Diabetes screen during tuberculosis contact investigations highlights opportunity for new diabetes diagnosis and reveals metabolic differences between ethnic groups.

Type 2 diabetes (T2D) is a prevalent risk factor for tuberculosis (TB), but most studies on TB-T2D have focused on TB patients, been limited to one community, and shown a variable impact of T2D on TB risk or treatment outcomes. We conducted a cross-sectional assessment of sociodemographic and metabolic factors in adult TB contacts with T2D (versus no T2D), from the Texas-Mexico border to study Hispanics, and in Cape Town to study South African Coloured ethnicities. The prevalence of T2D was 30.2% in Texas-Mexico and 17.4% in South Africa, with new diagnosis in 34.4% and 43.9%, respectively. Contacts with T2D differed between ethnicities, with higher smoking, hormonal contraceptive use and cholesterol levels in South Africa, and higher obesity in Texas-Mexico (p < 0.05). PCA analysis revealed striking differences between ethnicities in the relationships between factors defining T2D and dyslipidemias. Our findings suggest that screening for new T2D in adult TB contacts is effective to identify new T2D patients at risk for TB. Furthermore, studies aimed at predicting individual TB risk in T2D patients, should take into account the heterogeneity in dyslipidemias that are likely to modify the estimates of TB risk or adverse treatment outcomes that are generally attributed to T2D alone.

Osteoporosis-Related Health Behaviors in Men With Prostate Cancer and Survivors: Exploring Osteoporosis Knowledge, Health Beliefs, and Self-Efficacy.

This descriptive study aimed to (a) determine the extent of osteoporosis knowledge, perceived health beliefs, and self-efficacy with bone healthy behaviors in men with prostate cancer and survivors and (b) identify how dietary bone healthy behaviors are associated with these psychobehavioral and psychosocial factors. Three different questionnaires were used to measure osteoporosis knowledge, health beliefs, and self-efficacy in a group of men with prostate cancer and survivors. Bone health was assessed via dual-energy X-ray absorptiometry and calcium intake using a diet history. The prevalence of osteoporosis and low bone mass was high at over 70%. Participants had inadequate osteoporosis knowledge with a mean score of 43.3% ( SD = 18%) on the Facts on Osteoporosis Quiz. Participants scored low on the subscale measuring barriers to exercise (median = 11; interquartile range [IQR] = 6.5), indicating minimal barriers to exercise participation, and the subscale measuring the benefits of exercise scored the highest (median = 24; IQR = 3.5) compared with the other subscales. Men with prostate cancer and survivors were highly confident in their exercise and calcium self-efficacy (83.0%, IQR = 24.0% and 85.7%, IQR = 27.0%, respectively). Participants did not meet their calcium requirements or consume enough dairy products for optimum bone health. Men with prostate cancer and survivors have poor osteoporosis knowledge, but are confident in their self-efficacy of undertaking bone healthy behaviors. This confidence did not translate to specific dietary behaviors as they did not meet their calcium or dairy intake requirements. Implications for cancer survivors is that there is a need for bone health education programs among prostate cancer survivors. These programs should go beyond education and empowerment to provide practical guidance to maximize uptake of bone healthy behaviors.

Prevalence of osteoporosis in prostate cancer survivors II: a meta-analysis of men not on androgen deprivation therapy.

The prevalence of osteoporosis in men with prostate cancer (PCa) on androgen deprivation therapy (ADT) is well documented, with up to 53% affected by this bone condition. However, there has been less emphasis on the burden of severe bone loss in men with PCa but not undergoing ADT. Therefore, the purpose of this meta-analysis is to compile evidence from the literature on the bone health of hormone-naïve PCa patients and to compare it to the bone health of men with PCa on ADT. Three databases were searched for the relevant literature published from 1990 until January 2014. The pooled prevalence of osteoporosis, low bone mass, and normal bone mass were estimated for this patient group and compared with similar subgroups from a previously published meta-analysis. The prevalence of osteoporosis varies from 4 to 38% in hormone-naïve PCa patients, and men with more advanced disease have a higher prevalence of osteoporosis. Men with PCa on ADT have poorer bone health than their hormone-naïve counterparts, but the trend toward poorer bone health with metastatic disease remains. In conclusion, it was found that men with PCa experience poor bone health prior to treatment with ADT. These results suggest that all men with PCa should have regular bone health monitoring, whether they commence ADT or not, in order to prevent or indeed minimize the morbidity that accompanies osteoporosis.

Oxidative stress resulting from exposure of a human salivary gland cells to paraoxon: an in vitro model for organophosphate oral exposure.

Organophosphate (OP) compounds are used as insecticides, acaricides, and chemical agents and share a common neurotoxic mechanism of action. The biochemical alterations leading to many of the deleterious effects have been studied in neuronal cell lines, however, non-neuronal toxic effects of OPs are far less well characterized in vitro, and specifically in cell lines representing oral routes of exposure. To address this void, the human salivary gland (HSG) cell line, representing likely interactions in the oral cavity, was exposed to the representative OP paraoxon (PX; O,O-diethyl-p-nitrophenoxy phosphate) over a range of concentrations (0.01-100 µM) and analyzed for cytotoxicity. PX induced cytotoxicity in HSG cells at most of the exposure concentrations as revealed by MTT assay, however, the release of LDH only occurred at the highest concentration of PX tested (100 µM) at 48 h. Slight increases in cellular ATP levels were measured in PX-exposed (10 µM) HSG cells at 24 h. Exposing HSG cells to 10 µM PX also led to an increase in DNA fragmentation prior to loss of cellular membrane integrity implicating reactive oxygen species (ROS) as a trigger of toxicity. The ROS genes gss, gstm2, gstt2 and sod2 were upregulated, and the presence of superoxide following 10 µM PX exposure was determined via dihydroethidium fluorescence studies further implicating PX-induced oxidative stress in HSG cells.

Cd²âº-induced alteration of the global proteome of human skin fibroblast cells.

Cadmium (Cd(2+)) is a toxic heavy metal and a well-known human carcinogen. The toxic effects of Cd(2+) on biological systems are diverse and thought to be exerted through a complex array of mechanisms. Despite the large number of studies aimed to elucidate the toxic mechanisms of action of Cd(2+), few have been targeted toward investigating the ability of Cd(2+) to disrupt multiple cellular pathways simultaneously and the overall cellular responses toward Cd(2+) exposure. In this study, we employed a quantitative proteomic method, relying on stable isotope labeling by amino acids in cell culture (SILAC) and LC-MS/MS, to assess the Cd(2+)-induced simultaneous alterations of multiple cellular pathways in cultured human skin fibroblast cells. By using this approach, we were able to quantify 2931 proteins, and 400 of them displayed significantly changed expression following Cd(2+) exposure. Our results unveiled that Cd(2+) treatment led to the marked upregulation of several antioxidant enzymes (e.g., metallothionein-1G, superoxide dismutase, pyridoxal kinase, etc.), enzymes associated with glutathione biosynthesis and homeostasis (e.g., glutathione S-transferases, glutathione synthetase, glutathione peroxidase, etc.), and proteins involved in cellular energy metabolism (e.g., glycolysis, pentose phosphate pathway, and the citric acid cycle). Additionally, we found that Cd(2+) treatment resulted in the elevated expression of two isoforms of dimethylarginine dimethylaminohydrolase (DDAH I and II), enzymes known to play a key role in regulating nitric oxide biosynthesis. Consistent with these findings, we observed elevated formation of nitric oxide in human skin (GM00637) and lung (IMR-90) fibroblast cells following Cd(2+) exposure. The upregulation of DDAH I and II suggests a role of nitric oxide synthesis in Cd(2+)-induced toxicity in human cells.

Prevalence of osteoporosis in prostate cancer survivors: a meta-analysis.

Androgen deprivation therapy (ADT), which is used in the treatment of prostate cancer (PCa), is associated with increased morbidity. Severe bone loss is a major consequence of androgen ablation and with an increasing number of patients undergoing this treatment, the incidence of osteoporosis and fractures can be expected to increase with a significant impact on healthcare. To evaluate the prevalence of osteoporosis, we conducted a review of the literature on bone health in men with PCa undergoing ADT. A meta-analysis was conducted using the quality effects model, and sources of heterogeneity were further explored by consideration of discordant effect sizes of included studies in the meta-analysis and examining reasons thereof. Our analyses indicate that the prevalence of osteoporosis varies between 9 and 53 % with this variation partially explained by treatment duration, disease stage, ethnicity and site of osteoporosis measurement. While it is well known that a rapid decline in bone health amongst men with PCa on ADT occurs, this meta-analysis documents the high prevalence of osteoporosis in this population and reinforces the need of preventative approaches as part of usual care of PCa patients.

Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs.

The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.

Random measurements of adiponectin and IL-6 may not be indicative of the 24-h profile in critically ill patients.

CONTEXT: The anti-inflammatory role of adiponectin has prompted interest in a potential role in acute inflammatory conditions associated with critical illness. It is unclear whether a random adiponectin measurement adequately reflects the 24-h profile in critically ill patients. OBJECTIVE: To assess the temporal profile of total and high molecular weight (HMW) adiponectin and interleukin-6 (IL-6) in 15 critically ill patients. DESIGN: A prospective, observational study. SETTING: Level II intensive care unit in a metropolitan hospital. PATIENTS OR OTHER PARTICIPANTS: Fifteen critically ill patients expected to stay in the ICU for longer than 48 h were eligible for enrolment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serial, hourly measurements of total and HMW adiponectin and IL-6. RESULTS: Over a 24-h period, total and HMW adiponectin display considerable within-patient variability (coefficient of variation 34% and 87% respectively) and show no trend over time. Averaging 2 or 3 continuous measures reduced within-patient variability of both total and HMW adiponectin by up to 50% compared to one measure. There was a negative correlation between serum glucose and adiponectin (total P = 0·016, HMW P = 0·039). No relationship existed between adiponectin and IL-6 (total P = 0·62, HMW P = 0·35). CONCLUSIONS: Marked within-patient, hourly variability in total and HMW adiponectin is evident in critically ill patients. A random measurement may not be reflective of the 24-h profile in these patients. A negative correlation exists between adiponectin and blood glucose levels and a positive correlation between adiponectin and oxygen saturation. No clear relationship exists between adiponectin and IL-6.

Quantitative proteomic analysis revealed N'-nitrosonornicotine-induced down-regulation of nonmuscle myosin II and reduced cell migration in cultured human skin fibroblast cells.

The association of tobacco smoke with decreased cell motility and wound healing is well documented; however, the cellular mechanisms and specific toxic tobacco constituents responsible for this effect are not well understood. Tobacco-specific N-nitrosamines (TSNAs) are among the most important classes of carcinogens found in tobacco products. The TSNA N'-nitrosonornicotine (NNN) is present at relatively high levels in tobacco and its smoke, as well as second- and third-hand smoke. To investigate the cellular pathways that are perturbed upon NNN exposure, we employed a quantitative proteomic approach, utilizing stable isotope labeling by amino acids in cell culture and mass spectrometry, to assess the NNN-induced alteration of protein expression in GM00637 human skin fibroblast cells. With this approach, we were able to quantify 2599 proteins, 191 of which displayed significantly changed expression following NNN exposure. One of the main findings from our proteomic analysis was the down-regulation of six different subunits of myosin, particularly nonmuscle myosin II heavy chain, isoforms A, B, and C. In addition, we found the altered expression of several extracellular matrix proteins and proteins involved in cellular adhesion. Together, our quantitative proteomic results suggested that NNN exposure may interfere with fibroblast motility. An in vitro scratch wound assay result supported that NNN exposure reduced the ability of dermal fibroblast to migrate into the scratched area. The results from the present study offer novel insights into the cellular mechanisms of NNN toxicity and identify NNN as a specific tobacco constituent that contributes to decreased fibroblast migration.

Quantitative proteomic analysis revealed 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone-induced up-regulation of 20S proteasome in cultured human fibroblast cells.

The tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK), is a well-known carcinogen. Although the ability of the metabolically activated form of NNK to generate DNA adducts is well established, little is known about the cellular pathways perturbed by NNK in its native state. In this study, we utilized stable isotope labeling by amino acid in cell culture (SILAC), together with mass spectrometry, to assess the perturbation of protein expression in GM00637 human skin fibroblast cells upon NNK exposure. With this approach, we were able to quantify 1412 proteins and 137 of them were with significantly altered expression following NNK exposure, including the up-regulation of all subunits of the 20S proteasome core complex. The up-regulation of the 20S core complex was also reflected by a significant increase in 20S proteasome activities in GM00637, IMR90, and MCF-7 cells upon NNK treatment. Furthermore, the ß-adrenergic receptor (ß-AR) antagonist propranolol could attenuate significantly the NNK-induced increase in proteasome activity in all the three cell lines, suggesting that up-regulation of the 20S proteasome may be mediated through the ß-AR. Additionally, we found that NNK treatment altered the expression levels of other important proteins including mitochondrial proteins, cytoskeleton-associated proteins, and proteins involved in glycolysis and gluconeogenesis. Results from the present study provided novel insights into the cellular mechanisms targeted by NNK.