Oral anticoagulation reduces activated protein C less than protein C and other vitamin K-dependent clotting factors

Oral anticoagulant therapy, which is used for prophylaxis and management of thrombotic disorders, causes similar reductions in plasma levels of vitamin K-dependent procoagulant and anticoagulant clotting factor zymogens. When we measured levels of circulating activated protein C, a physiologically important anticoagulant and anti-inflammatory agent, in patients on oral anticoagulant therapy, the results unexpectedly showed that such therapy decreases levels of activated protein C substantially less than levels of protein C, prothrombin, and factor X, especially at lower levels of prothrombin and factor X. Thus, we suggest that oral anticoagulant therapy results in a relatively increased expression of the protein C pathway compared with procoagulant pathways not only because there is less prothrombin to inhibit activated protein C anticoagulant activity, but also because there is a disproportionately higher level of circulating activated protein C.     

Ischemic preconditioning reduces unloaded myocardial oxygen consumption in an in-vivo sheep model

OBJECTIVE: Ischemic preconditioning (IP) describes the adaptation of the myocardium to ischemic stress preceded by short periods of ischemia and reperfusion. However, its cardioprotective mechanisms are not completely understood. We assessed the effect of IP on ventricular energetics in an in-vivo sheep model. METHODS: IP was performed in six sheep by three 5 min aortic cross-clamping periods interspersed with 5 min of reperfusion during cardiopulmonary bypass and with six sheep as time-matched controls. Global myocardial ischemia was subsequently achieved by 30 min aortic cross-clamping with left ventricular unloading during normothermic cardiopulmonary bypass. Weaning from cardiopulmonary bypass was performed 40 min after reperfusion. At baseline, after treatment (IP or time-matched cardiopulmonary bypass), and up to 100 min after reperfusion, left ventricular pressure-volume loops were measured using a conductance catheter during a right heart bypass preparation. Contractility, diastolic function, and ventriculo-arterial coupling were evaluated. Ventricular energetics [the relation between myocardial oxygen consumption (MVO(2)) and systolic pressure-volume area (PVA)] was also evaluated. A right heart bypass was instituted to control the preload and to decompress the right ventricle completely, thereby eliminating parallel conductance variation and minimizing the contribution of the right ventricle to MVO(2). RESULTS: IP reduced unloaded MVO(2) (PVA-independent MVO(2)). Contractility, diastolic function, and ventriculo-arterial coupling in the IP group were better preserved than in the control group after ischemia-reperfusion. CONCLUSIONS: IP reduces unloaded MVO(2), and preserves contractility, diastolic function, and ventriculo-arterial coupling after 30 min global myocardial ischemia in an in-vivo sheep model.     

Strong general health care systems: a prerequisite to reach global tuberculosis control targets

We argue that tuberculosis control cannot reach its proposed global targets without investment in an adequate network of accessible, effective and comprehensive health services. Lessons from the past are reviewed. They underscore that passive case-detection and adequate case management is the central technical strategy for tuberculosis control. There is no compelling evidence to support active case-detection in the general population. We elaborate on why a strong health care system is a prerequisite in the framework of case-detection and treatment. The necessity to improve quality and accessibility of general health services for ensuring early detection and subsequent cure is demonstrated. It is argued why the need for strong public health care system becomes even more eminent in the light of the tuberculosis/HIV dual epidemics and of the rapid growth of unregulated private-for-profit services. We finally examine the financial gaps for tuberculosis control and discuss the need for allocating more resources to the strengthening of general health care systems.     

Incidence of surgical-site infections and the validity of the National Nosocomial Infections Surveillance System risk index in a general surgical ward in Santa Cruz, Bolivia.

OBJECTIVES: To estimate the frequency of and risk factors for surgical-site infections (SSIs) in Bolivia, and to study the performance of the National Nosocomial Infections Surveillance (NNIS) System risk index in a developing country. DESIGN: A prospective study with patient follow-up until the 30th postoperative day. SETTING: A general surgical ward of a public hospital in Santa Cruz, Bolivia. PATIENTS: Patients admitted to the ward between July 1998 and June 1999 on whom surgical procedures were performed. RESULTS: Follow-up was complete for 91.5% of 376 surgical procedures. The overall SSI rate was 12%. Thirty-four (75.6%) of the 45 SSIs were culture positive. A logistic regression model retained an American Society of Anesthesiologists score of more than 1 (odds ratio [OR], 1.87), a not-clean wound class (OR, 2.28), a procedure duration of more than 1 hour (OR, 1.81), and drain (OR, 1.98) as independent risk factors for SSI. There was no significant association between the NNIS System risk index and SSI rates. However, a "local" risk index constructed with the above cutoff points showed a linear trend with SSI (P < .001) and a relative risk of 3.18 for risk class 3 versus a class of less than 3. CONCLUSIONS: SSIs cause considerable morbidity in Santa Cruz. Appropriate nosocomial infection surveillance and control should be introduced. The NNIS System risk index did not discriminate between patients at low and high risk for SSI in this hospital setting, but a risk score based on local cutoff points performed substantially better.     

CHD5, a new member of the chromodomain gene family,is preferentially expressed in the nervous system

Chromatin remodeling is one of the mechanisms by which gene expression is regulated developmentally. Chromatin structure is controlled at least in part by post-translational modification of histones, as well as by chromodomain proteins. We have identified a novel gene encoding a protein with chromatin remodeling, helicase and DNA-binding motifs. This gene, called CHD5, is the fifth member of the CHD gene family identified in humans. This gene is most homologous to CHD3 and CHD4, which encode proteins that are part of the nucleosome remodeling and histone deacetylation (NuRD) complex. CHD5 is preferentially expressed in total brain, fetal brain, and cerebellum. It is also moderately expressed in the adrenal gland, but expression is undetectable in almost all other tissues examined. CHD5 maps within a small region of deletion on 1p36.3 in human neuroblastomas, a common pediatric tumor. We examined a panel of neuroblastoma cell lines for CHD5 expression, which was consistently low or undetectable in all these lines. Expression was also examined in a panel of 137 primary neuroblastomas, and low expression was highly correlated with 1p deletion, MYCN amplification, advanced stage, and unfavorable histology. These findings suggest that this gene may play a role in the development of the nervous system, and it may also play a role in the pathogenesis of neural tumors.     

DNA mismatch repair deficiency stimulates N-ethyl-N-nitrosourea-induced mutagenesis and lymphomagenesis

The primary role of the mismatch repair (MMR) system is the avoidance of mutations caused by replication and recombination errors. Furthermore, the lethality of methylating agents has been attributed to the processing of O(6)-methylguanine lesions in DNA by MMR. Loss of the MSH2 protein completely abolishes repair function and results in reduced cell killing by methylating agents and accelerated accumulation of methylation-damage-induced mutations. This has raised the question as to whether MMR is also involved in the cellular response to other genotoxic insults. Here we describe that in mice deficient for Msh2, lymphomagenesis was strongly accelerated by an ethylating agent, N-ethyl-N-nitrosourea (ENU), given at a dose that did not induce lymphomas in wild-type mice. This suggests that MMR deficiency and ENU-induced mutagenesis synergistically collaborate in inducing tumorigenesis. To study the interaction between MMR and ENU-induced DNA damage, we compared the lethality and mutagenicity of ENU in MSH2-proficient and -deficient mouse embryonic stem cells. Although MSH2-deficiency only slightly reduced the lethality of ENU, it strongly enhanced the mutagenicity of ENU. Mutation analysis of ENU-induced Hprt mutants revealed that base substitutions occurred predominantly at A-T base-pairs. These results suggest that MMR modulates the processing of ethylation damage at AT base-pairs.     

Evaluation of the Appropriateness of Pacemaker Mode Selection in Bradycardia Pacing:

Although guidelines for selection of the appropriate pacing mode have been published, little data is available on how closely these are followed in the clinical setting. All 738 patients (men 412, women 326; age 73.4 +/- 0.46 years; range 19-101 years) who underwent pacemaker implantation from 1996 to 2000 were reviewed to determine if the appropriate mode was selected based on the ACC/AHA guidelines with the data collected prospectively. Demographic, investigational, and implantation data including the presence of sinus disease and/or atrioventricular block, diagnosis, indication for pacing, ACC/AHA class indication for device therapy, recommended ACC/AHA mode, implanted mode, and reason for not using the recommended mode were entered into an SPSS data base. Of 738 patients, 708 were cross-tabulated for a match to the guidelines of which 358 (50.6%) had a mode selected that did not conform. The reasons were advanced physical disability (16%), physician choice without identifiable reason (21%), rate modulation selected without identifiable indication (16%), DDD implanted instead of VDD (25%), advanced age (9%), rare need for pacing (6%), a need for specific device features (5%), and unstable stimulation thresholds or difficult venous access (2%). In the treatment of bradyarrhythmias, deviation from the ACC/AHA indicated mode occurred in a substantial proportion of pacing system implantations. However, in many, the deviation appeared appropriate considering the patient's clinical status. Nevertheless, in a smaller proportion of patients the deviation appeared inappropriate requiring rectification. The two outstanding categories were: (1) elderly denied a dual chamber system with no clinical explanation and (2) selection of rate-modulated devices without any indication of chronotropic incompetence.     

Selenium and iodine supplementation of rural Tibetan children affected by Kashin-Beck osteoarthropathy

BACKGROUND: Kashin-Beck disease is an osteoarthropathy endemic in selenium- and iodine-deficient areas around Lhasa, Tibet. OBJECTIVE: We assessed the efficacy of selenium supplementation on disease progression. DESIGN: A double-blind, randomized controlled trial of selenium supplementation was carried out in 324 children aged 5-15 y who had Kashin-Beck disease. Two hundred eighty children received iodized oil before being randomly assigned to receive selenium or placebo, and a control group of 44 subjects was not supplemented at all. Clinical and radiologic signs, selenium status, urinary iodine, and thyroid function were evaluated at baseline and at 12 mo. RESULTS: The frequencies of joint pain, decreased joint mobility, and radiologic abnormalities were not significantly different between the 3 groups at 12 mo. Height-for-age z scores increased significantly in the subjects who received placebo and iodine or selenium and iodine. In contrast, unsupplemented control subjects did not recover from growth retardation. Serum selenium concentrations at 12 mo were within the reference range and were significantly greater in the selenium-iodine group than in the placebo-iodine group. Serum thyroid hormone concentrations were within the reference ranges after the administration of iodine, and these values were not significantly affected by selenium supplementation. CONCLUSIONS: The results of this study do not rule out the possibility that selenium may help to prevent the occurrence of Kashin-Beck disease. However, selenium supplementation had no effect on established Kashin-Beck disease, growth, or thyroid function once iodine deficiency was corrected. These results suggest that iodine, but not selenium, deficiency should be corrected in Tibetan children with Kashin-Beck disease.