Adolescent Cardiorespiratory Fitness and Risk of Cancer in Late Adulthood: Nationwide Sibling-Controlled Cohort Study.

Objective: To investigate whether the higher risks of certain cancers associated with high cardiorespiratory fitness can be explained by increased detection and unobserved confounders. Design: Nationwide sibling-controlled cohort study of adolescents. Setting: Sweden. Participants: 1 124 049 men of which 477 453 were full siblings, who underwent mandatory military conscription examinations between 1972 and 1995 at a mean age of 18.3 years. Main outcome measures: Hazard ratios (HR) and 95% confidence intervals (CI) of overall cancer diagnosis and cancer mortality, and 14 site-specific cancers (diagnosis or death), as recorded in the Swedish National Patient Register or Cause of Death Register until 31 December 2023, modelled using flexible parametric regressions. Results: Participants were followed until a median (maximum) age of 55.9 (73.5) years, during which 98 410 were diagnosed with cancer and 16 789 had a cancer-related death (41 293 and 6908 among full siblings respectively). The most common cancers were non-melanoma skin (27 105 diagnoses & 227 deaths) and prostate cancer (24 211 diagnoses & 869 deaths). In cohort analysis, those in the highest quartile of cardiorespiratory fitness had a higher risk of prostate (adjusted HR 1.10; 95% CI: 1.05 to 1.16) and skin cancer (e.g., non-melanoma HR 1.44; 1.37 to 1.50) compared to those in the lowest quartile, which led to a higher risk of any type of cancer diagnosis (HR 1.08; 1.06 to 1.11). However, those in the highest quartile had a lower risk of cancer mortality (HR 0.71; 0.67 to 0.76). When comparing full siblings, and thereby controlling for all behavioural, environmental, and genetic factors they share, the excess risk of prostate (HR 1.01; 0.90 to 1.13) and skin cancer (e.g., non-melanoma HR 1.09; 0.99 to 1.20) attenuated to the null. In contrast, the lower risk of overall cancer mortality was still statistically significant after control for such shared confounders (HR 0.78; 0.68 to 0.89). For other site-specific cancers, the influence of such confounding tended to vary, but none showed the same excess risk as prostate and non-melanoma skin cancer. Conclusions: The association between high levels of adolescent cardiorespiratory fitness and excess risk of some cancers, such as prostate and non-melanoma skin cancer, appears to be fully explained by unobserved confounders shared between full siblings. However, the protective association with cancer mortality persists even after control for such confounding.

Device-measured physical activity, sedentary time, and risk of all-cause mortality: an individual participant data analysis of four prospective cohort studies.

OBJECTIVES: To examine whether moderate-to-vigorous physical activity (MVPA) modifies the association between sedentary time and mortality and vice versa, and estimate the joint associations of MVPA and sedentary time on mortality risk. METHODS: This study involved individual participant data analysis of four prospective cohort studies (Norway, Sweden, USA, baseline: 2003-2016, 11 989 participants ≥50 years, 50.5% women) with hip-accelerometry-measured physical activity and sedentary time. Associations were examined using restricted cubic splines and fractional polynomials in Cox regressions adjusted for sex, education, body mass index, smoking, alcohol, study cohort, cardiovascular disease, cancer, and/or diabetes, accelerometry wear time and age. RESULTS: 6.7% (n=805) died during follow-up (median 5.2 years, IQR 4.2 years). More than 12 daily sedentary hours (reference 8 hours) was associated with mortality risk only among those accumulating <22 min of MVPA per day (HR 1.38, 95% CI 1.10 to 1.74). Higher MVPA levels were associated with lower mortality risk irrespective of sedentary time, for example, HR for 10 versus 0 daily min of MVPA was 0.85 (95% CI 0.74 to 0.96) in those accumulating <10.5 daily sedentary hours and 0.65 (95% CI 0.53 to 0.79) in those accumulating ≥10.5 daily sedentary hours. Joint association analyses confirmed that higher MVPA was superior to lower sedentary time in lowering mortality risk, for example, 10 versus 0 daily min of MVPA was associated with 28-55% lower mortality risk across the sedentary time spectrum (lowest risk, 10 daily sedentary hours: HR 0.45, 95% CI 0.31 to 0.65). CONCLUSIONS: Sedentary time was associated with higher mortality risk but only in individuals accumulating less than 22 min of MVPA per day. Higher MVPA levels were associated with lower mortality risk irrespective of the amount of sedentary time.

Impact of exercise interventions on physical fitness in breast cancer patients and survivors: a systematic review.

BACKGROUND: This systematic review aims to identify the effects of exercise interventions in patients with breast cancer (BCP) and survivors (BCS) on selected variables of physical fitness. METHODS: A comprehensive literature search was conducted using Medline and Scopus. Randomized controlled trials with isolated exercise interventions in BCP and BCS women (< 5 years from therapy completion) were included. The risk of bias (RoB) assessment was conducted using the Cochrane RoB-2-tool. Variables regarding cardiorespiratory fitness (CRF), strength (ST), fatigue (F) and health-related quality of life (HRQoL) were discussed. RESULTS: Of the 336 studies initially identified, 22 met all the inclusion criteria and were deemed eligible. RoB assessment indicated that the studies had predominantly "some concerns" or had "low RoB", with only 3 studies presenting a "high RoB". The mean duration and frequency of exercise interventions were 19 weeks and 3 sessions/week, performed at moderate intensity (65% VO2max and 66% 1RM, for aerobic and resistance-training interventions, respectively). CONCLUSIONS: Exercise interventions seem to be a valuable strategy in BCP to avoid the decline of CRF, ST, F and HRQoL. Conversely, improved physical function among BCS is observed for the same variables. Resistance training and combined interventions seem to provide the most encouraging variations of the selected outcomes. PROSPERO REGISTRATION ID: CRD42021237917.

Investigation of the analysis of wearable data for cancer-specific mortality prediction in older adults.

Cancer is an aggressive disease which imparts a tremendous socio-economic burden on the international community. Early detection is an important aspect in improving survival rates for cancer sufferers; however, very few studies have investigated the possibility of predicting which people have the highest risk to develop this disease, even years before the traditional symptoms first occur. In this paper, a dataset from a longitudinal study which was collected among 2291 70-year olds in Sweden has been analyzed to investigate the possibility for predicting 2-7 year cancer-specific mortality. A tailored ensemble model has been developed to tackle this highly imbalanced dataset. The performance with different feature subsets has been investigated to evaluate the impact that heterogeneous data sources may have on the overall model. While a full-features model shows an Area Under the ROC Curve (AUC-ROC) of 0.882, a feature subset which only includes demographics, self-report health and lifestyle data, and wearable dataset collected in free-living environments presents similar performance (AUC-ROC: 0.857). This analysis confirms the importance of wearable technology for providing unbiased health markers and suggests its possible use in the accurate prediction of 2-7 year cancer-related mortality in older adults.

Risk factors for COVID-19 diagnosis, hospitalization, and subsequent all-cause mortality in Sweden: a nationwide study.

We conducted a nationwide, registry-based study to investigate the importance of 34 potential risk factors for coronavirus disease 2019 (COVID-19) diagnosis, hospitalization (with or without intensive care unit [ICU] admission), and subsequent all-cause mortality. The study population comprised all COVID-19 cases confirmed in Sweden by mid-September 2020 (68,575 non-hospitalized, 2494 ICU hospitalized, and 13,589 non-ICU hospitalized) and 434,081 randomly sampled general-population controls. Older age was the strongest risk factor for hospitalization, although the odds of ICU hospitalization decreased after 60-69 years and, after controlling for other risk factors, the odds of non-ICU hospitalization showed no trend after 40-49 years. Residence in a long-term care facility was associated with non-ICU hospitalization. Male sex and the presence of at least one investigated comorbidity or prescription medication were associated with both ICU and non-ICU hospitalization. Three comorbidities associated with both ICU and non-ICU hospitalization were asthma, hypertension, and Down syndrome. History of cancer was not associated with COVID-19 hospitalization, but cancer in the past year was associated with non-ICU hospitalization, after controlling for other risk factors. Cardiovascular disease was weakly associated with non-ICU hospitalization for COVID-19, but not with ICU hospitalization, after adjustment for other risk factors. Excess mortality was observed in both hospitalized and non-hospitalized COVID-19 cases. These results confirm that severe COVID-19 is related to age, sex, and comorbidity in general. The study provides new evidence that hypertension, asthma, Down syndrome, and residence in a long-term care facility are associated with severe COVID-19.

Effect of Berry Polyphenols on Glucose Metabolism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The effect of berry polyphenols on glucose metabolism has been evaluated in several studies; however, the results are conflicting. A systematic review and meta-analysis was therefore conducted to evaluate the effect of berry polyphenol consumption on glucose metabolism in adults with impaired glucose tolerance or insulin resistance. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL (EBSCO), and Scopus were searched for randomized controlled trials published by June 2019. Of the 3240 articles found, 21 met inclusion criteria. Study-specific effects were calculated as mean differences, which were pooled using fixed-effect, inverse-variance weighting. Overall, berry polyphenol consumption did not have a clear effect on biomarkers of glucose metabolism compared with placebo or no treatment. Although some analyses showed statistically significant effects, these effects were too small to be of clinical relevance. The review protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews as CRD42019130811.

Bone-Specific Drugs and Osteonecrosis of Sites Other Than the Jaw: A Nationwide Cohort Study.

Bone-specific drugs (BSDs) increase the risk of osteonecrosis of the jaw (ONJ), but whether they increase the risk of osteonecrosis at other sites is not known. Two studies, a cohort study and a case-control study, were conducted using registry data on everyone who was residing in Sweden on December 31, 2005, and who was 50 years of age or older at the time (n = 3,523,912). In the cohort study, individuals prescribed a BSD during the period 2006-2017 (n = 217,387) were 1:1 matched with nonusers on birth year, sex, hip fracture status, and Swedish or foreign origin. In the case-control study, individuals diagnosed with osteonecrosis during 2006-2017 (n = 12,614) were 1:1 matched with individuals without a diagnosis of osteonecrosis on birth year, sex, and Swedish or foreign background. In the cohort study, osteonecrosis was diagnosed in 983 BSD users and 214 nonusers (adjusted hazard ratio [aHR] 4.02; 95% CI, 3.32-4.87), during a mean treatment time of 2.8 years. A similar association was observed in a subcohort where all individuals diagnosed with cancer (HR 4.82; 95% CI, 2.52-9.22). The greatest difference in incidence between BSD users and nonusers was observed in patients with a femoral neck fracture that was not treated with total hip arthroplasty or hemiarthroplasty (incidence rate difference, 77.8 cases per 10,000 person-years, p < .05). The risk of osteonecrosis was higher in users of denosumab (HR 1.93; 95% CI, 1.33-2.79) and users of zoledronic acid (HR 1.95; 95% CI, 1.31-2.91) than in users of other BSDs. The increased risk of osteonecrosis decreased after the end of therapy (p < .001 for time trend). The results were confirmed in the case-control study. In summary, use of BSDs, especially more potent BSDs, is associated with increased risk of osteonecrosis of sites other than the jaw. This increased risk decreases after the final dose of BSD. © 2020 American Society for Bone and Mineral Research.

The 9+ screening test score does not predict injuries in elite floorball players.

We aimed to examine whether the 9+ screening test score could predict injuries in elite floorball players. Eighty-four elite floorball players participated in the study. At baseline, two physiotherapists assessed the participants using the 9+ screening test. The test score reflects strength, stability, mobility, and functional movement pattern with an emphasis on the lower body and core. Injuries that occurred the following season (2013/2014) were recorded by medical staff, coaches, and/or self-reported by the players. Overall, there was no relationship between the 9+ screening test score and injury risk (OR = 0.96 per SD lower test score, P = .84). We, therefore, conclude that the 9+ screening test is not suited for overall injury risk prediction in elite floorball players. Whether the test may be used to predict risk of certain injury types more strongly related to inadequate mobility and strength (eg, muscle ruptures or strains) warrants further investigation.

A Phenomenographic Study of Swedish Nurse Anesthetists' and OR Nurses' Work Experiences.

In the complex OR environment, perioperative team members need to practice communication and teamwork to ensure safe, high-quality care. A lack of collaboration among professionals in the OR during surgery results in inefficiency, increased tension, and suboptimal patient care. The purpose of this study was to determine how nurse anesthetists and OR nurses experienced their work in the OR. We used a qualitative design with a phenomenographic approach and conducted 12 interviews in two surgical departments in the southern part of Sweden. We identified four categories of description: team member approach, professional awareness, lifelong learning approach, and safety and the patient's interest. We found that the nurses' work experiences in the OR were multifaceted and correlated with concepts of teamwork, safety, and communication.

Exposure to interpersonal violence and risk of post-traumatic stress disorder among women with borderline personality disorder.

BACKGROUND: This study aims to determine the validity of the Karolinska Interpersonal Violence Scale (KIVS), as a screening tool for PTSD, among women with borderline personality disorder (BPD) and severe suicidal behavior. METHOD: 106 women with BPD and at least two suicide attempts were assessed with the KIVS for exposure to interpersonal violence as a child and as an adult. The screening ability of the KIVS for the diagnosis of PTSD was analyzed using receiver operating characteristic curve analysis. RESULTS: PTSD diagnosis was valid for 61 (58%) women with BPD. The KIVS - exposure of lifetime interpersonal violence, displayed fair accuracy of predicting diagnosis of PTSD (area under the curve 0.79, confidence interval [0.71, 0.88]) and performed well (sensitivity 0.90 and specificity 0.62), with a cut-off score of 4 (range 0-10). Poly-traumatization was not significantly related to PTSD diagnosis as compared to single traumatization, whereas sexual victimization was significantly more prevalent in women with PTSD diagnosis, as compared to other types of traumatic events. CONCLUSION: A score of 4 or more on the KIVS - exposure to interpersonal lifetime violence presents well as a screening instrument for risk of PTSD, among women with BPD.

Dairy product intake and bone properties in 70-year-old men and women.

In the present population-based study including 70-year-old men and women, total dairy product intake was associated with a weak positive association with tibia trabecular and cortical cross-sectional areas. PURPOSE: Milk consumption has recently been suggested to increase fracture risk. Therefore, we aimed to investigate associations between dairy product consumption and peripheral bone properties. Furthermore, we explored whether consumption of milk and fermented dairy products affected bone properties differently. METHODS: The Healthy Aging Initiative is a population-based, cross-sectional study investigating the health of 70-year-old men and women. Out of the 2904 individuals who met the inclusion criteria, data on self-reported daily dairy product consumption (dl/day), peripheral quantitative computed tomography (pQCT) examinations at the 4 and 66% scan sites of the tibia and radius, and dual-energy X-ray absorptiometry (DXA) scans were collected from 2040 participants. Associations between dairy product consumption and bone properties were examined using multiple linear regression models adjusted for sex, muscle area, meal size, dietary protein proportion, current smoking status, and objectively measured physical activity. RESULTS: Total dairy product intake was associated with larger trabecular (2.296 (95% CI, 0.552-4.039) mm2, per dl/day increase, p = 0.01) and cortical cross-sectional areas (CSAs) in the tibia (1.757 (95% CI, 0.683-2.830 mm2, p = 0.001) as measured by pQCT and higher areal bone mineral density (aBMD) of the radius (3.231 (95% CI, 0.764-5.698) mg/cm2, p = 0.01) as measured by DXA. No other measurement in the tibia, radius, femoral neck, or lower spine was associated significantly with dairy product intake. Bone properties did not differ according to the type of dairy product consumed. CONCLUSION: No evidence of a negative association between dairy product consumption and bone health was found. Furthermore, total dairy product consumption was associated with increased CSAs in the tibia, regardless of dairy product type. Collectively, our findings indicate the existence of a weak but significant positive association between dairy product consumption bone properties in older adults.

Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: Changes Linked to Altered Striato-Thalamic-Cortical Functioning.

OBJECTIVE: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI). SETTING: Neurorehabilitation clinic. PARTICIPANTS: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27). MAIN MEASURES: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task. RESULTS: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001). The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%. CONCLUSION: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.

Risks of Myocardial Infarction, Death, and Diabetes in Identical Twin Pairs With Different Body Mass Indexes.

IMPORTANCE: Observational studies have shown that obesity is a major risk factor for cardiovascular disease and death. The extent of genetic confounding in these associations is unclear. OBJECTIVE: To compare the risk of myocardial infarction (MI), type 2 diabetes, and death in monozygotic (MZ) twin pairs discordant for body mass index (BMI). DESIGN, SETTING, AND PARTICIPANTS: A cohort of 4046 MZ twin pairs with discordant BMIs (difference >0.01) was identified using the nationwide Swedish twin registry. The study was conducted from March 17, 1998, to January 16, 2003, with follow-up regarding incident outcomes until December 31, 2013. MAIN OUTCOMES AND MEASURES: The combined primary end point of death or MI and the secondary end point of incident diabetes were evaluated in heavier compared with leaner twins in a co-twin control analysis using multivariable conditional logistic regression. RESULTS: Mean (SD) baseline age for both cohorts was 57.6 (9.5) years (range, 41.9-91.8 years). During a mean follow-up period of 12.4 (2.5) years, 203 MIs (5.0%) and 550 deaths (13.6%) occurred among heavier twins (mean [SD] BMI, 25.9 [3.6] [calculated as weight in kilograms divided by height in meters squared]) compared with 209 MIs (5.2%) and 633 deaths (15.6%) among leaner twins (mean [SD] BMI, 23.9 [3.1]; combined multivariable adjusted odds ratio [OR], 0.75; 95% CI, 0.63-0.91). Even in twin pairs with BMI discordance of 7.0 or more (mean [SE], 9.3 [0.7]), where the heavier twin had a BMI of 30.0 or more (n = 65 pairs), the risk of MI or death was not greater in heavier twins (OR, 0.42; 95% CI, 0.15-1.18). In contrast, in the total cohort of twins, the risk of incident diabetes was greater in heavier twins (OR, 2.14; 95% CI, 1.61-2.84). Finally, increases in BMI since 30 years before baseline were not associated with the later risk of MI or death (OR, 0.97; 95% CI, 0.89-1.05) but were associated with the risk of incident diabetes (OR, 1.13; 95% CI, 1.01-1.26). CONCLUSIONS AND RELEVANCE: In MZ twin pairs, higher BMI was not associated with an increased risk of MI or death but was associated with the onset of diabetes. These results may suggest that lifestyle interventions to reduce obesity are more effective in decreasing the risk of diabetes than the risk of cardiovascular disease or death.

Higher Prevalence of Type 2 Diabetes in Men Than in Women Is Associated With Differences in Visceral Fat Mass.

CONTEXT: We have previously found that visceral fat is a stronger predictor for cardiovascular risk factors than body mass index (BMI). OBJECTIVE: This study sought to investigate the prevalence of diabetes in elderly men and women in relation to objectively assessed visceral fat volume. DESIGN AND SETTING: The cohort consisted of a population-based sample of 705 men and 688 women, all age 70 y at the time of examination. MAIN OUTCOME MEASURES: Associations between body fat estimates, plasma glucose level, and diabetes prevalence were investigated using multivariable-adjusted statistical models. RESULTS: The prevalence of type 2 diabetes was 14.6% in men and 9.1% in women (P < .001). Mean BMI was slightly higher in men than in women (27.3 vs 26.6 kg/m2; P = .01), with a greater difference in mean visceral fat mass (1987 vs 1077 g; P < .001). After adjustment for physical activity and smoking, men had about/approximately twice the odds of having type 2 diabetes compared with women (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.38-2.76). The inclusion of BMI in this model did not change the risk associated with male sex (OR, 1.93; 95% CI, 1.34-2.77). However, when visceral fat was included as a covariate, male sex was not associated with increased risk of type 2 diabetes (OR, 0.77; 95% CI, 0.51-1.18). CONCLUSIONS: The higher prevalence of type 2 diabetes in older men than in older women was associated with larger amount of visceral fat in men. In contrast, differences in BMI was not associated with this difference.

Effects of estrogen and testosterone treatment on serotonin transporter binding in the brain of surgically postmenopausal women--a PET study.

Sex hormones and the serotonergic system interact in the regulation of mood, learning, memory and sexual behaviour. However, the mechanisms have not been fully explored. The serotonin transporter protein (5-HTT) regulates synaptic concentrations of serotonin and is a primary target for selective serotonin reuptake inhibitors. The aim of this study was to explore how estrogen treatment alone or in combination with testosterone affects 5-HTT binding potentials measured by positron emission tomography (PET) in specific brain regions of postmenopausal women. Ten healthy surgically postmenopausal women (years since oophorectomy 7.5 ± 4.0, mean ± SD) underwent PET examinations at baseline, after three months of estrogen treatment (transdermal estradiol 100 µg/24 hours) and after another three months of combined estrogen and testosterone (testosterone undecanoate 40 mg daily) treatment using the radioligand [(11)C] MADAM developed for examination of the serotonin transporter. The 5-HTT binding potentials decreased significantly in several cortical regions, as well as in limbic and striatal regions after both estrogen treatment alone and combined estrogen/testosterone treatment in comparison to baseline. The observed decrease in 5-HTT could either be due to direct effects on serotonin transporter expression or be the result of indirect adaptation to estrogen and /or testosterone effects on synaptic serotonin levels. Although the mechanism still needs further exploration, the study supports the view that gonadal hormones play a role in serotonin regulated mood disorders.

High aerobic fitness in late adolescence is associated with a reduced risk of myocardial infarction later in life: a nationwide cohort study in men.

AIMS: Cardiovascular disease is the leading cause of morbidity and mortality worldwide, and signs of atherosclerosis are present in all large arteries already in adolescence. We investigated the association between high physical fitness in late adolescence and myocardial infarction (MI) later in life. METHODS AND RESULTS: The study cohort comprised 743 498 Swedish men examined at the age of 18 years during conscription 1969-84. Aerobic fitness (Wmax) and muscle strength at conscription were measured using standardized methods. Myocardial infarctions occurring in the cohort were tracked through national registers. During a median follow-up period of 34 years, 11 526 MIs were registered in the cohort. After adjusting for age, body mass index (BMI), diseases, education, blood pressure, and socio-economic factors, one standard deviation increase in the level of physical fitness (Wmax) was associated with an 18% decreased risk of later MI [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.80-0.85]. The beneficial effects of Wmax were significant across all recognized BMI groups, ranging from lean (BMI < 18.5) to obese (BMI > 30) (P < 0.05 for all). However, obese men (BMI > 30) in the highest fourth of Wmax had a higher risk of MI than did lean men (BMI < 18.5) in the highest (HR 4.6, 95% CI 1.9-11.2), and lowest (HR 1.7, 95% CI 1.2-2.6) fourth of Wmax. CONCLUSIONS: We report a significant graded association between aerobic fitness in late adolescence and MI later in life in men. However, obese men with a high aerobic fitness had a higher risk of MI than lean men with a low aerobic fitness.

Effects of large-scale amino acid substitution in the polypeptide tether connecting the heme and molybdenum domains on catalysis in human sulfite oxidase.

Sulfite oxidase (SO) is a molybdenum-cofactor-dependent enzyme that catalyzes the oxidation of sulfite to sulfate, the final step in the catabolism of the sulfur-containing amino acids, cysteine and methionine. The catalytic mechanism of vertebrate SO involves intramolecular electron transfer (IET) from molybdenum to the integral b-type heme of SO and then to exogenous cytochrome c. However, the crystal structure of chicken sulfite oxidase (CSO) has shown that there is a 32 Å distance between the Fe and Mo atoms of the respective heme and molybdenum domains, which are connected by a flexible polypeptide tether. This distance is too long to be consistent with the measured IET rates. Previous studies have shown that IET is viscosity dependent (Feng et al., Biochemistry, 2002, 41, 5816) and also dependent upon the flexibility and length of the tether (Johnson-Winters et al., Biochemistry, 2010, 49, 1290). Since IET in CSO is more rapid than in human sulfite oxidase (HSO) (Feng et al., Biochemistry, 2003, 42, 12235) the tether sequence of HSO has been mutated into that of CSO, and the resultant chimeric HSO enzyme investigated by laser flash photolysis and steady-state kinetics in order to study the specificity of the tether sequence of SO on the kinetic properties. Surprisingly, the IET kinetics of the chimeric HSO protein with the CSO tether sequence are slower than wildtype HSO. This observation raises the possibility that the composition of the non-conserved tether sequence of animal SOs may be optimized for individual species.

Effects of interdomain tether length and flexibility on the kinetics of intramolecular electron transfer in human sulfite oxidase.

Sulfite oxidase (SO) is a vitally important molybdenum enzyme that catalyzes the oxidation of toxic sulfite to sulfate. The proposed catalytic mechanism of vertebrate SO involves two intramolecular one-electron transfer (IET) steps from the molybdenum cofactor to the iron of the integral b-type heme and two intermolecular one-electron steps to exogenous cytochrome c. In the crystal structure of chicken SO [Kisker, C., et al. (1997) Cell 91, 973-983], which is highly homologous to human SO (HSO), the heme iron and molybdenum centers are separated by 32 A and the domains containing these centers are linked by a flexible polypeptide tether. Conformational changes that bring these two centers into greater proximity have been proposed [Feng, C., et al. (2003) Biochemistry 42, 5816-5821] to explain the relatively rapid IET kinetics, which are much faster than those theoretically predicted from the crystal structure. To explore the proposed role(s) of the tether in facilitating this conformational change, we altered both its length and flexibility in HSO by site-specific mutagenesis, and the reactivities of the resulting variants have been studied using laser flash photolysis and steady-state kinetics assays. Increasing the flexibility of the tether by mutating several conserved proline residues to alanines did not produce a discernible systematic trend in the kinetic parameters, although mutation of one residue (P105) to alanine produced a 3-fold decrease in the IET rate constant. Deletions of nonconserved amino acids in the 14-residue tether, thereby shortening its length, resulted in more drastically reduced IET rate constants. Thus, the deletion of five amino acid residues decreased IET by 70-fold, so that it was rate-limiting in the overall reaction. The steady-state kinetic parameters were also significantly affected by these mutations, with the P111A mutation causing a 5-fold increase in the sulfite K(m) value, perhaps reflecting a decrease in the ability to bind sulfite. The electron paramagnetic resonance spectra of these proline to alanine and deletion mutants are identical to those of wild-type HSO, indicating no significant change in the Mo active site geometry.

Low bone mineral density is an independent risk factor for stroke and death.

BACKGROUND: Recent studies suggest a relationship between atherosclerotic disease and osteoporosis. The aim of the study was to investigate whether bone mineral density (BMD) was prospectively related to stroke and death. METHODS: BMD (g/cm(2)) was measured in 4,302 men and women (mean age 59 years, range 40-75) at baseline. The main outcome measures included validated strokes and death. RESULTS: After a mean follow-up time of 5.6 years (range 0-15.8 years), 139 strokes were registered and 224 subjects had died. After adjustment for age, sex and body mass index, decreased femoral neck BMD and osteoporosis were found to be independent predictors of stroke (hazard ratio, HR, for each standard deviation decrease in BMD = 1.23, 95% CI = 1.01-1.49, and HR for osteoporosis = 1.92, 95% CI = 1.11-3.30). After adjustment for the same variables, the risk of death during follow-up was related to femoral neck BMD (HR = 1.41, 95% CI = 1.21-1.64) and osteoporosis at baseline (HR = 2.05, 95% CI = 1.28-3.29). Adjustment also for smoking, hypertension, hyperlipidemia and diabetes did not change any of these results. CONCLUSIONS: We found that decreased BMD as well as osteoporosis of the femoral neck are independently associated with stroke and death. Given the impact of osteoporosis and stroke on morbidity and mortality, this relationship is of high interest for further studies.

Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice--brief report.

OBJECTIVE: Osteoprotegerin (OPG) is a tumor necrosis factor receptor-related cytokine, initially found to inhibit osteoclastogenesis. In the present study we investigated the effect of OPG treatment on atherosclerosis. METHODS AND RESULTS: Hypercholesterolemic apoe(-/-) mice were treated with recombinant 15 mg/kg OPG or vehicle injections twice a week for 10 consecutive weeks. Mice treated with OPG showed increased amounts of smooth muscle cells and collagen within the atherosclerotic lesions. OPG treatment did not affect atherosclerotic lesion size (8.2% versus 7.6%) or total vessel area but led to a 250% increase in lesion collagen, formation of mature collagen fibers in subendothelial fibrous caps, and upregulated mRNA for lysyl oxidase that promotes collagen crosslinking. In cell culture studies, OPG promoted cell proliferation in rat aortic smooth muscle cells. In contrast, OPG treatment did not affect markers of vascular or systemic inflammation. CONCLUSIONS: OPG treatment promotes smooth muscle accumulation, collagen fiber formation, and development of fibrous caps but does not affect inflammatory properties of atherosclerotic lesions. Its effects may contribute to plaque stabilization.