Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs

Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.     

The relationship between blood pressure and C-reactive protein in the Multi-Ethnic Study of Atherosclerosis (MESA).

OBJECTIVES: The goal of this study was to determine the relationship between resting blood pressure (BP) and C-reactive protein (CRP) in a multi-ethnic cohort of men and women from the Multi-Ethnic Study of Atherosclerosis (MESA). BACKGROUND: Several investigators have observed elevated levels of CRP in individuals with hypertension. Hypertension prevalence varies considerably across ethnic groups. Important questions remain regarding whether the relationship between hypertension and CRP is similar across ethnic and gender subgroups. METHODS: The MESA participants had CRP levels determined at the baseline clinical examination (N = 6,814). Hypertension, treated as a dichotomous variable (yes/no), was defined as a systolic or diastolic BP > or =140/90 mm Hg or a self-reported history of hypertension and use of antihypertensive medications. RESULTS: The geometric mean CRP in hypertensive participants was 2.3 +/- 0.07 mg/l compared with 1.6 +/- 0.07 mg/l among normotensive participants (p < 0.0001). The relative difference in CRP levels in hypertensives compared with normotensives was similar regardless of gender (13% in men and 13% in women). Ethnic comparisons showed that Chinese participants had the lowest CRP concentration but the largest difference in CRP by hypertension status (24%). Caucasians and African Americans had 10% to 15% higher CRP levels with hypertension, whereas Hispanics had no significant difference in CRP by hypertension status. CONCLUSIONS: This study confirms the existence of an independent association between hypertension and inflammation in both men and women. Ethnic group differences were evident, with the strongest association observed in Chinese participants and no difference in CRP levels by hypertension status in Hispanics.     

Indeterminate colitis: the real story

PURPOSE: Up to one in five patients undergoing surgery for ulcerative colitis will have ambiguous histology, with features of both ulcerative colitis and Crohn's disease, and are categorized as having indeterminate colitis. We hypothesized that functional outcomes in indeterminate colitis patients undergoing ileal pouch-anal anastomosis are comparable with those of ulcerative colitis patients undergoing ileal pouch-anal anastomosis. METHODS: Physician-conducted interviews of 120 consecutive ileal pouch-anal anastomosis patients with a preoperative diagnosis of ulcerative colitis were reviewed, with a mean follow-up of 54 months. All colectomy specimens were reviewed by a single pathologist. Any changes in histologic diagnosis from ulcerative colitis to indeterminate colitis or Crohn's disease, frequency of postoperative complications, pouch function, and long-term postoperative medication usage were recorded. RESULTS: Although postoperative fistulas were more common in indeterminate colitis than ulcerative colitis (26 vs. 10 percent; P = 0.02, chi-squared), no indeterminate colitis patient required a permanent ileostomy as compared with six ulcerative colitis patients. Long-term functional results were similar. Overall, two-thirds of patients developed pouchitis. Ulcerative colitis and Crohn's disease patients were more likely to have had >3 episodes of pouchitis (58 and 72 percent) compared with indeterminate colitis patients (29 percent; P = 0.006, chi-squared). A greater number of Crohn's disease patients required maintenance oral antibiotic therapy (64 percent) to achieve satisfactory functional results compared with both indeterminate colitis and ulcerative colitis patients (20 and 28 percent; P = 0.014, chi-squared). CONCLUSIONS: Although ileal pouch-anal anastomosis patients with indeterminate colitis have more postoperative fistulas, long-term function is equal to that of ulcerative colitis patients and better than Crohn's disease patients. Ileal pouch-anal anastomosis should be offered to patients with indeterminate colitis and those with severe colitis in whom clear differentiation between indeterminate colitis and ulcerative colitis cannot be made.     

Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning

Germ cells undergo epigenetic modifications as they develop, which suggests that they may be ideal donors for nuclear transfer (cloning). In this study, nuclei from confirmed embryonic germ cells were used as donors to determine whether they are competent for cloning and at which stage they are most competent. Embryos cloned from migrating 10.5-days-postcoitum (dpc) primordial germ cells (PGCs) showed normal morphological development to midgestation but died shortly thereafter. In contrast, embryos cloned from later-stage germ cells were developmentally delayed at midgestation. Thus, donor germ cell age inversely correlated with the developmental stage attained by cloned embryos. The methylation status of the H19- and Snrpn-imprinting control regions in germ cell clones paralleled that of the donors, and revealed that demethylation, or erasure of imprints, was already initiated in PGCs at 10.5 dpc and was complete by 13.5 dpc. Similarly, clones derived from male 15.5-dpc germ cells showed increased methylation correlating with the initiation of de novo methylation that resets imprints at this stage, and clones from neonatal germ cells showed nearly complete methylation in the H19 imprinting control region. These results indicate that the epigenetic state of the donor nucleus is retained in cloned embryos, and that germ cells are therefore inadequate nuclear donors for cloning because they are either erasing or resetting epigenetic patterns.     

An effective strategy for diagnosing occupational asthma: use of induced sputum

Monitoring airway inflammation by means of induced sputum cell counts seems to improve the management of asthma. We sought to assess whether such monitoring at the end of periods at and away from work combined with the monitoring of PEF could improve the diagnosis of occupational asthma. We enrolled subjects suspected of having occupational asthma. Serial monitoring of PEF was performed during 2 weeks at and away from work. At the end of each period, induced sputum was collected. Specific inhalation challenge was subsequently performed. PEF graphs were interpreted visually by five independent observers. Forty-nine subjects, including 23 with positive specific inhalation challenge, completed the study. The addition of sputum cell counts to the monitoring of PEF increased the specificity of this test, respectively, by 18 (range [r] 13.7-25.5) or 26.8% (r 24.8-30.4) depending if an increase of sputum eosinophils greater than 1 or 2% when at work was considered as significant. The sensitivity increased by 8.2% (r 4.1-13.4) or decreased by 12.3% (r 3.1-24.1) depending on the cutoff value in sputum eosinophils chosen (greater than 1 or 2%, respectively). The addition of sputum cell counts to PEF monitoring is useful to improve the diagnosis of occupational asthma.     

Effectiveness of diabetes mellitus screening recommendations

Screening guidelines proposed by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus have been endorsed by several medical societies. However, one-third of cases are undiagnosed, and complications at the time of diagnosis indicate that disease may have been present for several years before diagnosis. This study evaluates the effectiveness of the guidelines for detecting new cases of diabetes mellitus. By using a cross-sectional, representative sample of the United States (National Health and Nutritional Examination Survey, NHANES III), the guidelines are tested on adults, 20 years and older without a prior diagnosis of diabetes. Individuals are classified as nondiabetics (n = 6,241) or as having undiagnosed diabetes (n = 274) based on their blood glucose. Screening when one risk factor is present, as stated in the guidelines, has a true-positive rate of 100% and would require that 83% of the population be tested. Screening when two risk factors are present is more efficient, with a comparable true-positive rate (98%), but requires that only 59% of the population be tested. A notable finding is the earlier age of onset among minorities, which may be associated with other health disparities. Because diabetes occurs at younger ages in minorities, screening whites who are > or =40 and minorities > or =30 years of age has a high true-positive rate (95%) and also reduces testing (60%). The screening guidelines would be effective, if followed, and would essentially eliminate undiagnosed cases of diabetes.     

Depressive symptoms and heart rate variability in postmenopausal women

BACKGROUND: Depressive symptoms have been associated with increased cardiac morbidity and mortality rates, but the pathophysiologic mechanism linking depressive symptoms to cardiovascular outcome has yet to be fully understood. Lower heart rate variability has also been associated with increased risk of cardiac events in healthy individuals and in patients with coronary artery disease. Findings regarding a relationship between depressive symptoms and heart rate variability that could explain increased cardiovascular risk have been inconsistent across studies. METHODS: As an ancillary study to the Women's Health Initiative Observational Study, 3372 postmenopausal women aged 50 to 83 years were enrolled for further evaluation using 24-hour ambulatory electrocardiographic monitoring. A shortened version of the Center for Epidemiological Studies Depression Scale and the Diagnostic Interview Schedule were administered. Women with adequate electrocardiographic data and depressive symptom information and without coronary artery disease were analyzed (n = 2627). RESULTS: Two hundred sixty-nine women (10.2%) had depressive symptoms as measured using the 2 instruments. Women with depressive symptoms had a higher mean +/- SD heart rate (77.4 +/- 9.6 vs 75.5 +/- 8.5 beats/min) and lower heart rate variability than women without depressive symptoms. All differences remained significant after adjusting for age (P<.01). CONCLUSIONS: Women with depressive symptoms had significant reductions in heart rate variability and higher heart rates, suggestive of increased sympathetic tone. These findings may contribute to the increased cardiac morbidity and mortality rates associated with depression in other studies.     

Seasonality and daily weather conditions in relation to myocardial infarction and sudden cardiac death in Olmsted County, Minnesota, 1979 to 2002.

OBJECTIVES: We assessed the relationship of season and weather types with myocardial infarction (MI) and sudden cardiac death (SCD) in a geographically defined population, and tested the hypothesis that the increased risk in winter was related to weather. BACKGROUND: Winter peaks in coronary heart disease (CHD) have been documented. Yet, it is uncertain if seasonality exists for both incident events and deaths, and the role of weather conditions is not clear. METHODS: The daily occurrence of incident MI and SCD in Olmsted County was examined with data from the National Weather Service. Poisson regression models were used to assess the relative risks (RRs) associated with season and climatic variables. Subsequent analysis stratified SCD into those with and without antecedent CHD (unexpected SCD). RESULTS: Between 1979 and 2002, 2,676 MI and 2,066 SCD occurred. The age-, gender-, and year-adjusted RR of SCD, but not of MI, was increased in winter versus summer (1.17, 95% confidence interval [CI] 1.03 to 1.32) and in low temperatures (1.20, 95% CI 1.07 to 1.35, for temperatures below 0 degrees C vs. 18 degrees C to 30 degrees C). These associations were stronger for unexpected SCD than for SCD with prior CHD (p < 0.05). After adjustment for all climatic variables, low temperature was associated with a large increase in the risk of unexpected SCD (RR = 1.38, 95% CI 1.10 to 1.73), while the association with winter declined (RR = 1.06, 95% CI 0.83 to 1.35). CONCLUSIONS: These data suggest that the winter peak in SCD can be accounted for by daily weather.