Weak Risk Factor Research Articles

Inherited and Secondary Thrombophilia

Case Presentation 1: A healthy 19-year-old man presented with new chest pain and near syncope. Computed tomography pulmonary angiography showed a saddle pulmonary embolus. The patient denied recent travel, trauma, surgery, or hospitalization. His mother had 2 miscarriages at 10 weeks of gestation, and his maternal grandfather had deep venous thrombosis at 60 years of age. Case Presentation 2: A healthy 45-year-old woman reported new dyspnea and left calf pain. Computed tomography pulmonary angiography and compression venous duplex ultrasonography showed bilateral pulmonary emboli and acute left leg deep vein thrombosis, respectively. The patient denied exogenous hormone use, recent travel, trauma, surgery, or hospitalization. Her health maintenance was current, and she gave a family history of pernicious anemia, Grave disease, and amyotrophic lateral sclerosis. Laboratory analyses showed reduced hemoglobin (11.4 g/dL; normal, 12.0–15.5 g/dL), increased red blood cell distribution width (18.9%; normal, 11.9%–15.5%), and mild thrombocytopenia. Neither patient had previous venous thromboembolism, and both were referred to the Mayo Clinic Thrombophilia Center for apparent idiopathic venous thromboembolism. Thrombophilia is defined as a predisposition (susceptibility) to thrombosis. Thrombophilia is not a disease per se, but may be associated with a disease (eg, cancer), drug exposure (eg, oral contraceptives) or condition (eg, pregnancy or postpartum, secondary thrombophilia; Table 1), and thrombophilia may be inherited (Table 2).1 This concept is important because disease susceptibility does not imply an absolute requirement for primary or secondary prevention, or for treatment. Most persons with a thrombophilia do not develop thrombosis. Thus, thrombophilia must be considered in the context of other risk factors for incident thrombosis, or predictors of recurrent thrombosis, when estimating the need for primary or secondary prophylaxis, respectively. View this table: Table 1. Secondary Thrombophilia1 View this table: Table 2. Inherited Thrombophilia1 The role of special coagulation testing for an acquired or inherited thrombophilia is controversial. Thrombophilia testing should only be done if …

The effect of feto-maternal blood type incompatibility on development of gestational diabetes mellitus.

To assess the relation between fetal and maternal blood type (ABO, Rh) incompatibility and development of gestational diabetes mellitus (GDM). A total of 500 pregnant women underwent diagnostic test for GDM by a 100-g oral glucose tolerance test (OGTT) after an 8 to 12-h overnight fast participated in this study. OGTT was performed between the 24-28 weeks of gestation, but participants who were at high risk for GDM were tested after the first prenatal visit. In the postpartum period, maternal and infant blood types were determined. Presence of GDM was evaluated in terms of matched and unmatched fetal and maternal ABO and Rh blood types separately. GDM was detected in 235 participants. Unmatched ABO blood types between the mother-infant pairs were present in 44.7% (n=105) of GDM (+) and 35.8 % (n=95) of GDM (-) patients. Incompatible feto-maternal ABO blood type was positively correlated with development of GDM which was marginally significant. (p=0.045; R=1.2;95% CL; 1.004-1.48). However, Rh feto-maternal blood type incompatibility was not related with development of GDM. Feto-maternal ABO blood type incompatibility may be a weak risk factor for the development of GDM.

Maternal Hypothyroidism in Early Pregnancy and Infant Structural Congenital Malformations

Background. The question is debated on whether maternal hypothyroidism or use of thyroxin in early pregnancy affects the risk for infant congenital malformations. Objectives. To expand the previously published study on maternal thyroxin use in early pregnancy and the risk for congenital malformations. Methods. Data from the Swedish Medical Birth Register were used for the years 1996–2011 and infant malformations were identified from national health registers. Women with preexisting diabetes or reporting the use of thyreostatics, anticonvulsants, or antihypertensives were excluded from analysis. Risk estimates were made as odds ratios (ORs) or risk ratios (RRs) after adjustment for year of delivery, maternal age, parity, smoking, and body mass index. Results. Among 23 259 infants whose mothers in early pregnancy used thyroxin, 730 had a major malformation; among all 1 567 736 infants, 48012 had such malformations. The adjusted OR was 1.06 (95% CI 0.98–1.14). For anal atresia the RR was 1.85 (95% CI 1.00–1.85) and for choanal atresia 3.14 (95% CI 1.26–6.47). The risk of some other malformations was also increased but statistical significance was not reached. Conclusions. Treated maternal hypothyroidism may be a weak risk factor for infant congenital malformations but an association with a few rare conditions is possible.

Outcome-Driven Thresholds for Ambulatory Pulse Pressure in 9938 Participants Recruited From 11 Populations

Evidence-based thresholds for risk stratification based on pulse pressure (PP) are currently unavailable. To derive outcome-driven thresholds for the 24-hour ambulatory PP, we analyzed 9938 participants randomly recruited from 11 populations (47.3% women). After age stratification (<60 versus ≥60 years) and using average risk as reference, we computed multivariable-adjusted hazard ratios (HRs) to assess risk by tenths of the PP distribution or risk associated with stepwise increasing (+1 mm Hg) PP levels. All adjustments included mean arterial pressure. Among 6028 younger participants (68 853 person-years), the risk of cardiovascular (HR, 1.58; P=0.011) or cardiac (HR, 1.52; P=0.056) events increased only in the top PP tenth (mean, 60.6 mm Hg). Using stepwise increasing PP levels, the lower boundary of the 95% confidence interval of the successive thresholds did not cross unity. Among 3910 older participants (39 923 person-years), risk increased (P≤0.028) in the top PP tenth (mean, 76.1 mm Hg). HRs were 1.30 and 1.62 for total and cardiovascular mortality, and 1.52, 1.69, and 1.40 for all cardiovascular, cardiac, and cerebrovascular events. The lower boundary of the 95% confidence interval of the HRs associated with stepwise increasing PP levels crossed unity at 64 mm Hg. While accounting for all covariables, the top tenth of PP contributed less than 0.3% (generalized R(2) statistic) to the overall risk among the elderly. Thus, in randomly recruited people, ambulatory PP does not add to risk stratification below age 60; in the elderly, PP is a weak risk factor with levels below 64 mm Hg probably being innocuous.

Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium

Objective To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians.Design Pooled analyses of 20...

Smoking, postmenopausal hormone therapy and the risk of venous thrombosis: a population‐based, case–control study

In postmenopausal women, oral hormone therapy (HT) is responsible for more than two venous thrombosis (VT) events per 1,000 person-years of treatment (Rossouw et al, 2002). Recent evidence supports a synergistic effect of smoking and oral contraceptives on the risk of VT (Pomp et al, 2008). Because HT has similar components as oral contraceptives – oestrogen progestogen, albeit in lower doses - smokers could represent a group in whom the VT risk associated with HT is considerably increased. Although no interaction between smoking and HT was found in the Women’s Health Initiative (WHI) clinical trial (Cushman et al, 2004), the small number of smoking VT cases and the selection of healthy participants in that trial may limit the validity and generalizability of this null finding. Our aim was to investigate the presence of this interaction in a large population-based study.

Genome-wide scan of job-related exhaustion with three replication studies implicate a susceptibility variant at the UST gene locus

Job-related exhaustion is the core dimension of burnout, a work-related stress syndrome that has several negative health consequences. In this study, we explored the molecular genetic background of job-related exhaustion. A genome-wide analysis of job-related exhaustion was performed in the GENMETS subcohort (n = 1256) of the Finnish population-based Health 2000 study. Replication analyses included an analysis of the strongest associations in the rest of the Health 2000 sample (n = 1660 workers) and in three independent populations (the FINRISK population cohort, n = 10 753; two occupational cohorts, total n = 1451). Job-related exhaustion was ascertained using a standard self-administered questionnaire (the Maslach Burnout Inventory (MBI)-GS exhaustion scale in the Health 2000 sample and the occupational cohorts) or a single question (FINRISK). A variant located in an intron of UST, uronyl-2-sulfotransferase (rs13219957), gave the strongest statistical evidence in the initial genome-wide study (P = 1.55 × 10(-7)), and was associated with job-related exhaustion in all the replication sets (P < 0.05; P = 6.75 × 10(-7) from the meta-analysis). Consistent with studies of mood disorders, individual common genetic variants did not have any strong effect on job-related exhaustion. However, the nominally significant signals from the allelic variant of UST in four separate samples suggest that this variant might be a weak risk factor for job-related exhaustion. Together with the previously reported associations of other dermatan/chondroitin sulfate genes with mood disorders, these results indicate a potential molecular pathway for stress-related traits and mark a candidate region for further studies of job-related and general exhaustion.

Alcohol is a Risk Factor not for Thalamic but for Putaminal Hemorrhage: The Akita Stroke Registry

Although the risk factors of cerebral hemorrhage were established long ago, there is little agreement as to the risk factors for the site of cerebral hemorrhage. We obtained mass health screening data collected between 1990 and 2000 regarding 151,796 subjects from the Akita Prefectural Federation of Agricultural Cooperative for Health and Welfare. A first-ever cerebral hemorrhage occurring <3 years after the screening examination was defined as an event. Stroke events were determined from the Akita stroke registry between 1990 and 2003. Clinical risk factors for stroke, such as age, blood pressure, severe obesity (body mass index >30 kg/m(2)), low serum total cholesterol, hepatic disorder, renal disorder, and drinking habits were then assessed. Cerebral hemorrhage developed in 344 cases in the study population. The distribution of subtypes (putaminal hemorrhage [PH], thalamic hemorrhage [TH], and subcortical hemorrhage [SH]) were 122 cases (35.5%), 110 cases (32.0%), and 44 cases (12.8%), respectively. We evaluated the risk factors by multiple logistic regression analysis among these 3 groups. Age was a significant risk factor among these 3 groups, but blood pressure was not a risk factor in SH. Low serum cholesterol and drinking habits were significant risk factors only in PH. Hepatic disorder was a strong risk factor in PH and a weak risk factor in TH. Interestingly, a drinking habit was a significant risk factor only in PH. Drinking habits had been a risk factor for cerebral hemorrhage, but it was a risk factor not for PH and not for TH or SH.

Invited commentary

Darwood and colleagues, in “Twenty year review of abdominal aortic aneurysm (AAA) screening in men in the country of Gloucestershire, UK,” follow a large series of men (52,960) longitudinally using ultrasound to make some important observations about AAA screening programs. The present study confirms the results of many of the previously reported large AAA screening programs; namely, that screening programs are associated with a reduction in the number and proportion of ruptured AAAs (Fig 3 in their text). Similarly, the present study documents that patients in a screening program, when they eventually undergo AAA repair, have lower mortality rates (3.9% for screened vs 6.7% for non-screened; P = .0047). However, there are some important differences in the design and results of the present study compared with previous trials that bear mention. For example, in the present study, patients with aortic diameters of 2.6 cm and greater were examined, as opposed to 2.9 cm and greater in previous studies. This small 3 mm difference led to important clinical observations. After 10 years of follow-up in the group of men with aortic diameters of 2.6 to 2.9 cm, 15% of men developed an AAA of >5.4 cm! Another 13 men presented with a ruptured AAA. Further, when the group of men with aortic diameters of 2.5 cm or less were examined, 0.19% (95 men) were found to have aortic diameters of >3.0 cm. Ultimately, a total of 80 men (0.16%) whose initial scans were considered “normal” had either had an aneurysm repair or died from a ruptured AAA. While these numbers are small in terms of the utility of rescreening, it does suggest that we cannot merely assure our patients that they are “not likely to get a significant AAA in their life.” The authors suggest that extending surveillance to men with an initial aortic diameter of 2.6 to 2.9 cm may yield a significant number of large, life-threatening AAAs. Based on these data, I agree that re-ultrasounding the >65-year-old male makes sense. However, the duration between imaging needs to be determined. Finally, perhaps the most important observation from the present study is that initial aortic diameters decreased over the 20-year interval of study from 21 mm to 17 mm. Importantly, this decline occurred across all aortic diameters, not just in the larger aortic diameters. This observation is especially important when contrasted with reports regarding operative and endovascular interventions for AAAs, which have, for the most part, reported increasing numbers. The authors are quick to point out that this observation is not likely a technical issue with the ultrasound screening. While this study was not intended to provide a cause and effect relationship, the authors conclude by suggesting that attempts at risk factor modification for coronary disease (eg, better blood pressure control, decreased smoking, and improved cholesterol management) may be positively impacting aortic diameter. As aortic diameter may end up being a weak risk factor for cardiac death, any serendipitous, beneficial effects of all the pharmacologic therapies (beta-blockers, ACE inhibitors, statins, etc) we prescribe for the elderly to prevent cardiac events on aortic diameter and possibly AAA incidence is most welcome, even if we don't understand why. Twenty-year review of abdominal aortic aneurysm screening in men in the county of Gloucestershire, United KingdomJournal of Vascular SurgeryVol. 56Issue 1PreviewAn ultrasound screening program for abdominal aortic aneurysms (AAAs) in men began in Gloucestershire in 1990 and has been running for 20 years. This report examines the workload and results. Full-Text PDF Open Archive

Association between degenerative spondylolisthesis and spinous process fracture after interspinous process spacer surgery

Spinous process fracture is a recognized complication associated with interspinous process spacer (IPS) surgery. Although occasionally identified by plain radiographs, computed tomography (CT) appears to identify a higher rate of such fractures. Although osteoporotic insufficiency fracture is considered a contraindication for IPS surgery, a formal risk factor analysis for this complication has not previously been reported. To identify risk factor(s) associated with early spinous process fracture after IPS surgery. Prospective cohort study of 39 consecutive patients with lumbar stenosis and neurogenic claudication undergoing IPS surgery at a single institution. Patients underwent preoperative dual-energy X-ray absorptiometry (DXA) scans, lumbar spine CT, and plain radiographs. Postoperatively, patients underwent repeat CT imaging within 6 months of surgery and serial radiographs at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. Preoperative CT scans were analyzed by calculating average Hounsfield units for a 1 cm(2) area of the midsagittal reconstructed image for four separate locations: midvertebral body, subcortical bone subjacent to the superior margin of the midspinous process, subcortical bone above the inferior margin of the midspinous process, and the midspinous process. Thirty-eight patients underwent IPS surgery at a total of 50 levels (38 L4-L5, 12 L3-L4; 26 one-level, 12 two-level). One patient underwent laminectomy at index surgery and was excluded from the analysis. Implants included 34 titanium X-STOP (Medtronic, Memphis, TN, USA), 8 polyaryletheretherketone X-STOP (Medtronic, Memphis, TN, USA), and 8 Aspen (Lanx, Broomfield, CO, USA) devices. Eleven spinous process fractures were identified by CT in 11 patients (22.0% of levels). No fractures were apparent on plain radiographs. The rate of spondylolisthesis observed on preoperative radiographs was 100% (11 of 11) among patients with fractures compared with 33.3% (9 of 27) of patients without fracture (p=.0001). Overall, 21 of 39 patients in this series had spondylolisthesis, and the rate of fracture in this group was 52%. Among patients without spondylolisthesis, the fracture rate was 0%. A trend was observed toward decreased DXA lumbar spine and hip T-scores among fracture patients versus nonfracture patients (0.2 ± 1.7 vs. 0.8 ± 1.7; p=.389; -1.1 ± 1.4 vs. -0.3 ± 1.4; p=.201), but these differences were not significant. Similarly, bone density based on CT measurements at four different locations revealed a trend toward decreased density among fracture patients, but these differences were not significant. Degenerative spondylolisthesis appears strongly associated with the occurrence of spinous process fracture after IPS surgery. There is a trend toward increased fracture risk in patients with decreased bone mineral density as measured by both DXA scan and CT-based volume averaging of Hounsfield units, but osteoporosis appears to be a relatively weaker risk factor. The association between spondylolisthesis and fracture observed in this study may account for the relatively poorer outcome of IPS surgery in patients with spondylolisthesis that has been reported in previous series.

Recent Safety Concerns With Proton Pump Inhibitors

There have been recent concerns about the safety of proton pump inhibitors (PPIs). We focus here on 3 specific concerns-the possible interaction between PPIs and clopidogrel, the postulated link between PPI use and fractures, and the possibility that long-term PPI use might lead to hypomagnesemia. There is evidence for an in vitro interaction between clopidogrel and at least some PPIs. The Food and Drug Administration (FDA) has warned against the use of certain PPIs by patients on clopidogrel. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole. PPI use may be a weak risk factor for certain fractures, but the quality of evidence is relatively poor and there is a strong possibility of confounding. The mechanism whereby PPI use might increase fracture risk is unknown. Currently, no additional measures concerning calcium supplementation or bone mineral density monitoring are recommended for patients on a PPI. The FDA has suggested monitoring serum magnesium levels in patients on PPI therapy. The mechanism and frequency of PPI-induced hypomagnesemia are unclear. PPI treatment should not be withheld from patients who genuinely require it, but the PPI should be taken in the lowest effective dose and only for as long as clinically indicated. The same is, of course, true for all medicines. The benefits of PPI therapy greatly outweigh the risks.

Child maltreatment and adult violent offending: population-based twin study addressing the ‘cycle of violence’ hypothesis

Associations between child maltreatment and adult violence, often termed the 'cycle of violence', are well documented. However, the nature of such links after appropriate control for confounding remains uncertain. We aimed to determine whether child maltreatment causes adult violent offending or whether suggested links are due to genetic or family environment confounding. A total of 18 083 20- to 47-year-old twins from the Swedish population-based Study of Twin Adults: Genes and Environment (STAGE) participated. We linked information on self-reported child maltreatment with national register data on convictions for adult crime. We used a case-control design to elucidate associations among unrelated individuals and also conducted within-discordant twin pair analyses to estimate the influence of familial confounding on this association. The odds ratio (OR), adjusted for age, sex and education, for violent offending in maltreated children grown up versus unrelated controls was 1.98 [95% confidence interval (CI) 1.52-2.57]. However, the association decreased to 1.18 (95% CI 0.62-2.25) when maltreated children were compared to their non-maltreated twins, suggesting substantial confounding by genetic or family environmental factors (within-twin OR<1.98) and a weak, non-significant causal effect (within-twin OR>1.00). Familial confounding was also pronounced for the association between child maltreatment and any offending. Childhood maltreatment was found to be a weak causal risk factor for adult violent offending; hence, reducing maltreatment might decrease violent crime less than previously expected. Instead, considerable familial confounding of the link between child maltreatment and adult violent offending suggests that prevention strategies need to address overlapping genetic and/or family environmental liability for abusive and violent behavior.

Physiological Effects of the Plasma Kallikrein-Kinin System: Roles of the Blood Coagulation Factor XII (Hageman Factor)

For many decades the intrinsic coagulation research has focused on factor XII (Hageman factor; FXII) and its significant role as a sole instigating factor driving the stabilization of thrombotic clotting. FXII is a relatively weak risk factor for although its amidolytic and proteolytic function renders its presence important. Accumulating evidence suggests that FXII is pivotally involved in pathologic coagulation. In particular, the role of FXII in initiation and propagation of the blood coagulation and fibrinolytic systems has impeccable scientific support to the extent of which the existence of a pathway of thrombosis is now generally accepted. The concept, although not a new one to scientists in the field of coagulation, is a caveat to the pathologic clot forming FXII concept in that it appears to cause a conceptual shift in de-emphasizing the inherent complexity of FXII activation representing a spectrum of responses. For instance, FXII contributes to the activation of inflammation and complement systems and influences catecholamine release from the adrenal system, suggesting that FXII can trigger multiple signaling pathways upon activation. The nature and duration of each of the FXII-dependent pathways may depend not only on the kind of stimulus, but also it may haveD distinct response pattern under normal and pathophysiologic conditions. Because a plethora of pathophysiological pathways are influenced by FXII, additional studies into its role as an important first step behind regulating common daily stresses may promise to provide new insight to better understand the unique and subtle biology behind FXII.

Bromocriptine: A Sympatholytic, D2-Dopamine Agonist for the Treatment of Type 2 Diabetes

Bromocriptine is a sympatholytic D2-dopamine agonist that has been approved for the treatment of type 2 diabetes. Based on animal and human studies, timed bromocriptine administration within 2 h of awakening is believed to augment low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the central nervous system (CNS), resulting in a reduction in postmeal plasma glucose levels due to enhanced suppression of hepatic glucose production. Bromocriptine has not been shown to augment insulin secretion or enhance insulin sensitivity in peripheral tissues (muscle). Addition of bromocriptine to poorly controlled type 2 diabetic patients treated with diet alone, metformin, sulfonylureas, or thiazolidinediones produces a 0.5–0.7 decrement in HbA1c. Bromocriptine also reduces fasting and postmeal plasma free fatty acid (FFA) and triglyceride levels. In a 52 double-blind, placebo-controlled study in type 2 diabetic patients, bromocriptine reduced the composite cardiovascular end point by 40%. The mechanism of the drug’s beneficial effect on cardiovascular disease remains to be determined. ### Introduction Type 2 diabetes is a chronic metabolic disorder characterized by insulin resistance, impaired β-cell function, and multiple other metabolic/endocrine abnormalities (1). Because of its multifactorial pathogenesis, restoration of normoglycemia is difficult to achieve and requires multiple antidiabetic medications that have different mechanisms of action and can be used in combination to produce an additive effect (1,2). Therefore, the development of antidiabetic agents that have novel mechanisms of action and can be used in combination with currently approved medications for the treatment of type 2 diabetes is highly desirable. Type 2 diabetic patients are at high risk for atherosclerotic cardiovascular complications (3). Although hyperglycemia is a risk factor for coronary artery disease and stroke, it is a relatively weak risk factor compared with other more established risk factors such as dyslipidemia, hypertension, obesity, and the insulin resistance (metabolic) syndrome (4, …

Plasminogen Activator Inhibitor-1 Gene Polymorphisms in Pre-Eclampsia

Pre-eclampsia (P-EC) is a multisystem disorder of pregnancy, characterized by new-onset hypertension and proteinuria. Deregulation of the coagulation cascade and hypofibrinolysis appear to play a central role in the development of this disease. After a brief review of the genetic basis of P-EC and the role of genes encoding proteins involved in coagulation, we focus on polymorphisms of the plasminogen activator inhibitor (PAI-1) gene. The most relevant association studies between PAI-1 gene polymorphisms and P-EC are reviewed. Results indicate that the 4G/4G genotype of the -675 4G/5G polymorphism represents a weak risk factor for P-EC.

Guidelines on travel‐related venous thrombosis

Long duration travel is a weak risk factor for the development of venous thromboembolism (VTE). The incidence of VTE after flights of >4 h is 1 in 4656 and for flights of more than 8 h in low and intermediate risk flyers is around 0.5%. Severe symptomatic pulmonary embolism in the period immediately after travel is extremely rare after flights of <8 h. In flights over 12 h the rate is 5 per million. VTE may be attributable to travel if it occurs up to 8 weeks following the journey. The risk of travel-related thrombosis is higher in individuals with pre-existing risk factors for the development of VTE. There is no evidence for an association between dehydration and travel-associated VTE and so whilst maintaining good hydration is unlikely to be harmful it cannot be strongly recommended for prevention of thrombosis (recommendation grade 2, level of evidence, B). There is indirect evidence that maintaining mobility may prevent VTE and, in view of the likely pathogenesis of travel-related VTE, maintaining mobility is a reasonable precaution for all travellers on journeys over 3 h (2B). Global use of compression stockings and anticoagulants for long distance travel is not indicated (1C). Assessment of risk should be made on an individual basis but it is likely that recent major surgery (within 1 month), active malignancy, previous unprovoked VTE, previous travel-related VTE with no associated temporary risk factor or presence of more than one risk factor identifies those travellers at highest thrombosis risk (1C). Travellers at the highest risk of travel-related thrombosis undertaking journeys of >3 h should wear well fitted below knee compression hosiery (2B). Where pharmacological prophylaxis is considered appropriate, anticoagulants as opposed to anti-platelet drugs are recommended based on the observation that, in other clinical scenarios, they provide more effective thromboprophylaxis. Usual contraindications to any form of thromboprophylaxis need to be borne in mind (2C).

Time since prior fracture is a risk modifier for 10-year osteoporotic fractures

The objective of this study was to assess the importance of time since prior fracture as a risk factor for future osteoporotic fractures and how it affects 10-year fracture rates. We identified 39,991 women 45 years of age or older undergoing baseline bone mineral density (BMD) testing (1990-2007) from a regional database that contains dual-energy X-ray absorptiometry (DXA) results for Manitoba, Canada. Health service records were used to identify nontrauma ICD-9-CM fracture codes preceding DXA, grouped as "major" fractures (n = 5178; hip, spine, forearm, and humerus) or "minor" fractures (n = 3479; ribs, sternum, pelvis, trunk, clavicle, scapula, patella, tibia/fibula, and ankle). Time since prior fracture was coded in years as less than 1, 1 to 5, 5 to 10, and more than 10. Incident fractures (ie, hip, spine, forearm, and humerus) after BMD testing were identified (mean follow-up 4.2 years, maximum 10 years) and studied in Cox proportional-hazards models adjusted for age, BMD T-score, and other covariates. After BMD testing, n = 1749 (4.4%) women experienced an incident fracture. Prior major fracture was a strong risk factor for incident fracture, greatest risk in the first year [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.60-2.25], declining by more than 10 years (HR 1.62, 95% CI 1.25-2.10). Prior minor fracture was a weaker risk factor, greatest in the first year (HR 1.45, 95% CI 1.13-1.87) and no longer significant by 1 to 5 years. Major and minor fractures both showed a time-dependent decline in importance as risk factors. In conclusion, time since prior fracture modifies future fracture risk, but prior fractures of the hip, spine, forearm, and humerus remain strong risk factors even 10 years later. Fracture risk assessment should emphasize the importance of prior fractures at these sites.

A Novel Mutation (G2172→C) in the Factor V Gene in a Chinese Family with Hereditary Activated Protein C Resistance

Background Activated protein C resistance (APC-R) was a major risk factor for venous thromboembolism(VTE) in Caucasians, and at least 90% of APC-R were associated with the point mutation of factor V (FV) gene (Arg506 → Gln, FV Leiden). However, this genetic defect was extremely rare in Asian population. Objective To identify the genetic defect of FV in a Chinese family with APC-R associated with VTE. Methods We describe a Chinese family with a history of venous thrombosis. Blood samples were obtained from five family members (including the proband) for screening APC-R by coagulation assay and the genetic defect of FV using direct sequencing. Results Four out of five members had APC-R. We identified a novel mutation (G2172→C) in exon 13 of the FV gene, which was present in all the individuals with APC-R but was absent in the individual without APC-R. This mutation is predicted to result in the replacement of glutamate by aspartate at position 666, close to one of the APC cleavage sites. Conclusions We have identified, for the first time, a novel mutation (G2172→C) of FV that was associated with APC-R in a Chinese family with VTE. We speculate that this mutation interferes with cleavage at Arg679 by APC. The incomplete penetrance of thrombotic phenotype in this family, similar to that conferred by FV Leiden, suggests that it might be a weak risk factor for VTE.

Association analysis of CβS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer’s disease in Chinese

Folate deficiency and elevated plasma homocysteine play important roles in pathogenesis of Alzheimer's disease (AD). The aim of this study was to test the association of folate metabolism-related genes, cystathionine beta-synthase gene (CbetaS) and 5, 10-methylenetetrahydrofolate dehydrogenase gene (MTHFD1), with sporadic AD. The CbetaS 844ins68 polymorphism was determined by PCR and the MTHFD1 G1958A single nucleotide polymorphism (rs2236225) by PCR-RFLP. No significant difference of allele and genotype contributions of the CbetaS polymorphism between AD cases and controls was detected, before and after stratification by APOE epsilon4-carrying status, age/age at onset and genders. No significant difference of allele and genotype contributions of the MTHFD1 polymorphism between AD cases and controls was detected in total samples. When stratified by age/at onset age, we found that A allele and AA genotype frequencies in cases were higher than in controls and the differences were close to significant [A vs. G, P = 0.032, Odds ratio (OR) 1.642, 95% CI 1.040-2.591; AA + GA vs. GG, P = 0.068, OR 1.665, 95% CI 0.961-2.885; AA vs. GG, P = 0.059, OR 3.458, 95% CI 0.894-13.369] in <65 years groups, which suggested that the MTHFD1 G1958A A allele might be a weak risk factor for early onset AD although it needs further confirmation.

Cigarette Smoking and Drinking Water Source: Correlation with Clinical Features and Pathology of Superficial Bladder Carcinoma

Objective: Water source and cigarette smoking are related to clinical characteristics and pathology of superficial transitional cell carcinoma of the bladder. Methods: Tumor number, dimension, G-grade, T-stage, recurrences, cigarette smoking and water supply were recorded in patients harboring Ta–T1 G1–3 transitional cell carcinoma of the bladder. Results: Of 577 patients, 61% had multiple and 36% recurrent tumors. Two hundred and forty-one patients (42%) were current smokers and 188 (33%) were former smokers. Bottled water was the only drinkable source for 249 (45%) patients, municipal water supply for 177 (32%), artesian wells for 38 (7%), spring water for 7 (1%) and mixed source for 89 (16%). By adopting a cut-off of 30 years of smoking, patients affected by recurrent tumors varied from 22 to 43% (p = 0.0001). T1 tumors were more frequent in patients drinking nonbottled water (p = 0.03). Nonbottled supply was more frequent in never smokers (p = 0.015) and could represent a weak risk factor not detectable in smokers. Conclusions: Cigarette smoking correlates with the number of recurrences. T1 tumors were statistically more frequent in patients taking nonbottled drinking water. Chlorinated water supply was more frequent among patients who did not present cigarette smoking as a risk factor.