Acute hemorrhagic complications are associated with lower coated-platelet levels in non-lacunar brain infarction.

BACKGROUND: Coated platelets are procoagulant platelets observed upon dual agonist stimulation with collagen and thrombin. Coated-platelet levels are elevated in patients with non-lacunar ischemic stroke and decreased in patients with spontaneous intracerebral hemorrhage as compared with controls. OBJECTIVE: To investigate whether acute hemorrhagic complications occurring during the initial hospital admission for non-lacunar ischemic stroke are associated with lower coated-platelet levels. PATIENTS/METHODS: Coated-platelet levels were determined in 385 consecutive patients with non-lacunar stroke. Hemorrhagic complications were defined as either intracranial hemorrhage or significant extracranial bleeding (drop in hemoglobin of ≥ 2 g dL(-1) ). The rate of acute hemorrhagic complication was compared among subjects categorized into tertiles of coated-platelet levels using an exact Cochrane-Armitage trend test. Logistic regression was used to estimate the adjusted odds of hemorrhagic complication associated with coated-platelet levels. RESULTS: Hemorrhagic complications were present in 15 (3.9%) cases. Of these, four had intracranial hemorrhage and 11 had extracranial hemorrhage. The occurrence of hemorrhagic complications differed among the coated-platelet tertiles: 10.2% for the first tertile (coated-platelet levels < 35.5%), 1.5% for the second tertile and 0% for the third tertile (coated-platelet levels ≥ 47.5%, trend test). Logistic regression showed that the odds of hemorrhagic complication in those with levels < 35.5% were 14.59 times the odds for patients with levels ≥ 35.5% (95% CI: 3.24-65.7). CONCLUSIONS: Lower levels of procoagulant platelets are associated with acute hemorrhagic complications following non-lacunar ischemic stroke. These results suggest a role for coated-platelets in risk/benefit assessment in the early stages of stroke.

Prospective evaluation of protein C and factor VIII in prediction of cancer-associated thrombosis.

Venous thromboembolism (VTE) is a preventable disease, yet it is one of the leading causes of death among patients with cancer. Improving risk stratification mechanisms will allow us to personalize thrombo-prophylaxis strategies. We sought to evaluate Collagen and Thrombin Activated Platelets (COAT-platelets) as well as protein C and factor VIII as biomarkers predictive of cancer-associated thrombosis in a prospective cohort of patients with cancer. Protein C was selected as a candidate based on bioinformatics prediction. Blood samples were collected before chemotherapy. All specimen processing was blinded to clinical data. Surveillance and adjudication of the main outcome of VTE was performed for up to 1 year. We used Cox proportional hazard regression to measure the association of biomarkers and incident events using SAS 9.2 for all statistical analysis. Death was modeled as a competing event. Among 241 patients followed for an average of 10.4 months, 15% died and 13% developed a VTE. COAT-platelets were not predictive of VTE. Low levels of pre-chemotherapy protein C (<118%) (HR 2.5; 95% CI 1.1-5.5) and high baseline factor VIII (>261% I) (HR 3.0; 95% CI 1.1-8.0) were predictive of VTE after adjusting for age, Khorana prediction risk, metastatic disease and D dimer. In addition, low protein C was predictive of overall mortality independent of age, metastatic disease and functional status (HR 2.8; 95% CI 1.3-6.0). Addition of these biomarkers to cancer-VTE risk prediction models may add to risk stratification and patient selection to optimize thrombo-prophylaxis.

Treatment of upper-extremity deep vein thrombosis.

BACKGROUND: Upper extremity deep vein thrombosis (DVT) can result in fatal pulmonary embolism if not treated. Patients with malignancy may be at particularly high risk. Heparin or low-molecular-weight heparin followed by warfarin has been used as standard treatment for lower extremity DVT. However, a paucity of studies exist reporting the efficacy and safety of these regimens in patients with upper extremity DVT. We studied the effectiveness and safety of treatment with dalteparin sodium followed by warfarin and also dalteparin sodium monotherapy for 3 months in patients with confirmed upper extremity DVT. METHODS: Consecutive patients with confirmed upper extremity DVT received daily dalteparin sodium for 5-7 days followed by warfarin therapy for 3 months (phase I) or dalteparin sodium monotherapy for 3 months (phase II). The primary outcome measure was the incidence of new symptomatic venous thromboembolism during the 3-month follow-up period. The outcome measure of safety was the incidence of major and minor bleeding. RESULTS: Of 631 consecutive patients screened, 74 were eligible and 67 enrolled. No patients receiving either phase I (0%; 95% CI, 0-12%) or phase II (0%; 95% CI, 0-9%) therapy had venous thromboembolism on 3-month follow-up. One patient (4%; 95% CI, 0-18%) receiving phase I therapy experienced major bleeding. Five patients died during the follow-up period; none were attributed to pulmonary embolism. CONCLUSIONS: Patients with upper extremity DVT may be treated safely with either dalteparin sodium followed by warfarin or dalteparin sodium monotherapy for 3 months with a good prognosis.

Serum bone biomarkers and oral/systemic bone loss in humans.

UNLABELLED: We recently reported that subantimicrobial-dose doxycycline (SDD) significantly reduced serum bone-resorption biomarkers in subgroups of post-menopausal women. We hypothesize that changes in serum bone biomarkers are associated not only with systemic bone mineral density (BMD) changes, but also with alveolar bone changes over time. One hundred twenty-eight eligible post-menopausal women with periodontitis and systemic osteopenia were randomly assigned to receive SDD or placebo tablets twice daily for two years, adjunctive to periodontal maintenance. Sera were analyzed for bone biomarkers. As expected, two-year changes in a serum bone biomarker were significantly associated with systemic BMD loss at the lumbar spine (osteocalcin, bone-turnover biomarker, p = 0.0002) and femoral neck (osteocalcin p = 0.0025). Two-year changes in serum osteocalcin and serum pyridinoline-crosslink fragment of type I collagen (ICTP; bone-resorption biomarker) were also significantly associated with alveolar bone density loss (p < 0.0001) and alveolar bone height loss (p = 0.0008), respectively. Thus, we have shown that serum bone biomarkers are associated with not only systemic BMD loss, but with alveolar bone loss as well. CLINICAL TRIAL REGISTRATION INFORMATION: Protocol registered at ClinicalTrials.gov, NCT00066027.

Coated-platelet levels and progression from mild cognitive impairment to Alzheimer disease.

OBJECTIVES: Coated-platelets are a subset of platelets produced by dual-agonist activation with collagen and thrombin. These platelets retain full-length amyloid precursor protein on their surface, are elevated in patients with amnestic as compared to nonamnestic mild cognitive impairment (MCI), and correlate with disease progression in Alzheimer disease (AD). Prompted by these findings, we investigated the association between coated-platelet production in amnestic MCI and rate of progression to AD. METHODS: Coated-platelet levels were assayed in 74 patients with amnestic MCI who were subsequently followed longitudinally for up to 36 months in an outpatient dementia clinic. Levels are reported as percent of cells converted into coated-platelets. Subjects were categorized into tertiles of coated-platelet levels. The distributions of time to progression to AD were estimated for each tertile using cumulative incidence curves and compared statistically using a log-rank test. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: The 24-month cumulative incidence of progression to AD was different among tertiles: 4% for the first tertile (lowest coated-platelet levels), 13% for the second tertile, and 37% for the third tertile (overall log-rank test, p = 0.02). The hazard rate of progression to AD for patients in the highest coated-platelet tertile was 5.1 times that for patients in the lowest tertile (p = 0.04), whereas the hazard rate for the middle tertile was similar to that for the lowest tertile (hazard rate ratio = 1.5, p = 0.7). CONCLUSIONS: Elevated coated-platelet levels in patients with amnestic MCI are associated with increased risk for progression to AD.

Doxycycline effects on serum bone biomarkers in post-menopausal women.

We previously demonstrated that subantimicrobial-dose-doxycycline (SDD) treatment of post-menopausal osteopenic women significantly reduced periodontal disease progression, and biomarkers of collagen destruction and bone resorption locally in periodontal pockets, in a double-blind placebo-controlled clinical trial. We now hypothesize that SDD may also improve biomarkers of bone loss systemically in the same women, consistent with previous studies on tetracyclines (e.g., doxycycline) in organ culture and animal models of bone-deficiency disease. 128 post-menopausal osteopenic women with chronic periodontitis randomly received SDD or placebo tablets daily for 2 years adjunctive to periodontal maintenance therapy every 3-4 months. Blood was collected at baseline and at one- and two-year appointments, and sera were analyzed for bone resorption and bone formation/turnover biomarkers. In subsets of the study population, adjunctive SDD significantly reduced serum biomarkers of bone resorption (biomarkers of bone formation were unaffected), consistent with reduced risk of future systemic bone loss in these post-menopausal women not yet on anti-osteoporotic drugs.

Lower coated-platelet levels are associated with early hemorrhagic transformation in patients with non-lacunar brain infarction.

BACKGROUND: Coated-platelets, representing a subset of platelets with procoagulant potential, are elevated in patients with non-lacunar ischemic stroke and decreased in patients with spontaneous intracerebral hemorrhage. However, within the non-lacunar patient population there are individuals with lower levels of coated-platelets, which raises the possibility that these individuals would be susceptible to early hemorrhagic transformation (HT) of ischemic stroke. OBJECTIVE: Because extremes in coated-platelet potential may be associated with either thrombotic or hemorrhagic events, we undertook a pilot study to investigate whether there is an association between coated-platelet production and the presence of early HT in patients with non-lacunar ischemic stroke. PATIENTS AND METHODS: Coated-platelet levels were determined in 115 consecutive eligible patients with a diagnosis of non-lacunar ischemic stroke. Early HT was determined on CT scan examination and confirmed by MRI studies. The distribution of coated-platelet levels was summarized using the median and interquartile range (25th-75th percentiles) and compared statistically between patients with and without early HT using the non-parametric Wilcoxon rank sum test. RESULTS: The median coated-platelet level in all non-lacunar stroke patients was 38.0% (interquartile range 30.5-48.3%). Early HT was detected in 11 patients (9.6%), and these patients had significantly lower coated-platelet levels compared with those without early HT [median 25.1% (interquartile range 20.4-35.5%) vs. 39.2% (31.6-49.5%), P = 0.003]. CONCLUSIONS: Lower levels of coated-platelets are associated with the presence of early HT in patients with non-lacunar ischemic stroke.

Optimal combination of estimating equations in the analysis of multilevel nested correlated data.

Multilevel nested, correlated data often arise in biomedical research. Examples include teeth nested within quadrants in a mouth or students nested within classrooms in schools. In some settings, cluster sizes may be large relative to the number of independent clusters and the degree of correlation may vary across clusters. When cluster sizes are large, fitting marginal regression models using Generalized Estimating Equations with flexible correlation structures that reflect the nested structure may fail to converge and result in unstable covariance estimates. Also, the use of patterned, nested working correlation structures may not be efficient when correlation varies across clusters. This paper describes a flexible marginal regression modeling approach based on an optimal combination of estimating equations. Particular within-cluster and between-cluster data contrasts are used without specification of the working covariance structure and without estimation of covariance parameters. The method involves estimation of the covariance matrix only for the vector of component estimating equations (which is typically of small dimension) rather than the covariance matrix of the observations within a cluster (which may be of large dimension). In settings where the number of clusters is large relative to the cluster size, the method is stable and is highly efficient, while maintaining appropriate coverage levels. Performance of the method is investigated with simulation studies and an application to a periodontal study.

Cumulative incidence of vitamin B12 deficiency in patients with Alzheimer disease.

BACKGROUND: Although vitamin B12 is routinely measured in patients with Alzheimer disease (AD) at the time of the initial diagnosis, it is not known if repeat vitamin B12 measurements are indicated to detect new deficiency cases. We aimed to determine the incidence of de-novo vitamin B12 deficiency over a period of 3 years in a cohort of AD patients without a prior diagnosis of vitamin B12 deficiency and with initial vitamin B12 levels greater than 350 ng/L. METHODS: Vitamin B12 levels were measured at the time of AD diagnosis and repeated 3 years later in 102 consecutive patients, unless a diagnosis of B12 deficiency was made in the interim. RESULTS: Vitamin B12 deficiency was diagnosed in 7 patients, corresponding to a cumulative incidence in the cohort studied of 7.6% after 3 years of follow-up. Statistical comparison of initial and repeat vitamin B12 measurements in patients that completed follow-up showed a significant reduction in levels (p=0.003). Among the 79 subjects with follow-up, 17 patients (22%, 95% CI, 13%-32%) had a repeat level less than 350 ng/L. No significant correlates of deficiency incidence were identified. CONCLUSION: Our pilot data indicate that vitamin B12 levels decreased in this cohort of AD patients putting a substantial percentage at risk of deficiency and reaching deficiency state in a meaningful number of patients. Repeat screening for B12 deficiency after approximately 2 years of follow-up seems warranted in order to prevent hematological and neurological manifestations that may significantly alter their quality of life.

Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody.

OBJECTIVE: To examine the association of treatment response and disease duration with changes in rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody levels among patients with rheumatoid arthritis (RA). METHODS: The study sample included 66 RA patients who completed double-blind, randomized clinical protocols and for whom baseline and followup serum samples were available. Anti-CCP and RF levels were measured using commercially available assay kits. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the association of response and disease duration with declines in antibody levels. RESULTS: Patients had a mean +/- SD age of 49.9 +/- 12.0 years and were predominantly female (n = 51; 77%). The mean +/- SD duration between the times at which the baseline and followup serum samples were obtained was 13.7 +/- 8.6 months. Among the 64 subjects with positive antibody at baseline, 33 (52%) experienced a > or =25% reduction in the anti-CCP antibody level during the course of treatment, and 35 patients (55%) had a > or =25% reduction in RF. After adjustment for the baseline anti-CCP antibody level, only a shorter disease duration (< or =12 months) was significantly associated with a decline in the level of anti-CCP antibody (OR 3.0, 95% CI 1.0-8.8), and no association with treatment response was observed. Conversely, treatment response was the only significant determinant of a decrease in RF levels (OR 3.6, 95% CI 1.2-10.4). CONCLUSION: Shorter disease duration predicts greater declines in anti-CCP antibody levels with treatment in RA. Although treatment response is a robust determinant of a decrease in RF, it does not appear to be associated with declines in the anti-CCP antibody level.

Incidence, duration, and prevalence of Escherichia coli O157:H7 fecal shedding by feedlot cattle during the finishing period.

The objective was to describe variability in prevalence, incidence, and duration of fecal shedding of naturally occurring E. coli O157:H7 by a group of feedlot cattle over time. One hundred steers, randomly assigned to 10 pens, were fed a high-concentrate finishing diet for 136 days (19 weeks). Rectal feces from each animal were tested for E. coli O157:H7 every week for 19 weeks. E. coli O157:H7 was recovered from each animal that completed the study and was detected from at least one animal every week. Average pen prevalence of cattle shedding E. coli O157:H7 varied significantly over time (P < 0.0001) and across pens (P < 0.0001), ranging from 1 to 80%. Pairwise comparisons of mean pen prevalence of E. coli O157:H7 between weeks and estimation of the predicted probability of an incident case of E. coli O157:H7 over time allowed the definition of three distinct phases--namely, the preepidemic, epidemic, and postepidemic periods. Average pen prevalence varied significantly over time (P < 0.01) and across pens (P < 0.001) for all time periods. The odds of an incident case were significantly greater during epidemic and postepidemic periods relative to the preepidemic period (P = 0.0002 and P = 0.03, respectively). Duration of infection was significantly longer for first or second infections that began during epidemic or postepidemic periods relative to the preepidemic period (P < 0.001). Both incidence and duration of shedding peaked during the epidemic period. Pen-level prevalence of cattle shedding E. coli O157:H7 was affected by both incidence and duration of shedding and could be explained by time- or pen-dependent risk factors, or both.

All-digital image capture and whole-field analysis of ciliary beat frequency.

We hypothesized that a high-speed all-digital video imaging system, with computerized analysis, would precisely capture and measure ciliary beat frequency (CBF) and would shorten the time from data capture to data analysis. We compared a conventional analog video system with a new high-speed digital system we developed for CBF analysis. Using ciliated primary bovine bronchial epithelial cells we made simultaneous analog and digital CBF measurements of the same region of interest (ROI) while temperature was varied. This yielded nearly identical data over a wide range of frequencies (7-15 Hz) using either system. Unlike the digital system however, the analog system did not accurately detect CBF above 15 Hz (temperatures higher than 30 degrees C). We also compared ROI analysis with a new analysis algorithm we have named whole-field analysis (WFA). WFA measurement of CBF agreed with ROI and reduced operator time required to analyse data by more than 90% compared with the analog system. We conclude that all-digital computerized CBF analysis correlates closely with standard video methods, markedly speeds up data analysis and provides new ways, including WFA, to analyse entire fields of motile cilia simultaneously. We have termed this system 'Sisson-Ammons Video Analysis' (SAVA).

Evaluation of friction during sliding tooth movement in various bracket-arch wire combinations.

Frictional forces during simulated sliding tooth movement were measured with a model that was representative of the clinical condition. The model allowed tipping of the tooth until contact was established between the arch wire and diagonally opposite corners of the bracket wings; it also allowed rotation until the wire contacted opposite corners of the ligature tie, or the buccal shield with self-ligating brackets, and the base of the slot. Conventional and self-ligating stainless steel brackets as well as conventional ceramic brackets, and ceramic brackets with a stainless steel slot, all with 0.022 inch bracket slot, were tested with 0.019 x 0.025 inch arch wires of stainless steel, nickel titanium, and beta titanium. Each of the 12 bracket-arch wire combinations was tested 10 times. No significant interaction was detected between brackets and arch wires (P = .89), but the bracket and arch wire effects were significant (P < .001). The pairwise differences between conventional and self-ligating stainless steel brackets and ceramic brackets with stainless steel slot were not significant. However, the conventional ceramic brackets generated significantly higher friction than the other brackets tested. Beta titanium arch wires produced higher frictional forces than nickel titanium arch wires, but no significant differences were found between each of the two and stainless steel arch wires. Attempts to identify differences in surface scratches of the arch wires produced by the different brackets were unsuccessful.

Factors used by program directors to select residents.

A national, stratified random sample of 405 graduate medical education program directors was surveyed on the way they selected their residents. The results from the 237 respondents reaffirm earlier studies which found that the interview was the most important selection variable. The results indicate that the recent increase in competition for residency positions has increased the importance of academic variables. For example, 86 percent of the respondents stated that they would not rank a candidate who had not passed the National Board of Medical Examiners Part I examination. Because 86 percent also stated that they give preference in ranking students to those who have done well in an elective at their hospitals, the senior year of medical school may be used as a "residency chase" rather than for the general professional education of the physician.