Interactive effects of obesity and physical fitness on risk of ischemic heart disease.

BACKGROUND/OBJECTIVES: Obesity and low physical fitness are known risk factors for ischemic heart disease (IHD), but their interactive effects are unclear. Elucidation of interactions between these common, modifiable risk factors may help inform more effective preventive strategies. We examined interactive effects of obesity, aerobic fitness and muscular strength in late adolescence on risk of IHD in adulthood in a large national cohort. SUBJECTS/METHODS: We conducted a national cohort study of all 1 547 407 military conscripts in Sweden during 1969-1997 (97-98% of all 18-year-old males each year). Aerobic fitness, muscular strength and body mass index (BMI) measurements were examined in relation to IHD identified from outpatient and inpatient diagnoses through 2012 (maximum age 62 years). RESULTS: There were 38 142 men diagnosed with IHD in 39.7 million person years of follow-up. High BMI or low aerobic fitness (but not muscular strength) was associated with higher risk of IHD, adjusting for family history and socioeconomic factors. The combination of high BMI (overweight/obese vs normal) and low aerobic fitness (lowest vs highest tertile) was associated with highest IHD risk (incidence rate ratio, 3.11; 95% confidence interval (CI), 2.91-3.31; P<0.001). These exposures had no additive and a negative multiplicative interaction (that is, their combined effect was less than the product of their separate effects). Low aerobic fitness was a strong risk factor even among those with normal BMI. CONCLUSIONS: In this large cohort study, low aerobic fitness or high BMI at age 18 was associated with higher risk of IHD in adulthood, with a negative multiplicative interaction. Low aerobic fitness appeared to account for a similar number of IHD cases among those with normal vs high BMI (that is, no additive interaction). These findings suggest that interventions to prevent IHD should begin early in life and include not only weight control but aerobic fitness, even among persons of normal weight.

Sociodemographic, psychiatric and somatic risk factors for suicide: a Swedish national cohort study.

BACKGROUND: More effective prevention of suicide requires a comprehensive understanding of sociodemographic, psychiatric and somatic risk factors. Previous studies have been limited by incomplete ascertainment of these factors. We conducted the first study of this issue using sociodemographic and out-patient and in-patient health data for a national population. METHOD: We used data from a national cohort study of 7,140,589 Swedish adults followed for 8 years for suicide mortality (2001-2008). Sociodemographic factors were identified from national census data, and psychiatric and somatic disorders were identified from all out-patient and in-patient diagnoses nationwide. RESULTS: There were 8721 (0.12%) deaths from suicide during 2001-2008. All psychiatric disorders were strong risk factors for suicide among both women and men. Depression was the strongest risk factor, with a greater than 15-fold risk among women or men and even higher risks (up to 32-fold) within the first 3 months of diagnosis. Chronic obstructive pulmonary disease (COPD), cancer, spine disorders, asthma and stroke were significant risk factors among both women and men (1.4-2.1-fold risks) whereas diabetes and ischemic heart disease were modest risk factors only among men (1.2-1.4-fold risks). Sociodemographic risk factors included male sex, unmarried status or non-employment; and low education or income among men. CONCLUSIONS: All psychiatric disorders, COPD, cancer, spine disorders, asthma, stroke, diabetes, ischemic heart disease and specific sociodemographic factors were independent risk factors for suicide during 8 years of follow-up. Effective prevention of suicide requires a multifaceted approach in both psychiatric and primary care settings, targeting mental disorders (especially depression), specific somatic disorders and indicators of social support.

A Nuclear localization signal in herpesvirus protein VP1-2 is essential for infection via capsid routing to the nuclear pore.

To initiate infection, herpesviruses must navigate to and transport their genomes across the nuclear pore. VP1-2 is a large structural protein of the virion that is conserved in all herpesviruses and plays multiple essential roles in virus replication, including roles in early entry. VP1-2 contains an N-terminal basic motif which functions as an efficient nuclear localization signal (NLS). In this study, we constructed a mutant HSV strain, K.VP1-2ΔNLS, which contains a 7-residue deletion of the core NLS at position 475. This mutant fails to spread in normal cells but can be propagated in complementing cell lines. Electron microscopy (EM) analysis of infection in noncomplementing cells demonstrated capsid assembly, cytoplasmic envelopment, and the formation of extracellular enveloped virions. Furthermore, extracellular virions isolated from noncomplementing cells had similar profiles and abundances of structural proteins. Virions containing VP1-2ΔNLS were able to enter and be transported within cells. However, further progress of infection was prevented, with at least a 500- to 1,000-fold reduction in the efficiency of initiating gene expression compared to that in the revertant. Ultrastructural and immunofluorescence analyses revealed that the K.VP1-2ΔNLS mutant was blocked at the microtubule organizing center or immediately upstream of nuclear pore docking and prior to gene expression. These results indicate that the VP1-2 NLS is not required for the known assembly functions of the protein but is a key requirement for the early routing to the nuclear pore that is necessary for successful infection. Given its conservation, we propose that this motif may also be critical for entry of other classes of herpesviruses.

A single mutation responsible for temperature-sensitive entry and assembly defects in the VP1-2 protein of herpes simplex virus.

Evidence for an essential role of the herpes simplex virus type 1 (HSV-1) tegument protein VP1-2 originated from the analysis of the temperature-sensitive (ts) mutant tsB7. At the nonpermissive temperature (NPT), tsB7 capsids accumulate at the nuclear pore, with defective genome release and substantially reduced virus gene expression. We compared the UL36 gene of tsB7 with that of the parental strain HFEM or strain 17 and identified four amino acid substitutions, 1061D → G, 1453Y → H, 2273Y → H, and 2558T → I. We transferred the UL36 gene from tsB7, HFEM, or strain 17 into a KOS background. While KOS recombinants containing the HFEM or strain 17 UL36 gene exhibited no ts defect, recombinants containing the tsB7 UL36 VP1-2 exhibited a 5-log deficiency at the NPT. Incubation at the NPT resulted in little or no virus gene expression, though limited expression could be detected in a highly delayed fashion. Using shift-down regimes, gene expression recovered and recapitulated the time course normally observed, indicating that the initial block was in a reversible pathway. Using temperature shift-up regimes, a second defect later in the replication cycle was also observed in the KOS.ts viruses. We constructed a further series of recombinants which contained subsets of the four substitutions. A virus containing the wild-type (wt) residue at position 1453 and with the other three residues being from tsB7 VP1-2 exhibited wt plaquing efficiency. Conversely, a virus containing the three wt residues but the single Y → H change at position 1453 from tsB7 exhibited a 4- to 5-log drop in plaquing efficiency and was defective at both early and late stages of infection.

Autocatalytic activity of the ubiquitin-specific protease domain of herpes simplex virus 1 VP1-2.

The herpes simplex virus (HSV) tegument protein VP1-2 is essential for virus entry and assembly. VP1-2 also contains a highly conserved ubiquitin-specific protease (USP) domain within its N-terminal region. Despite conservation of the USP and the demonstration that it can act on artificial substrates such as polyubiquitin chains, identification of the relevance of the USP in vivo to levels or function of any substrate remains limited. Here we show that HSV VP1-2 USP can act on itself and is important for stability. VP1-2 N-terminal variants encompassing the core USP domain itself were not affected by mutation of the catalytic cysteine residue (C65). However, extending the N-terminal region resulted in protein species requiring USP activity for accumulation. In this context, C65A mutation resulted in a drastic reduction in protein levels which could be stabilized by proteosomal inhibition or by the presence of normal C65. The functional USP domain could increase abundance of unstable variants, indicating action at least in part, in trans. Interestingly, full-length variants containing the inactive USP, although unstable when expressed in isolation, were stabilized by virus infection. The catalytically inactive VP1-2 retained complementation activity of a VP1-2-negative virus. Furthermore, a recombinant virus expressing a C65A mutant VP1-2 exhibited little difference in single-step growth curves and the kinetics and abundance of VP1-2 or a number of test proteins. Despite the absence of a phenotype for these replication parameters, the USP activity of VP1-2 may be required for function, including its own stability, under certain circumstances.

Aerobic fitness in late adolescence and the risk of cancer and cancer-associated mortality in adulthood: A prospective nationwide study of 1.2 million Swedish men.

BACKGROUND: The incidence of cancer has steadily risen. It is important to identify modifiable predictors in early life that may decrease cancer risks and mortality. The present study aims to investigate the relationship between aerobic fitness in adolescence and the subsequent risk of cancer and cancer-associated mortality. METHODS: The study included 1 185 439 Swedish men born between 1950 and 1980 that participated in the military conscription (mean age = 18 years). The results from the aerobic fitness test (Wmax) was linked to the risk of cancer and cancer-associated mortality during a 40-years' follow-up using Cox proportional hazards models. A co-sibling design was employed to take familial factors into account. RESULTS: During a mean follow-up of 27 years 15 093 cases of cancer and 4900 cancer-associated mortalities were registered. Higher Wmax (per additional 1 SD) was associated with a decreased risk of cancer at 40 years of follow-up (HR 0.93; 95% CI 0.91-0.96 for cancer and HR 0.82 95% CI 0.76-0.87 for cancer-associated mortality) but not at 5 years of follow-up (HR 1.03; 95% CI 0.99-1.07; and HR 1.04; 95% CI 0.97-1.12). In the co-sibling model the protective effects of high Wmax were increased at 40 years of follow-up for cancer (HR 0.91; 95% CI 0.85-0.98) and cancer-associated mortality (HR 0.78; 95% CI 0.68-0.89). CONCLUSIONS: These findings identify in late adolescence a potentially modifiable predictor of cancer, with higher aerobic fitness associated with a decreased risk of cancer incidence and mortality later in life.

Phosphorylation of the medium chain subunit of the AP-2 adaptor complex does not influence its interaction with the tyrosine based internalisation motif of TGN38.

Tyrosine based motifs conforming to the consensus YXXphi (where phi represents a bulky hydrophobic residue) have been shown to interact with the medium chain subunit of clathrin adaptor complexes. These medium chains are targets for phosphorylation by a kinase activity associated with clathrin coated vesicles. We have used the clathrin coated vesicle associated kinase activity to specifically phosphorylate a soluble recombinant fusion protein of mu2, the medium chain subunit of the plasma membrane associated adaptor protein complex AP-2. We have tested whether this phosphorylation has any effect on the interaction of mu2 with the tyrosine based motif containing protein, TGN38, that has previously been shown to interact with mu2. Phosphorylation of mu2 was shown to have no significant effect on the in vitro interaction of mu2 with the cytosolic domain of TGN38, indicating that reversible phosphorylation of mu2 does not play a role in regulating its direct interaction with tyrosine based internalisation motifs. In addition, although a casein kinase II-like activity has been shown to be associated with clathrin coated vesicles, we show that mu2 is not phosphorylated by casein kinase II implying that another kinase activity is present in clathrin coated vesicles. Furthermore the kinase activity associated with clathrin coated vesicles was shown to be capable of phosphorylating dynamin 1. Phosphorylation of dynamin 1 has previously been shown to regulate its interaction with other proteins involved in clathrin mediated endocytosis.

Ovarian cancer tumor marker behavior in asymptomatic healthy women: implications for screening.

Ovarian cancer screening protocols generally have been limited by inadequate recognition of the normal behavior of tumor markers in women at risk of ovarian cancer. We have characterized the behavior of five serum tumor markers in a large cohort of healthy women and examined the implications for screening. Serial measurements of CA125, HER-2/neu, urinary gonadotropin peptide, lipid-associated sialic acid, and Dianon marker 70/K were obtained during 6 years of follow-up of 1257 healthy women at high risk of ovarian cancer. We analyzed individual-specific tumor marker behavior and explored methods that can exploit this information to develop individual-specific screening rules. These five tumor markers behaved approximately independently. Substantial heterogeneity was observed among women in the behavior of each tumor marker, particularly CA125. Intraclass correlation (ICC), or the proportion of total variability that occurs between individuals, was approximately 0.6 for log-transformed CA125 and urinary gonadotropin peptide, and less than 0.4 for the other markers. This degree of tumor marker heterogeneity among healthy women, and the relative independence of these markers, has important implications for screening and diagnostic tests. Independence of markers results in the clinically useful fact that the combined false positive rate from screening with multiple markers may be estimated by the sum of individual false positive rates. Heterogeneity of tumor marker patterns in healthy women implies that a fixed screening cutoff level is suboptimal to a degree that depends strongly on ICC. Using information on longitudinal measurements and ICC, individual-specific screening rules may be developed with the potential to improve early detection of ovarian cancer.

Glutathione S-transferase theta 1 gene deletion and risk of acute myeloid leukemia.

Individuals with a homozygous deletion of the glutathione S-transferase theta 1 (GSTT1) gene lack GSTT1 enzymatic detoxification of environmental carcinogens by conjugation with glutathione. The GSTT1 gene deletion has been associated with carcinogen-induced chromosomal changes in lymphocytes, and some but not all epidemiological evidence has suggested that the GSTT1 gene deletion may increase susceptibility to myelodysplasia. We conducted a case-control study to test whether individuals with an inherited homozygous deletion of the GSTT1 gene are at increased risk of acute myeloid leukemia (AML). The GSTT1 and GST mu 1 (GSTM1) genotypes were determined by PCR using lymphocyte or bone marrow DNA from 297 AML patients and 152 controls. AML patients were selected from Southwest Oncology Group clinical studies, and controls were identified by random digit dialing in Washington state. No association was observed between the GSTT1 gene deletion and AML [race-adjusted odds ratio (OR), 0.94; 95% confidence interval (CI), 0.55-1.60] or between the GSTM1 gene deletion and AML (race-adjusted OR, 1.26; 95% CI, 0.85-1.88). Patients with secondary AML had a slightly higher prevalence of the GSTT1 and GSTM1 gene deletions compared with de novo AML patients or controls, but this was consistent with chance. Exploratory analyses of AML cytogenetics suggested a few associations, i.e., between the GSTT1 gene deletion and trisomy 8, and between the GSTM1 gene deletion and non-8 trisomies or inv(16). These results do not support the hypothesis that the GSTT1 gene deletion is related to the incidence of AML.

In vitro activity of pleconaril and AG7088 against selected serotypes and clinical isolates of human rhinoviruses.

BACKGROUND: We tested the in vitro activity of pleconaril and AG7088 against five numbered human rhinovirus (HRV) serotypes and 46 clinical HRV isolates of undefined serotype recovered from patients with common colds. Antiviral effect of pleconaril and AG7088 were assessed by cytophathic effect (CPE) inhibition assays in Ohio HeLaI cells using microscopic and spectrophotometric methods. Both compounds were tested at concentrations of 1.0, 0.1 and 0.01 microg/ml. For the numbered HRV serotypes, the median EC(50) value determined by the microscopic CPE inhibition was slightly better for AG7088 compared to pleconaril (P=0.02) but was similar by spectrophotometric assay (P=0.15). For clinical HRV isolates the median EC(50) value determined microscopically was 0.01 microg/ml range, <0.01-0.04 microg/ml) for AG7088 compared to 0.07 microg/ml (range, <0.01->1 microg/ml) for pleconaril (P<0.001). The median EC(50) value determined by spectrophotometric assay was 0.01 microg/ml (range, <0.01-0.04 microg/ml) for AG7088 compared to 0.04 microg/ml (range, <0.01->1 microg/ml) for pleconaril (P<0.001). By either the microscopic or spectrophotometric methods the median EC(50) value of AG7088 was <1.0 microg/ml for all isolates and was >10.0 microg/ml of pleconaril for approximately 9% of isolates. In vitro AG7088 appeared to be more potent and to have a broader antirhinoviral spectrum than pleconaril among clinical HRV isolates. The clinical relevance of these in vitro results needs to be determined in controlled clinical trials.

Employee fitness and wellness programs in the workplace.

Worksite fitness and health promotion programs have grown exponentially in the past 15 years. To examine the impact of these programs, the literature through 1988 was reviewed. In general, fitness and wellness programs result in increased levels of fitness and a reduction in the risk factors for coronary heart disease. Recent research using control groups has found relations between reduction in health care costs, absenteeism, and turnover and implementation of comprehensive health promotion programs. Issues related to participation rates, program implementation, and evaluation are also addressed.

Does perchlorate in drinking water affect thyroid function in newborns or school-age children?

Perchlorate is known to suppress thyroid function by inhibiting uptake of iodide by the human thyroid at doses of 200 mg/day or greater. A study was conducted to investigate the potential effects of perchlorate in drinking water on thyroid function in newborns and school-age children. A total of 162 school-age children and 9784 newborns were studied in three proximate cities in northern Chile that have different concentrations of perchlorate in drinking water: Taltal (100 to 120 micrograms/L), Chañaral (5 to 7 micrograms/L), and Antofagasta (non-detectable: < 4 micrograms/L). Among schoolchildren, no difference was found in thyroid-stimulating hormone levels or goiter prevalence among lifelong residents of Taltal or Chañaral compared with those of Antofagasta, after adjusting for age, sex, and urinary iodine. No presumptive cases of congenital hypothyroidism were detected in Taltal or Chañaral; seven cases were detected in Antofagasta. Neonatal thyroid-stimulating hormone levels were significantly lower in Taltal compared with Antofagasta; this is opposite to the known pharmacological effect of perchlorate, and the magnitude of difference did not seem to be clinically significant. These findings do not support the hypothesis that perchlorate in drinking water at concentrations as high as 100 to 120 micrograms/L suppresses thyroid function in newborns or school-age children.

Comparison of participation in federal worksite and community health promotion programs.

The extent to which employees rely on the worksite exclusively for health promotion programs was examined in a cross-sectional study of 10 federal worksites. Responses were received from 3,403 of the 5,757 employees surveyed (59%). Fewer than 10% of employees exclusively used agency programs for physical fitness, nutrition, substance abuse, smoking cessation, and support group meetings. A higher percentage participated in health risk assessment (27%), health and disease risk education activities (17%), medical care services (23%), personal safety and first aid training 26%, and stress management programs (17%) only at the worksite. Men were more likely than women to participate exclusively in workplace programs.

Characteristics of health promotion programs in Federal worksites: findings from the Federal Employee Worksite Project.

PURPOSE: To describe how well-established health promotion programs at selected federal worksites were designed, organized, and implemented and to identify factors related to employee participation. DESIGN: This descriptive study related characteristics of the health promotion program, worksites, and workforce to employee participation and perceptions of program impacts. SETTING: The study was conducted at 10 established federal worksite health promotion programs in various regions of the country. SUBJECTS: A total of 3403 of 5757 federal employees (59%) sampled completed employee surveys. MEASURES: Study data were collected from on-site observations, interviews, focus groups, and employee surveys. RESULTS: Overall, program participation rates were high, and employees reported positive impacts on their health and attitudes toward the agency. Participation in health screening, perceived program convenience, and perceived support by management and others were important determinants of participation and of perceived work-related outcomes. CONCLUSIONS: Although site selection and response rate limit generalizability, the sites evaluated represent a broad cross-section of different types and sizes of agencies. The findings should be relevant in many other settings. Study programs compare favorably with private sector programs. Employees viewed the programs very positively. The most cogent challenge in justifying these, and perhaps other, worksite programs is that most participants already or simultaneously engage in health promotion activities elsewhere "on their own."

Health promotion programs in small worksites: results of a national survey.

PURPOSE: This study documents the prevalence of workplace health promotion activities at small worksites with 15 to 99 employees. DESIGN: A random sample of U.S. worksites stratified by size and industry (n = 3628) was drawn using American Business Lists. MEASURES: Each worksite was surveyed using a computer-assisted telephone interview system to document activities related to health promotion and related programs, worksite policies regarding health and safety, health insurance, and philanthropic activities. SUBJECTS: Participation varied by industry and size, with an overall response rate for eligible worksites of 78% for a total sample of 2680 worksites. DATA ANALYSIS: Data were analyzed using SUDAAN statistical software. RESULTS: Approximately 25% of worksites with 15 to 99 employees offered health promotion programs to their employees, compared with 44% of worksites with 100+ employees. As with the larger worksites, the most common programs for worksites with 15 to 99 employees were those related to occupational safety and health, back injury prevention, and CPR. The majority of worksites in both size categories had alcohol, illegal drug, smoking, and occupant protection policies. The majority of both small and large worksites also offered group health insurance to their employees (92% and 98%, respectively), with many of the worksites also extending benefits to family members and dependents (approximately 80% for both business sizes). CONCLUSIONS: The results indicated that small worksites are providing programs to their employees, with a primary focus on job-related hazards. Small worksites also have formal policies regarding alcohol, drug use, smoking, and seatbelt use and offer health insurance to their employees at a rate only slightly lower than that of large worksites.

Locating and linking to medical care HIV-positive persons without a history of care: findings from the California Bridge Project.

The California Bridge Project was developed to actively locate out-of-treatment HIV-positive persons and link them to HIV care and treatment services. Three hundred and twenty five clients had never received HIV medical care. Among these clients the average time from HIV diagnosis to contact with project staff was one-and-a-half years. Nearly three-fourth of clients were persons of color and almost half were men who have sex with men (MSM). The project was effective in linking 29.2% of clients to medical care. First contact to linkage required an average of 15.4 client contacts. During these encounters project staff assessed clients' risk behaviors and physical and mental health status and addressed real or perceived barriers to care. Latinos were over two times (adjusted OR = 2.33, p=0.034) and African Americans over three times (adjusted OR = 3.69, p=0.002) more likely than whites to be linked to medical care. Success in linking persons of color to medical care may have been because the majority of project staff were persons of color who were purposely hired with characteristics similar to those of the target population. The Bridge Project demonstrates the challenges faced in attempting to link HIV-positive persons from underserved and marginalized populations to medical care.

Prenatal stress reduces fertility of male offspring in mice, without affecting their adult testosterone levels.

The male offspring of mice stressed by crowding during the final third of pregnancy showed reductions in sexual behavior and fertility. When paired with receptive females, their latencies to mount and to achieve intromission and ejaculation were greater than controls, and 30% of them failed to ejaculate in the 100-min test. When housed continuously for 4 days with females, 31% of them failed to impregnate their partners, compared with 4% of controls. The sexual receptivity of the untreated females paired with prenatally stressed males was not affected. Resting testosterone levels of prenatally stressed males did not differ from those of controls, and the pattern of rise and fall of testosterone during a 60-min interaction with a female showed only minor differences. The results suggest a central, rather than peripheral, mediation of the behavioral effects of prenatal stress.