Miracle-dz/UniFAR-FTUs huggingface dataset:
You can’t walk or bike yourself out of the health effects of poverty: active school transport, child obesity, and blind spots in the public health literature

Mainstream public health theories of obesity attribute current, unprecedented numbers of obese youth to changes in eating practices and levels of physical activity, in turn leading to greater energy consumption and lesser energy expenditure. While substantial research has examined energy consumption among school-age children, key modes of energy expenditure such as active school transport (AST) remain underexplored. Using AST data obtained from the California Safe Routes to Schools program and child health data from the California Physical Fitness Test, we examined the association between AST and child obesity among school-age children and disambiguated this relationship introducing the variable poverty. We found that greater AST correlated with higher rates of child obesity and higher rates of child poverty, which in turn correlated with worse child health and obesity rates. Our findings suggest that child poverty explains the positive relationship between AST and child obesity that has puzzled investigators. Our analysis also reveals recurring blind spots in the public health literature, which often acknowledges that poverty begets poor health yet calls for environmental changes while rarely calling for eliminating poverty, one critical social determinant of health, even as these determinants have become legitimate objects of scientific inquiry. We propose that while environmental changes may improve the health of the poor, the only effective way to improve child health and reduce child obesity is to eliminate or dramatically reduce child poverty, a sociopolitical issue. This study is part of a larger project evaluating socio-political determinants of child health.
The Gluco- and Liporegulatory and Vasodilatory Effects of Glucose-Dependent Insulinotropic Polypeptide (GIP) Are Abolished by an Antagonist of the Human GIP Receptor

A truncated form of human glucose-dependent insulinotropic polypeptide (GIP), GIP(3–30)NH2, was recently identified as an antagonist of the human GIP receptor. This study examined the ability of GIP(3–30)NH2 to antagonize the physiological actions of GIP in glucose metabolism, subcutaneous abdominal adipose tissue blood flow (ATBF), and lipid metabolism in humans. Eight lean subjects were studied by measuring arteriovenous concentrations of metabolites and ATBF on three different occasions during hyperglycemic-hyperinsulinemic clamps with concomitant infusions of GIP, GIP(3–30)NH2, or both GIP and GIP(3–30)NH2. During infusion of GIP(3–30)NH2 alone and in combination with GIP, insulin levels and the total glucose amount infused to maintain the clamp were lower than during GIP alone. In addition, ATBF remained constant during the antagonist and increased only slightly in combination with GIP, whereas it increased fivefold during GIP alone. Adipose tissue triacylglyceride (TAG) and glucose uptake decreased, and the free fatty acid/glycerol ratio increased during the antagonist alone and in combination with GIP. The changes in glucose infusion rates and plasma insulin levels demonstrate an inhibitory effect of the antagonist on the incretin effect of GIP. In addition, the antagonist inhibited GIP-induced increase in ATBF and decreased the adipose tissue TAG uptake, indicating that GIP also plays a crucial role in lipid metabolism.
Comparative study of drug intervention in treatment of rural middle-aged and elderly people with knee osteoarthritis in Fengxian District, Shanghai

The aim of this study is to perform intervention treatment with loxoprofen, diacerein and glucosamine for middle-aged and elderly knee osteoarthritis (KOA) patients and compare the efficacy and safety of the aforementioned three drugs on KOA as well as providing basis for standard treatment protocol for the exploration of KOA. 153 KOA patients who were proved in the project of KOA epidemiological survey on rural middle-aged and elderly people in Fenxian District, Shanghai City were taken as the subject of study. Random, open and self-control methods were adopted to conduct intervention treatment by dividing into three groups: loxoprofen, diacerein and glucosamine treatment group. Evaluation method for index of severity and activity of KOA by lequesne was referred to make follow-up visit, fill in questionnaire on drug adverse reaction, registration form of drug distribution and recycle. Intervention treatments with loxoprofen, diacerein and glucosamine were carried out for KOA patients and significant differences (p<0.05) were seen between self-control groups in the aspect of knee pain, 15 m walking time (t/s), activities of daily life and comprehensive evaluation for patient. The overall response rates of the drug intervention in three groups are 90.20, 74.51 and 88.24%, respectively with R(-)1 = 0.4424, R(-)2 = 0.5825 and R(-)3 = 0.4751 by Ridit analysis. Considering c2 = 6.7253, p<0.05, the efficacy of loxoprofen and glucosamine turned out to be better, followed by that of diacerein; the adverse reaction of the three drugs are quite slight. With certain efficacy for KOA and slight adverse reaction, the intervention treatment of loxoprofen, diacerein and glucosamine can be used for normalized treatment of KOA. The use of drug intervention treatment can postpone the progression of KOA. Key words: Rural area, knee osteoarthritis, drug intervention.
Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy

AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction. In this study, we discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 and its channel activity within minutes. Treatment with two AMPK activators, metformin or AICAR, inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1. Metformin induced a dose-dependent inhibition of TRPA1-mediated calcium influx. Conversely, in diabetic db/db mice, AMPK activity was impaired in DRG neurons, and this was associated with a concomitant increase in membrane-associated TRPA1 and mechanical allodynia. Notably, these molecular and behavioral changes were normalized following treatment with AMPK activators. Moreover, high-glucose exposure decreased activated AMPK levels and increased agonist-evoked TRPA1 currents in cultured DRG neurons, and these effects were prevented by treatment with AMPK activators. Our results identify AMPK as a previously unknown regulator of TRPA1 channels. AMPK modulation of TRPA1 could thus serve as an underlying mechanism and potential therapeutic molecular target in painful diabetic neuropathy.
Adherence Within and Between Lifestyle Physical Activity Groups in Project PRIME

Background: Interventions that teach strategies for integrating physical activity into a person’s daily routine are becoming more common. These interventions have been found to increase physical activity behavior, although the increases have not been large. The small to moderate changes in physical activity can result from participants having insufficient adherence to the intervention protocol to produce an intervention effect. Given that adherence is likely to affect the power to find a treatment effect, it should be tracked. This study examined changes in adherence over 6 months for a lifestyle physical activity intervention. Methods: Participants were 244 sedentary adults who took part in the Project PRIME lifestyle physical activity intervention. Adherence was assessed separately for a group-based intervention (PRIME G) and a telephone- and mail-based intervention (PRIME C). Markers of adherence were completion of homework, self-monitoring of physical activity, attendance at class (PRIME G only), and .
SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis–related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant β-cell dedifferentiation, followed by a time-dependent decrease in functional β-cell mass—all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor β1 (TGFβ1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of β-cell mass was then found to result from TGFβ1-triggered epithelial-mesenchymal transition (EMT) by β-cells, rather than resulting directly from β-cell apoptosis. Mechanistically, TGFβ1-treated β-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in β-cells ameliorated β-cell EMT and β-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGFβ1-mediated β-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in β-cells.
Engineering Glucose Responsiveness Into Insulin

Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a “smart” insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia. The approach added saccharide units to insulin to create insulin analogs with affinity for both the insulin receptor (IR) and mannose receptor C-type 1 (MR), which functions to clear endogenous mannosylated proteins, a principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the discovery of MK-2640, and its in vitro and in vivo preclinical properties are detailed in this report. In glucose clamp experiments conducted in healthy dogs, as plasma glucose was lowered stepwise from 280 mg/dL to 80 mg/dL, progressively more MK-2640 was cleared via MR, reducing by ∼30% its availability for binding to the IR. In dose escalations studies in diabetic minipigs, a higher therapeutic index for MK-2640 (threefold) was observed versus regular insulin (1.3-fold).
Mechanisms to Elevate Endogenous GLP-1 Beyond Injectable GLP-1 Analogs and Metabolic Surgery

Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of “GLP-1 equivalents” (∼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)–deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (∼5–30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (∼300–400 pmol/L), drastically reducing glucose in Gipr null and Leprdb/db mice in a GLP-1 receptor–dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens.
Highly Angiogenic, Nonthrombogenic Bone Marrow Mononuclear Cell–Derived Spheroids in Intraportal Islet Transplantation

Highly angiogenic bone marrow mononuclear cell–derived spheroids (BM-spheroids), formed by selective proliferation of the CD31+CD14+CD34+ monocyte subset via three-dimensional (3D) culture, have had robust angiogenetic capacity in rodent syngeneic renal subcapsular islet transplantation. We wondered whether the efficacy of BM-spheroids could be demonstrated in clinically relevant intraportal islet transplantation models without increasing the risk of portal thrombosis. The thrombogenic potential of intraportally infused BM-spheroids was compared with that of mesenchymal stem cells (MSCs) and MSC-derived spheroids (MSC-spheroids). The angiogenic efficacy and persistence in portal sinusoids of BM-spheroids were examined in rodent syngeneic and primate allogeneic intraportal islet transplantation models. In contrast to MSCs and MSC-spheroids, intraportal infusion of BM-spheroids did not evoke portal thrombosis. BM-spheroids had robust angiogenetic capacity in both the rodent and primate intraportal islet transplantation models and improved posttransplant glycemic outcomes. MRI and intravital microscopy findings revealed the persistence of intraportally infused BM-spheroids in portal sinusoids. Intraportal cotransplantation of allogeneic islets with autologous BM-spheroids in nonhuman primates further confirmed the clinical feasibility of this approach. In conclusion, cotransplantation of BM-spheroids enhances intraportal islet transplantation outcome without portal thrombosis in mice and nonhuman primates. Generating BM-spheroids by 3D culture prevented the rapid migration and disappearance of intraportally infused therapeutic cells.
Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease

Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Krüppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of Klf6 increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of KLF6 in podocytes reduced the expression of synthesis of cytochrome c oxidase 2 with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of KLF6 in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.
Adverse pregnancy outcomes and imbalance in angiogenic growth mediators and oxidative stress biomarkers is associated with advanced maternal age births: A prospective cohort study in Ghana

Background Advanced maternal age (AMA) has been associated with negative pregnancy outcomes. Oxidative stress (OS) and defective placental dysfunction are contributing factors. This study determined the association between AMA and adverse pregnancy outcomes, OS biomarkers and angiogenic growth mediators (AGMs) in normal pregnancies. Methods This prospective cohort study conducted at the Obstetrics and Gynaecology (O&G) Department of the Komfo Anokye Teaching Hospital (KATH) finally included 175 normal pregnant women comprising, 58 AMA (35–45 years), 55 (30–34 years) and 62 optimal childbearing age (20–29 years). Venous blood samples were collected at 28–32 weeks for soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PIGF), 8-epiprostaglandinF2-α (8-epi-PGF2α) and total antioxidant capacity (TAC) assays. Results Pregnancies of AMA had a significantly higher levels of sFlt-1, 8-epi-PGF2α and 8-epi-PGF2α: PIGF ratio but a reduced level of PIGF, TAC and PIGF: sFlt-1 ratio compared to 20–29 years (p<0.0001). A significant negative correlation between AMA and PIGF (r = -0.294; p = 0.038); TAC (r = -0.215; p = 0.001) and PIGF: sFlt-1 ratio (r = -0.457; p<0.0001) and a positive correlation with sFlt-1 (r = 0.269; p = 0.017), 8-epiPGF2α (r = 0.277; p = 0.029) and 8-epi-PGF2: PIGF ratio (r = 0.461; p<0.0001) levels were observed. The adjusted odds ratio (aOR), and 95% confidence interval, and p value for the significant independent adverse outcomes associated with AMA were emergency caesarean section [21.7 (5.9–121.3), p<00001], elective caesarean section [2.7(0.9–5.8), p = 0.0105], stillbirth [12.6(1.4–82.1), p<0.0001], post-partum haemorrhage [4.3(1.1–18.5), p = 0.0094], preterm delivery [8.2(3.5–28.4), p<0.0001], low birth weight babies [9.7(2.8–29.3), p<0.0001], birth asphyxia [3.8(1.6–12.7), p = 0.0054], Apgar score ≤ 7 after 5 min for babies [10.1(4.7–23.2), p<0.0001], placental abruption [3.5(1.3–8.4), p = 0.0117] and intrauterine growth restriction (IUGR) [4.6(2.3–12.9), p = 0.0001]. Conclusion AMA pregnancies correlate with adverse pregnancy outcomes and imbalance in OS biomarkers and AGMs. It is incumbent on health care givers to provide effective antenatal care among AMA mothers as early identification of these imbalance and treatment can prevent adverse pregnancy outcomes.
Feline pancreatitis: current concepts and treatment guidelines

PANCREATITIS is becoming increasingly recognised as a clinical entity in cats. It has always been notoriously difficult to diagnose. Recently, diagnosis has been aided by newer, more sensitive diagnostic tools; however, no test is 100 per cent sensitive or specific, and pancreatitis therefore remains a diagnostic challenge. This article provides an overview of the anatomy and physiology of the pancreas, the pathophysiology involved in pancreatitis and the associated risk factors and clinical signs. It also presents practical guidance on the diagnosis and management of both mild and severe disease in cats.
Is the risk of low birth weight or preterm labor greater when maternal stress is experienced during pregnancy? A systematic review and meta-analysis of cohort studies

Antenatal stress is linked to fetal risks that increase the chances of neonatal complications and reduction of child cognitive ability. Therefore, we aimed to evaluate if maternal stress affects fetal, neonatal or child development. The following databases were searched: MEDLINE (1966 to May 2016), Embase (1980 to May 2016), LILACS (1982 to May 2016) and CENTRAL (1972 to May 2016). Observational studies published in English and Portuguese were included whether there was any relationship between fetal and neonatal outcome, such as birth weight, preterm labor, child development with pregnant women that were subjected to any stress type during at least one month of follow-up. Two independent reviewers screened eligible articles, extracted data and assessed the risk of bias. Thus, 8 cohort studies with about 8,271 pregnant women and 1,081,151 children proved eligible. Results suggested a significant association between antenatal stress exposure and increasing rates of low birth weight (Odds ratio (OR) 1.68 [95% Confidential Interval (CI) 1.19, 2.38]). However, there was no statistically significance difference between non-exposed and exposed groups related to preterm labor (OR 1.98 [95% CI 0.91 to 4.31]; I2 = 68%, p = 0.04). Although, results were inconsistent with primary analysis suggesting a significant association between antenatal stress exposure and the occurrence of higher rates of preterm birth (OR 1.42 [95% CI 1.05 to 1.91]; I2 = 68%, p = 0.04) in the sensitivity analysis. Furthermore, the current review has suggested that stress perceived during antenatal negatively influences fetal life and child development. Yet, further studies are necessary with adequate sample size and longer follow-up time to confirm our findings.
Effects of Ramipril and Rosiglitazone on Cardiovascular and Renal Outcomes in People With Impaired Glucose Tolerance or Impaired Fasting Glucose

OBJECTIVE—Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS—A total of 5,269 people aged ≥30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS—Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84–1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75–1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60–31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68–0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). CONCLUSIONS—Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.