Abstract Introduction Depression and diabetes are highly prevalent worldwide and often co-exist, worsening outcomes for each condition. Barriers to diagnosis and treatment are exacerbated in low and ...middle-income countries with limited health infrastructure and access to mental health treatment. The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study tests the sustained effectiveness and cost-effectiveness of a multi-component care model for individuals with poorly-controlled diabetes and depression in diabetes clinics in India. Materials and methods Adults with diabetes, depressive symptoms (Patient Health Questionnaire-9 score ≥ 10), and ≥ 1 poorly-controlled cardiometabolic indicator (either HbA1c ≥ 8.0%, SBP ≥ 140 mm Hg, and/or LDL ≥ 130 mg/dl) were enrolled and randomized to the intervention or usual care. The intervention combined collaborative care, decision-support, and population health management. The primary outcome is the between-arm difference in the proportion of participants achieving combined depression response (≥ 50% reduction in Symptom Checklist score from baseline) AND one or more of: ≥ 0.5% reduction in HbA1c, ≥ 5 mm Hg reduction in SBP, or ≥ 10 mg/dl reduction in LDL-c at 24 months (12-month intervention; 12-month observational follow-up). Other outcomes include control of individual parameters, patient-centered measures (i.e. treatment satisfaction), and cost-effectiveness. Results The study trained seven care coordinators. Participant recruitment is complete – 940 adults were screened, with 483 eligible, and 404 randomized (196 to intervention; 208 to usual care). Randomization was balanced across clinic sites. Conclusions The INDEPENDENT model aims to increase access to mental health care and improve depression and cardiometabolic disease outcomes among complex patients with diabetes by leveraging the care provided in diabetes clinics in India ( clinicaltrials.gov number: NCT02022111 ).
Kisspeptin is a novel therapeutic target for infertility. A single kisspeptin‐54 (KP‐54) injection acutely stimulates the release of reproductive hormones in women with hypothalamic amenorrhea (HA), ...a commonly occurring condition characterized by absence of menstruation; however, twice‐daily administration of KP‐54 results in tachyphylaxis. We determined the time course of desensitization to twice‐daily KP‐54 injections, compared the effects of twice‐daily and twice‐weekly administration regimens of KP‐54, and studied the effects of long‐term twice‐weekly administration of KP‐54 on the release of reproductive hormones in women with HA. When KP‐54 was administered twice daily, responsiveness to luteinizing hormone (LH) diminished gradually, whereas responsiveness to follicle‐stimulating hormone (FSH) was nearly abolished by day 2. Twice‐weekly KP‐54 administration resulted in only partial desensitization, in contrast to the complete tolerance achieved with twice‐daily administration. Women with HA who were treated with twice‐weekly KP‐54 injections had significantly elevated levels of reproductive hormones after 8 weeks as compared with treatment with saline. No adverse effects were observed. This study provides novel pharmacological data on the effects of KP‐54 on the release of reproductive hormones in women with HA.
Clinical Pharmacology & Therapeutics (2010) 88 6, 840–847. doi: 10.1038/clpt.2010.204
To investigate the relation between head trauma and incidence of dementia in a prospective population-based study.
Whether head trauma increases the risk of dementia and AD remains controversial. It ...has been suggested that the risk might be particularly increased for carriers of the APOE-epsilon4 allele.
The study population included 6645 participants of the prospective population-based Rotterdam Study, aged 55 years or older, who were free of dementia at baseline. Head trauma with loss of consciousness was measured at baseline by a self-report to a physician and detailed the number of head traumas, time since head trauma, and duration of loss of consciousness. The cohort was followed for incident dementia that was diagnosed according to international criteria. Logistic regression was used to calculate the risk of dementia after adjusting for age, gender, and education.
No increased risk of dementia or AD was found for persons with a history of head trauma with loss of consciousness (relative risk RR for dementia = 1.0, 95% CI, 0.5-2.0; RR for AD = 0.8, 95% CI, 0.4-1.9). Multiple head traumas, time since head trauma, and duration of unconsciousness did not significantly influence the risk of dementia. In addition, the APOE-epsilon4 allele did not modify the relationship.
This study suggests that mild head trauma is not a major risk factor for dementia or AD in the elderly. In addition, this study does not concur with previous cross-sectional studies suggesting an interaction with the APOE genotype.
Abstract Rates of maternal morbidity and mortality are rising in the United States. Non-Hispanic Black women are at highest risk for these outcomes compared to those of other race/ethnicities. Black ...women are also more likely to be late to prenatal care or be inadequate users of prenatal care. Prenatal care can engage those at risk and potentially influence perinatal outcomes but further research on the link between prenatal care and maternal outcomes is needed. The objective of this article is to review literature illuminating the relationship between prenatal care utilization, social determinants of health, and racial disparities in maternal outcome. We present a theoretical framework connecting the complex factors that may link race, social context, prenatal care utilization, and maternal morbidity/mortality. Prenatal care innovations showing potential to engage with the social determinants of maternal health and address disparities and priorities for future research are reviewed.
Impaired materno-placental perfusion causes two important obstetric complications, fetal growth restriction and preeclampsia. This study investigated whether adenoviral vector-mediated overexpression ...of vascular endothelial growth factor (VEGF) in the uterine arteries (UtAs) increases uterine artery blood flow (UBF). First-generation adenovirus vectors (5 x 10(11) particles) containing the VEGF gene (Ad.VEGF-A or -D) or the beta-galactosidase reporter gene (Ad.lacZ) were injected into the UtAs of pregnant sheep (n=6) at 88-102 days of gestation (term=145 days). UBF was measured using Doppler sonography before, and 4-7 days after injection. Mean UBF increased significantly from 233+/-156 (s.d.) ml min(-1) to 753+/-415 ml min(-1) following Ad.VEGF-A injection (P=0.005, n=5); Ad.lacZ infection had no significant effect. Organ bath experiments on uterine arterial sections 4-7 days after injection showed that, compared with Ad.lacZ vessels, Ad.VEGF-A-transduced vessels had a reduced contractile response to phenylephrine (E max 148+/-10.9 vs E max 228.2+/-27.5, P<0.05) but increased relaxation with bradykinin (pD2 (-log EC50) values 9.11+/-0.01 vs 8.65+/-0.11, P<0.05). Injection of Ad.VEGF-A into the UtAs increases UBF by enhancing vasodilatation. This may provide the basis for therapy in pregnancies complicated by uteroplacental insufficiency.
To examine the association between postmenopausal hormone replacement therapy (HRT) and the trajectory of global cognitive change with age.
The Modified Mini-Mental State Examination (MMSE) was ...administered to a population sample of 2,073 nondemented, community-dwelling female residents of Cache County, UT, aged 65 and older. Current and past HRT and other medications at a baseline interview and at follow-up 3 years later were assessed. Between interviews, a telephone Women's Health Questionnaire was administered to assess initial exposure, duration, and recency of HRT. Generalized estimating equation marginal models were used to evaluate the cross-sectional and longitudinal relations of HRT and modified MMSE score. Also assessed were effects with multivitamins and calcium supplements as exposures likely to reflect a "healthy lifestyle" among HRT users. Model covariates included the presence of APOE epsilon4 alleles, age, education, concurrent depression, several chronic diseases, and self-perceived general health.
Age, lower education, depression, and APOE epsilon4 were all associated with lower baseline modified MMSE scores. With these covariates in the model, lifetime HRT use was associated with better baseline modified MMSE scores and a slower rate of decline. Stratification by APOE genotype did not alter these effects. Apparent benefits with HRT were attenuated but remained significant after elimination of scores from participants with incident dementia. A significant interaction between age and HRT indicated the strongest effects in women aged 85 and older. Measures of age at initial use of HRT, duration, and recency of exposure did not improve the models. No effects were seen with the "healthy lifestyle" control exposures.
In a population cohort of older women, lifetime HRT exposure was associated with improved global cognition and attenuated decline over a 3-year interval. Improvements were greatest in the oldest old.
There is limited information characterizing young adults (18–35 years) (YA) with diabetes, especially those admitted for hyperglycemic emergencies. The study aims were to examine associations of ...patient-level characteristics with hyperglycemic emergency hospitalization and to identify variations based on diabetes type and glycemic control.
We conducted retrospective analysis of 273 YA admitted to an inner-city hospital with diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic nonketotic syndrome (HHS). T-tests, Chi-Square tests, and ANOVA identified differences in demographics, diabetes history, clinical indicators, complications/comorbidities, and hospital admission stratified separately by diabetes type (1 vs 2) and admission HbA1c < 9% (75 mmol/mol), ≥9% to 12% (108 mmol/mol), ≥12%).
Mean admission HbA1c was 12.4% (112 mmol/ml). HbA1c was ≥9.0% for 90.5%. The main DKA/HHS trigger was medication nonadherence (57.9%), with 35.6% presenting with new-onset type 2 diabetes. Only 3.7% utilized outpatient diabetes clinics, 38.8% were re-hospitalized within the year, and 69% lacked insurance. Diabetes complications (44.7%) and psychiatric co-morbidities (35.5%) were common. Significantly more YA with type 1 diabetes had insurance, whereas YA with type 2 diabetes had higher admission HbA1c. YA with HbA1c ≥12% were more likely to be Black and lack insurance.
YA hospitalized for DKA/HHS in an inner-city hospital tended to have severely uncontrolled diabetes. Many already had comorbidities and diabetes complications, high use of acute care services and low use of diabetes specialty services. YA characteristics varied by diabetes type and HbA1c. Overall, a substantial percentage lacked insurance, potentially impacting healthcare utilization patterns and medication adherence, and leading to DKA/HHS admissions.
AMP-activated protein kinase (AMPK) is a drug target for treatment of metabolic and cardiovascular complications. Extracts of Gentianaceace plants exhibit anti-diabetic and anti-atherosclerotic ...effects, however, whether their phyto-constitutents activate AMPK remains to be determined.
Molecular docking of Gentiana lutea constituents was performed with crystal structure of human α2β1γ1 trimeric AMPK (PDB ID: 4CFE). Binding of Amarogentin (AG) to α2 subunit was confirmed through isothermal titration calorimetry (ITC) and in vitro kinase assays were performed. L6 myotube, HUH7 and endothelial cell cultures were employed to validate in silico and in vitro observations. Lipid lowering and anti-atherosclerotic effects were confirmed in streptozotocin induced diabetic mice via biochemical measurements and through heamatoxylin and eosin, Masson's trichrome and Oil Red O staining.
AG interacts with the α2 subunit of AMPK and activates the trimeric kinase with an EC50 value of 277 pM. In cell culture experiments, AG induced phosphorylation of AMPK as well as its downstream targets, acetyl-coA-carboxylase (ACC) and endothelial nitric oxide synthase (eNOS). Additionally, it enhanced glucose uptake in myotubes and blocked TNF-α induced endothelial inflammation. Oral supplementation of AG significantly attenuated diabetes-mediated neointimal thickening, and collagen and lipid deposition in the aorta. It also improved circulating levels of lipids and liver function in diabetic mice.
In conclusion, AG exerts beneficial vasculo-metabolic effects by activating AMPK.
Amarogentin, a naturally occurring secoiridoid glycoside, is a promising lead for design and synthesis of novel drugs for treatment and management of dyslipidemia and cardiovascular diseases.
•Amarogentin activates trimeric α2β1γ1 AMP-activated kinase (AMPK).•Docking studies reveal that Amarogentin binds to the evolutionarily conserved Auto-Inhibitory Domain (AID) of α- subunit.•Amarogentin prevents endothelial inflammation and promotes glucose uptake in L6 myotubes.•In diabetic mice, Amarogentin exerts lipid lowering and anti-atherosclerotic effects.
Background: Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the ...effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown.
Aim: The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA.
Methods: We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed.
Results: On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 ± 3.5 IU/liter; FSH, 9.1 ± 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 ± 2.2 IU/liter, P < 0.05; FSH, 0.5 ± 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed.
Conclusion: Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.
Subcutaneous administration of kisspeptin-54 acutely and potently stimulates gonadotrophin release in women with hypothalamic amenorrhoea, but twice-daily administration over a 2-week period leads to desensitisation to its effects.
To develop evidence-based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient-important outcomes including, but not limited to, pain, function, infection, ...hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA).
We developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations.
The panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality.
This guideline provides evidence-based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient-important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.
PDF
