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Mark J Oertel,1 Leland Graves,1 Eyad Al-Hihi,2 Vincent Leonardo,3 Christina Hopkins,2 Kristin DeSouza,2 Rajib K Bhattacharya1 1Division of Endocrinology, Metabolism and Genetics, Department of Medicine, 2Department of Internal Medicine, 3Department of Enterprise Analytics, University of Kansas Medical Center, Kansas City, KS, USA Background: Fractures in older patients are common, morbid, and associated with increased risk of subsequent fractures. Inpatient and outpatient management and treatment of fractures can be costly. With more emphasis placed on quality care for Medicare beneficiaries, we studied if patients were receiving proper screening for osteoporosis and treatment after diagnosis of fracture. This study aims to determine if adequate screening and treatment for osteoporosis occurs in the postfracture period.Methods: A retrospective analysis of Medicare beneficiaries aged 67 years or older was gathered from a single institution in both inpatient and outpatient visits. Based on International Classification of Diseases ninth revision codes, primary diagnosis of fractures of neck and trunk, upper limb, and lower limb were obtained in addition to current procedural terminology codes for fracture procedures. We studied patients who had been screened for osteoporosis with a bone mineral study or received osteoporosis treatment after their fracture.Results: Medicare beneficiaries totaling 1,375 patients were determined to have an inclusion fracture between June 1, 2013 and November 30, 2014. At the time of our analysis on December 1, 2014, 1,219 patients were living and included in the analysis. Of these patients, 256 (21.0%) either received osteoporosis testing with bone mineral density or received treatment for osteoporosis. On sex breakdown, 208/820 (25.4%) females received proper evaluation or treatment of osteoporosis in comparison to 48/399 (12.0%) males. This is in comparison to the Centers for Medicare and Medicaid Services’ national average of 19.1% for osteoporosis management in females.Conclusion: A minority of studied patients received evaluation or treatment for osteoporosis after their fracture. Postfracture investigation and treatment for osteoporosis in Medicare beneficiaries is inadequate. If improved, Medicare costs could be reduced by prevention of future fractures. Future studies could determine how best to ensure this intervention occurs. Keywords: osteoporosis, inpatient management, postfracture evaluation, post-fracture treatment

Rajib K Bhattacharya, Niralee Vaishnav, Richard M Dubinsky Departments of Endocrinology, Metabolism and Genetics and Neurology, University of Kansas Medical Center, Kansas City, KS, USA Background: Impaired ambulation, frequent falls, and prolonged immobilization combined with the high rate of vitamin D deficiency in people with multiple sclerosis (MS) could lead to an increased risk of hip fracture. Methods: A retrospective cohort analysis of 20 years of the Nationwide Inpatient Sample (AHRQ.gov), a 20% stratified yearly sample of USA hospital admissions from the year 1988–2007, was performed. Based on International Classification of Diseases Ninth Revision (ICD9) codes, admissions with a primary diagnosis of acute hip fracture (ICD9 code 226.xx) and a secondary diagnosis of MS (ICD9 code 340) was identified. Indirect adjustment was used to compare the prevalence of MS in this population with that of the USA. Significance was set a priori at P

Rajib K Bhattacharya, Jonathan D Mahnken, Sally K RiglerUniversity of Kansas School of Medicine, Kansas City, KS, USABackground: Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality in older adults. Although diabetes mellitus is a risk factor for pneumonia, the clinical impact of blood glucose level at the time of admission is not clear. Our goal was to examine the association between admission hyperglycemia and subsequent mortality, length of stay, and readmission outcomes in older adults with CAP.Methods: A retrospective observational study was conducted using hospital data for community-acquired pneumonia admissions in 857 persons from January 1, 2008 to December 31, 2010. We examined the effects of admission glucose level on mortality, length of stay, and 30 day readmission, adjusted for demographic factors and comorbidity.Results: The mean age of the sample was 64 years, and 51% of the subjects were female. Inpatient mortality occurred in 4.6% and the median length of stay was 5 days (interquartile range 3–9 days). Readmission within 30 days occurred in 17%. We found little impact of first glucose measures on in-hospital mortality (P = 0.94), length of stay (P = 0.95), and 30-day readmission (P = 0.56). Subjects 65 years and older trended towards higher in-hospital mortality. Older age, cancer, heart failure, and cirrhosis were associated with adverse outcomes.Conclusion: Glucose level upon admission for community-acquired pneumonia was not associated with adverse outcomes within 30 days in older adults.Keywords: community-acquired pneumonia, hyperglycemia, readmission rates, hospital mortality

Rajib K Bhattacharya,1 Mohit Khera,2 Gary Blick,3 Harvey Kushner,4 Martin M Miner51Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA; 2Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA; 3Circle Medical LLC, Norwalk, CT, USA; 4Biometrics, Auxilium Pharmaceuticals, Malvern, PA, USA; 5Men's Health Center, Miriam Hospital, Providence, RI, USABackground: Testosterone levels naturally decline with age in men, often resulting in testosterone deficiency (hypogonadism). However, few studies have examined hypogonadal characteristics and treatment in older (≥65 years) men.Objective: To compare data at baseline and after 12 months of testosterone replacement therapy (TRT) in hypogonadal men ≥65 vs 75-year-old subcohort were not significantly different from subcohorts aged 65–74 years and

Purpose: Assess incidence, severity, and glucose excursion outcomes in thyroid eye disease (TED) patients receiving the insulin-like growth factor-1 receptor inhibitor teprotumumab from 3 clinical trials., Design: Analysis of pooled glycemic data over time., Participants: Eighty-four teprotumumab- and 86 placebo-treated active TED patients from the phase 2 and phase 3 (OPTIC) controlled clinical trials and 51 teprotumumab-treated patients from the OPTIC extension (OPTIC-X) trial., Methods: Eight intravenous infusions were given over 21 weeks. Phase 2 serum glucose was measured at weeks 1, 4, 15, and 21, with fasting measurements at weeks 1 and 4. Serum glucose was measured at each study visit in OPTIC and OPTIC-X, with fasting measurements at weeks 1 and 4 (in patients without diabetes) or all visits (in patients with diabetes). In all studies, hemoglobin A1c (HbA1c) was measured at baseline, 12, and 24 weeks plus weeks 36 and 48 in OPTIC-X., Main Outcome Measures: Serum glucose and HbA1c., Results: In the phase 2 and 3 studies, 9 hyperglycemic episodes occurred in 8 teprotumumab patients; mean HbA1c level increased 0.22% from baseline to week 24 (to 5.8%; range, 5.0%-7.9%) versus 0.04% in patients receiving the placebo (to 5.6%; range, 4.6%-8.1%). At study end, 78% (59/76) of teprotumumab patients and 87% (67/77) of patients receiving placebo had normoglycemic findings. Normoglycemia was maintained in 84% (57/68) of patients receiving teprotumumab and 93% (64/69) of patients receiving placebo. Among baseline prediabetic patients, 43% (3/7) remained prediabetic in both groups, and 29% (2/7) of teprotumumab patients and 14% (1/7) of patients receiving placebo had diabetic findings at week 24. OPTIC-X patients trended toward increased fasting glucose and HbA1c whether initially treated or retreated with teprotumumab. Fasting glucose commonly rose after 2 or 3 infusions and stabilized thereafter. Most hyperglycemic incidents occurred in patients with baseline prediabetes/diabetes but were controlled with medication. No evidence was found for progression or increased incidence of hyperglycemia with subsequent doses., Conclusions: Serious glycemic excursions are uncommon in patients with normoglycemia before teprotumumab therapy. Patients with controlled diabetes or impaired glucose tolerance can be treated safely if baseline screening, regular monitoring of glycemic control, and timely treatment of hyperglycemia are practiced., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Evaluating the linkage between soil erosion and sediment connectivity for export assessment in different landscape patterns at catchment scale is valuable for optimization of soil and water conservation (SWC) practices. Present research attempts to identify the soil erosion susceptible (SES) sites in Kangsabati River Basin (KRB) using machine learning algorithm (decision trees, decision trees cross validation, CV, Extreme Gradient Boosting, XGB CV and bagging CV) taken thirty five variables, for investigating the linkage between erosion rates and sediment connectivity to assess the sediment export at sub-basin level employing connectivity index (IC) and Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) sediment delivery ratio (SDR) model. Based on AUC of receiving operating curve in validation test, excellent capacity of extreme Gradient Boosting, XGB CV and bagging CV (0.95, 0.90) than decision tree and decision tree CV (0.78, 0.82), exhibits about 18.58 % of basin areas facing susceptible to very high erosion. Conversely, considering universal soil loss equation (RUSLE) parameters, InVEST-SDR model estimated about 64.24 % of soil loss rate occurred from high SES in where sediment export rate become very high (136.995 t/ha -1 /y -1 ). The IC result show that high sediment connectivity (<-4.4) measured in high SES of laterite and bare land in upper catchment, and double crop agricultural areas in lower catchment, while least connectivity (>-7.1) observed in low SES of dense forest, vegetation cover and settlement built-up areas. Pearson correlation matrix revealed that four landscape indices category i.e. edge metrics (p < 0.01), aggregation metrics (p < 0.001), shape metrics (p < 0.01-0.001) and diversity metrics (p < 0.01) signified the influence of landscape patterns on IC and SES. Accordingly, RUSLE, SDR and landscape matrices reveals that maximum sediment export rate associated with high connective delivery outlet and high SES in laterite, double crop and bare land due to simple landscape and greater homogeneity, whilst minimum export rate related with low connectivity and low SES in dense forest, vegetation cover and settlement built up area causes of fragmented landscape and spatial heterogeneity. Finally, findings could immense useful for formulating the optimizing measures of SWC in the watershed., Competing Interests: Declaration of competing interest We have declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Geriatric patients with complex health care needs can benefit from interprofessional (IP) care; however, a major gap in health professional education is determining how to prepare future providers for IP collaboration. Effective IP team behavior assessment tools are needed to teach, implement, and evaluate IP practice skills. After review of IP evaluation tools, the Standardized Patient Encounter Evaluation Rubric (SPEER) was created to evaluate team dynamics in IP practice sites.Independent sample t-tests between faculty and learner SPEER scores showed learners scored themselves 15 points higher than their faculty scores ( p < .001). Cronbach's α showed high internal consistency (α = 0.91). Paired t-tests found that learners identified improvements in the team's ability to address the patient's education needs and to allow the patients to voice their expectations. Faculty identified improvements in the teams' ability to make recommendations. Faculty evaluations of learner teams showed improvements in raw ratings on all but two items. Qualitative data analysis for emergent themes showed learners desired team functioning feedback and how teamwork could improve to provide optimal IP care.In conclusion, the SPEER can help faculty and learners identify growth in their teams' ability to perform key IP skills in clinical sites.

Riverine ecosystem services to human beings are dynamically evaluated by harmonic relationships; however, over growing human service demands (HSDs) are leading to deteriorate the river health resilience. In this study, an assessment index system of river health involving pressure-state-response (PSR) based on twenty indicators of riparian, channel geomorphic, hydroecological, and social attributes was developed to detect the multifunctional reliability and resilience of river system integrity for HSDs at upper (US), middle (MS), and lower segments (LS) of Kangsabati River using fuzzy logic, analytical hierarchical process (AHP), and entropy weight-based multi-criteria decision matrix (MCDM) methods. Borda integrating MCDM results revealed that overall indicator performance is high health score in US (77), medium score in MS (69), but mostly unhealthy score in LS (34); thus, entropy-MCDM models give highest rank to US, medium rank to MS, and least rank to LS, while AHP and fuzzy MCDM models assigned as high priority rank to MS, medium rank to US, and least rank to LS, respectively. According to model validation performances, entropy-MCDM models (RMSE < 2.48) are rationalized to the harmonic relationship of riverine system, whereas fuzzy and AHP-MCDM models (RMSE < 2.79) are signified to HSDs, and these results are closer to real problems. With the acceptability of AHP-MCDM models through the percentage change (73.89%) and intensity change (17.16) assessment, it points that over HSDs are crucial factors for river health degradation. Moreover, final outcome of the present research helps to find out the sick river health sites for ecological restoration., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introducing health policy to interprofessional graduate students, anchoring health policy to older adult health needs, while conveying how current policy issues will affect their individual careers is challenging, yet essential, for health profession education. This novel program integrated graduate level health profession learners from medicine, nurse practitioner, pharmacy, psychology, social work, physical therapy and occupational therapy disciplines. The aim was to embed health policy into an existing interprofessional (IP) geriatrics course at an academic medical center. Selection of disciplines was based on prior collaborative work and faculty interest. The objectives were to 1. Introduce current health policies that affect older adults; 2. Understand the effects of health policy and social determinants of health on the older adults in their future practice; 3. Challenge learners to apply their knowledge and develop health advocacy strategies for older adults; and 4) Teach the importance of teamwork in interprofessional practice within a geriatric population.The health policy curriculum impacted 487 learners for 12 sessions over three years. Four themes emerged with the sessions: health policy awareness, interprofessional appreciation, patient care "pearls," and pharmacological considerations in geriatrics. Each of the eight modules generated thoughtful recommendations by the learners, providing a glimpse into future workforce priorities.

Objective: Thyroid eye disease (TED) is a debilitating autoimmune disease characterized by ocular and periorbital tissue inflammation, proptosis, and visual impairment. The known risk factors for TED include radioactive iodine therapy, female sex, and smoking. The risk factors for severe TED include hyperthyroidism, male sex, smoking, and diabetes; however, little is known about how diabetes mellitus (DM) influences TED. This claims-based analysis examined TED characteristics in patients with and without diabetes., Methods: Symphony database (2010-2015 U.S. claims) was mined for patients with ≥1 Graves' disease diagnosis code and ≥1 TED-associated eye code, including proptosis, strabismus, diplopia, lid retraction, exposure keratoconjunctivitis, and optic neuropathy (ON). DM status was determined based on type 1 or type 2 diabetes coding. Sight-threatening TED was defined as ≥1 ON or exposure keratoconjunctivitis code., Results: A total of 51 220 patients were identified. Of them, 2618 (5.1%) and 12 846 (25.1%) had type 1 and type 2 DM, respectively. Patients with and without DM had similar characteristics, but patients with DM were more often men (type 1: 30.3%, type 2: 28.7% vs no DM: 20.5%; both P < .001) and older at the first TED code. In patients with DM, strabismus (25.4%, 22.6% vs 19.9%) and diplopia (38.6%, 37.9% vs 29.9%) occurred more often but proptosis occurred less often (42.3%, 46.3% vs 58.5%; all P < .001). Sight-threatening TED occurred more often in patients with DM because of higher ON rates., Conclusion: Patients with TED and DM may have more extraocular muscle involvement. Furthermore, the higher prevalence of severe TED stemmed from higher ON rates, possibly associated with diabetes-related vasculopathies. These hypothesis-generating data warrant further exploration., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Kangsabati basin located in tropical plateau region faces multiple problems of soil erosion susceptibility (SES), soil fertility deterioration, and sedimentation in reservoirs. Hence, identification of SES zones in thirty-eight sub-basins (SB) for basin prioritization is necessary. The present research addressed the issue by using four multi-criteria decision-making (MCDM) models: VlseKriterijumska optimizacija I Kompromisno Resenje (VIKOR), technique for order preference by similarity to ideal solution (TOPSIS), simple additive weighing (SAW), compound factor (CF). To determine the best fitted method from MCDM for erosion susceptibility (ES), a comparison has been made with Soil and Water Assessment Tool (SWAT), where fifteen morphometric parameters were considered for MCDM, and meteorological data, soil, slope and land use land cover (LULC) were considered for SWAT model. Two validation indices of percentage change and intensity change were used for evaluation and comparison of MCDM results. With SWAT model performance, SWAT calibration and uncertainty analysis programs (CUP) was used for sensitive analysis of SWAT parameters on flow discharge and sediment load simulation. The results showed that 23, 16, 18 SB have high ES; therefore they were given 1 to 3 ranks, whereas 31, 37, 21SB have low ES, hence given 38 to 36 rank as predicted by MCDM methods and SWAT. MCDM validation results depict that VIKOR and CF methods are more acceptable than TOPSIS and SAW. Calibration (flow discharge R 2 0.86, NSE 0.75; sediment load R 2 0.87, NSE 0.69) and validation (flow discharge R 2 0.79, NSE 0.55; sediment load R 2 0.79, NSE 0.76) of SWAT model indicated that simulated results are well fitted with observed data. Therefore, VIKOR reflects the significant role of morphometric parameters on ES, whereas SWAT reflects the significant role of LULC, slope, and soil on ES. However, it could be concluded that VIKOR is more effective MCDM method in comparison to SWAT prediction., Competing Interests: We are no conflict of interest in this work., (© 2020 Elsevier B.V. All rights reserved.)

Background: An interprofessional and cross-cultural pedagogical project in community health for students in nursing, social work, anthropology and medicine at the end of the bachelor's degree begun in 2014. After a rural context fieldwork in several Santal villages of West Bengal (India), students had to conduct a research project, based on a community-health topic., Aims: This paper describes how such a pedagogical project, introducing students to ethnographic research, can initiate new ways of thinking for possible future health interventions in rural communities., Methods: An inductive approach based on ethnography was used during the fieldwork, including observations, interviews, focus groups and local documentation., Results: Our observations led to the finding that actions in rural health cannot be initiated without: promoting an interprofessional/interdisciplinary perspective and a culture of complexity and reflectivity; considering local populations in transition and not in a fixed homogenous situation; understanding more than imposing; taking into account local disease classification and local pragmatic solutions; considering the dialogue between bio-medicine and therapeutic pluralism; considering local perceptions and practices; considering care itineraries/pathways; and finally being conscious of our apostolic function., Conclusion: Our interprofessional pedagogical project promotes a bottom-up approach in dialogue with a global health vision., Competing Interests: The author(s) declared no potential conflict of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2020.)

Late-onset hypogonadism is an underdiagnosed and easily treated condition defined by low serum testosterone levels in men older than 65 years. When treated, a significant improvement in quality of life may be reached in this rapidly rising sector of the population. During the evaluation, laboratory tests and a full medication review should be performed to exclude other illnesses or adverse effects from medications. The major goal of treatment in this population is treating the symptoms related to hypogonadism. There has not been clear evidence supporting universally giving older men with low serum testosterone levels and hypogonadal symptoms testosterone replacement therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities. Despite limitations, registries can provide an opportunity to accumulate data regarding disease management in a typical patient population, including diagnosis, treatment, and outcomes., Materials and Methods: The Testim Registry in the United States (TRiUS) was a prospective, 12-month, observational cohort registry of men prescribed Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.) for the first time; patients previously on other forms of testosterone replacement therapy (TRT) were eligible to participate in the study as well. The registry recorded total testosterone (TT) and free testosterone (FT) levels, prostate-specific antigen (PSA), sexual function, mood/depression, and cardiometabolic and anthropometric criteria before and after TRT. Changes over time were analyzed by analysis of variance, and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables., Results: At baseline, 849 patients from 72 sites were enrolled, with 743 of 849 started on 5 g gel/day (50 mg testosterone/day) and 106 of 849 started on 10 g gel/day (100 mg testosterone/day). Mean TT and FT levels increased significantly after 3 months of TRT (TT level, 16.8 ± 9.87 nmol/L [485 ± 284 ng/dL], P < 0.001; FT level, 286.3 ± 224.9 pmol/L [82.5 ± 64.8 pg/mL], P < 0.001) and were maintained at eugonadal levels. Mean PSA levels increased significantly (P = 0.004) from 1.12 ± 1.11 μg/L (1.12 ± 1.11 ng/mL) at baseline to 1.26 ± 1.22 μg/L (1.26 ± 1.22 ng/mL) after 12 months of TRT, although changes were well within guidelines (< 1.4 μg/L/year increase). Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months., Conclusion: Testosterone deficiency symptoms improved with TRT use in men; sexual function and mood/depression improvements were seen before metabolic improvements. Prostate-specific antigen levels increased, although increases were within guideline-determined safety limits.

Background: Although hypogonadism is common in men with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), testosterone levels after testosterone replacement therapy (TRT) in this population have not been reported., Methods: The Testim Registry in the United States (TRiUS) was the first prospective, observational registry of men with hypogonadism who were prescribed TRT. The TRiUS cohorts with (n = 82) and without (n = 767) HIV/AIDS were followed during 12 months of treatment with Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.). Total testosterone (TT) and free testosterone levels, symptoms of depression, sexual function, body composition profiles, and prostate-specific antigen levels were evaluated., Results: The HIV/AIDS and non-HIV/AIDS cohorts differed at baseline in age (48.3 vs 52.5 years), TT level (13.0 vs 9.6 nmol/L), duration of hypogonadism (27.1 vs 14.6 months), prior TRT (36.6% vs 22.6%), body mass index (26.5 vs 32.0 kg/m2), and antidepressant (29% vs 15%) and opioid (20% vs 10%) use (P ≤ 0.01 for all comparisons). During the 12 months, both cohorts experienced significant elevations in TT and free testosterone levels to within normal ranges. Sexual function and depression scores improved and antidepressant medication use decreased in both cohorts. Body composition profiles improved significantly (P ≤ 0.05) in men without HIV/AIDS and remained stable in men with HIV/AIDS during the 12 months of follow-up., Conclusion: This 12-month, non-placebo-controlled, observational study of Testim® use in men with and without HIV/AIDS suggests that TRT may provide clinical benefits irrespective of the patient's HIV/AIDS status. This conclusion is supported by the higher testosterone levels, better sexual function, lower depression scores, and better body composition profiles found in both groups. However, given the loss of patients to follow-up, these results may reflect a bias toward drug responders.

Objective: The aim of this study was to determine whether people with Parkinson's disease (PD) are overrepresented in a national cohort of hip-fracture admissions., Background: Frequent falls, combined with a higher rate of osteoporosis in people with PD, should lead to an increased risk of hip fracture., Methods: This work was a retrospective cohort analysis from the Nationwide Inpatient Sample from 1988 to 2007, a stratified sample of 20% of U.S. hospital admissions. Admissions with a primary diagnosis of acute hip fracture were identified, as was a subset with a secondary diagnosis of PD., Results: A total of 3.63% of 1,066,404 hip-fracture admissions had PD. When compared to the population of prevalence among patients with hip fracture, the prevalence of PD was up to 4.48 times (95% confidence interval [CI]: 4.46, 4.49) more than predicted, and when adjusted for gender and age, it was 4.02 (95% CI: 4.00, 4.03)., Conclusions: In this 20-year nationwide sample of hip fractures, patients with PD were overrepresented by a factor of 4., (Copyright © 2012 Movement Disorder Society.)

Objective: Among patients with hypogonadism-associated comorbidities, opioid users have the highest incidence of hypogonadism. Data from the Testim Registry in the United States were analyzed to determine the efficacy of testosterone replacement therapy in opioid users vs nonusers., Design: Prospective, 12-month observational cohort registry., Subjects: Hypogonadal men (N = 849) prescribed Testim (but not necessarily testosterone replacement) for the first time., Interventions: Testim 1% testosterone gel (5-10 g/day)., Outcome Measures: Total and free testosterone, sex hormone-binding globulin, prostate-specific antigen, sexual function, mood/depression, and anthropometric data were assessed. Changes from baseline were analyzed using repeated measures mixed-effects analysis of variance; multiple linear regressions of changes in testosterone levels with sexual function, mood, and opioid use were computed., Results: 90/849 patients (10.6%) reported opioid use at baseline; 75/90 (83%) used opioids for ≥ 30 days prior to baseline. Baseline total testosterone and prostate-specific antigen were not statistically different between opioid users and nonusers; there was a trend for higher sex hormone-binding globulin (P = 0.08) and lower free testosterone (P = 0.05) in opioid users. After 1 month, both opioid users and nonusers had significant (P < 0.001) increases in total and free testosterone, which continued through 12 months. Sexual function and mood improved significantly in both opioid users and nonusers over 12 months, and significantly correlated with change in total testosterone., Conclusions: Testosterone replacement therapy increased serum testosterone in hypogonadal opioid users and nonusers alike. The data suggest that with testosterone replacement, hypogonadal opioid users might be expected to have similar improvements in sexual function and mood as opioid nonusers., (Wiley Periodicals, Inc.)

Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research.

Introduction: Up to 30% of erectile dysfunction (ED) patients treated with phosphodiesterase type 5 (PDE5) inhibitors do not show improved sexual function, which may be due in part to low serum testosterone. Hypogonadal patients already receiving testosterone replacement therapy (TRT) likewise can still suffer from symptoms of sexual dysfunction. In these patient populations, augmenting with, or switching, TRT treatment may improve sexual function., Aim: To determine if 12-month treatment with a testosterone gel improves sexual function in hypogonadal men, as measured by the Brief Male Sexual Function Inventory (BMSFI), and in subgroups defined by low testosterone, PDE5 inhibitor use, and prior TRT., Methods: The Testim Registry in the United States (TRiUS) was a large (N = 849) multicenter registry of hypogonadal men treated with Testim (testosterone 1%) topical gel and followed for 12 months., Main Outcome Measures: Data collected at suggested visits (baseline; 1, 3, 6, and 12 months) included total testosterone (TT), free testosterone (FT), BMSFI scores, physical exam, and body measurements., Results: TRiUS had 271 patients with baseline testosterone and BMSFI measurements. At 12 months of TRT, TT and FT levels significantly increased from baseline (P < 0.001), with mean ± standard deviation final TT = 17.37 ± 8.61 nmol/L (500.6 ± 248.2 ng/dL) and FT = 240.1 ± 296.0 pmol/L (69.2 ± 85.3 pg/mL). The mean total BMSFI score significantly increased from baseline at 12 months (27.4 ± 10.3 to 33.8 ± 9.8, P < 0.001) and at each visit in all domains (sex drive/libido, erectile function, ejaculatory function, level of bother), overall and for all subgroups. Regression analysis indicated that increased total BMSFI score was significantly associated with increased TT levels at 6 months., Conclusions: In hypogonadal patients, 12-month administration of topical testosterone gel resulted in increased TT and FT levels and significantly improved sexual function. All subgroups studied, including men taking PDE5 inhibitors for ED and those previously on TRT, demonstrated significant improvement in sexual function from baseline scores., (© 2011 International Society for Sexual Medicine.)

Purpose: We measured prostate specific antigen after 12 months of testosterone replacement therapy in hypogonadal men., Materials and Methods: Data were collected from the TRiUS (Testim® Registry in the United States), an observational registry of hypogonadal men on testosterone replacement therapy (849). Participants were Testim naïve, had no prostate cancer and received 5 to 10 gm Testim 1% (testosterone gel) daily., Results: A total of 451 patients with prostate specific antigen and total testosterone values were divided into group A (197 with total testosterone less than 250 ng/dl) and group B (254 with total testosterone 250 ng/dl or greater). The groups differed significantly in free testosterone and sex hormone-binding globulin, but not in age or prostate specific antigen. In group A but not group B prostate specific antigen correlated significantly with total testosterone (r=0.20, p=0.005), free testosterone (r=0.22, p=0.03) and sex hormone-binding globulin (r=0.59, p=0.002) at baseline. After 12 months of testosterone replacement therapy, increase in total testosterone (mean±SD) was statistically significant in group A (+326±295 ng/dl, p<0.001; final total testosterone 516±28 ng/dl) and group B (+154±217 ng/dl, p<0.001; final total testosterone 513±20 ng/dl). After 12 months of testosterone replacement therapy, increase in prostate specific antigen was statistically significant in group A (+0.19±0.61 ng/ml, p=0.02; final prostate specific antigen 1.26±0.96 ng/ml) but not in group B (+0.28±1.18 ng/ml, p=0.06; final prostate specific antigen 1.55±1.72 ng/ml). The average percent prostate specific antigen increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall the greatest prostate specific antigen was observed after 1 month of treatment and decreased thereafter., Conclusions: Patients with baseline total testosterone less than 250 ng/dl were more likely to have an increased prostate specific antigen after testosterone replacement therapy than those with baseline total testosterone 250 ng/dl or greater, supporting the prostate saturation hypothesis. Clinicians should be aware that severely hypogonadal patients may experience increased prostate specific antigen after testosterone replacement therapy., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Testosterone deficiency (TD) is prevalent among men seeking medical attention and may be associated with other comorbidities., Objective: The Testim(®) Registry in the United States (TRiUS), a large, multicenter, prospective, 12-month observational cohort registry, was established to quantify symptoms and comorbidities of hypogonadal men in real-world clinical settings and to evaluate the effect of testosterone replacement therapy (TRT)., Methods: Eligible TRiUS participants were hypogonadal men prescribed Testim(®) (1% testosterone gel) for the first time. Evaluated baseline parameters included: total testosterone (TT), free testosterone (FT), sex hormone-binding globulin (SHBG), prostate-specific antigen (PSA), anthropometrics (height, weight, waist, hip, and body mass index [BMI]), lipids, blood glucose, sexual dysfunction, mood/depression, and cardiovascular and metabolic risk factors. Parameters were correlated to TT and age using bivariate correlation and to the combination of TT and age using multiple linear regression., Results: TRiUS had 849 registrants (baseline TT: 286.5 ± 151.8 ng/dL; FT: 40.8 ± 62.1 pg/mL; SHBG: 28.2 ± 15.0 nmol/L; PSA: 1.12 ± 1.11 ng/mL). Eighty-six percent were overweight/obese, with a BMI ≥ 25 kg/m(2), and 57% were aged 40 to 59 years, with a mean (± standard deviation) age of 52.1 ± 12.3 years. Total testosterone levels were significantly lower in men aged ≥ 65 years. The most common comorbid conditions and cardiovascular risk factors included: smoking, metabolic syndrome, hypertension, dyslipidemia, and coronary artery disease. Weak but statistically significant inverse correlations were noted between TT and sexual dysfunction, fasting glucose, systolic blood pressure, BMI, and Framingham risk scores. Patients with obesity or metabolic syndrome had significantly lower TT levels, particularly among younger and middle-aged patients., Conclusions: Untreated hypogonadal middle-aged men exhibited a high prevalence of cardiometabolic risk factors that were correlated to TT levels. This suggests that TD is associated with adverse medical conditions that pose serious health risks, especially in a younger age demographic than previously thought. Clinicians may want to consider TT testing in unhealthy, middle-aged patients with symptoms of TD.

Isothiocyanates have potential chemopreventive and antitumor effects. In the present study, we examined the actions of PEITC and sulphoraphane in modulating the activity of protein kinase C (PKC) and telomerase in cervical cancer cell line HeLa. These tumor markers are highly activated in human cancers. These compound efficiently downregulated the antiapoptotic isoforms (PKC-alpha, -betaII, -epsilon, and -zeta) as well as telomerase, whereas the proapoptotic form (PKC-delta) was upregulated. Studies were performed to measure the degree of apoptotic cell death induced by either isothiocyanates alone, or in combination with adriamycin or etoposide. Apoptosis was evident from mitochondrial cytochrome c release, apoptotic index and caspases 3 and 8 activation. Results showed that pretreatment exhibited better efficacy in sensitizing HeLa cells toward apoptosis by modulating PKCs, telomerase. This effect of isothiocyanates might prove to be of considerable value in synergistic therapy of cancer such that the drug dose level could be minimized.

Prostate cancer is the leading cause of cancer-related death in men, incidences of which are increasing gradually in India. Protein kinase C (PKC), an enzyme, gets overexpressed in prostate cancer and results in a resistance to chemotherapy. Telomerase, a reverse transcriptase, is highly activated in prostate cancer cells. Both of these enzymes can be considered as potential molecular markers for prostate cancer. The present study investigates the effects of natural isothiocyanate phenethyl isothiocyanate (PEITC) in modulating the activities of PKC and telomerase in the androgen-independent human prostate adenocarcinoma (PC-3) cell line. We observed that PEITC downregulated the antiapoptotic isoforms (PKC alpha and epsilon) efficiently and zeta moderately. Basal level of PKC delta, a proapoptotic form, was very poor and its modulation was not significant. PEITC also inhibited the activity of telomerase. Studies were conducted to measure the degree of apoptotic cell death induced either by PEITC alone or in combination with adriamycin or etoposide. Apoptosis was evident from the release of mitochondrial cytochrome c, apoptotic index, and by the induction of caspases 3 and 8. PEITC exhibited remarkable efficacy in sensitizing PC-3 cells to undergo cell death by adriamycin and etoposide, which might prove to be of considerable value in synergistic therapy of cancer.

Chronic arsenic exposure causes skin diseases, gastrointestinal and neurological disorders, diabetes and cancer in various organs. Oxidative stress associated with arsenic exposure cause genetic instabilities and may initiate carcinogenesis. Phytochemicals present in vegetables, fruits, spices, tea, and medicinal plants, have shown to suppress experimental carcinogenesis in various organs. The aim of the present study was to elucidate the protective effect of some of the phytochemicals against the arsenite induced DNA damage in normal mammalian V79 cells. Comet assay was used for assessment of DNA damage and 2', 7'-dichlorofluorescein dihydroacetate for estimation of ROS generated by arsenite. The effect of the phytochemicals was observed during simultaneous treatment with arsenic, before arsenite exposure and during repair experiments. Of all the phytochemicals tested against arsenic, curcumin gave better protection during simultaneous treatment and resveratrol during pre treatment, which was evident both from comet assay and ROS generation experiments. During pre treatment a longer duration of treatment with lower dose of phytochemicals proved fruitful in reducing the genotoxicity. During repair experiments the phytochemicals enhanced recovery of DNA damage and ellagic acid gave promising results. The results indicated that natural phytochemicals may have the efficacy in reducing arsenic induced genotoxicity, in scavenging ROS and in enhancing the process of DNA repair in V79 cells.

Chronic exposure of humans to high concentrations of arsenic in drinking water is associated with skin lesions, peripheral vascular disease, hypertension, blackfoot disease and a high risk of cancer. Arsenic induces single strand breaks, DNA-protein crosslinks and apurinic sites in DNA, which are prerequisites for induction of cancer. Amelioration of such damages with natural compounds could be an effective strategy to combat arsenic toxicity. Curcumin is the active ingredient of turmeric, a common household spice, which is a rich source of polyphenols and this compound has been extensively studied as a chemopreventive agent against many types of cancer. The present study investigates whether curcumin could counteract the DNA damage caused by arsenic as assessed by single cell gel electrophoresis (SCGE) using peripheral blood lymphocytes, from healthy donors. It was observed that DNA damage induced by arsenic could be efficiently reduced by curcumin and the effect was more pronounced when lymphocytes were pre-incubated with curcumin prior to arsenic insult. Arsenic caused DNA damage by generation of reactive oxygen species (ROS) and enhancement of lipid peroxidation levels. Curcumin counteracted the damage by quenching ROS, decreasing the level of lipid peroxidation and increasing the level of phase II detoxification enzymes like catalase, superoxide dismutase and glutathione peroxidase. Curcumin also enhanced the DNA repair activity against arsenic induced damage. The expression of polymerase, a repair enzyme, was found to be highly elevated when arsenite induced damaged cells were allowed to repair in presence of curcumin. Results indicate that curcumin has significant role in confronting the deleterious effect caused by arsenic, which could be an economic mode of arsenic mitigation among rural population in West Bengal, India.

Curcumin (diferuloylmethane), a natural cancer chemopreventive compound, has been tested for its action in acute myeloblastic leukemia cell line HL-60. The results clearly show that curcumin induces apoptosis in these cells as evidenced by the release of cytochrome c from mitochondria to the cytosol and increase in the DNA content in sub G1 region as observed in FACS analysis. Apoptosis is apparently mediated by up-regulation of apoptotic gene bax and simultaneous down-regulation of anti-apoptotic gene bcl-2 followed by activation of caspases 3 and 8 and degradation of PARP. Telomerase, a reverse transcriptase, has been found to be activated in more than 80% of human cancers and, therefore, can be considered as a potential marker for tumorigenesis. Certain natural compounds have the potential of inhibiting telomerase activity leading to suppression of cell viability and induction of apoptosis. The present study shows that curcumin-induced apoptosis coincides with the inhibition of telomerase activity in a dose dependent manner.

Background: Few data are available on the safety and efficacy of once-weekly oral bisphosphonate therapy in breast cancer survivors., Objective: Our objective was to determine whether risedronate, 35 mg weekly, is efficacious and safe in preventing bone loss associated with chemotherapy-induced menopause., Design: The study was a randomized, double-blind, placebo-controlled clinical trial over 12 months., Setting and Participants: Participants included 87 newly postmenopausal women with status post chemotherapy, recruited from a breast cancer clinic in an academic medical center., Intervention: Participants were randomly assigned to receive risedronate 35 mg/wk or placebo., Main Outcome Measures: The primary outcomes were the 12-month changes in spine and hip bone mineral density. Secondary outcomes included changes in markers of bone resorption (urine N-telopeptide cross-linked collagen type I) and formation (osteocalcin, N-terminal propeptide of type I procollagen, and bone-specific alkaline phosphatase)., Results: After 12 months, bone mineral density increased by 1.2% at the spine and 1.3% at the hip in women on risedronate vs. significant decreases for women in the placebo group of 0.9% at the spine and 0.8% at the hip (P < 0.01, difference between groups). N-telopeptide cross-linked collagen type I, a marker of bone resorption, decreased by 19.3%, and N-terminal propeptide of type I procollagen, a marker of bone formation, decreased by 26.6% in participants on active therapy compared with increases in the control group. Risedronate was well tolerated, and the retention rate was 95% at 1 yr., Conclusions: Risedronate once weekly prevented bone loss and reduced bone turnover in women with breast cancer treated with chemotherapy. Early measures to prevent bone loss should be considered in this cohort of breast cancer survivors.

The groundwater arsenicals have brought dreadful misery for the people residing in the endemic regions of West Bengal, India. Arsenic-related anomalies include arsenicosis, hyperkera-tosis, gastric complications, liver fibrosis, peripheral neuropathy, and cancer. Some of these diseases have been frequently associated with overproduction of reactive oxygen species that cause DNA damage and improper functioning of body's antioxidant defense mechanism. Natural polyphenols present in tea serve as excellent antioxidants. In the present study, an attempt has been made to elucidate the role of representative polyphenols and extracts of green and black tea in modulating sodium arsenite (As III)-induced DNA damage in normal human lymphocytes. Comet assay was used to detect the DNA damage. Arsenic-induced oxidative stress was measured with generation of reactive oxygen species, lipid peroxidation, and activity of some antioxidant enzymes. Expression of some repair enzymes such as poly(ADP-ribose) polymerase and DNA polymerase beta was measured to assess the effect of tea on DNA repair. Tea afforded efficient reduction of As III-induced DNA damage in human lymphocytes. Tea also quenched the excessive production of reactive oxygen species by arsenic, reduced the elevated levels of lipid peroxidation, and increased the activity of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase. Furthermore, tea enhanced recovery of DNA damage, which was indicative of repair as confirmed by unscheduled DNA synthesis and pronounced expression of DNA repair enzyme poly(ADP-ribose) polymerase. It is speculated that the antioxidant potential and repair-inducing capacity of tea might help in combating the severe genotoxic effects induced by arsenic in the human population.

Telomerase, a reverse transcriptase that maintains telomere length, is highly activated in tumor cells and practically absent in somatic cells and hence considered a potential marker for tumorigenesis. A connection between telomerase activity and resistance to apoptosis has been established. Telomerase, therefore, has been proposed to represent a novel and potentially selective target for cancer therapy. Several synthetic compounds have been developed in recent years with a view to inhibit telomerase activity with telomere shortening below a critical length resulting in apoptosis. Such compounds are always highly toxic. Many plant-derived products act through the induction of apoptosis as a mechanism to suppress carcinogenesis. Curcumin, a phenolic compound isolated from the rhizome of the plant Curcuma longa Linn., has been reported to possess anti-tumor, apoptotic and anti-angiogenic properties. Apoptosis has emerged as the major mechanism by which anti-tumor agents eliminate pre-neoplastic cells or cells progressed to malignancy. The present study was undertaken to examine the mechanism of curcumin-induced apoptosis in human leukemia cell line K-562 with particular emphasis on the role of curcumin on telomerase activity. Induction of apoptosis by curcumin is initiated by the release of cytochrome c from mitochondria into the cytosol, and evidenced by the increase in DNA content in the sub-G1 region as obtained from FACS analysis. Apoptosis is mediated by the activation of caspases 3 and 8, up-regulation of the apoptotic gene bax with concomitant down-regulation of the anti-apoptotic gene bcl-2. Using TRAP assay it has been observed that curcumin inhibits telomerase activity in a dose and time-dependent manner, the inhibition being due to suppression of translocation of telomerase reverse transcriptase (TERT), a catalytic subunit, from cytosol to nucleus. Most significantly, the inhibition of telomerase activity by curcumin correlates with several parameters of apoptosis. The results suggest that telomerase status plays an important role in the induction of apoptosis in K-562 cells by curcumin.

Programmed cell death or apoptosis is a physiological process by which genetically damaged cells or undesired cells can be eliminated. Various morphological and molecular changes undergoing during the process of apoptosis are the formation of apoptotic blebs of the cell membrane, cell shrinkage, condensation of chromatin and the disruption of deoxyribonucleic acid (DNA) into typical fragments of multiples of 180 base pairs. These changes can be detected in a number of ways. DNA ladder formation, which is observed following gel electrophoresis technique although is widely accepted but does not reflect the DNA breakdown in individual cell and also may miss contributions from small sub-populations in a heterogeneous cell population. Alkaline comet assay as measured by single cell gel electrophoresis, on the other hand, accurately measures DNA fragmentation on a single cell level and allows analysis of subpopulation of cells. The assay was originally developed for measuring DNA damage of cells exposed to any genotoxic agent. However, the comet image generated by an apoptotic cell is different from that obtained with a cell treated for a short time with a genotoxic agent. Correlation of comet formation with various other established parameters of apoptosis is very important. The present study aims to correlate different features of apoptosis with the formation of comet tail in human leukemia K-562 cells using tea extracts. Apoptosis as measured by formation of apoptotic bodies, flow cytometric analysis, activation of caspase 3 and 8, and expressions of apoptosis related genes such as bcl-2 and bax showed high degree of correlation with comet tail moment. This indicates that comet assay can accurately reflect measure of DNA fragmentation and hence can be used to detect a cell undergoing apoptosis.

Although caffeine is not carcinogenic, its hydrolysed product, caffeidine causes human cancer, possibly through endogenous nitrosation to form mononitroso caffeidine (MNC). MNC undergoes enzymatic demethylation and reacts with cellular nucleophiles, notably DNA, via the formation of a putative imidazole diazonium ion. Its interaction with proteins has not been reported. The present work is based on the hypothesis that some active metabolites of MNC covalently interact with cellular DNA and/or proteins to initiate carcinogenesis. We report here the synthesis of a possible reactive metabolite of MNC, viz., N, 1-methyl-4(N-methyl-N-nitrosamino)-imidazole-5-carboxylic acid (MNIC). Its structure has been determined by uv, ir, nmr and mass spectral analyses and its interaction with egg albumin and human serum protein has been examined by uv and CD spectroscopy. We concluded that metabolic activation of MNC occurs through the formation of MNIC. Avoiding consumption of salted tea or coffee that prevents the intake of caffeidine will possibly eliminate the risk of MNC carcinogenicity.

Treatment of human leukemic cell lines HL-60 and K-562 with extracts of green and black tea and their polyphenols epigallocatechin gallate and theaflavins, respectively, showed a dose dependent inhibition of growth as a result of cytotoxicity and suppression of cell proliferation. Based on the IC50 values obtained from cytotoxicity data it was clearly evident that black tea was as efficient as green tea. Analysis of polyphenol contents of tea extracts revealed that not only epigallocatechin gallate, which is a predominant polyphenol of green tea, but also theaflavin that is abundantly present in black tea affords significant chemotherapeutic action by imparting cytotoxicity to human leukemic cells. Electrophoretic analysis of fragmented DNA from treated cells displayed characteristic ladder pattern. Flow cytometric analysis revealed the dose dependent increase in sub-G1 peak. These criteria confirmed that cytotoxic activity of green and black tea was due to induction of apoptosis. Such induction was found to be mediated through activation of caspases 3 and 8, particularly caspase 3 and by altering apoptosis related genes as evident by down-regulation of Bcl-2 and up-regulation of Bax proteins.

Induction of apoptosis is an important approach to cancer control. Apart from morphological changes in cells, apoptosis is characterized by fragmentation of nuclear DNA. The characteristic DNA ladder formation that is observed on gel electrophoresis does not reflect the DNA breakdown in individual cells; contributions from small subpopulations are usually overlooked. On the other hand, alkaline comet assay as measured by single cell gel electrophoresis accurately measures DNA fragmentation at a single cell level. The comet assay was originally developed as a cytogenetic test to measure the genotoxicity of various chemicals. However, the comet image generated by an apoptotic cell is different from that obtained with a cell treated for a short time with a genotoxic agent. In the present study using human leukemic cells, typical apoptotic features such as morphological characteristics, FACS analysis, caspase activation, and expression of apoptosis-related genes as induced by tea polyphenols have been found to correlate with the comet tail formation. It is apparent from the high degree of correlation observed between the comet tail moment and each parameter of apoptosis that the comet assay can accurately reflect the measure of DNA fragmentation and, hence, can be used to detect a cell undergoing apoptosis.

Since the early 1980s, an alarming problem of groundwater arsenic (As) contamination has devastated many districts of West Bengal in India. People drinking As-contaminated water have been suffering severe health problems such as hyperkeratosis, blackfoot disease, neuropathy, and cancer of various sites. DNA damage and genetic instability induced by the inorganic arsenicals present in water are thought to be prerequisites for the initiation of carcinogenesis. Many natural polyphenols, which are consumed through our daily diet, possess excellent cancer chemopreventive properties. Tea, a popular beverage worldwide and rich in polyphenols, has exhibited many health benefits. The present study was conducted to examine the anticlastogenic action of tea extracts (both green and black) against the As-induced chromosomal aberrations. We also evaluated the role of tea in inducing antioxidant enzymes such as superoxide dismutase and catalase to provide protection against the oxidative stress induced by As. Our results demonstrated that tea extracts, particularly Darjeeling tea extract, are effective in counteracting the clastogenicity (chromatid breaks, in particular) of the most potent form of As, sodium arsenite. The antioxidant function of tea in reducing clastogenicity may be partly due to the induction of phase II detoxification enymes, such as superoxide dismutase and catalase. Our results suggest that the use of tea may be an effective approach in combating the health crisis generated by As.

The Gangetic plain of West Bengal, India, has been engulfed by a disastrous environmental calamity of arsenic contamination of the ground water. Chronic arsenic toxicity caused by drinking arsenic-contaminated water has been one of the worst health hazards gradually affecting nine districts of West Bengal since the early 1980s. Over and above hyperpigmentation and keratosis,weakness, burning sensation of the eyes, swelling of the legs, liver fibrosis, chronic lung disease, gangrene of the toes, neuropathy, and skin cancer are other manifestations. Induction of cancer is frequently associated with DNA damage, changes in ploidy of cells, and non-random chromosome aberrations. Counteraction of these genotoxic and cytogenetic abnormalities with natural dietary polyphenols could be a useful strategy to combat arsenic-induced DNA damage and thereby cancer. A review of the literature showed that it is the antioxidant property of tea polyphenols that affords protection against various types of cancer. The present study was conducted to investigate whether the extracts of green tea and black tea (Darjeeling and Assam) as well as their polyphenols could ameliorate this arsenic-induced genotoxicity. The normal mammalian cell culture derived from male Chinese hamster lung fibroblast cells (V79) was used as the test system to assess the genotoxicity by micronucleus assay. The results showed that both green tea and black tea extracts have equal potential in modulating the arsenic-induced genotoxicity. This effect was perhaps induced by the constituent polyphenols present in green and black tea. In addition, the repair activity of the damaged cells was enhanced when treated with these tea extracts and their polyphenols. Thus, tea and its polyphenols may have a promising role in counteracting the devastating effects of arsenic.

Tiliacora racemosa and Semecarpus anacardium, the two plants frequently used in Ayurvedic medicine for the treatment of cancerous diseases, have been selected to examine their action in four human tumour cell lines: acute myeloblastic leukaemia (HL-60), chronic myelogenic leukaemia (K-562), breast adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown in appropriate media the ethanol extract of T. racemosa root, the total alkaloids isolated from this organ and S. anacardium nut oil prepared according to the Ayurvedic principle were found to have cytotoxic activity. The alkaloid fraction from T. racemosa had maximum cytotoxicity and was effective against all four cell lines. S. anacardium oil was cytotoxic only in leukaemic cells. These herbal preparations were not cytotoxic towards normal human lymphocytes, suggesting their action is specific for tumour cells. On microscopic examination the cells treated with these agents exhibited characteristic morphological features of apoptosis, such as cell shrinkage, and the formation of apoptotic bodies. Fluorescent staining with propidium iodide revealed distinct chromatin condensation and nuclear fragmentation. The apoptotic index paralleled the cytotoxic parameters, and fragmented DNA extracted free of genomic DNA from treated cells displayed a typical ladder pattern on gel electrophoresis. Apoptosis induced by alkaloids and phenolics, the active principles present in T. racemosa and S. anacardium, respectively, was found to be mediated by the activation of caspases., (Copyright (c) 2004 John Wiley & Sons, Ltd.)

We assessed the ability of some natural products--namely, curcumin, resveratrol, indole-3-carbinol, and ellagic acid--to modify the DNA damaging ability of the alkylating carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in cultured Chinese hamster lung fibroblast cells (CH V-79). MNNG produced DNA single strand breaks in a dose- and time-dependent manner, as observed by increase in the tail moments of the comet, when the cells were subjected to alkaline single cell gel electrophoresis. When the cells were treated in the presence of each of the natural compounds, the DNA damage caused by MNNG was considerably reduced. This effect was found to be dose related. Preincubation of cells with each of these compounds individually afforded significant protection to DNA against damage caused by subsequent treatment with MNNG, indicating a true chemopreventive role of these substances. The most remarkable aspect of the present study was that all four compounds helped in the recovery of DNA damage by accelerating DNA repair efficiency in the damaged cells. This was further substantiated by the observation on unscheduled DNA synthesis. Our results suggest that these agents are chemopreventive by virtue of their ability to protect DNA as well as to induce DNA repair.

Arsenic, a naturally ocurring chemical element, is considered hazardous to human health. Inorganic arsenic compounds were found to induce cytotoxicity in Chinese hamster V-79 cells in culture. The arsenite form was more toxic than arsenate. Extracts of green and two varieties of black tea, as well as their principal polyphenols, (-)-epigallocatechingallate and theaflavin, efficiently counteracted the cytotoxic effects of arsenic compounds. On the basis of the amount of tea extract that afforded 50% protection to the cells from arsenic induced cytotoxicity, black tea was found to be as effective as green tea. The protective effect was attributable to the contents of not only (-)-epigallocatechingallate but also of theaflavin, the latter being a predominant polyphenol present in black tea.

Modulation of events characteristic of carcinogenesis or of cancer cells is being emphasized as a rational strategy to control cancer. Green tea polyphenol epigallocatechin gallate (EGCG) has been shown to be highly active as a cancer chemopreventive agent. Certain cellular and molecular events relevant to carcinogenesis are also modified by EGCG. The present investigation was carried out to examine the effects of EGCG on the cytogenetic change and DNA damage induced by toxicant H(2)O(2) and carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Chinese hamster V-79 cells in culture. Cytogenetic change as evident by the formation of micronuclei and DNA damage in the form of comet tail length during single cell gel electrophoresis was found to be significantly suppressed by EGCG in a dose dependent manner. Cells preincubated with EGCG were protected from subsequent damage by the genotoxic agents. Apoptosis, a highly organized physiological mechanism to eliminate injured or abnormal cells, is also implicated in multistage carcinogenesis. Initiated cells, cells at promotional stage or fully transformed cells can be eliminated through apoptosis. It was observed that EGCG suppressed growth and proliferation of K-562 cells derived from human chronic myelogenic leukemia. Morphological features of treated cells and characteristic DNA fragmentation revealed that the cytotoxicity was due to induction of apoptosis. This was mediated by activation of caspase 3 and caspase 8. Results show that EGCG not only protects normal cells against genotoxic hazard but also eliminate cancer cells through induction of apoptosis., (Copyright 2002 Elsevier Science B.V.)

Diospyrin, a bisnaphthoquinonoid natural product, and three synthetic derivatives have been tested for their action in four human cancer cell lines: acute myeloblastic leukemia (HL-60), chronic myelogenic leukemia (K-562), breast adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown in appropriate media several derivatives elicited cytotoxicity as assessed by Trypan Blue dye exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide reduction and DNA synthesis. Diethyl ether derivative (D7) was most effective in this regard while the parent compound diospyrin (D1) was least active (D7>D3>D2>D1). D7 was not cytotoxic toward normal human lymphocytes, suggesting its action is specific for tumor cells. On microscopic examination D7-treated cells exhibited characteristic morphological features of apoptosis, such as cell shrinkage and formation of apoptotic bodies. Fluorescent staining with propidium iodide revealed distinct chromatin condensation and nuclear fragmentation. The apoptotic index paralleled cytotoxic parameters, and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern. D7-induced apoptosis was mediated via activation of caspase 3 and caspase 8.

Investigation has been conducted to delineate the action of some phenolic compounds of natural origin in four human tumor cell lines: acute myeloblastic leukemia (HL-60), chronic myelogenic leukemia (K-562), breast adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown in appropriate media the phenolics curcumin, yakuchinone B, resveratrol and capsaicin exhibited growth inhibition as assessed by trypan blue dye exclusion. It was evident from the results of the MTT reduction assay and [(3)H]thymidine incorporation into nuclear DNA that the phenolics were cytotoxic and inhibited cell proliferation. Dose response studies indicated curcumin to be most cytotoxic towards HL-60, K-562 and MCF-7 but did not show much activity in HeLa cells. On the other hand, yakuchinone B, although less active than curcumin, displayed cytotoxicity towards all four cell lines. Resveratrol was cytotoxic only in leukemic cells, while capsaicin was marginally cytotoxic. All these phenolics did not elicit any cytotoxic activity as judged by the above parameters towards lymphocytes purified from normal human blood. When cells treated with phenolics were stained with propidium iodide and examined under a fluorescent microscope, characteristic apoptotic features such as chromatin condensation and nuclear fragmentation were observed. Scoring of cells with apoptotic and non-apoptotic features showed positive correlation of apoptotic index with dose of phenolic, and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern. These phenolics which have human exposure are known cancer chemopreventive agents and their action as inducers of apoptosis in tumor cells suggest their potential use in a strategy for cancer control.