The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes.

OBJECTIVE: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future. METHODS: All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured. RESULTS: Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels. CONCLUSIONS: SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01762046.

The ageing of HIV: implications for geriatric medicine.

The prevalence of human immunodeficiency virus (HIV) in the over 50 age group is increasing as a consequence of younger adults ageing with HIV, in addition to new diagnoses in later life. We conducted searches in MEDLINE for English language studies published between January 1984 and January 2010 using search terms 'HIV', 'AIDS', 'HIV testing' and 'HIV complications' and selected articles relevant to adults aged 50 years and over. The prevalence, natural history and complications of HIV infection and treatment in older adults are reviewed. In 2007 the Centers for Disease Control and Prevention in the United States reported that 16.8% of new diagnoses of HIV that year were in individuals aged over 50 years. Older adults are vulnerable to late or missed diagnosis, and poorer treatment outcomes, due to the misconception that they are not at risk. A heightened awareness of HIV as a possible diagnosis in older adults is becoming increasingly important. As the HIV population ages, the emergence of disease and treatment complications such as cardiovascular disease, osteoporosis and dementia are evident. Management of older adults with HIV and multiple co-morbidities presents challenges to infectious diseases physicians and geriatricians alike. Inclusion of older adults in future HIV clinical trials will help design healthcare models to provide for this growing population.

A new ankle foot orthosis for running.

Traumatic knee injuries in automobile accidents and sports often lead to damage of the peroneal nerve. A lack of control of muscles innervated by the peroneal nerve due to this damage, results in the inability to dorsiflex and evert the foot and to extend the toes. This condition is commonly known as foot drop. Foot drop reduces the stability in the body while walking and running and may also cause injury due to lack of foot clearance during the swing phase of the gait. Traditionally, an ankle foot orthosis (AFO), comprised of a moulded sheet of plastic that conforms around the posterior calf and distally contains all or part of the calcaneous as well as the plantar foot, is used to treat foot drop. The intent of this orthosis is to dorsiflex the foot to provide clearance during the swing phase of walking and running. Traditional AFO results in increased pressures due to a decrease in dorsiflexion range of motion at the ankle and make the orthosis increasingly uncomfortable to wear. Several other existing designs of foot drop AFO suffer from similar inadequacies. To address these issues, a new AFO was developed. The device was successfully used by one person with foot drop without issues for more than one year. This new design conforms to the lower anterior shin and dorsum of the foot using dorsiassist Tamarack ankle joints to allow for greater plantar and dorsiflexion range of motion. While still limiting ankle inversion it does allow for more ankle eversion. This orthosis can be discretely worn inside shoes due to its smaller size, and can be worn for a longer period of time without discomfort.

Diagnosis and management of asthma in older adults.

Despite comprehensive guidelines established by the European Global Initiative for Asthma and the U.S. National Asthma Education and Prevention Program on the diagnosis and management of asthma, its mortality in older adults continues to rise. Diagnostic and therapeutic problems contribute to older patients being inadequately treated. The diagnosis of asthma rests on the history and characteristic pulmonary function testing (PFT) with the demonstration of reversible airway obstruction, but there are unique problems in performing this test in older patients and in its interpretation. This review aims to address the difficulties in performing and interpreting PFT in older patients because of the effects of age-related changes in lung function on respiratory physiology. The concept of "airway remodeling" resulting in "fixed obstructive" PFT and the relevance of atopy in older people with asthma are assessed. There are certain therapeutic issues unique to older patients with asthma, including the increased probability of adverse effects in the setting of multiple comorbidities and issues surrounding effective drug delivery. The use of beta 2-agonist, anticholinergic, corticosteroid, and anti-immunoglobulin E treatments are discussed in the context of these therapeutic issues.

The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention program.

CONTEXT: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. RESULTS: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance. CONCLUSIONS: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

The effects of usual footwear on balance amongst elderly women attending a day hospital.

OBJECTIVE: to examine the effects of footwear on balance in a sample of older women attending a day hospital. DESIGN: this was a crossover trial with a quasi-randomised allocation. SETTING: assessments took place in the geriatric day hospital. SUBJECTS: a cohort of 100 older women aged 60 years and over attending a day hospital. METHODS: demographic data and a brief falls history were recorded. Participant's footwear was assessed using a footwear assessment form. A Berg Balance Scale (BBS) was completed under two conditions--shoes on and shoes off with order counter-balanced. RESULTS: the mean BBS was 39.07 (SD 9.14) with shoes on and 36.54 (SD 10.39) with shoes off (P < 0.0001). Balance scores were significantly higher with shoes on for 10 of the 14 Berg subcategories. Lower barefoot BBS scores were associated with a greater beneficial effect of footwear on balance (P < 0.001). Shoe characteristics were not associated with change in the BBS score. CONCLUSIONS: Wearing their own footwear significantly improved participants' balance compared to being barefoot. The greatest benefit of footwear was seen in those with the poorest balance. Further studies should investigate whether particular types of footwear are associated with greater benefit.

An unusual case of primary hyperparathyroidism with profoundly elevated parathyroid hormone levels.

OBJECTIVE: To report the case of a man who presented with profoundly elevated parathyroid hormone levels in the setting of hypercalcemia, a palpable neck mass, renal disease, and metabolic bone disease. METHODS: We describe the clinical, imaging, and laboratory findings of the patient, including results from genetic testing of the CDC73 gene (HRPT2), and review the relevant literature. RESULTS: A 28-year-old man with a history of childhood abdominal neuroblastoma treated with chemotherapy and field radiation therapy presented with a 2-week history of persistent left scapular pain and swelling. He had a freely mobile, 1-cm, homogeneous, nontender, firm nodule in the right anterior neck. Parathyroid hormone concentration at hospital admission was 1127 pg/mL. Single-photon emission computed tomography after intravenous administration of technetium Tc 99m-labeled sestamibi revealed an intense focus of abnormal radiotracer uptake on early and delayed images in the right anterior inferior neck. Computed tomography imaging of the chest and neck revealed a 1.9-cm, smooth, calcified nodule posterior to the right lobe of the thyroid gland and diffusely osteopenic bones with trabecular resorption and numerous scattered lucent regions consistent with brown tumors. On bilateral neck exploration, a right inferior parathyroid mass and the left superior parathyroid gland were excised. The remaining 2 parathyroid glands were identified intraoperatively and appeared normal. Genetic testing of the CDC73 gene did not detect germline mutations. CONCLUSIONS: This case highlights the overlap between the clinical findings seen in primary hyperparathyroidism and parathyroid carcinoma. Enhanced understanding of the genetic and molecular bases of primary hyperparathyroidism and parathyroid carcinoma should aid in the diagnosis of these diseases and the care of affected patients.

Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program.

OBJECTIVE: Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo. RESEARCH DESIGN AND METHODS: We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year. RESULTS: None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05). CONCLUSIONS: We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.

Genetic susceptibility to type 2 diabetes and implications for antidiabetic therapy.

Despite major advances in our knowledge of glycemic pathophysiology and the availability of multiple therapeutic options to confront type 2 diabetes, unraveling the complex link between genetic risk and environmental factors in this burgeoning epidemic has proven difficult. Linkage approaches have clarified the etiology of monogenic diabetic syndromes and congenital lipodystrophies, and candidate gene association studies have identified a number of common variants implicated in type 2 diabetes. This year we have witnessed the advent of genome-wide association scanning: As many as nine genetic loci have now been reproducibly associated with type 2 diabetes in five genome-wide scans. Of particular interest are preliminary explorations of the connections between genetic risk and pharmacologic response. An improved understanding of genetic mechanisms should allow us to test whether behavioral or pharmacologic therapies can be tailored and thus the tremendous disease burden inflicted by type 2 diabetes alleviated.

Sunitinib (sutent)-induced thyrotoxicosis due to destructive thyroiditis: a case report.

Numerous drugs have been associated with destructive thyroiditis (subacute thyroiditis). Sunitinib, a tyrosine kinase inhibitor employed in renal cell carcinoma and gastrointestinal stromal tumors, has recently been linked to destructive thyroiditis with resultant hypothyroidism. We report a patient with transient overt thyrotoxicosis followed by hypothyroidism, apparently related to sunitinib therapy.

Management of transient ischemic attack: 2005.

Transient ischemic attack is a common presenting problem to clinicians. Historically, these events were defined by the resolution of new neurologic symptoms within a 24-h time-frame; however, recent data suggests that a 1-h time frame is more appropriate. New imaging techniques and clinical evidence suggests that transient ischemic attacks present a higher risk of impending stroke than previously thought. This has led to a redefinition of what constitutes an attack, and also to a focus on both earlier investigation and treatment of correctable causes. New antiplatelet agents are now available and pose a challenge as to how they should be prescribed. Carotid endarterectomy is the standard of care for a subset of transient ischemic attack patients with significant carotid stenosis. Carotid angioplasty and stenting are more recent developments that may further expand treatment options.