Novel techniques for assessment of bone tissue material properties.

PURPOSE OF REVIEW: The purpose of this review will be to shed light on novel techniques for assessment of bone tissue material properties. RECENT FINDINGS: Recently there has been an increase in modalities to investigate bone tissue material properties. Historically, clinicians treating patients with bone disorders have relied upon the use of bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA). Although DXA provides an ability to screen at a large-scale population level, it only explains about 60% of the fracture risk. Recent advances include the use of imaging modalities, responses to load, and novel infrared (IR) techniques. SUMMARY: These newer techniques have not reached a point for population level screening; however, they may inform the science of bone biology further and help discern various bone disease states.

Acculturative Stress and Depressive Symptoms Among Chinese Immigrants: the Role of Gender and Social Support.

The USA has among the largest immigrant population of any country in the world, and over the past few decades, the proportion of Chinese immigrants in the USA has increased significantly. Immigrants may experience substantial acculturative stress as they learn to navigate their new environment, and this stress can contribute to depressive symptoms and poor mental health. Social support can help mitigate the effects of stress on depressive symptoms, but the protective effects of social support have been reported to differ between men and women. Thus, the present study examined associations of acculturative stress and depressive symptoms among Chinese immigrants and explored whether the effects of social support on depressive symptoms varied by gender. Participants included 620 foreign-born Chinese men and women who completed questionnaires on acculturative stress, social support, and depressive symptoms. In nested regression analyses, acculturative stress was positively associated with depressive symptoms among both men and women. However, the interaction of social support and acculturative stress on depressive symptoms was statistically significant among men (ß = - 0.89, p < 0.001), but not women (ß = - 0.43, p = 0.21). These findings suggest that social support moderates the association of acculturative stress with depressive symptoms, but only among Chinese immigrant men. Future research should explore factors that can enhance resilience and mitigate acculturative stress effects on psychological well-being among Chinese immigrant women.

Mitochondrial Membrane Intracellular Communication in Healthy and Diseased Myocardium.

Research efforts in the twenty-first century have been paramount to the discovery and development of novel pharmacological treatments in a variety of diseases resulting in improved life expectancy. Yet, cardiac disease remains a leading cause of morbidity and mortality worldwide. Over time, there has been an expansion in conditions such as atrial fibrillation (AF) and heart failure (HF). Although past research has elucidated specific pathways that participate in the development of distinct cardiac pathologies, the exact mechanisms of action leading to disease remain to be fully characterized. Protein turnover and cellular bioenergetics are integral components of cardiac diseases, highlighting the importance of mitochondria and endoplasmic reticulum (ER) in driving cellular homeostasis. More specifically, the interactions between mitochondria and ER are crucial to calcium signaling, apoptosis induction, autophagy, and lipid biosynthesis. Here, we summarize mitochondrial and ER functions and physical interactions in healthy physiological states. We then transition to perturbations that occur in response to pathophysiological challenges and how this alters mitochondrial-ER and other intracellular organelle interactions. Finally, we discuss lifestyle interventions and innovative therapeutic targets that may be used to restore beneficial mitochondrial and ER interactions, thereby improving cardiac function.

Sex Differences in Coronary Microvascular Function in Individuals With Type 2 Diabetes.

Cardiovascular (CV) disease fatality rates are higher for women compared with men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), the ratio of adenosine-stimulated to rest myocardial blood flow (MBF), is an indicator of coronary microvascular dysfunction and predicts major adverse CV events. We performed a post hoc analysis to determine whether there was a sex disparity in coronary microvascular dysfunction among 46 men and 27 women with well-controlled type 2 diabetes and without clinical evidence of obstructive CAD. We found that women had a higher rest MBF, lower CFR, and worse diastolic function compared with men. In addition, rest MBF was positively correlated with worse diastolic function in women. We previously showed that mineralocorticoid blockade improved CFR in men and women with type 2 diabetes, implicating aldosterone in the pathophysiology of coronary microvascular dysfunction. We therefore examined aldosterone levels and found that women had larger increases in aldosterone in response to an angiotensin-II infusion than did men. In conclusion, among individuals with type 2 diabetes and good cardiometabolic control, women had worse myocardial perfusion and diastolic function compared with men. The greater aldosterone responsivity in women may be a mechanism for this sex effect.

Islet Cell Associated Autoantibodies and C-Peptide Levels in Patients with Diabetes and Symptoms of Gastroparesis.

INTRODUCTION: Individuals with diabetes are at increased risk for complications, including gastroparesis. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting in decreased beta-cell function. Glutamic acid decarboxylase-65 antibody (GADA) is the most commonly used test to assess autoimmunity while C-peptide level is used to assess beta-cell function. Patients with type 2 diabetes mellitus (T2DM), who are GADA positive, are labeled latent autoimmune diabetes in adults (LADA). OBJECTIVE: To characterize patients with T1 and T2DM who have symptoms of gastroparesis using GADA and C-peptide levels and to look for association with the presence of gastroparesis and its symptom severity. DESIGN: 113 T1DM and 90 T2DM patients with symptoms suggestive of gastroparesis were studied. Symptom severity was assessed using Gastroparesis Cardinal Symptom Index (GCSI). Serum samples were analyzed for GADA and C-peptide. RESULTS: Delayed gastric emptying was present in 91 (81%) of T1DM and 60 (67%) of T2DM patients (p = 0.04). GADA was present in 13% of T2DM subjects [10% in delayed gastric emptying and 20% in normal gastric emptying (p = 0.2)]. Gastric retention and GCSI scores were mostly similar in GADA positive and negative T2DM patients. GADA was present in 45% of T1DM subjects [46% in delayed gastric emptying and 41% in normal gastric emptying (p = 0.81)]. Low C-peptide levels were seen in 79% T1DM patients and 8% T2DM. All seven T2DM patients with low C-peptide were taking insulin compared to 52% of T2DM with normal C-peptide. CONCLUSION: GADA was present in 13% while low C-peptide was seen in 8% of our T2DM patients with symptoms of gastroparesis. Neither did correlate with degree of delayed gastric emptying or symptom severity. CLINICALTRIALSGOV IDENTIFIER: NCT01696747.

Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer.

BACKGROUND: Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10-20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM. CASE PRESENTATION: A 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy. CONCLUSION: New onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM.

Plasminogen Activator Inhibitor-1 and Pericardial Fat in Individuals with Type 2 Diabetes Mellitus.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is implicated in the pathophysiology of cardiovascular disease (CVD) and increased in individuals with type 2 diabetes mellitus (T2DM). Adipose tissue produces PAI-1, and pericardial fat is a CVD risk factor. We sought to determine the relationship between PAI-1 and pericardial fat in males and females with well-controlled T2DM. METHODS: The study population consisted of 32 males and 19 females, aged 35-70 years with T2DM, without clinical evidence of CVD or other active medical problems except for hypertension. Subjects were studied under good cardiometabolic control. Study procedures included fasting blood work and cardiovascular imaging. Cardiac magnetic resonance imaging of the heart was used to identify and quantify pericardial fat from the bifurcation of the pulmonary trunk to the last slice containing cardiac tissue. RESULTS: PAI-1 was positively correlated with pericardial fat (ß = 0.72, r = 0.72, P < 0.001) as well as with homeostatic model assessment of insulin resistance (r = 0.31, P = 0.03) and serum triglycerides (r = 0.27, P = 0.05). In a multivariable regression model, controlling for insulin sensitivity, triglycerides, and body mass index, pericardial fat was independently associated with PAI-1 (ß = 0.80, P < 0.001). CONCLUSIONS: PAI-1 is positively associated with pericardial fat in individuals with T2DM.

Baroreflex Sensitivity Impairment During Hypoglycemia: Implications for Cardiovascular Control.

Studies have shown associations between exposure to hypoglycemia and increased mortality, raising the possibility that hypoglycemia has adverse cardiovascular effects. In this study, we determined the acute effects of hypoglycemia on cardiovascular autonomic control. Seventeen healthy volunteers were exposed to experimental hypoglycemia (2.8 mmol/L) for 120 min. Cardiac vagal baroreflex function was assessed using the modified Oxford method before the initiation of the hypoglycemic-hyperinsulinemic clamp protocol and during the last 30 min of hypoglycemia. During hypoglycemia, compared with baseline euglycemic conditions, 1) baroreflex sensitivity decreases significantly (19.2 ± 7.5 vs. 32.9 ± 16.6 ms/mmHg, P < 0.005), 2) the systolic blood pressure threshold for baroreflex activation increases significantly (the baroreflex function shifts to the right; 120 ± 14 vs. 112 ± 12 mmHg, P < 0.005), and 3) the maximum R-R interval response (1,088 ± 132 vs. 1,496 ± 194 ms, P < 0.001) and maximal range of the R-R interval response (414 ± 128 vs. 817 ± 183 ms, P < 0.001) decrease significantly. These findings indicate reduced vagal control and impaired cardiovascular homeostasis during hypoglycemia.

Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes.

Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic ACE inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25 mg, hydrochlorothiazide (HCTZ) 12.5 mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race, and statin use. Treatment with spironolactone improved coronary microvascular function, raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.

Sclerostin: recent advances and clinical implications.

PURPOSE OF REVIEW: Discovery of the Wnt signaling pathway and understanding the central role of osteocyte in skeletal homeostasis have been the major advances in skeletal biology over the past decade. Sclerostin, secreted mainly (but not exclusively) by osteocytes, has emerged as a key player in skeletal homeostasis. This review highlights the most relevant recent advances. RECENT FINDINGS: Sclerostin by inhibiting Wnt signaling pathway decreases bone formation and osteoblast differentiation and promotes osteoblast apoptosis. Ability to measure serum sclerostin levels better clarified the role of sclerostin in various physiologic and pathologic states. Early clinical trials with antibodies to sclerostin have produced robust increases in bone mineral density, and fracture prevention trials are underway. SUMMARY: Since the discovery of Wnt signaling pathway and sclerostin's association with high bone mass, there has been a remarkable progress. Clinical trials with fracture endpoints, already underway, should expand osteoanabolic therapeutic horizon in the very near future. Measurement of sclerostin levels in a number of conditions has advanced our knowledge about pathophysiology of skeletal and nonskeletal disorders in an altogether new light.

Aldosterone and myocardial extracellular matrix expansion in type 2 diabetes mellitus.

Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m², mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II-stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus.

Osteomalacia as a result of vitamin D deficiency.

Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents.

Osteomalacia as a result of vitamin D deficiency.

Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents.

Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies.

OBJECTIVE: Observational studies assessing the association of combination therapy of metformin and sulfonylurea on all-cause and/or cardiovascular mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the effects of combination therapy of sulfonylureas and metformin on the risk of all-cause mortality and cardiovascular disease (CVD) among people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A MEDLINE search (January 1966-July 2007) was conducted to identify observational studies that examined the association between combination therapy of sulfonylureas and metformin on risk of CVD or all-cause mortality. From 299 relevant reports, 9 were included in the meta-analysis. In these studies, combination therapy of metformin and sulfonylurea was assessed, the risk of CVD and/or mortality was reported, and adjusted relative risk (RR) or equivalent (hazard ratio and odds ratio) and corresponding variance or equivalent was reported. RESULTS: The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetes prescribed combination therapy of sulfonylureas and metformin were 1.19 (0.88-1.62) for all-cause mortality, 1.29 (0.73-2.27) for CVD mortality, and 1.43 (1.10-1.85) for a composite end point of CVD hospitalizations or mortality (fatal or nonfatal events). CONCLUSIONS: The combination therapy of metformin and sulfonylurea significantly increased the RR of the composite end point of cardiovascular hospitalization or mortality (fatal and nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy, or sulfonylurea monotherapy); however, there were no significant effects of this combination therapy on either CVD mortality or all-cause mortality alone.

DPP-4 inhibitors as a new target of action for Type 2 diabetes mellitus: a focus on vildagliptin.

The purpose of this review is to highlight the role of the incretin system and discuss the role of dipeptidyl peptidase (DPP)-4 inhibitors as potential treatment for diabetes, drawing attention to some of the available clinical trial data that support the use of such agents. The DPP-4 enzyme is involved in the breakdown of glucagon-like peptide (GLP)-1, an incretin that has a very short half-life. DPP-4 inhibitors delay the degradation of GLP-1, in turn extending the action of insulin and suppressing the release of glucagon. Endogenous and exogenous GLP-1 not only stimulates the release of insulin, but also reduces the secretion of glucagon. The latter action may be very important and represents a neglected aspect of the treatment of diabetes. The focus of the review is on one of the DPP-4 inhibitors, vildagliptin, since there is much recently published data on this drug. Vildagliptin has been shown to decrease hemoglobin A1C by 0.5-0.8% either alone or in combination. Generally, it is found to be well tolerated and safe, at least in the short term.