Epstein-Barr virus infection correlates with the expression of COX-2, p16(INK4A) and p53 in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL), a germinal-center related B cell neoplasm in almost all cases, is characterized by scarcity of the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 95 cases of cHL were studied. Five-micrometer sections were prepared and stained with hematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, COX-2, p53, p16, ki-67 and cleaved caspase-3. In-situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS. There were 49 nodular sclerosis, 32 mixed cellularity, 8 lymphocyte-rich, and 6 lymphocyte-depleted subtypes in this series of cases. EBV, COX-2, p16(INK4A) and p53 were detected in 55% (52/95), 64% (61/95), 62% (59/95), and 65% (62/95) of the cases respectively. EBV was detected in 62% (38/61), 70% (41/59), and 69% (43/62) of COX2, p16 and p53 positive cases respectively. On the other hand, EBV-non-infected cases of cHL are associated with 59% (20/34), 69% (25/36), and 73% (24/33) of COX2, p16 and p53 negative cases respectively. In conclusion, EBV infection is associated with the expression of COX-2, p16(INK4A) and p53. EBV might be the dominant factor in determining the expression of these three proteins.

The potential impact of an HIV vaccine with limited protection on HIV incidence in Thailand: a modeling study.

BACKGROUND: The RV144 trial on the ALVAC/AIDSVAX candidate HIV vaccine, carried out in Thailand, showed short-lived protection against infection. METHODS: Using a deterministic compartmental model we explored the potential impact of this vaccine on heterosexual HIV transmission in Thailand. Both one-off vaccination strategies, as well as strategies with regular boosting, either annually or every two years, were explored. Both targeting the general adult population and prioritizing sex workers were modeled. The impact of risk compensation among high risk groups, as well as whether higher levels of safe sex in high risk groups could be an alternative to vaccination, was studied. RESULTS: One-off vaccination campaigns had only transient effects, and boosting appears to be a key component of successful vaccination campaigns. Intensive vaccination campaigns may reduce HIV incidence by up to 75% after 10 years of vaccination. Targeting only sex workers has a smaller impact but has a more favorable cost-benefit ratio. Risk compensation has the potential of undoing much of the benefits of a vaccination program and may even increase incidence. In contrast, higher levels of safe sex among sex workers would provide a viable alternative to vaccinating this group. DISCUSSION: The new vaccine holds promise for controlling HIV in Thailand and similar countries. In view of the short lived protection of the vaccine, regular boosting of immunity as well as avoidance of risk compensation are essential. Targeting sex workers would achieve the greatest reduction in incidence per vaccination and may be considered for expensive vaccines but its cost-effectiveness has to be compared to alternatives.

A successful chronic care program in Al Ain-United Arab Emirates.

BACKGROUND: The cost effective provision of quality care for chronic diseases is a major challenge for health care systems. We describe a project to improve the care of patients with the highly prevalent disorders of diabetes and hypertension, conducted in one of the major cities of the United Arab Emirates. SETTINGS AND METHODS: The project, using the principles of quality assurance cycles, was conducted in 4 stages.The assessment stage consisted of a community survey and an audit of the health care system, with particular emphasis on chronic disease care. The information gleaned from this stage provided feedback to the staff of participating health centers. In the second stage, deficiencies in health care were identified and interventions were developed for improvements, including topics for continuing professional development.In the third stage, these strategies were piloted in a single health centre for one year and the outcomes evaluated. In the still ongoing fourth stage, the project was rolled out to all the health centers in the area, with continuing evaluation. The intervention consisted of changes to establish a structured care model based on the predicted needs of this group of patients utilizing dedicated chronic disease clinics inside the existing primary health care system. These clinics incorporated decision-making tools, including evidence-based guidelines, patient education and ongoing professional education. RESULTS: The intervention was successfully implemented in all the health centers. The health care quality indicators that showed the greatest improvement were the documentation of patient history (e.g. smoking status and physical activity); improvement in recording physical signs (e.g. body mass index (BMI)); and an improvement in the requesting of appropriate investigations, such as HbA1c and microalbuminurea. There was also improvement in those parameters reflecting outcomes of care, which included HbA1c, blood pressure and lipid profiles. Indicators related to lifestyle changes, such as smoking cessation and BMI, failed to improve. CONCLUSION: Chronic disease care is a joint commitment by health care providers and patients. This combined approach proved successful in most areas of the project, but the area of patient self management requires further improvement.

Associations of cardiovascular risk factors in Al Ain, United Arab Emirates.

BACKGROUND: Over the last 30 years the citizens of the United Arab Emirates have experienced major changes in life-style secondary to increased affluence. Currently, 1 in 5 adults have diabetes mellitus, but the associations (clustering) among risk factors, as well as the relevance of the concept of the metabolic syndrome, in this population is unknown. AIM: To investigate the prevalence and associations among cardiovascular risk factors in this population, and explore to what extent associations can be explained by the metabolic syndrome according to ATP-III criteria. METHOD: A community based survey, of conventional risk factors for cardiovascular disease was conducted among 817 national residents of Al Ain city, UAE. These factors were fasting blood sugar, blood pressure, lipid profile, BMI, waist circumference, smoking, or CHD family history. Odds ratios between risks factors, both unadjusted and adjusted for age and sex as well as adjusted for age, sex, and metabolic syndrome were calculated. RESULTS: Various risk factors were positively associated in this population; associations that are mostly unexplained by confounding by age and sex. For example, hypertension and diabetes were still strongly related (OR 2.5; 95% CI 1.7-3.7) after adjustment. An increased waist circumference showed similar relationship with hypertension (OR 2.3; 95% CI 1.5-3.5). Diabetes was related to an increased BMI (OR 1.5; 96% CI 1.0-2.3). Smoking was also associated with diabetes (OR 1.9, 95% CI 1.0-3.3).Further adjustment for metabolic syndrome reduced some associations but several remained. CONCLUSION: In this population risk-factors cluster, but associations do not appear to be explained by the presence/absence of the ATP-III metabolic syndrome. Associations provide valuable information in planning interventions for screening and management.

Potential benefits of controlling coronary heart disease risk factors in the United Arab Emirates.

BACKGROUND: Cardiovascular risk factors including obesity, diabetes, hypertension, and dyslipidemia, are highly prevalent in the United Arab Emirates. In spite of significant awareness initiatives, little is known about the potential benefits of controlling these risk factors. AIMS: To assess the prevalence of preventable risk factors for coronary heart disease (CHD), and the likely benefits of controlling these risk factors. METHODS: In a health survey stratified by self-reported hypertension, we enrolled 349 hypertensive and 641 normotensive subjects of diverse ethnicity in Al-Ain city, and measured CHD risk factors. We used the Framingham risk score to estimate the proportion of CHD potentially preventable by controlling hypertension, dyslipidemia, diabetes mellitus (DM), and smoking. RESULTS: Smoking was similar in the two groups (hypertensives 13.2% vs. normotensives 14.2%). The prevalence of diabetes, dyslipidemia [mean (SD) triglycerides, high-density lipoprotein-cholesterol (HDL-C)], overweight/obesity, and thus the 10-year Framingham risk were all significantly (p < 0.001) higher among hypertensive than normotensives. CONCLUSION: Prevention of type 2 DM, aggressive control of hypertension and dyslipidemia, and smoking cessation could potentially reduce the 10-year incidence of CHD. Barriers include lack of awareness of this problem among the general population and health care providers.

Modulation of mammary tumor development in Tg.NK (MMTV/c-neu) mice by dietary fatty acids and life stage-specific exposure to phytoestrogens.

Breast cancer is a major public health problem among women worldwide. Phytoestrogens and dietary fat composition are being investigated to elucidate the role of nutrition in breast cancer risk. Both epidemiological and rodent studies suggest that the chemopreventive effect of phytoestrogens depends on timing of exposure. We investigated spontaneous mammary tumor development in female heterozygous MMTV/c-neu (Tg.NK) mice upon isoflavone exposure on background diets rich in either n-6 or n-3 polyunsaturated fatty acids (PUFAs). Three different exposure protocols were used, either from conception to weaning, or from weaning onwards, or lifelong. Mice fed diets high in n-3 PUFAs developed mammary tumors 15 weeks later than mice fed n-6 PUFA diets. In the latter mice, isoflavone exposure from weaning onwards resulted in a significant decrease in tumor incidence and a delay in tumor onset. Therefore, the effects of phytoestrogen exposure on tumor formation appear to depend on the composition of the background diet and on the timing of exposure within the life cycle.

Finding patients eligible for antiretroviral therapy using TB services as entry point for HIV treatment.

OBJECTIVE: To estimate the proportion of antiretroviral therapy (ART) eligible adults (15-49 years) with tuberculosis potentially identifiable through tuberculosis services using a CD4 count below 350 cells/mm3 as cut-off value for ART initiation. METHODS: Using TB notification rate data, HIV seroprevalence data, and estimates of the size of the adult population (15-49 years) in 18 sub-Saharan African countries with an HIV seroprevalence of > 5%, calculations of the number of ART eligible adults with tuberculosis presenting to tuberculosis services were made. Assumptions were made on the tuberculosis notification rates in the age-group 15-49 years, the HIV-infected population with a CD4 count below 350 cells/mm3 and the relative risk of developing tuberculosis, and average duration from HIV infection to death. The probability of having a CD4+ count below 350 cells/mm3 given a diagnosis of tuberculosis was estimated using Bayes' theorem, and estimates of the number of patients with a CD4 count below 350 cells/mm3 identifiable through tuberculosis were made. The number needed to screen to identify one ART eligible patient through tuberculosis services was estimated for each country. RESULTS: ART eligible adults with tuberculosis potentially identifiable through tuberculosis services in the 18 countries ranged from 2% to 18% of the total HIV-infected adult population with a CD4+ count below 350 cells/mm3 and would average 10% of all such HIV patients. The number needed to screen to identify ART eligible patients through tuberculosis services ranged from 1.4 to 4.2, against 8.6 to 65.4 if adults aged 15-49 are randomly screened for low CD4 counts. CONCLUSION: Tuberculosis services are an important entry point for identifying ART eligible patients. Given that dually infected patients identified through tuberculosis services contributed to 10% of the HIV-infected adult population with a CD4 cell count below 350 cells/mm3 in the 18 sub-Saharan African countries, major efforts are required beyond the tuberculosis services in detecting patients that should benefit from ART. However, the low number needed to screen gives opportunity to use tuberculosis services in AIDS control and ART scaling-up programmes.

Interphase chromosome positioning affects the spectrum of radiation-induced chromosomal aberrations.

In interphase, chromosomes occupy defined nuclear volumes known as chromosome territories. To probe the biological consequences of the described nonrandom spatial positioning of chromosome territories in human lymphocytes, we performed an extensive FISH-based analysis of ionizing radiation-induced interchanges involving chromosomes 1, 4, 18 and 19. Since the probability of exchange formation depends strongly on the spatial distance between the damage sites in the genome, a preferential formation of exchanges between proximally positioned chromosomes is expected. Here we show that the spectrum of interchanges deviates significantly from one expected based on random chromosome positioning. Moreover, the observed exchange interactions between specific chromosome pairs as well as the interactions between homologous chromosomes are consistent with the proposed gene density-related radial distribution of chromosome territories. The differences between expected and observed exchange frequencies are more pronounced after exposure to densely ionizing neutrons than after exposure to sparsely ionizing X rays. These experiments demonstrate that the spatial positioning of interphase chromosomes affects the spectrum of chromosome rearrangements.

Breast cancer screening, outside the population-screening program, of women from breast cancer families without proven BRCA1/BRCA2 mutations: a simulation study.

PURPOSE: We assessed the cost-effectiveness of mammography screening for women under the age of 50, from breast cancer families without proven BRCA1/BRCA2 mutations, because current criteria for screening healthy women from breast cancer families are not evidence-based. METHODS: We did simulation studies with mathematical models on the cost-effectiveness of mammography screening of women under the age of 50 with breast cancer family histories. Breast cancer screening was simulated with varying screening intervals (6, 12, 18, and 24 months) and screening cohorts (starting at ages 30, 35, 40, and 45, and continuing to age 50). Incremental costs of screening were compared with those of women ages 50 to 52 years, the youngest age group currently routinely screened in the nationwide screening program of the Netherlands, to determine cost-effectiveness. Sensitivity analyses were done to explore the effects of model assumptions. The cost-effectiveness of breast cancer screening for women over the age of 50 was not debated. RESULTS: The most effective screening interval was found to be 12 months, which, however, seems only to be cost-effective in a small group of women under the age of 50 with at least two affected relatives, including at least one affected in the first degree diagnosed under the age of 50. Significantly, early breast cancer screening never seemed to be cost-effective in women with only one affected first-degree or second-degree relative. CONCLUSION: Annual breast cancer screening with mammography for women under the age of 50 seems to be cost-effective in women with strong family histories of breast cancer, even when no BRCA1/BRCA2 mutation was found in affected family members.

Reduced risk of surgical site infections through surveillance in a network.

OBJECTIVE: To estimate the effect of multicentre surveillance for nosocomial infections on patients' risk of surgical site infection (SSI). DESIGN: Prospective multi-centre cohort study, from January 1996 to December 2000. SETTING: Acute care hospitals in The Netherlands. STUDY PARTICIPANTS: All 50 hospitals performing surveillance for one of seven selected procedures in the Dutch surveillance network for nosocomial infections PREZIES were invited. Thirty-seven hospitals participated (74%) and provided information on 21 920 operations, after which 885 (4%) SSI occurred. INTERVENTIONS: The surveillance comprised the following: Development of surveillance methodology by multidisciplinary team; use of a standardized registration protocol and software; regular training of data collectors; anonymous inter-hospital comparison of infection rates and feedback of results; appointment of one contact person per hospital, responsible for data collection; and dissemination of results to other health care professionals. Regular discussion of both successful and failing prevention strategies that had been instituted based on the surveillance results. OUTCOME MEASURE: Risk of SSI. RESULTS: The risk of infection was reduced for patients who had an operation during the fourth surveillance year (RR = 0.69; 95% confidence interval (CI) = 0.52-0.89) and decreased further for patients operated on during the fifth surveillance year (RR = 0.43; CI = 0.24-0.76) as compared with patients who underwent surgery within one year of the start of surveillance in their hospital. No significant risk reduction was observed for patients operated on during the second and third surveillance years. CONCLUSION: Surveillance, supported by participation in a surveillance network, reduced the risk of SSI in surgical patients registered in the Dutch surveillance network PREZIES. Our results suggest that infection control teams need to be perseverant and that surveillance programmes should be given time before evaluation.

Hospital-related determinants for surgical-site infection following hip arthroplasty.

OBJECTIVE: To determine hospital-related risk factors for surgical-site infection (SSI) following hip arthroplasty. DESIGN: Prospective, multicenter cohort study based on surveillance data and data collected through a structured telephone interview. With the use of multilevel logistic regression, the independent effect of hospital-related characteristics on SSI was assessed. SETTING: Thirty-six acute care hospitals in the Dutch surveillance network for nosocomial infections (PREZIES), from 1996 to 2000. PATIENTS: Thirteen thousand six hundred eighty patients who underwent total or partial hip arthroplasty. RESULTS: A high annual volume of operations was associated with a reduced risk of SSI (risk-adjusted risk ratio [RR] per 50 extra operations, 0.85; 95% confidence interval [CI95], 0.74-0.97). With each extra full-time-equivalent infection control staff member per 250 beds available for prevention of SSI, the risk for SSI was decreased (RR, 0.48; CI95, 0.16-1.44), although the decrease was not statistically significant. Hospital size, teaching status, university affiliation, and number of surgeons and their years of experience showed no important association with the risk of SSI. CONCLUSION: Undergoing surgery in a hospital with a low volume of operations increases a patient's risk of SSI.

Effects of soy-derived isoflavones and a high-fat diet on spontaneous mammary tumor development in Tg.NK (MMTV/c-neu) mice.

Phytoestrogens such as isoflavonoids and lignans have been postulated as breast cancer protective constituents in soy and whole-grain cereals. We investigated the ability of isoflavones (IFs) and flaxseed to modulate spontaneous mammary tumor development in female heterozygous Tg.NK (MMTV/c-neu) mice. Two different exposure protocols were applied, either from 4 wk of age onward (postweaning) or during gestation and lactation (perinatal). In the postweaning exposure study, mice were fed IFs or flaxseed in a high-fat diet. In addition, flaxseed in a low-fat diet was tested. Postweaning exposure to IFs and flaxseed tended to accelerate the onset of mammary adenocarcinoma development, although tumor burden at necropsy was not changed significantly. Perinatal IF exposure resulted in enhanced mammary gland differentiation, but palpable mammary tumor onset was not affected. However, tumor burden at necropsy in the perinatal exposure study was significantly increased in the medium- and high-IF dose groups. Comparison of both exposure scenarios revealed a strongly accelerated onset of tumor growth after perinatal high-fat diet exposure compared with the low-fat diet. This study shows that breast cancer-modulating effects of phytoestrogens are dependent both on the background diet and on the timing of exposure in the life cycle.

Influence of promoter variants of interleukin-10, interleukin-9, and tumor necrosis factor-alpha genes on respiratory syncytial virus bronchiolitis.

Previously, we reported genetic associations between severe respiratory syncytial virus (RSV) bronchiolitis in infants and polymorphisms in the interleukin (IL)-4 and IL-4 receptor alpha (IL-4Ralpha) genes, providing evidence for involvement of T helper type 2 cytokines in the pathogenesis of RSV bronchiolitis. We expanded our studies to polymorphisms in genes encoding IL-9, IL-10, and tumor necrosis factor (TNF)-alpha, using both a transmission/disequilibrium test and a case-control approach. Children homozygous for the IL-10 -592C or -592A allele had a higher risk of hospitalization for RSV bronchiolitis than did heterozygous carriers (odds ratio [OR], 1.73 vs. 2.55; 95% confidence interval [CI], 1.13-2.66 vs. 1.21-5.39). In children hospitalized at < or =6 months of age, a significant association between RSV bronchiolitis and the IL-10 -592C allele was found (OR, 1.61; 95% CI, 1.10-2.35). No significant associations of TNF-alpha and IL-9 polymorphisms with RSV bronchiolitis were observed. We also explored the interactions between different polymorphisms and found an interaction between the IL-4Ralpha Q551R and IL-10 C-592A polymorphisms.

Quitting smoking may restore hematological characteristics within five years.

PURPOSE: To describe the cross-sectional association of counts of total and subtypes of leukocytes, platelets, and selected characteristics of red blood cells with intensity of cigarette smoking and smoking cessation. METHODS: The study population consisted of 16,254 men and women 20-70 years of age who participated in the Dutch European Prospective Investigation into Cancer and nutrition (EPIC) subcohort, 1995-1997. Linear regression analysis was performed, for both sexes separately, to study the relation between various measurements of smoking habits and hematologic characteristics. RESULTS: Among current smokers, in both genders, packyears and daily number of cigarettes were associated with increased leukocytes (6-19%), lymphocytes (4-14%), monocytes (3-9%), neutrophils (7-24%), platelets (1-5%), mean corpuscular volume (0.4-2%), hematocrit (0.3-4%), hemoglobin (0.3-4%), and mean corpuscular hemoglobin (0.8-2%). In subjects who had quit smoking within two years before blood measurement, hematological characteristics in most cells were similar as in never smokers, whereas normal counts of lymphocytes and monocytes were observed only 2-5 years after quitting. CONCLUSIONS: Our findings suggest a marked influence of current smoking habits on leukocyte counts and, to a lesser extent, on counts of erythrocytes and platelets. Following smoking cessation, at least five years have to pass before changes in all hematological parameters may return to normal values.