Determinants of imminent fracture risk in postmenopausal women with osteoporosis.

In elderly women with osteoporosis, prior fracture, low BMD, impaired physical functioning, poorer general health, and recent falls were all direct predictors of imminent (in next year) fracture risk. Prior fracture, older age, worse health, impaired cognitive functioning, and recent falls indirectly increased imminent risk by reducing physical functioning/general health. INTRODUCTION: This study was designed to examine determinants of imminent risk of osteoporotic fracture (i.e., next 1-2 years) in postmenopausal women. METHODS: This retrospective cohort study used data from Caucasian women age 65 or older with osteoporosis who participated in the observational Study of Osteoporotic Fractures (SOF). We examined potential direct and indirect predictors of hip and nonvertebral fractures in 1-year follow-up intervals including anthropometric measures, bone mineral density (T-score), fracture since age 50, physical function, cognition, medical conditions, recent (past year) falls, and lifestyle factors. Clinically related variables were grouped into constructs via factor analysis. These constructs and selected individual variables were incorporated into a theoretical structural equation model to evaluate factors that influence imminent risk. RESULTS: Among 2261 patients, 19.4% had a nonvertebral fracture and 5.5% had a hip fracture within 1 year of a study visit between 1992 and 2008. Prior fracture, lower T-scores, lower physical functioning, and recent falls all directly increased 1-year risk of nonvertebral fracture. For both nonvertebral and hip fractures, prior fracture and recent falls influenced risk indirectly through general health, while cognition influenced risk via physical functioning. Age influenced both physical functioning and general health. CONCLUSIONS: Several established risk factors for 10-year fracture risk also played a role in predicting imminent risk of fracture (e.g., T-scores, prior fracture), as did falls, cognition, physical functioning, and general health. Fracture risk assessments should also consider falls and fall risk factors as well as established bone-related risk factors in assessing imminent fracture risk.

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. INTRODUCTION: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. METHODS: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). RESULTS: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). CONCLUSIONS: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Medication persistence and risk of fracture among female Medicare beneficiaries diagnosed with osteoporosis.

We examined the relationship between persistent osteoporosis medication use and fracture risk among female Medicare beneficiaries diagnosed with osteoporosis using Medicare claims, 2009-2012. Persistent use was associated with reduced risk of fracture and significantly lower total health care costs in the follow-up period. Results were consistent using different analytical methods. INTRODUCTION: This study aimed to examine the relationship between medication persistence and fracture risk among female Medicare beneficiaries diagnosed with osteoporosis. METHODS: Elderly female Medicare beneficiaries diagnosed with osteoporosis and initiated on osteoporosis medication January 1, 2009-June 30, 2011, were included. Persistent medication use was defined as continuous use (no gap ≥ 60 days) for 1 year or longer. The key outcome was fragility fracture. A difference-in-difference analysis was performed at the log scale of fracture rate using a Poisson regression model with months 1-6 before medication initiation as the pre-initiation period and up to 18 months after as the post-initiation period. Total health care costs were compared using a similar approach. Sensitivity analyses were conducted using different pre- and post-initiation periods. RESULTS: The study included 294,369 patients; 32.9% were persistent osteoporosis medication users and 67.1% non-persistent (< 12 months continuous use). Fracture incidence rates were 16.2 per 100 patient-years pre-initiation and 4.1 post-initiation for persistent users; corresponding rates for non-persistent users were 19.0 and 7.3 per 100 patient-years. The adjusted post-/pre-initiation fracture rate ratios were 0.284 for persistent and 0.411 for non-persistent users. The ratio of the two rate ratios was 0.692 (persistent vs. non-persistent, p < 0.0001), suggesting a significantly greater fracture rate reduction for persistent users. Adjusted cost ratios were significantly lower for persistent users. Sensitivity analyses results were similar. CONCLUSIONS: Persistent use of osteoporosis medications was associated with reduced risk of fracture and significantly lower total health care costs. Payers and patients would benefit from interventions aimed at improving medication persistence.

Estimating the long-term functional burden of osteoporosis-related fractures.

Although fractures are associated with short-term reductions in functional status, there is limited information on longer-term burden of fracture. This study documents evidence of an association between fractures and significant declines and functional health and activities that persist but attenuate beyond two years. INTRODUCTION: Although fractures are associated with short-term reductions in functional status and may have other short-term effects on healthcare utilization (hospitalization and follow-up care), there is limited information on long-term burden of fracture beyond 12 to 24 months post-fracture. Analysis of the long-term health burden can inform policymakers, health care practitioners, and payers. METHODS: We acquired a data set containing the 1992-2012 Health and Retirement Survey data linked to the same individuals' Medicare claims. Fracture cases (n = 745) were matched to non-fracture controls using propensity scores matching. A regression-adjusted difference-in-difference (DD) approach was used to compare the change in functional status measures from baseline to two post-fracture periods for fracture cases relative to the change over the same time periods for matched controls. Self-reported measures of functional status were examined: limitations to activities of daily living (ADLs), limitations to instrumental activities of daily living (IADLs), a mobility index, a gross motor skills index, a fine motor skills index, and self-reported general health status. RESULTS: Fracture cases reported increases in limitations to ADLs, difficulties with mobility, difficulties with gross motor skills, and difficulties with fine motor skills in each HRS collection period (the survey is administered every 2 years) following the fracture or index date (thus up to two years later) than matched controls (all p values < 0.05). The magnitude of these effects diminished in the second post-fracture wave (two to four years after fracture/index date), but they were still statistically significant. CONCLUSIONS: Results suggest that fractures are associated with significant declines in some measures of functional activities up to two years following the fracture. The effects persist beyond two years but are smaller in magnitude.

Predictors of near-term fracture in osteoporotic women aged ≥65 years, based on data from the study of osteoporotic fractures.

Using data from the Study of Osteoporotic Fractures (SOF), several clinical characteristics predictive of near-term (1-year) risk of hip and non-vertebral fracture among elderly osteoporotic women were identified, and a subset of those for hip fracture was incorporated into a risk assessment tool. Additional research is needed to validate study findings. INTRODUCTION: While several risk factors are known to contribute to long-term fracture risk in women with osteoporosis, factors predicting fracture risk over a shorter time horizon, such as over a 1-year period, are less well-established. METHODS: We utilized a repeated-observations design and data from the Study of Osteoporotic Fractures to identify factors contributing to near-term risk of hip fracture and any non-vertebral fracture, respectively, among osteoporotic women aged ≥65 years. Potential predictors of hip fracture and any non-vertebral fracture over the 1-year period subsequent to each qualifying SOF exam were examined using multivariable frailty models. Because the discriminative ability of the hip fracture model was acceptable, a corresponding risk-prediction tool was also developed. RESULTS: Study population included 2499 women with osteoporosis, who contributed 6811 observations. Incidence of fracture in the 1-year period subsequent to each exam was 2.2% for hip fracture and 6.6% for any non-vertebral fracture. Independent predictors of hip fracture included low total hip T-score, prior fracture, and risk factors for falls (multivariable model c-statistic = 0.71 (95% CI 0.67-0.76)). Independent predictors of any non-vertebral fracture included age, total hip T-score, prior falls, prior fracture, walking speed, Parkinson's disease or stroke, and smoking (multivariable model c-statistic = 0.62 (0.59-0.65)). CONCLUSIONS: Several clinical characteristics predictive of hip and non-vertebral fracture within a 1-year follow-up period among elderly women with osteoporosis were identified, and a subset of those for hip fracture was incorporated into a risk assessment tool. Assessment of these risk factors may help guide osteoporosis treatment choices by identifying patients in whom there is urgency to treat. Additional research is needed to validate the findings of this study and the accuracy of the risk assessment tool.

Teriparatide treatment patterns in osteoporosis and subsequent fracture events: a US claims analysis.

UNLABELLED: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following teriparatide initiation. In an administrative claims analysis of over 11,407 patients, approximately one in eight patients had a new or recurrent fragility-related fracture in the 2 years following teriparatide initiation. INTRODUCTION: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following the initiation of teriparatide in a real-world setting. METHODS: This retrospective study used data from the 2002 to 2011 MarketScan® Commercial and Medicare Supplemental Databases to identify patients 50 years and older with a diagnosis of osteoporosis (ICD-9-CM code 733.0x) who were initiating teriparatide. Patients were required to have continuous medical and pharmacy benefit coverage for the 12 months prior to and 24 months following teriparatide initiation (index event). Teriparatide treatment patterns (persistence and adherence) were described, as was the use of antiresorptive therapy. The primary study outcome was the presence of a new or recurring fragility fracture following the initiation of teriparatide. RESULTS: A total of 11,407 patients met the study criteria (mean age = 69.5, standard deviation = 10.6 years; 92.0% female). One in four (25.6%) patients had fragility fracture claims in the year prior to teriparatide initiation, of which 64.0% were on existing antiresorptive therapy. Overall, 13.4% (n = 1527) of patients had a new or recurrent fracture during the 2-year follow-up period. Forty-eight percent of patients on teriparatide treatment were considered persistent; fragility fractures were more common among patients nonpersistent with teriparatide (15.2%) than among those persistent with teriparatide (11.4%). A higher fracture rate (35.7%) was observed in the cohort with previous fragility fracture then those without pre-index fractures (24%). CONCLUSION: More than 13.4% of patients had new or recurrent fragility-related fractures during the 2 years following the initiation of teriparatide; these fractures were more in common in patients with pre-existing fractures and the patients who were nonpersistent with teriparatide.

Patterns of treatment among a cohort of older low-income adults starting new medications for osteoporosis.

UNLABELLED: Among 125,954 new users of osteoporosis (OP) medications, 77 % of subjects stopped OP medications, and 23 % of subjects added or started a new OP medication during follow-up, with the first addition or start of a new OP medication occurring in a mean of 739 days after original OP treatment. INTRODUCTION: We described patterns and predictors of OP medication use, focusing on treatment changes over time. METHODS: We analyzed health and pharmacy insurance claims for a large cohort of low-income Medicare beneficiaries with a drug benefit for the years 1998-2008. Study subjects had documented Medicare claims and no receipt of OP medications (i.e., bisphosphonate, raloxifene, calcitonin, teriparatide, or hormonal therapy) during a baseline of 180 days. Subjects were then required to start an OP medication. Baseline patient and prescriber characteristics were assessed in multivariable Cox regression models to identify correlates of adding or starting a new OP medication. Fractures, bone mineral density testing, and visits with endocrinologists or rheumatologists occurring after baseline were also examined as correlates. RESULTS: We included 125,954 new users of OP medications with a mean age of 78 years, 97 % female, and 92 % white. OP medication prescribers included specialists (i.e., endocrinologists or rheumatologists) (6.2 %), orthopedic surgeons (1.0 %), primary care providers (64.9 %), other physicians (3.7 %), and missing (24.1 %). Seventy-seven percent of subjects stopped OP medications, and 23 % of subjects added or started a new OP medication during follow-up, with the first addition or start of a new OP medication occurring in a mean of 739 days after original OP treatment; 4 % added or started a new OP medication more than once. In fully adjusted models, many baseline variables correlated with starting a second OP medication. Post-baseline fractures [hazard ratio (HR) 1.76, 95 % confidence interval (CI) 1.71-1.82] and bone mineral density testing (HR 2.94, 95 % CI 2.86-3.03) were strong predictors. CONCLUSION: Approximately one quarter of patients starting an OP medication added or started a new OP medication during follow-up. Long-term sequential treatment strategy trials would inform optimal medication treatment for OP.

The use of granulocyte colony-stimulating factors in a Canadian outpatient setting.

BACKGROUND: Data on real-life utilization of granulocyte colony-stimulating factors (g-csfs) in Canada are limited. The objective of the present study was to describe the reasons for, and the patterns of, g-csf use in selected outpatient oncology clinics in Ontario and Quebec. METHODS: In a retrospective longitudinal cohort study, a review of medical records from 9 Canadian oncology clinics identified patients being prescribed filgrastim (fil) and pegfilgrastim (peg). Patient characteristics, reasons for g-csf use, and treatment patterns were descriptively analyzed. RESULTS: Medical records of 395 patients initiating g-csf therapy between January 2008 and January 2009 were included. Of this population, 80% were women, and breast cancer was the predominant diagnosis (59%). The most commonly prescribed g-csf was fil (56% in Ontario and 98% in Quebec). The most frequent reason for g-csf use was primary prophylaxis (42% for both fil and peg), followed by secondary prophylaxis (37% fil, 41% peg). Those proportions varied by tumour type and chemotherapy regimen. Delayed g-csf administration (more than 1 day after the end of chemotherapy) was frequently observed for fil, but rarely reported for peg, and that finding was consistent across tumours and concurrent chemotherapy regimens. CONCLUSIONS: The use of g-csf varies with the malignancy type and the provincial health care setting. The most commonly prescribed g-csf agent was fil, and most first g-csf prescriptions were for primary prophylaxis. Delays were frequently observed for patients receiving fil, but were rarely reported for those receiving peg.

Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids.

Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism. This study recruited 138 monozygotic (MZ) and dizygotic (DZ) twins aged 18-65 years and measured serum oxylipins, endocannabinoids, bile acids and steroids using liquid chromatography mass-spectrometry (LC-MS). In this classic twin design, the similarities and differences between MZ and DZ twins are modelled to estimate the contribution of genetic and environmental influences to variation in lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxyeicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxyeicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)] and 14­hydroxy-docosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with the endocannabinoid docosahexaenoy-lethanolamide [0.52 (95% CI: 0.15,0.72)]. For others such as 13-hydroxyoctadecatrienoic acid and lithocholic acid the contribution of environment to variation was stronger. With increased understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends pre-existing knowledge of the genetic and environmental influences on the human lipidome.

Mandelonitrile beta-glucuronide: synthesis and characterization.

Mandelonitrile beta-glucuronide, the compound patented as Laetrile, has been synthesized from rabbit liver uridine diphosphate-glucuronosyl transferase immobilized on beaded sepharose, has been analyzed by thin-layer chromatography, nuclear magnetic resonance, and gas chromatography-mass spectrometry, and has been tested for cytotoxicity and mutagenic activity with Salmonella typhimurium strains TA 98 and TA 100. Several commercial laetrile preparations contained no glucuronide; they contained amygdalin and neoamygdalin instead. Mandelonitrile, mandelonitrile glucuronide, and a mixture of amygdalin and neoamygdalin were each found to be mutagenic.

Changes in bone mineral density (BMD): a longitudinal study of osteoporosis patients in the real-world setting.

In clinical practice, the frequency of patients achieving improved T-scores and the expected change in bone mineral density (BMD) according to osteoporosis drugs is unknown. We found that osteoporosis medications infrequently achieve improved femoral neck T-scores over 1.2 years. BMD increases were more often seen with IV bisphosphonates and denosumab. PURPOSE: To determine the frequency of osteoporosis patients achieving improvement in T-scores and quantify the change in bone mineral density (BMD) over time according to osteoporosis medication use. METHODS: The study included all patients receiving clinical care at United Osteoporosis Centers, Gainesville, GA, 1995-2015, who had at least two measures of femoral neck BMD (N = 1232). We evaluated successive pairs of BMD tests to describe the distribution of transitions between T-score categories. Generalized estimating equations were used to estimate %BMD change between successive pairs of BMD tests according to osteoporosis medication, adjusted for age, sex, height, weight, baseline BMD, previous fracture, and follow-up time. RESULTS: Mean (±SD) age was 68 (±10) years, and 90% of patients were women. Mean baseline T-score was - 2.04 (± 0.85). In total, 1232 patients had 4918 pairs of successive BMD tests, with a mean 1.2 years (± 0.9) between assessments. Frequency of transition to an improved T-score category was 41% when prior T-score ≤ - 3.5, and 15% when prior T-score - 1.99 to - 1.50. Most individuals (69%) remained in the same T-score category. BMD increased 0.54% (95% CI 0.23-0.85%) with IV bisphosphonates and 1.23% (95% CI 0.56-1.90%) with denosumab, whereas no significant change was seen with oral bisphosphonates, teriparatide, or raloxifene. CONCLUSIONS: Osteoporosis patients are unlikely to improve femoral neck T-scores over 1.2 years. Additional studies are needed to determine the optimal time to repeat BMD testing while receiving osteoporosis treatment and to determine whether fracture risk is reduced in patients who achieve target T-scores.

Effect of storage time and temperature on the results of analysis of synovial and mesothelial fluids.

REASONS FOR PERFORMING STUDY: Delays between collection and laboratory analysis of equine body fluid samples are common in practice; however, the effects of delays on the accuracy of results and diagnostic interpretation are unknown. OBJECTIVES: To assess the effects of storage time and temperature combination on protein and cell parameters of equine synovial and mesothelial cavity fluids and determine whether any changes affect clinicopathological interpretation. STUDY DESIGN: In vitro experiment. METHODS: Body fluid samples obtained from horses during diagnostic investigation were divided into 7 aliquots and total protein concentration (TP), total nucleated cell count (TNCC) and neutrophil morphology were analysed immediately (T0 ) and at 24 (T24 ), 48 (T48 ) and 72 h (T72 ) after storage at 4 or 22°C. Linear mixed models were used to analyse effects of fluid type and storage conditions on TP, TNCC and neutrophil morphology grade. Changes in interpretation of samples over time and diagnostic performance at each analysis point were recorded. RESULTS: A total of 32 samples were collected from 23 horses. Storage had no effect on TP. Cell count was influenced by fluid type and was significantly reduced at T72 for storage at 4°C and T24 , T48 and T72 for 22°C (P<0.001). Neutrophil morphology grade was significantly greater at T24 , T48 and T72 than at T0 for both 4 and 22°C (P<0.001). For 9 samples, the diagnostic interpretation changed over time. Specificity and positive predictive value at each analysis point was 100%; however, sensitivity and negative predictive value decreased with greater storage duration and temperature. CONCLUSIONS: Alterations in the TNCC and neutrophil morphology of body fluid samples occur when analysis is delayed, especially with higher storage temperatures, and may influence interpretation and clinical decision-making. Body fluid samples should be analysed as soon as possible after collection to minimise preanalytical errors due to storage.

Association of bovine papillomavirus type 2 and bracken fern with bladder cancer in cattle.

The bladder cancer syndrome that often accompanies chronic enzootic hematuria in cattle grazing on pastures infested by bracken fern has been experimentally reproduced in animals fed a diet of bracken. The experimentally induced tumors were histologically and pathologically indistinguishable from the naturally occurring ones and comprised two main types: (a) carcinoma of the urothelium identical to that seen in humans; and (b) hemangioendotheliomas of the subjacent capillaries. Often the two types of tumor occurred together in the same bladder. In animals experimentally immunosuppressed with azathioprine "bracken type" hemangiomas developed in the bladder lining. DNA of bovine papillomavirus (BPV) type 2 was found in 46% (7 of 15) of the natural cancer cases and in 69% (9 of 13) of the experimentally induced lesions, independently of histological type and including the hemangiomas of the azathioprine-treated animals, suggesting a close association between BPV and bovine bladder neoplasia. Moreover, BPV-2 DNA was found in experimental animals that had not been inoculated with BPV at all or had been inoculated with a different BPV type and had been kept in isolation, suggesting that BPV can persist in a latent state and be activated when the animal is exposed to the bracken cocarcinogens and to immunosuppressants.

Predicting imminent risk for fracture in patients aged 50 or older with osteoporosis using US claims data.

UNLABELLED: Patient characteristics contributing to imminent risk for fracture, defined as risk of near-term fracture within the next 12 to 24 months, have not been well defined. In patients without recent fracture, we identified factors predicting imminent risk for vertebral/nonvertebral fracture, including falls, age, comorbidities, and other potential fall risk factors. PURPOSE: Several factors contribute to long-term fracture risk in patients with osteoporosis, including age, bone mineral density, and fracture history. Some patients may be at imminent risk for fracture, defined here as a risk of near-term fracture within 12-24 months. Many patient characteristics contributing to imminent risk for fracture have not been well defined. This case-control study used US commercial and Medicare supplemental insured data for women and men without recent fracture to identify factors associated with imminent risk for fracture. METHODS: Patients included were aged ≥50 with osteoporosis, had a vertebral or nonvertebral fracture claim (index date; fracture group) or no fracture claim (control group) from January 1, 2006, to September 30, 2012, continuously enrolled and without fracture in the 24 months before index. Potential risk factors during the period before fracture were assessed. RESULTS: Using data from 12 months before fracture, factors significantly associated with imminent risk for fracture were previous falls, older age, poorer health status, specific comorbidities (psychosis, Alzheimer's disease, central nervous system disease), and other fall risk factors (wheelchair use, psychoactive medication use, mobility impairment). Similar findings were observed with data from 24 months before fracture. CONCLUSIONS: In patients with osteoporosis and no recent fracture, falls, older age, poorer health status, comorbidities, and other potential fall risk factors were predictive of imminent risk for fracture. Identification of factors associated with imminent risk for vertebral/nonvertebral fracture may help identify and risk stratify those patients most in need of immediate and appropriate treatment to decrease fracture risk.

Norepinephrine-induced hypertension in Guillain Barré syndrome.

Systemic haemodynamics, plasma catecholamine levels and diurnal variation of arterial pressure were studied in a 20-year-old patient with hypertension during Guillain Barré syndrome after complete resolution of the illness. Transient arterial hypertension during the course of Guillain Barré syndrome is characterized by an increased total peripheral resistance associated with elevated circulating norepinephrine levels, suggesting an over-activity of the sympathetic nervous system as the underlying mechanism of the elevated blood pressure.

Embolic stroke in a woman with mitral valve prolapse who used oral contraceptives.

A case of angiographically-documented embolism is presented in a patient using oral contraceptives (OC) with marked mitral valve prolapse (MVP) and an atrial thrombus. OC use has been shown to decrease levels of antithrombin III and increase platelet coagulant activity. This increased coagulability may increase the risk of intra-atrial thrombus formation and subsequent cerebral embolism in patients with MVP. We believe that MVP, especially when redundant valve leaflets are recognized, may be a relative contraindication to OC use.

PIP: A 21-year old women taking oral contraceptives suffered thromboembolic stroke associated with mitral valve prolapse. She had been using an unspecified oral contraceptive for 3 months postpartum, and had smoked a pack a day for 5 years. She complained of sudden right orbital headache, left-sided weakness and pain. Clinical exam showed left sided anopsia, facial paralysis, tongue protrusion, parietal sensory deficit, and loss of position sense. Computed tomography suggested a lesion near the right middle cerebral artery; and cerebral angiography revealed an 8 x 2 mm filling defect in that artery. A midsystolic click without a murmur was evident in the cardiac exam. Thickened, redundant mitral valve leaflets with marked prolapse, and a mass on the atrial side of the posterior leaflet appeared on the echocardiogram. The atrial thrombus was considered the source of the apparent embolism in the cerebral artery. Oral contraceptives have been found to increase the risk of thrombotic stroke and venous thromboembolism. Therefore, women with known mitral valve prolapse or leaflets may be advised not to use the pill.

A single amino acid alteration in murine PrP dramatically alters TSE incubation time.

In order to investigate mutations linked to human TSEs, we have used the technique of gene targeting to introduce specific mutations into the endogenous murine PrP gene which resulted in a P101L substitution (Prnp(a101L)) in the murine PrP gene. This mutation is equivalent to the 102L mutation in the human PrP gene which is associated with Gerstmann-Sträussler syndrome. Since the mutated gene is in the correct chromosomal location and control of the mutant gene expression is identical to that of the wild type murine PrP gene, the precise effect of the 101L mutation in the uninfected and TSE infected mouse can be investigated in this transgenic model. Mice homozygous for this mutation (101LL) while showing no spontaneous TSE disease were more susceptible to TSE disease than wild type mice following inoculation with GSS infectivity. Disease was transmitted from these mice to mice both with and without the Prnp(a101L) allele. The 101L mutation does not therefore produce spontaneous genetic disease in mice but does dramatically alter incubation periods following TSE infection. Additionally, a rapid TSE transmission was demonstrated associated with extremely low amounts of PrP(Sc).

Recruitment and retention of participants in prevention trials involving family-based interventions.

Family-based preventive intervention trials in the area of child conduct problems face serious challenges regarding the recruitment and subsequent retention of participants. This article focuses on the problems and strategies pertinent to recruitment and retention in prevention research. The issues are discussed first with respect to initiating and maintaining a longitudinal sample, and then engaging and sustaining families in a preventive intervention. General principles are illustrated by EARLY ALLIANCE, a recently launched preventive intervention trial aimed at reducing children's risk for conduct disorder, substance abuse, and school failure. Recommendations for enhancing recruitment and retention are offered.