Biomarkers of sarcopenia in clinical trials-recommendations from the International Working Group on Sarcopenia.

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7-8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

Evaluation of two doses of ceftiofur crystalline free acid sterile suspension for treatment of metritis in lactating dairy cows.

The objectives of this study were to evaluate efficacy of a 2-dose regimen of ceftiofur crystalline free acid sterile suspension (CCFA-SS) for treatment of acute metritis in lactating dairy cows under field conditions and to provide additional safety and injection site tolerance data for injections at the base of the ear. Cows at 15 dairies with rectal temperature ≥ 39.5°C and fetid uterine discharge ≤ 10 d postcalving were randomly assigned by blocks of 2, based on order of entry and without regard to parity, to treatment with saline (1.5 mL/45.5 kg of body weight, n=509) or CCFA-SS (6.6 mg of ceftiofur equivalents/kg of body weight, n=514). Treatments were administered by subcutaneous injection in the posterior aspect of the ear where it attaches to the head; the first dose was administered on study d 0 and the second dose was administered in the contra lateral ear on study d 3. Rectal temperatures were recorded on study d 1 to 4 and 5 or 6 and cows were clinically evaluated daily from study d 1 to 13. Cows that exhibited increased adverse clinical signs of poor health or complications associated with metritis were categorized as a treatment failure and administered escape therapy. Each cow received a veterinary physical examination on study d 5 or 6 to determine if she should be removed from the study and on study d 14 to determine clinical cure or failure to cure. Clinical cure was defined as rectal temperature <39.5°C and non-fetid and purulent or mucopurulent discharge on study d 14 and no escape therapy administered. The injection procedure was scored after each injection (study d 0 and 3) and injection sites and ear carriage were scored on study d 5 or 6, 14, and 57±3. Of the 1,023 cows enrolled, 7 were completely censored due to protocol deviations and 34 were removed for protocol deviations or medical conditions not related to metritis. Clinical cure rate was higher for CCFA-SS than for saline (74.3 vs. 55.3%) and rectal temperatures for each of study d 1 to 5 or 6 were lower for CCFA-SS than saline. Injection procedure indices showed that CCFA-SS could be practically and safely administered using commercial dairy facilities. Although injection site scores were higher for CCFA-SS than saline at study d 5 or 6 and 14, ≥98.6% of ears were normal on d 57±3. Thus, a 2-dose treatment with CCFA-SS given 72h apart increased metritis clinical cure rate and was well tolerated in dairy cows.

Remission of paroxysmal atrial fibrillation with iron reduction in haemophilia A.

SUMMARY: Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12-15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression. Radiofrequency ablation was considered in both the cases but deferred considering refusal of consent by the patients to undergo the procedure. Remission of arrhythmias has been reported in patients with iron-overload syndromes. Body iron stores assessed by serum ferritin levels were elevated in both men but neither had the C282Y or H63D genes for haemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases. Iron reduction may be an effective treatment for arrhythmias apart from the classic iron-overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing.

Psychotropic medication use and risk of adverse cardiovascular events in women with suspected coronary artery disease: outcomes from the Women's Ischemia Syndrome Evaluation (WISE) study.

OBJECTIVE: This study investigated the relation between psychotropic medication use and adverse cardiovascular (CV) events in women with symptoms of myocardial ischaemia undergoing coronary angiography. METHOD: Women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) were classified into one of four groups according to their reported antidepressant and anxiolytic medication usage at study intake: (1) no medication (n = 352); (2) anxiolytics only (n = 67); (3) antidepressants only (n = 58); and (4) combined antidepressant and anxiolytics (n = 39). Participants were followed prospectively for the development of adverse CV events (for example, hospitalisations for non-fatal myocardial infarction, stroke, congestive heart failure and unstable angina) or all-cause mortality over a median of 5.9 years. RESULTS: Use of antidepressant medication was associated with subsequent CV events (HR 2.16, 95% CI 1.21 to 3.93) and death (HR 2.15, 95% CI 1.16 to 3.98) but baseline anxiolytic use alone did not predict subsequent CV events and death. In a final regression model that included demographics, depression and anxiety symptoms, and risk factors for cardiovascular disease, women in the combined medication group (that is, antidepressants and anxiolytics) had higher risk for CV events (HR 3.98, CI 1.74 to 9.10, p = 0.001 and all-cause mortality (HR 4.70, CI 1.7 to 2.97, p = 0.003) compared to those using neither medication. Kaplan-Meier survival curves indicated that there was a significant difference in mortality among the four medication groups (p = 0.001). CONCLUSIONS: These data suggest that factors related to psychotropic medication such as depression refractory to treatment, or medication use itself, are associated with adverse CV events in women with suspected myocardial ischaemia.

A Community Health Advisor Program to reduce cardiovascular risk among rural African-American women.

The Uniontown, Alabama Community Health Project trained and facilitated Community Health Advisors (CHAs) in conducting a theory-based intervention designed to reduce the risk for cardiovascular disease (CVD) among rural African-American women. The multiphased project included formative evaluation and community organization, CHA recruitment and training, community intervention and maintenance. Formative data collected to develop the training, intervention and evaluation methods and materials indicated the need for programs to increase knowledge, skills and resources for changing behaviors that increase the risk of CVD. CHAs worked in partnership with staff to develop, implement, evaluate and maintain strategies to reduce risk for CVD in women and to influence city officials, business owners and community coalitions to facilitate project activities. Process data documented sustained increases in social capital and community capacity to address health-related issues, as well as improvements in the community's physical infrastructure. This project is unique in that it documents that a comprehensive CHA-based intervention for CVD can facilitate wide-reaching changes in capacity to address health issues in a rural community that include improvements in community infrastructure and are sustained beyond the scope of the originally funded intervention.

The pharmacology and therapeutic relevance of endocannabinoid derived cyclo-oxygenase (COX)-2 products.

The discovery of anandamide and 2-arachidonyl glycerol (2-AG) as naturally occurring mammalian endocannabinoids has had important and wide-reaching therapeutic implications. This, to a large extent, ensues from the complexity of endocannabinoid biology. One facet of endocannabinoid biology now receiving increased attention is the cyclo-oxygenase-2 (COX-2) derived oxidation products. Anandamide and 2-AG are oxidized to a range of PG-ethanolamides and PG-glyceryl esters that closely approaches that of the prostaglandins (PGs) formed from arachidonic acid. The pharmacology of these electrochemically neutral PG-ethanolamides (prostamides) and PG-glyceryl esters appears to be unique. No meaningful interaction with natural or recombinant prostanoid receptors is apparent. Nevertheless, in certain cells and tissues, prostamides and PG-glyceryl esters exert potent effects. The recent discovery of selective antagonists for the putative prostamide receptor has been a major advance in further establishing prostamide pharmacology as an entity distinct from prostanoid receptors. Since discovery of the prototype prostamide antagonist (AGN 204396), rapid progress has been made. The latest prostamide antagonists (AGN 211334-6) are 100 times more potent than the prototype and are, therefore, sufficiently active to be used in living animal studies. These compounds will allow a full evaluation of the role of prostamides in health and disease. To date, the only therapeutic application for prostamides is in glaucoma. The prostamide analog, bimatoprost, being the most effective ocular hypotensive drug currently available. Interestingly, PGE(2)-glyceryl ester and its chemically stable analog PGE(2)-serinolamide also lower intraocular pressure in dogs. Nevertheless, the therapeutic future of PGE(2)-glyceryl ester is more likely to reside in inflammation.

Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes.

BACKGROUND AND PURPOSE: A prostamide analogue, bimatoprost, has been shown to be effective in reducing intraocular pressure, but its precise mechanism of action remains unclear. Hence, to elucidate the molecular mechanisms of this effect of bimatoprost, we focused on pharmacologically characterizing prostaglandin FP receptor (FP) and FP receptor variant (altFP) complexes. EXPERIMENTAL APPROACH: FP receptor mRNA variants were identified by reverse transcription-polymerase chain reaction. The FP-altFP4 heterodimers were established in HEK293/EBNA cells co-expressing FP and altFP4 receptor variants. A fluorometric imaging plate reader was used to study Ca2+ mobilization. Upregulation of cysteine-rich angiogenic protein 61 (Cyr61) mRNA was measured by Northern blot analysis, and phosphorylation of myosin light chain (MLC) by western analysis. KEY RESULTS: Six splicing variants of FP receptor mRNA were identified in human ocular tissues. Immunoprecipitation confirmed that the FP receptor is dimerized with altFP4 receptors in HEK293/EBNA cells co-expressing FP and altFP4 receptors. In the studies of the kinetic profile for Ca2+ mobilization, prostaglandin F2alpha (PGF2alpha) elicited a rapid increase in intracellular Ca2+ followed by a steady state phase. In contrast, bimatoprost elicited an immediate increase in intracellular Ca2+ followed by a second phase. The prostamide antagonist, AGN211335, selectively and dose-dependently inhibited the bimatoprost-initiated second phase of Ca2+ mobilization, Cyr61 mRNA upregulation and MLC phosphorylation, but did not block the action of PGF2alpha. CONCLUSION AND IMPLICATIONS: Bimatoprost lacks effects on the FP receptor but may interact with the FP-altFP receptor heterodimer to induce alterations in second messenger signalling. Hence, FP-altFP complexes may represent the underlying basis of bimatoprost pharmacology.

Ischemia-reperfusion injury in cadaveric nonheart beating, cadaveric heart beating and live donor renal transplants.

PURPOSE: Ischemia-reperfusion injury is gaining importance in transplantation as being responsible for allograft dysfunction. Ischemia occurs during kidney procurement, which is shortest in LDs, and prolonged in cadaveric HBDs and NHBDs. MATERIALS AND METHODS: Renal transplants from 17 LDs, 15 HBDs and 19 NHBDs were assessed during reperfusion for biochemical markers of ischemia-reperfusion injury and assessed clinically. Central venous blood sampling was assayed for free radicals using electron spin resonance and tissue injury biomarkers, namely lactate dehydrogenase, fatty acid binding protein, alanine aminopeptidase, lactate and total antioxidants. RESULTS: The return to stable renal function was more rapid in LD renal transplants, while recovery continued from 3 months after hospital discharge in NHBD renal transplants. Injury markers, such as lactate dehydrogenase, fatty acid binding protein, alanine aminopeptidase and lactate, were raised at the time of reperfusion, especially in NHBD renal transplants. Free radical release measured by electron spin resonance showed 2 phase release, that is early (0 to 10-minute) and late (20 to 40-minute) release. In NHBD, HBD and LD renal transplants the index of free radical release in the early phase was 1.43, 1.36 and 1.20, and in the late phase it was 1.43, 1.38 and 0.97, respectively (each ANOVA p <0.05). CONCLUSIONS: NHBD renal transplants were accompanied by a greater release of free radicals at reperfusion (NHBD > HBD > LD), which was associated with an increase in tissue injury markers at reperfusion. This was reflected in a slower return to stable renal function in NHBD compared to HBD and LD renal transplants.

Reperfusion injury in renal transplantation: comparison of LD, HBD and NHBD renal transplants.

Comparison of reperfusion injury in kidneys transplanted from LD, HBD or NHBD donors is presented in the paper. Central venous blood samples (taken during perioperative period) was assessed for free radicals, total antioxidant activity and various markers of tissue injury. There was demonstrable ischemia reperfusion injury occurring at the time of revascularization, which was particularly notable in kidneys transplanted from NHBD donors.

Measuring recovery after a hip fracture using the SF-36 and Cummings scales.

The objective of this study was to assess outcomes of traditional treatment of fractures using the SF-36 and the Cummings Hip Scale. In designing randomized clinical trials, it is necessary to determine the timing of assessment either for progress or for the main outcome. We set out to document the recovery of patients after surgery for hip fracture using current standard methods of medical care. This was a prospective study of a cohort of patients. Patients who were receiving standard medical care completed the SF-36 and the Cummings Hip Scale at previously determined times postoperatively. The SF-36 has eight subscales, including assessments of physical function, physical role behaviors, bodily pain, mental health, social role, emotional role, vitality and general health. Thirty-eight patients completed the questionnaires at 1 year postoperatively as well as previous time points. On the Cummings Hip Scale and the physical function, bodily pain, mental health, social function, emotional role, vitality and general health subscales of the SF-36, recovery is near complete at 6 months. Only the physical role subscale differs, with a statistically significant difference between the values at 6 months and 1 year, (p = 0.02). Patients attained over 90% of the 1 year value by 6 months for all except the physical role subscale. The physical role subscale reached 85%. For a hip fracture patient who is on the road to recovery, the majority of the recovery has therefore taken place by 6 months.

Developing community capacity and improving health in African American communities.

Community-based programs have produced mixed results. Community capacity is thought to be a major determinant of program effectiveness. Thus, enhancing community capacity may increase the beneficial effects of existing programs and enhance future program effectiveness. This highlights the need to focus on understanding the components of capacity and the methods of enhancing capacity. Although we are just beginning to examine and understand key concepts, community capacity is probably influenced by both relatively nonmodifiable characteristics (such as demographic factors, institutional resources, and social structures) and relatively modifiable characteristics (such as knowledge, skills, and the ability and willingness of members and agencies to work collaboratively). In their relationships with community members and agencies, academicians and public health practitioners may help acquire categorical funding to enhance opportunities to build community capacity and their own capacity as well. The relationship between academicians/practitioners and community members/agencies probably is influenced by a host of characteristics which determine the degree to which capacity can be built. This paper discusses: the key components of capacity; the factors that influence building capacity through collaborations; a community health advisor (CHA) model which both builds on sociocultural aspects of African American culture and is consistent with methods for building community capacity; and how modifications to this model allow it to be compatible with categorically funded projects.

History of anxiety disorders is associated with a decreased likelihood of angiographic coronary artery disease in women with chest pain: the WISE study.

OBJECTIVES: We sought to evaluate the ability of psychiatric anxiety-disorder history to discriminate between women with and without angiographic coronary artery disease (CAD) in a population with chest pain. BACKGROUND: A total of 435 women with chest pain underwent a diagnostic battery including coronary angiography in order to improve testing guidelines for women with suspected CAD. METHODS: Women referred for coronary angiography completed questionnaires assessing prior treatment history for anxiety disorder and current anxiety-related symptoms. Analyses controlled for standard CAD risk factors. RESULTS: Forty-four women (10%) reported receiving prior treatment for an anxiety disorder. This group acknowledged significantly higher levels of autonomic symptoms (e.g., headaches, muscle tension [F = 25.0, p < 0.0011 and higher behavioral avoidance scores (e.g., avoidance of open places or traveling alone by bus [F = 4.2, p < 0.05]) at baseline testing compared with women without prior anxiety problems. Women with an anxiety-disorder history did not differ from those without such a history with respect to the presence of inducible ischemia or use of nitroglycerin, although they were younger and more likely to describe both "tight" and "sharp" chest pain symptoms and to experience back pain and episodes of nocturnal chest pain. Logistic regression results indicated that the positive-anxiety-history group was more likely to be free of underlying significant angiographic CAD (odds ratio = 2.74, 95% confidence interval 1.15 to 6.5, p = 0.03). CONCLUSIONS: Among women with chest pain symptoms, a history of anxiety disorders is associated with a lower probability of significant angiographic CAD. Knowledge of anxiety disorder history may assist in the clinical evaluation of women with chest pain.

Succinylcholine-induced hyperkalemia in a patient with mucositis secondary to chemotherapy.

OBJECTIVE: To report a case of fatal hyperkalemia owing to succinylcholine administration in a patient with mucositis secondary to chemotherapy. DESIGN: Case report. SETTING: Adult intensive care unit (ICU) at Dartmouth-Hitchcock Medical Center. PATIENTS: One patient with mucositis secondary to chemotherapy. MEASUREMENTS AND MAIN RESULTS: A 37-yr-old female with recently diagnosed acute myelogenous leukemia was admitted to the ICU with mental status changes and progressive dyspnea requiring intubation and mechanical ventilation. Before ICU admission, the patient had suffered from painful mucositis causing severe dysphagia and bleeding, which was thought to be the result of chemotherapy. By the 10th ICU day, the patient's respiratory and mental status improved and the patient was successfully extubated. However, 8 hrs after extubation, she gradually developed severe respiratory distress, requiring reintubation and mechanical ventilation. The patient was given 14 mg of etomidate and 100 mg of succinylcholine intravenously. Immediately after the intubation, she suffered cardiac arrest. Her serum potassium level was 13.1 mEq/L and HCO3- was 16 mEq/L. The resuscitation attempt was unsuccessful, and the patient was pronounced dead. CONCLUSION: Oral mucositis is a frequent and potentially severe complication of cancer chemotherapy. We believe that mucositis was a contributing factor to this case of fatal hyperkalemia after administration of succinylcholine, with a mechanism similar to that reported with thermal injury. Only nondepolarizing muscle relaxants should be used in patients who are at risk for mucositis. Mucositis should be added to the list of conditions in which succinylcholine is contraindicated.

Weight loss attempts and attitudes toward body size, eating, and physical activity in American Indian children: relationship to weight status and gender.

OBJECTIVE: This study examined dieting, weight perceptions, and self-efficacy to eat healthy foods and engage in physical activity and their relationships to weight status and gender among American Indian elementary schoolchildren. RESEARCH METHODS AND PROCEDURES: Data for this study were collected as part of the baseline examination for the Pathways study. Participants were 1441 second- through third-grade American Indian children in 41 schools representing seven tribes in Arizona, New Mexico, and South Dakota who filled out a questionnaire and had heights and weights taken. RESULTS: Forty-two percent of the children were overweight or obese. No differences were found between overweight/obese and normal weight children for healthy food intentions or self-efficacy. Heavier children (especially those with body mass index > 95th percentile) were more likely to have tried to lose weight or were currently trying to lose weight. No gender differences were found. Normal weight children chose a slightly heavier body size as most healthy compared with overweight/obese children. DISCUSSION: The results indicate that children are concerned about their weight and that weight modification efforts are common among overweight American Indian children. School, community, and family-based programs are needed to help young people adopt lifelong healthful eating and physical activity practices.

High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A.

An open-label multicentre trial was conducted to evaluate high-dose DDAVP (desmopressin acetate) intranasal spray (Stimate; 1.5 mg mL(-1)), for the control of bleeding in 333 patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease, or symptomatic carriers of haemophilia A. Overall, 278 patients received 2170 doses of high-dose DDAVP intranasal spray (1.5 mg mL(-1)). Using study-defined guidelines, patients evaluated the efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) as 'excellent' or 'good' in 743 (95%) of 784 bleeding episodes. It demonstrated 'excellent' results in 384 (93%) of 413 administrations for prophylaxis and in eight of eight uses prior to acute surgical or dental procedures. When used for the treatment of menorrhagia, the efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) was rated as 'excellent' after 655 (92%) of 721 daily uses. Of 2170 doses of high-dose DDAVP intranasal spray (1.5 mg mL(-1)), 172 (8%) were associated with adverse events. A total of 272 adverse events were reported among 80 patients. Of these, 239 (88%) were mild or moderate in intensity and only one patient was removed from the study due to an adverse event. These results demonstrate the safety and efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) for control of bleeding episodes in patients with mildly decreased levels of factor VIII, von Willebrand factor, or both.

Failure of bipolar hemiarthroplasty: a retrospective review of 31 consecutive bipolar prostheses converted to total hip arthroplasty.

Bipolar hemiarthroplasty has been widely used for the treatment of femoral neck fractures in elderly patients. Outcome studies show excellent results with near preoperative ambulation and lasting, painless hip function. However, what has only recently been considered is that, in some cases, failure of bipolar hemiarthroplasty may be due to wear of the thin, ultra-high-molecular weight polyethylene (UHMWPE) insert between the inner and outer bearings of the prosthesis with subsequent generation of particulate debris, periprosthetic osteolysis, and stem loos ening. We reviewed 31 consecutive bipolar hemiarthroplasties converted to total hip arthroplasties by a single surgeon between 1986 and 1994. The average time to failure was 38 months. Fifty-six percent of the cases showed radiographic evidence of osteolysis around the stem. Radiographic migration of the bipolar head of more than 1 mm into the pelvis, suggestive of cartilage wear, occurred in 67% of the cases. Among the patients with radiographic osteolysis and a loose stem at the time of revision, 92% showed a characteristic histiocytic and giant cell reaction to polyethylene particles in tissue obtained during surgery. The UHMWPE liners from the retrieved outer shells showed an average wear rate of 0.7 mm per year. Recent studies comparing bipolar to unipolar hemiarthroplasty show little difference between the two with regard to morbidity, mortality, or functional outcome. In light of our findings, it might be prudent to reconsider the design and indications for bipolar hemiarthroplasty.

Psychosocial variables are associated with atherosclerosis risk factors among women with chest pain: the WISE study.

OBJECTIVE: We investigated associations between atherosclerosis risk factors (smoking behavior, serum cholesterol, hypertension, body mass index, and functional capacity) and psychological characteristics with suspected linkages to coronary disease (depression, hostility, and anger expression) in an exclusively female cohort. METHODS: Six hundred eighty-eight middle-aged women with chest pain warranting clinical investigation completed a comprehensive diagnostic protocol that included quantitative coronary angiography to assess coronary artery disease (CAD). Primary analyses controlled for menopausal status, age, and socioeconomic status variables (income and education). RESULTS: High depression scores were associated with a nearly three-fold risk of smoking (odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.4-5.7) after covariate adjustment, and women reporting higher depression symptoms were approximately four times more likely to describe themselves in the lowest category of functional capacity (OR = 3.7, 95% CI = 1.7-7.8). High anger-out scores were associated with a four-fold or greater risk of low high-density lipoprotein cholesterol concentration (<50 mg/dl; OR = 4.0, 95% CI = 1.4-11.1) and high low-density lipoprotein cholesterol concentration (>160 mg/dl; OR = 4.8, 95% CI = 1.5-15.7) and a larger body mass index (OR = 3.5, 95% CI = 1.1-10.8) after covariate adjustment. CONCLUSIONS: These results demonstrate consistent and clinically relevant relationships between psychosocial factors and atherosclerosis risk factors among women and may aid our understanding of the increased mortality risk among women reporting high levels of psychological distress.