Effect of a single dose of zoledronic acid on bone mineral density and trabecular bone score in Indian postmenopausal osteoporotic women with and without type 2 diabetes mellitus - A prospective cohort pilot study.

PURPOSE: The objectives were to study the effect of a single dose of intravenous (IV) zoledronic acid (ZA) on changes in bone mineral density (BMD) (lumbar spine (LS), hip, & distal forearm), trabecular bone score (TBS) and bone turnover markers (BTMs) in postmenopausal osteoporotic women with and without diabetes over 12 months. METHODS: Patients were divided into two groups: type 2 diabetes mellitus (T2DM) (n = 40) and non-DM (n = 40). Both groups received a single dose of 4 mg IV ZA at baseline. The BMD with TBS and BTMs (ß-CTX, sclerostin, P1NP) were measured at baseline, six months, and 12 months. RESULTS: At baseline, BMD in all three sites was similar in both groups. T2DM patients were older and had lower BTMs than non-DM patients. The mean increase in LS-BMD (gram/cm2) at 12 months in T2DM and the non-DM group was 3.6 ± 4.7% and 6.2 ± 4.7 %, respectively (P = 0.01). However, the age adjusted mean difference in LS BMD increment between two groups at one year was - 2.86 % (-5.02% to -0.69%), P = 0.01. There was a comparable change in BMD at other two sites, BTMs, and TBS in both the groups over one year follow-up. CONCLUSION: The gain in the LS-BMD was significantly lower in T2DM group compared to non-DM subjects over 12 months after a single IV infusion of 4 mg ZA. The explanation for this could be low bone turnover in diabetes subjects at baseline.

Epigenetics of the Pathogenesis and Complications of Type 2 Diabetes Mellitus.

Epigenetics of type 2 diabetes mellitus (T2DM) has widened our knowledge of various aspects of the disease. The aim of this review is to summarize the important epigenetic changes implicated in the disease risks, pathogenesis, complications and the evolution of therapeutics in our current understanding of T2DM. Studies published in the past 15 years, from 2007 to 2022, from three primary platforms namely PubMed, Google Scholar and Science Direct were included. Studies were searched using the primary term 'type 2 diabetes and epigenetics' with additional terms such as 'risks', 'pathogenesis', 'complications of diabetes' and 'therapeutics'. Epigenetics plays an important role in the transmission of T2DM from one generation to another. Epigenetic changes are also implicated in the two basic pathogenic components of T2DM, namely insulin resistance and impaired insulin secretion. Hyperglycaemia-i nduced permanent epigenetic modifications of the expression of DNA are responsible for the phenomenon of metabolic memory. Epigenetics influences the development of micro-and macrovascular complications of T2DM. They can also be used as biomarkers in the prediction of these complications. Epigenetics has expanded our understanding of the action of existing drugs such as metformin, and has led to the development of newer targets to prevent vascular complications. Epigenetic changes are involved in almost all aspects of T2DM, from risks, pathogenesis and complications, to the development of newer therapeutic targets.

Thyroid Function Abnormalities and Outcomes in Hospitalized Patients with COVID-19 Infection: A Cross-Sectional Study.

Thyroid gland can be affected by the COVID-19 infection. The pattern of thyroid function abnormality reported in COVID-19 is variable; in addition, some drugs used in COVID-19 patients like glucocorticoids and heparin can affect the thyroid function tests (TFT). We conducted an observational, cross-sectional study of thyroid function abnormalities with thyroid autoimmune profile in COVID-19 patients with varying severity from November 2020 to June 2021. Serum FT4, FT3, TSH, anti-TPO, and anti-Tg antibodies were measured before the initiation of treatment with steroids and anti-coagulants. A total of 271 COVID-19 patients were included in the study, of which 27 were asymptomatic and remaining 158, 39, and 47 were classified to mild, moderate and severe categories, respectively, according to MoHFW, India criteria. Their mean age was 49±17 years and 64.9% were males. Abnormal TFT was present in 37.2% (101/271) patients. Low FT3, low FT4, and low TSH were present in 21.03%, 15.9% and 4.5% of patients, respectively. Pattern corresponding to sick euthyroid syndrome was the most common. Both mean FT3 and FT3/FT4 ratio decreased with increasing severity of COVID-19 illness (p=0.001). In multivariate analysis, low FT3 was associated with increased risk of mortality (OR 12.36, 95% CI: 1.23-124.19; p=0.033). Thyroid autoantibodies were positive in 58 (27.14%) patients; but it was not associated with any thyroid dysfunction. Thyroid function abnormality is common among COVID-19 patients. Both low FT3 and FT3/FT4 ratio are indicators of disease severity while low FT3 is a prognostic marker of COVID-19 associated mortality.

Pituitary Dysfunction Following Snakebite Envenomation: A Clinico-Radiological Assessment of 15 Cases and Review of the Literature.

Background: Snakebite envenomation (SE) is an important tropical disease in India, causing significant morbidity and mortality among patients. The hormonal deficiencies due to the involvement of the pituitary in case of SE can present in either acute or delayed setting. Hypopituitarism (HP) is often an underrecognized and relatively rarely reported complication of this neglected disease. Methods: We present here the data of 15 patients diagnosed to have HP following systemic SE and are being currently followed-up in the Endocrinology outpatient department of a tertiary care hospital of South India. The study was approved by the Institute ethics committee, and informed onsent was taken from all the study patients. The study was a record-based retrospective analysis of the patients with HP following SE. Clinical data including lag time in diagnosis and type of snake were determined. Further, hormonal data including all the anterior pituitary functions (thyroid stimulating hormone, free T4, cortisol, insulin-like growth factor (IGF-1) luteinizing hormone, follicular-stimulating hormone, testosterone; prolactin) and water deprivation test to determine diabetes insipidus (DI) in patients with polyuria on follow-up were extracted from the records and the hospital information system. An experienced neuroradiologist examined the magnetic resonance imaging (MRI) findings of the pituitary. Results: The mean age of the patients was 43 ± 9 years and 80% were male. Around 90% of patients belonged to upper-lower socioeconomic status according to the modified Kuppuswamy scale. The commonest snake species reported was Russell's viper. Thirteen patients had delayed HP. The median duration from snakebite to onset of HP symptoms was 1 year (range 0.33-10 years). However, the median time from snakebite to the diagnosis of HP was 7 years (range 1-13 years). Central hypothyroidism and hypogonadism were present in all subjects. However, central hypocortisolism was noted in 93% of patients. Low IGF-1 was noted in all the six patients where data were available. One patient had partial central DI. Thirteen out of 15 patients had reduction of pituitary volume in MRI. Conclusion: HP in patients with SE can appear slowly and the diagnosis is frequently delayed for years. Following snakebite, multiple pituitary hormone deficiencies associated with radiological abnormalities like a significant reduction in the pituitary volume are common.

Application of Twin-Screw Melt Granulation to Overcome the Poor Tabletability of a High Dose Drug.

Pharmaceutical tablet manufacturing has seen a paradigm shift toward continuous manufacturing and twin-screw granulation-based technologies have catalyzed this shift. Twin-screw granulator can simultaneously perform unit operations like mixing, granulation, and drying of the granules. The present study investigates the impact of polymer concentration and processing parameters of twin-screw melt granulation, on flow properties and compaction characteristics of a model drug having high dose and poor tabletability. Acetaminophen (AAP) and polyvinylpyrrolidone vinyl acetate (PVPVA) were used as a model drug (90-95% w/w) and polymeric binder (5-10%w/w), respectively, for the current study. Feed rate (~650-1150 g/h), extruder screw speed (150-300 rpm), and temperature (60-150°C) were used as processing variables. Results showed the reduction in particle size of drug in the extrudates (D90 of 15-25 µm from ~80 µm), irrespective of processing condition, while flow properties were a function of polymer concentration. Overall, good flowability of the products and their tablets with optimum tensile strength can be obtained through using high polymer concentration (i.e., 10% w/w), lower feed rate (~650 g/h), lower extruder screw speed (150 rpm), and higher processing temperatures (up to 120°C). The findings from the current study can be useful for continuous manufacturing of tablets of high dose drugs with minimal excipient loading in the final dosage form.

The short physical performance battery and incident heart failure among older women: the OPACH study.

OBJECTIVE: Reduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high. METHODS: Women (n = 5325; mean age 79 ± 7 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0-3), low (4-6), medium (7-9), or high (10-12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time. RESULTS: Incident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34-3.66), 1.63 (1.11-2.38), 1.39 (1.00-1.94), and 1.00 (referent; P-trend<0.001). Higher HF risk was associated with lower SPPB in women with major modifiable HF risk factors including obesity (HR per 3-unit SPPB decrement: present HR = 1.41, absent HR = 1.41), hypertension (present HR = 1.45, absent HR = 1.30), diabetes (present HR = 1.32, absent HR = 1.44), and lower accelerometer-measured MVPA (<45 min/day HR = 1.29, ≥45 min/day HR = 1.60); all P-interaction>0.10. CONCLUSION: Lower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.

Comparison of islet cell function, insulin sensitivity, and incretin axis between Asian-Indians with either impaired fasting glucose or impaired glucose tolerance, and normal healthy controls.

AIMS: The objective of this study was to compare the islet cell function, insulin sensitivity, and incretin axis between Asian-Indian subjects with either impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). MATERIALS AND METHODS: Prediabetes subjects underwent a mixed meal tolerance test(MMTT) after overnight fasting. Samples for glucose, insulin, glucagon, and glucagon-like peptide-1 (GLP-1) were collected at 0, 30, 60, and 120 min. Insulin secretion sensitivity index -2 (ISSI-2) for beta-cell function and Matsuda index for insulin sensitivity were assessed. Alpha cell function was assessed by measuring the area under the curve (AUC) 0-120 glucagon/AUC0-120 glucose. RESULTS: A total of sixty subjects were recruited with 20 in each group. The beta-cell function represented by ISSI-2 was impaired in prediabetes subjects as compared to NGT group (IFG: 2.09 ± 0.44 vs. NGT: 3.04 ± 0.80, P < 0.0001, and IGT: 2.33 ± 0.59 vs. NGT: 3.04 ± 0.80, P = 0.002). Similarly, AUC0-120 glucagon/AUC0-120 glucose was also lower in prediabetes group as compared to healthy controls (IFG: 0.41(0.54) vs. NGT: 1.07(0.39), P = 0.003 and IGT: 0.57(0.38) vs. NGT: 1.07(0.39), P = 0.001). CONCLUSION: Asian-Indian prediabetes subjects have reduced beta-cell function with lesser glucagon secretion during MMTT as compared to normal healthy controls.

Repeated victorious and defeat experiences induce similar apical dendritic spine remodeling in CA1 hippocampus of rats.

In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or losing social conflicts. Territorial male wild-type Groningen (WTG) rats were allowed multiple daily attacks (>20 times) on intruder males in the resident-intruder paradigm. Frequent winning experiences are known to facilitate uncontrolled aggressive behavior reflected in aggressive attacks on anesthetized males which was also observed in the winners in this study. Both winners and losers were socially housed during the experiments; winners with females to stimulate territorial behavior, and losers with two other losing male rats. Twenty-four hours after the last social encounter, brains from experienced residential winners and repeatedly defeated intruder rats were collected and neuronal morphology in selected brain regions was studied via Golgi-Cox staining. Results indicate that spine density in the apical dendrites of the hippocampal CA1 reduced similarly in both winners and losers. In addition, winners showed increased spine densities at the proximal segments (20-30 µm) of the basolateral amygdala neurons and losers tended to show a decreased spine density at the more proximal segments of the infralimbic region of prefrontal cortex neurons. No effect of winning and losing was observed in the medial amygdala. The atrophic effect of repeated defeats in hippocampal and prefrontal regions was anticipated despite the fact that social housing of the repeatedly losing intruder males may have played a protective role. The reduction of hippocampal spine density in the winners seems surprising but supports previous findings in hierarchical dominant males in rat colonies. The dominants showed even greater shrinkage of the apical dendritic arbors of hippocampal CA3 pyramidal neurons compared to the stressed subordinates.

Secondary diabetes as a rare complication of glycogen storage disease 1a: case report and review of literature.

Glycogen storage diseases (GSDs) are disorders of carbohydrate metabolism and hypoglycemia is their hallmark. Secondary diabetes with glycogen storage disease, which seems rather paradoxical, has been rarely reported. A 13-year-old girl previously diagnosed to have GSD 1a presented to the emergency with multiple episodes of vomiting and loss of consciousness. She had hyperglycemia, ketonuria, hyperlactatemia and metabolic acidosis, suggestive of diabetic ketosis with acidosis possibly contributed by both high serum lactate and serum ketones. Her glycated hemoglobin was high, with detectable serum insulin levels, which suggested secondary diabetes in the background of GSD Ia. Her management posed a therapeutic challenge. She was managed with insulin and achieved good glycemic control. We wish to conclude that GSD may rarely lead to secondary diabetes as a complication and the management is complex owing to the nature of the disease. Insulin remains the mainstay of the treatment.

Decreased dendritic spine density in posterodorsal medial amygdala neurons of proactive coping rats.

There are large individual differences in the way animals, including humans, behaviorally and physiologically cope with environmental challenges and opportunities. Rodents with either a proactive or reactive coping style not only differ in their capacity to adapt successfully to environmental conditions, but also have a differential susceptibility to develop stress-related (psycho)pathologies when coping fails. In this study, we explored if there are structural neuronal differences in spine density in brain regions important for the regulation of stress coping styles. For this, the individual coping styles of wild-type Groningen (WTG) rats were determined using their level of offensive aggressiveness assessed in the resident-intruder paradigm. Subsequently, brains from proactive (high-aggressive) and reactive (low-aggressive) rats were Golgi-cox stained for spine quantification. The results reveal that dendritic spine densities in the dorsal hippocampal CA1 region and basolateral amygdala are similar in rats with proactive and reactive coping styles. Interestingly, however, dendritic spine density in the medial amygdala (MeA) is strikingly reduced in the proactive coping rats. This brain region is reported to be strongly involved in rivalry aggression which is the criterion by which the coping styles in our study are dissociated. The possibility that structural differences in spine density in the MeA are involved in other behavioral traits of distinct coping styles needs further investigation.

Short Physical Performance Battery and Incident Cardiovascular Events Among Older Women.

Background The Short Physical Performance Battery (SPPB) is an inexpensive, reliable, and easy-to-implement measure of lower-extremity physical function. Strong evidence links SPPB scores with all-cause mortality, but little is known about its relationship with incident cardiovascular disease (CVD). Methods and Results Women (n=5043, mean age=79±7) with no history of myocardial infarction or stroke completed 3 timed assessments-standing balance, strength (5 chair stands), and usual gait speed (4 m walk)-yielding an SPPB score from 0 (worst) to 12 (best). Women were followed for CVD events (myocardial infarction, stroke, or CVD death) up to 6 years. Hazard ratios were estimated for women with Very Low (0-3), Low (4-6), Moderate (7-9), and High (10-12) SPPB scores using Cox proportional hazard models adjusted for demographic, behavioral, and health-related variables including objective measurements of physical activity, blood pressure, lipids, and glucose levels. Restricted cubic splines tested linearity of associations. With 361 CVD cases, crude incidence rates/1000 person-years were 41.0, 24.3, 16.1, and 8.6 for Very Low, Low, Moderate, and High SPPB categories, respectively. Corresponding fully adjusted hazard ratios (95% CIs) were 2.28 (1.50-3.48), 1.70 (1.23-2.36) 1.49 (1.12-1.98), and 1.00 (referent); P-trend <0.001. The dose-response relationship was linear (linear P<0.001; nonlinear P>0.38). Conclusions Results suggest SPPB may provide a measure of cardiovascular health in older adults beyond that captured by traditional risk factors. Because of its high test-retest reliability and low administrative burden, the SPPB should be a routine part of office-based CVD risk assessment.

Rodent models of social stress and neuronal plasticity: Relevance to depressive-like disorders.

Exposure to severe or persistent social stress may lead to the development of psychiatric disorders such as anxiety and depression. These mood disorders are associated with structural alterations of neural architecture in limbic brain regions that control emotion, mood and cognition. Structural remodeling may either be a sign of successful adaptation, or of failure to do so. In neuropsychiatric disorders like depression structural remodeling involves apoptosis, reduced neurogenesis, and structural remodeling of neuronal dendrites which most likely reflects the latter. Here we review key findings from animal models of psychosocial stress that have been used to gain insights into the relation between stress-related behavioral disorders like depression and structural plasticity. Specifically, we focus on models having a high face validity like social defeat stress in the resident-intruder paradigm and chronic stress of social subordination in social housing conditions. Moderate to severe social stress appears to stimulate plasticity and neuronal growth in regions of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. A major focus of the current review is to characterize social stress induced structural changes in these brain regions, aiming to provide insight in pathways and factors that underlie behavioral effects of stress and depression.

Risk of Fracture in Women with Sarcopenia, Low Bone Mass, or Both.

OBJECTIVES: To determine whether women with sarcopenia and low bone mineral density (BMD) are at greater risk of clinical fractures than those with sarcopenia or low BMD alone. DESIGN: Women's Health Initiative (WHI) Observational and Clinical trials. SETTING: Three U.S. clinical centers (Pittsburgh, PA; Birmingham, AL; Phoenix/Tucson, AZ). PARTICIPANTS: Women (mean age 63.3 ± 0.07) with BMD measurements (N = 10,937). MEASUREMENTS: Sarcopenia was defined as appendicular lean mass values corrected for height and fat mass. Low BMD was defined as a femoral neck T-score less than -1.0 based on the Third National Health and Nutrition Examination Survey reference database for white women. Cox proportional hazards analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We followed women for incident fractures over a median of 15.9 years. RESULTS: Participants were classified into mutually exclusive groups based on BMD and sarcopenia status: normal BMD and no sarcopenia (n = 3,857, 35%), sarcopenia alone (n = 774, 7%), low BMD alone (n = 4,907, 45%), and low BMD and sarcopenia (n = 1,399, 13%). Women with low BMD, with (HR = 1.72, 95% CI = 1.44-2.06) or without sarcopenia (HR = 1.58, 95% CI = 1.37-1.83), had greater risk of fracture than women with normal BMD; the difference remained statistically significant after adjustment for important covariates. Women with low BMD, with (HR = 2.78, 95% CI = 1.78-4.30 and without (HR = 2.42, 95% CI = 1.63-3.59) sarcopenia had higher risk of hip fractures. Women with sarcopenia alone had similar HRs to women with normal BMD. CONCLUSION: Compared to women with normal BMD.

Nonpharmacologic management of hypertension: a multidisciplinary approach.

PURPOSE OF REVIEW: Nonpharmacologic lifestyle modification interventions (LMIs), such as increasing physical activity, dietary modification, weight-loss, reducing alcohol consumption and smoking cessation, are effective strategies to lower resting blood pressures (BPs) in prehypertensive or hypertensive patients. However, the limited time shared between a physician and a patient is not adequate to instill an adoption of LMI. The purpose of this review is to therefore highlight evidence-based BP lowering, LMI strategies that can feasibly be implemented in clinical practices. RECENT FINDINGS: Interventions focusing on modifying physical activity, diet, weight-loss, drinking and smoking habits have established greater efficacy in reducing elevated BP compared with providing guideline recommendations based on national guidelines. Alone greater reductions in BP can be achieved through programmes that provide frequent contact time with exercise, nutrition and/or wellness professionals. Programmes that educate individuals to lead peer support groups can be an efficient method of ensuring compliance to LMI. SUMMARY: Evidence of a multidisciplinary approach to LMI is an effective and attractive model in managing elevated BP. This strategy is an attractive model that provides the necessary patient attention to confer lifestyle maintenance.

Testing alternative hypotheses regarding the association between behavioral inhibition and language development in toddlerhood.

Studies have reported an inverse association between language development and behavioral inhibition or shyness across childhood, but the direction of this association remains unclear. This study tested alternative hypotheses regarding this association in a large sample of toddlers. Data on behavioral inhibition and expressive and receptive language abilities were collected from 816 twins at ages 14, 20, and 24 months. Growth and regression models were fit to the data to assess the longitudinal associations between behavioral inhibition and language development from 14 to 24 months. Overall, there were significant associations between behavioral inhibition and expressive language, and minimal associations with receptive language, indicating that the association is better explained by reticence to respond rather than deficient language development.