to sensory, physical, cognitive, and communication difficulties. The prevalence of disability was associated with age and no schooling, but not associated with poverty. People with disabilities had significantly lower well-being scores and reduced access to health services, work, rehabilitation, education, government social welfare, and disaster management than people without disability. Having a disability and negative family attitudes were reported as barriers for people with disabilities participating in work, community meetings, religious activities, and social activities., Conclusions: The prevalence of disability among adults in District 2 of Quezon City and in Ligao City is higher than the estimated national prevalence of disability derived from the 2010 Philippines census. Disability is also associated with lower well-being and reduced participation across a number of domains of community life.

We report indomethacin as a photoresist that can be dry-deposited (as well as spin-coated), and developed in weak aqueous base. This is the first reported patterning of indomethacin as a resist material. Nanometer-scale patterns were achieved through DUV photolithography and the underlying patterning mechanism was investigated.

Background: The Philippines has ratified the United Nations Convention on the Rights of Persons with Disabilities and recently passed domestic legislation protecting the sexual and reproductive rights of people with disability. However women in the Philippines continue to report barriers to sexual and reproductive health services, and there is limited empirical evidence available to inform policy makers' efforts to respond. This study aims to contribute to the available evidence by examining service providers' perceptions of disability and their experiences providing sexual and reproductive health services to women with disability., Methods: The study was conducted as part of a larger three-year program of participatory action research that aims to improve the sexual and reproductive health of women with disabilities in the Philippines. Fourteen in-depth interviews and two focus group discussions were conducted with a total of thirty-two sexual and reproductive health service providers in Quezon City and Ligao. Qualitative data were analysed to identify key themes in participants' discussion of service provision to women with disability., Results: Analysis of service providers' accounts suggests a range of factors undermine provision of high quality sexual and reproductive health services to women with disability. Service providers often have limited awareness of the sexual and reproductive health needs of women with disability and inadequate understanding of their rights. Service providers have had very little training in relation to disability, and limited access to the resources that would enable them to provide a disability inclusive service. Some service providers hold prejudiced attitudes towards women with disability seeking sexual and reproductive health services, resulting in disability-based discrimination. Service providers are also often unaware of specific factors undermining the health of women with disability, such as violence and abuse., Conclusion: Recent legislative change in the Philippines opens a window of opportunity to strengthen sexual and reproductive health service provision across the country. However the development of services that are disability-inclusive will require substantial efforts to address supply-side barriers such as prejudiced service provider attitudes and limited capacity. Disability inclusion must be prioritised for the national goal of responsible parenthood and reproductive health to be realised for all.

Background: In many contexts, women with disability have less access to sexual and reproductive health information, screening, prevention, and care services than women without disability. Women with disability are also known to be more likely to experience physical and sexual violence than women without disability. In the Philippines, health service providers often have little awareness of the sexual and reproductive experiences of women with disability and limited capacity to provide services in response to their needs. Very limited data are available to inform development of disability-inclusive sexual and reproductive health, and violence prevention and response, services in the country. This paper presents the protocol for W-DARE (Women with Disability taking Action on REproductive and sexual health), a three-year program of participatory action research that aims to improve the sexual and reproductive health of women with disability in the Philippines., Design: W-DARE is a disability-inclusive program that will use mixed methods to 1) increase understanding of factors influencing the sexual and reproductive health of women with disability, and 2) develop, implement and evaluate local interventions to increase supply of and demand for services. W-DARE will generate data on the prevalence of disability in two districts; the wellbeing and community participation of people with and without disability, and identify barriers to community; and describe the sexual and reproductive health needs and experiences, and service-related experiences of women with disability. These data will inform the development and evaluation of interventions aiming to improve access to sexual and reproductive health services, and violence prevention and response services, for women with disability. Local women with disabilities, their representative organisations, and SRH service providers will be involved as members of the research team across all stages of the research., Discussion: This three-year study will provide evidence about factors undermining the sexual and reproductive health of women with disability in a lower-middle income country, and provide new insights about what may be effective in increasing access to services in settings of limited resources. Findings will be relevant across Asia and the Pacific. Analysis of the program will also provide evidence about disability-inclusion in participatory action research approaches.

Strain-promoted click chemistry of nucleosides and nucleotides with an azido group directly attached to the purine and pyrimidine rings with various cyclooctynes in aqueous solution at ambient temperature resulted in efficient formation (3 min to 3 h) of fluorescent, light-up, triazole products. The 2- and 8-azidoadenine nucleosides reacted with fused cyclopropyl cyclooctyne, dibenzylcyclooctyne, or monofluorocyclooctyne to produce click products functionalized with hydroxyl, amino, N-hydroxysuccinimide, or biotin moieties. The 5-azidouridine and 5-azido-2'-deoxyuridine were similarly converted to the analogous triazole products in quantitative yields in less than 5 min. The 8-azido-ATP quantitatively afforded the triazole product with fused cyclopropyl cyclooctyne in aqueous acetonitrile (3 h). The novel triazole adducts at the 2- or 8-position of adenine or 5-position of uracil rings induce fluorescence properties which were used for direct imaging in MCF-7 cancer cells without the need for traditional fluorogenic reporters. FLIM of the triazole click adducts demonstrated their potential utility for dynamic measuring and tracking of signaling events inside single living cancer cells.

Objective: Hispanics in Puerto Rico (PR) have a high prevalence of metabolic syndrome (met-syn), partially explained by low physical activity (PA) and possibly low cardiorespiratory fitness (VO2peak). Met-syn is also associated with lipodystrophy in HIV infected (HIV+) adults taking antiretroviral therapies. However, associations between met-syn, VO2peak, PA, sedentary behavior and lipodystrophy among HIV+ Hispanics have not been adequately reported. We tested the following hypotheses: 1) HIV+ Hispanics with lipodystrophy (HIV-Lipo) would have a higher prevalence of met-syn, lower VO2peak and PA, and higher sedentary behavior compared with those without lipodystrophy (HIV-no-Lipo) and without HIV infection (Non-HIV); and 2) met-syn would be inversely associated with VO2peak and PA, and directly associated with sedentary behavior., Methods: Ninety Hispanic adults (32 HIV-Lipo, 28 HIV-no-Lipo, 30 Non-HIV) completed measurements of VO2,peak, anthropometry, PA and sedentary behavior with accelerometry, blood pressure, fasting glucose, insulin, and lipids. ANOVA and chi-square tests were used to detect differences between groups, and regression analyses to test associations between variables., Results: More HIV-Lipo (69%) had met-syn compared with HIV-no-Lipo (39%) and Non-HIV (37%) (P = 0.002). Sedentary behavior and PA were not different, but VO2peak differed between all groups: lowest in HIV-Lipo and highest in non-HIV. PA and sedentary behavior were not associated with met-syn, but PA was directly associated with VO2peak (R2 = 0.26, p < 0.01). Also, a lower odds ratio for met-syn was observed with higher VO2peak (0.87; 95% CI: 0.83-0.95)., Conclusion: Met-syn is related to lipodystrophy in HIV+ Hispanics in PR, and high VO2peak may protect against met-syn in this population.

Populations of hematopoietic stem cells and progenitors are quite heterogeneous and consist of multiple cell subsets with distinct phenotypic and functional characteristics. Some of these subsets also appear to be interconvertible and oscillate between functionally distinct states. The multipotent hematopoietic cell line EML has emerged as a unique model to study the heterogeneity and interconvertibility of multipotent hematopoietic cells. Here we describe extensive phenotypic and functional heterogeneity of EML cells which stems from the coexistence of multiple cell subsets. Each of these subsets is phenotypically and functionally heterogeneous, and displays distinct multilineage differentiation potential, cell cycle profile, proliferation kinetics, and expression pattern of HSC markers and some of the key lineage-associated transcription factors. Analysis of their maintenance revealed that on a population level all EML cell subsets exhibit cell-autonomous interconvertible properties, with the capacity to generate all other subsets and re-establish complete parental EML cell population. Moreover, all EML cell subsets generated during multiple cell generations maintain their distinct phenotypic and functional signatures and interconvertible properties. The model of EML cell line suggests that interconvertible multipotent hematopoietic cell subsets coexist in a homeostatically maintained dynamic equilibrium which is regulated by currently unknown cell-intrinsic mechanisms.

In the present study, we carried out a structure-activity analysis in Trichomonas vaginalis of a series of adenosine and uridine analogues. The most potent compounds were found to be 2' and 3' modified adenosine analogues some of which are potent inhibitors of S-adenosylhomocysteine hydrolase. The 9-(2-deoxy-2-fluoro-β,D-arabinofuranosyl)adenine compound was more potent than metronidazole, a current FDA approved and commonly prescribed drug for treatment of trichomoniasis. Its IC(50) was 0.09 μM compared to 0.72 μM for metronidazole., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We have investigated the photochemical grafting of organic alkenes to atomically flat ZnO(10 ̅10) single crystals and ZnO nanorods as a way to produce functional molecule-semiconductor interfaces. Atomic force microscopy shows that photochemical grafting produces highly conformal, smooth molecular layers with no detectable changes in the underlying structure of the ZnO terraces or steps. X-ray photoelectron spectroscopy measurements show that grafting of a methyl ester-terminated alkene terminates near one monolayer, while alkenes bearing a trifluoroacetamide-protected amine form very smooth multilayers. Even with multilayers, it is possible to deprotect the amines and to link a second molecule to the surface with excellent efficiency and without significant loss of molecules from the surface. This demonstrates that the use of photochemical grafting, even in the case of multilayer formation, enables multistep chemical processes to be conducted on the ZnO surface. Photoresponse measurements demonstrate that functionalization of the surface does not affect the ability to induce field effects in the underlying ZnO, thereby suggesting that this approach to functionalization may be useful for applications in sensing and in hybrid organic-inorganic transistors and related devices., (© 2011 American Chemical Society)

Radical-mediated thiodesulfonylation of the vinyl and (α-fluoro)vinyl sulfones, derived from aldehydes and ketones, with aryl thiols in organic or aqueous medium provided access to vinyl and (α-fluoro)vinyl sulfides. The vinyl sulfides were formed predominantly with E stereochemistry independent of the stereochemistry of the starting vinyl sulfones.

Objective: Multipotent hematopoietic cell line EML can differentiate into myeloid, erythroid, megakaryocytic, and B-lymphoid lineages, but it remained unknown whether EML cells have T-cell developmental potential as well. The goal of this study was to determine whether the coculture with OP9 stromal cells expressing Notch ligand Delta-like 1 (OP9-DL1) could induce differentiation of EML cells into T-cell lineage., Materials and Methods: EML cells were cocultured with control OP9 or OP9-DL1 stromal cells in the presence of cytokines (stem cell factor, interleukin-7, and Fms-like tyrosine kinase 3 ligand). Their T-cell lineage differentiation was assessed through flow cytometry and reverse transcription polymerase chain reaction expression analysis of cell surface markers and genes characterizing and associated with specific stages of T-cell development., Results: The phenotypic, molecular, and functional analysis has revealed that in EML/OP9-DL1 cocultures with cytokines, but not in control EML/OP9 cocultures, EML cell line undergoes T-cell lineage commitment and differentiation. In OP9-DL1 cocultures, EML cell line has differentiated into cells that 1) resembled double-negative, double-positive, and single-positive stages of T-cell development; 2) initiated expression of GATA-3, Pre-Talpha, RAG-1, and T-cell receptor-Vbeta genes; and 3) produced interferon-gamma in response to T-cell receptor stimulation., Conclusions: These results support the notion that EML cell line has the capacity for T-cell differentiation. Remarkably, induction of T-lineage gene expression and differentiation of EML cells into distinct stages of T-cell development were very similar to previously described T-cell differentiation of adult hematopoietic stem cells and progenitors in OP9-DL1 cocultures. Thus, EML/OP9-DL1 coculture could be a useful experimental system to study the role of particular genes in T-cell lineage specification, commitment, and differentiation.

The c-kit receptor plays a vital role in self-renewal and differentiation of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). We have discovered that besides c-kit, the murine multipotent HSC/MPP-like cell line EML expresses the transcript and protein for a truncated intracellular form of c-kit receptor, called tr-kit. Notably, the tr-kit transcript and protein levels were down-regulated during cytokine-induced differentiation of the HSC/MPP-like cell line EML into myeloerythroid lineages. These findings prompted us to analyze tr-kit expression in purified murine fetal liver and bone marrow cell populations containing long-term repopulating (LTR) HSCs, short-term repopulating (STR) HSCs, MPPs, lineage-committed progenitors, and immature blood cells. Remarkably, these studies have revealed that in contrast to more widespread expression of c-kit, tr-kit is transcribed solely in cell populations enriched for LTR-HSCs, STR-HSCs, and MPPs. On the other hand, cell populations in which HSCs and MPPs are either present at a much lower frequency or are absent altogether, cells representing more advanced stages of differentiation into lymphoid and myeloid lineages do not express tr-kit. The observation that tr-kit is co-expressed with c-kit only in more primitive HSC- and MPP-enriched cell populations raises an exciting possibility that tr-kit functions either as a new component of the stem cell factor (SCF)/c-kit pathway or is involved in a novel signaling pathway, present exclusively in HSC and MPPs. Taken together, these findings necessitate functional characterization of tr-kit and analysis of its potential role in the self-renewal, proliferation, and/or differentiation of HSC and multipotent progenitors.

The Wnt-beta-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt-Ca(2+) signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of alphabeta lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4(+)CD8(+) thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting beta-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of beta-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt-Ca(2+) pathway alters canonical Wnt signaling and is critical for normal T cell development.

A cleaning validation method, ion chromatographic method with conductivity detection was developed and validated for the determination of traces of a clean-in-place (CIP) detergent. It was shown to be linear with a squared correlation coefficient (r(2)) of 0.9999 and average recoveries of 71.4% (area response factor) from stainless steel surfaces and 101% from cotton. The repeatability was found to be 2.17% and an intermediate precision of 1.88% across the range. The method was also shown to be sensitive with a detection limit (DL) of 0.13 ppm and a quantitation limit (QL) of 0.39 ppm for EDTA, which translates to less than 1 microL of CIP diluted in 100mL of diluent in both cases. The EDTA signal was well resolved from typical ions encountered in water samples or any other interference presented from swabs and surfaces. The method could be applied to cleaning validation samples. The validated method could be included as a suitable one for rapid and reliable cleaning validation program.

Anion chromatography with conductivity detection was chosen as the analytical technique for the development of a cleaning validation method for clean-in-place (CIP) detergents. The method was developed and validated for the determination of traces of the detergent CIP-200. It was shown to be linear with a squared correlation coefficient (r(2)) of 0.9999 and the accuracy experiments presented average recoveries of 88.2% (area response factor) from stainless steel surfaces. The repeatability was found to be 1.6% and an intermediate precision of 1.9% across the range. The method was also shown to be sensitive with an average Detection Limit (DL) of 0.23 ppm and a Quantitation Limit (QL) of 0.70 ppm based on the amount of phosphate in the detergent sample. The phosphate signal was well resolved from typical ions encountered in water samples or any other interference presented from swabs and surfaces. The method was applied to cleaning validation samples and proved to be suitable for rapid and reliable quality control.

A high performance liquid chromatography (HPLC) method for the detection of traces of LpHse (4-tert-amylphenol and 2-phenylphenol) has been developed and validated. The method was shown to be linear in the range from 0.5 to 10.00 ppm in solution. The method was also shown to be accurate with a recovery of up to 95% by area response for amylphenol and up to 94% by area response for phenylphenol from metal surfaces (4''x4'' un-polished 304 stainless steel plates) by means of swab material. The reproducibility of the method was determined to be 1.61% by area response and 1.52% by height response for amylphenol and 5.40% by area response and 13.77% by height response for phenylphenol from solutions reported as the pooled relative standard deviation. The developed method was also shown to be rugged by comparisons of different preparations by different analysts. The limit of detection was established to be 0.076 ppm by peak area, 0.079 ppm by peak height for amylphenol and 0.34 ppm by peak area, 0.82 ppm by peak height for phenylphenol from solution, and 1.77 ppb by peak area, 1.23 ppm by peak height for amylphenol and 1.23 ppm by peak area, 1.44 ppm by peak height for phenylphenol from recovery from metal studies. The limit of quantitation was established to be 0.25 ppm by peak area, 0.26 ppm by peak height for amylphenol and 1.14 ppm by peak area, 2.73 ppm by peak height for phenylphenol from solution, and 3.89 ppm by peak area, 4.11 ppm by peak height for amylphenol and 4.11 ppm by peak area, 4.79 ppm by peak height for phenylphenol from recovery from metal plates studies. This method can be employed to determine the presence of LpHse residues in cleaned equipments where the detergent was used.

Field bioassays were conducted to determine the efficacy of the intradomiciliary treatments of thermal fogging and ULV with formulations of cypermethrin, lambda-cyhalothrin and chlorpyrifos by using an Aedes aegypti strain from Playa municipality, Havana City, Cuba. The results show in all cases that the thermal treatments are more efficient than those of ULV. As regards chlorpyrifos 48 EC insecticide it caused in both types of treatment 100% of mortality without adding DDVP (Dichlorvos 50%), whereas for cypermethrin 25 EC it was obtained 100% of mortality in thermal treatments with DDVP or without it. It was not so for the ULV treatments that should be applied with DDVP to be efficient. The efficacy of Icon 2.5 EC and of lambda-cyhalothrin 2.5 EC behaves similarly to that of cypermethrin; however, treatments with ULV are not efficient even when they are potentiated with DDVP.

In this double-blind study, the efficacy and tolerability of a single dose of almotriptan (6.25 or 12.5 mg) was compared with placebo in the treatment of three consecutive migraine attacks of moderate or severe intensity. Of 1013 randomized patients, 722 evaluable patients completed the study. The total number of attacks relieved (severe or moderate pain reduced to mild or no pain) at 2 h post-dose was significantly higher (P < 0.001) after treatment with almotriptan 6.25 or 12.5 mg compared with placebo (60% and 70% vs. 38%, respectively). Moreover, a consistent response was achieved across and within patients for almotriptan 6.25 or 12.5 mg compared with placebo (pain relief in at least two out of three attacks within 2 h for 64% and 75% vs. 36%, respectively) and less than one-third of the patients relapsed within 24 h. Almotriptan was well tolerated with no significant differences between the almotriptan and placebo treatment groups in the percentage of patients reporting adverse events. Overall, the 12.5-mg dose was associated with the most favourable efficacy/tolerability ratio and is, therefore, the recommended dose.

The effects of fumaric and lactic acid on the total numbers of aerobic, psychrotrophic, and coliform bacteria on vacuum-packaged ground beef patties at 0, 1, 3, 5, 7, 10, and 14 days of storage at 4°C were studied. Fumaric acid treatments resulted in greater reductions in microbial growth than lactic acid treatments. When 5.0% fumaric acid was used, the lag phase was prolonged and microbial growth was reduced ( P < 0.05), with total aerobic, psychotrotrophic, and coliform populations reaching net maximum growths of only 1.46, 1.44, and 0.98 log units, respectively, after storage at 4°C for 10 days. Increasing the acid concentrations significantly decreased the growth of all microorganisms. The 5.0% lactic acid was the most inhibitory against coliforms, resulting in a 3.88-1og unit reduction after 10 days of storage.

Lean beef surfaces were inoculated with Escherichia coli O157:H7 and Listeria monocytogenes and then sanitized with fumaric, acetic, or lactic acid alone and in combined solutions of those acids at 55°C for 5 s. The initial inoculum level was 8.62 log CFU/cm 2 and 5.13 log CFU/cm 2 for L. monocytogenes and E. coli O157:H7, respectively. Fumaric acid at a concentration of 1% was the most effective acid in reducing the populations of L. monocytogenes by up to 1 log unit and E. coli O157:H7 by up to 1.3 log units when compared with acetic or lactic acids. The rank order of acids tested against the growth of L. monocytogenes and E. coli O157:H7 was fumaric acid followed by lactic and acetic acids. Fumaric acid at concentrations of 1.0% and 1.5% was more effective than any of the combined solutions of acids.

Pyomyositis, an endemic disease of tropical origin, is increasingly reported in temperate zones, especially in patients with diabetes mellitus and in the immunocompromised. A 28-year-old renal transplant recipient presented with perforating skin lesions (Kyrle's disease), thigh pain, and swelling associated with fever. A gallium scan of the thigh led to surgical exploration and a diagnosis of pyomyositis. To our knowledge, the association of Kyrle's disease with pyomyositis has not been reported before. The significance of this combination of conditions in our patient remains unexplained.

Effects of pancopride (5 and 10 mg, intravenously), on lower oesophageal sphincter pressure (LOESP), were assessed in healthy volunteers by means of oesophageal manometry. After pancopride 10 mg, the LOESP was higher than placebo and 5 mg pancopride but there were no differences among the three treatments (P = 0.42). The areas under the curve were similar without differences, neither with absolute measurements (P = 0.53) nor after a baseline correction (P = 0.16). In conclusion, pancopride has no clinically relevant effect on lower oesophageal sphincter pressure.

The purpose of this investigation was to determine whether increased endurance exercise capacity alters total hepatic cytochrome P-450 content and cytochrome P-450 (CYP1A and CYP2B) mediated hepatic microsomal mixed-function oxidase drug metabolism. Twenty adult male Sprague-Dawley rats were randomly assigned to either a control (C) or an endurance trained group (ET). ET rats were progressively trained 5 d.wk-1 for 11 wk. Both C and ET rats were administered in random order single posttraining doses of probe drugs theophylline (probe for CYP1A) and antipyrine (probe for CYP2B). Soleus muscle citrate synthase activity of ET rats was significantly greater (P < 0.01) than for C rats (mean +/- SD; C, 26.4 +/- 1.3 mumol.g-1.min-1; ET, 46.1 +/- 2.7). In contrast, total liver cytochrome P-450 content was not significantly different (P > 0.01) among C and ET rats (mean +/- SD; C, 0.554 +/- 0.055 nmol.mg-1 liver protein; ET, 0.604 +/- 0.080). Likewise, the posttraining C and ET single-sample plasma clearances of theophylline (mean +/- SD; C, 1.89 +/- 0.360 1.h-1.kg-1 total liver weight; ET, 2.08 +/- 0.49) and antipyrine (mean +/- SD; C, 6.44 +/- 1.56 1.h-1.kg-1 total liver weight; ET, 6.51 +/- 1.02) were not significantly different (P > 0.01). Therefore, it was concluded that strenuous endurance training of 11 wk duration did not alter total hepatic cytochrome P-450 content or CYP1A or CYP2B activity.

The purpose of this study was to compare ground reaction forces (vertical and lateral) produced during commonly used high and low impact aerobic dance maneuvers. Eight experienced aerobic dance instructors were the volunteer subjects. During the first session, three subjects were videotaped performing 10 high and 10 low impact maneuvers that they commonly used in their own class routines. Seven of the high and nine of the low impact maneuvers were then selected and used in sessions 2 and 3. During the second session, all subjects became proficient in performing the chosen maneuvers to music while striking an AMTI force platform with the right foot. During the third session, ground reaction force data generated during footstrike were recorded for each movement. Of the maneuvers examined, 5 high and four low impact maneuvers were used in the data analysis. It was found that maximum vertical active peak and vertical impact peak forces were lower for the low impact maneuvers. Maximum lateral active peak and lateral impact peak forces were similar and highly variable in magnitude for the 2 types of dance. The lower vertical loads produced in low impact dancing may make this type of dance better for minimizing lower extremity overuse injuries in aerobic dance. However, there does not seem to be any advantage in emphasizing the use of low impact dance for minimizing lower extremity injuries that evolve from lateral shear forces.

The transfer of water across the airway epithelium is closely related to the transepithelial potential difference (PD). Thus, PD should be directly involved in the regulation of airway intraluminal water content and, by extension, mucus rheology. Experiments by Boucher and co-workers (J Appl Physiol, 1980; 48: 169; and 1981; 51: 706) indicated that the values of PD in the small airways of dogs were considerably lower than in the trachea or mainstem bronchus. This fact suggests that water is increasingly removed from the airway lumen in the cephalad direction, and provides a possible mechanism whereby airway flooding is avoided as the total airway cross-section diminishes mouthward. We investigated this possibility by collecting and analysing mucus from the small airways and trachea of anaesthetized dogs and comparing our findings with measurements of PD. Mucus was collected on a cytology brush placed against the wall of the airway. Tracheal samples were taken from the lower lateral or anterior trachea, while small airway samples were taken from a 6th or 7th generation bronchus, chosen at random from either side. Measurements of PD were made at comparable sites. The mucus was analysed for its viscoelastic properties using the magnetic microrheometer technique. PD in the 6th-7th generation bronchus was significantly less than in the lower trachea (4.1 +/- 1.3 vs 17.2 +/- 7.1 mV). The rigidity of mucus collected from the small airways (log mechanical impedance (G*) at 100 rad.s-1) was significantly less than in the trachea (2.81 +/- 0.22 vs 3.01 +/- 0.29).(ABSTRACT TRUNCATED AT 250 WORDS)

Normal cells in culture respond to cell density by altering their proliferation rates and their pattern of protein expression. Primary avian tendon (PAT) cells are a case in point where procollagen production increases approximately 10-fold at high cell density while proliferation almost ceases. In an earlier report focusing on the cell density regulation of procollagen expression, the signaling mechanism communicating the presence of other cells was shown to have the characteristics of a loosely bound component of the cell layer. Extending these studies to the cell density regulation of proliferation, the cell density signal (CDS) was again shown to be altered by medium agitation, stimulating cell division. Agitation, however, was only disruptive to cell signaling when there was a high ratio of medium to cells. When sufficient cells were present, agitation was less effective. Therefore, the CDS controlling procollagen production and the CDS controlling the inhibition of growth seemed to be linked because the signaling mechanism is disrupted in a parallel manner by agitation. However, the proliferative response of PAT cells is more complex in that there is also a positive influence at moderate cell density (> 2 x 10(4) cells/cm2) on the rate of cell division. As a consequence, PAT cells would not proliferate into an area of low cell density, but within the same dish would rapidly fill an area of moderate density. PAT cells were capable of filling a gap between high cell density areas if the gap was less than 2 mm. Medium agitation also affected cells at low cell density in a different manner. It was inhibitory if all the cells were at low cell density but it was stimulatory if the cells at low cell density were in close proximity to cells at high cell density. In addition, medium conditioned by agitation over cells at a high cell density would stimulate cells at low cell density to divide and grow out into low cell density regions. Using the growth-promoting activity of the conditioned medium as an assay, this component of the CDS was shown to have unique characteristics: heat, pH, dithiothreitol (DTT) stable; tris ion and protease sensitive. By gel exclusion chromatography it was larger than 100 kDa. But after DTT treatment its mobility shifted to < 30 kDa while retaining activity.

Insulin production requires a prolonged extraction process. An ultrasound method of insulin extraction was developed to increase efficiency. Application of ultrasound resulted in a significant increase in the extraction process as a result of pancreas tissue dispergation, destruction of the pancreas cells, intensive mixing, separation of particles, and increase in the interphase pancreas-extractive medium. Optimal technological parameters of insulin extraction were established: ultrasound frequency, 19.5 kHz, specific intensity of ultrasound, 3.3 W/cm(2); time of ultrasound exposure, 5-10 min; and influence of cavitation process. Effectiveness of insulin extraction depends on the properties of the extractive medium. Optimal conditions were pH, 1.6-1.7, concentration of alcohol, 75%, temperature of extractive mixture, 13-17 degrees C; ratio of ground pancreas to liquid extractive medium, 1 : 3.

An optimal time of 45 min was established for extraction of rennin (chymosin) from abomasa using ultrasound. Effect of swelling of raw material and increased temperature of extraction medium (45 degrees C) was established. As rennin is resistant to ultrasound treatment and enhanced temperatures, ultrasound extraction results in a significant increase in the yield and activity. However, purified rennins were sensitive to ultrasound action. There were found changes of the electrophoretic properties and amino acid composition. Physicochemical properties were different and quality characteristics were higher for ultrasonic extracted rennin than for the control, particularly specific clotting activity, proteolytic activity, and rheological properties of curd. However, nonspecific proteolysis, coefficient of rennin effectivity, appearance, odor, solubility, moisture, protein, and NaCI content were similar. Ultrasonic extraction caused a decrease in the total viable counts of microorganisms of rennin, because of the short time of extraction.

Crystalline insulin was obtained from the pancreas by the method of ultrasound extraction. Extreme changes of pancreas structure were noticed, including rupture of the cells of pancreatic islands and decomposition of pancreatic tissue with the formation of micro-and macro-canals. These changes facilitate the migration of solvent inside the structure and washing out beta cell content. Structural changes were maximal in the peripheral parts of the pancreas and in frozen pancreas treated by ultrasound. A rapid filming method recorded factors influencing the extraction process-the dispersing effect of ultrasound, the rapid destruction of pancreatic particles, and the swelling and intensive pulsation of small particles in the ultrasound field. Experimental, control, and standard insulin preparations were nearly identical in Physicochemical properties and ether quality characteristics: activity determined by a biological method and electrophoresis; homogeneity and purity determined by circle chromatography; fractions of insulin determined by starch gel electrophoresis; amino acid composition; solubility; and content of moisture, zinc, and nitrogen.