The DosR regulon of M. tuberculosis and antibacterial tolerance.

Adaptation of Mycobacterium tuberculosis to an anaerobic dormant state that is tolerant to several antibacterials is mediated largely by a set of highly expressed genes controlled by DosR. A DosR mutant was constructed to investigate whether the DosR regulon is involved in antibacterial tolerance. We demonstrate that induction of the regulon is not required for drug tolerance either in vivo during a mouse infection or in vitro during anaerobic dormancy. Thus, drug tolerance observed in these models is due to other mechanisms such as the bacilli simply being in a non-replicating or low metabolic state. Our data also demonstrate that the DosR regulon is not essential for virulence during chronic murine infection. However, decreased lung pathology was observed in the DosR mutant. We also show that the DosR regulon genes are more highly conserved in environmental mycobacteria, than in pathogenic mycobacteria lacking a latent phase or environmental reservoir. It is possible that the DosR regulon could contribute to drug tolerance in human infections; however, it is not the only mechanism and not the primary mechanism for tolerance during a mouse infection. These data suggest that the regulon evolved not for pathogenesis or drug tolerance but for adaptation to anaerobic conditions in the environment and has been adapted by M. tuberculosis for survival during latent infection.

Analysis of trials evaluating combinations of acetylsalicylic acid and dipyridamole in the secondary prevention of stroke.

BACKGROUND: Stroke is one of the leading causes of morbidity and mortality in the United States. Patients who suffer a cerebrovascular event are at high risk of a recurrence, and secondary prevention is crucial to reducing the burden of cerebrovascular disease. Acetylsalicylic acid (ASA, aspirin) is an established method of stroke prophylaxis. OBJECTIVE: This review investigates whether the addition of dipyridamole to ASA further reduces the risk of stroke recurrence. METHODS: To identify clinical trials of the use of combinations of ASA and dipyridamole in the prevention of recurrent stroke in patients who have suffered a first stroke or transient ischemic attack, the English-language literature was searched from 1966 through May 2001 using the MEDLINE, International Pharmaceutical Abstracts, EMBASE, and BIOSIS databases. The search terms used were dipyridamole, aspirin, acetylsalicylic acid, ischemic stroke, and cerebrovascular disorders. CONCLUSIONS: Of the 5 published studies, 3 earlier studies detected no differences in outcome when dipyridamole was added to ASA therapy for stroke prophylaxis. Two more recent trials found that the addition of dipyridamole to ASA therapy provided further reduction in the risk of secondary cerebrovascular events compared with placebo and with ASA alone. Further studies are needed to confirm long-term benefit.

The pattern of dyslipidemia among urban African-Americans with type 2 diabetes.

OBJECTIVE: To analyze lipid profiles from a large sample of African-American patients with type 2 diabetes who receive care at an urban outpatient diabetes clinic. RESEARCH DESIGN AND METHODS: Fasting serum lipid profiles of 4,014 African-Americans and 328 Caucasians with type 2 diabetes were retrieved from a computerized registry. American Diabetes Association criteria were applied to classify LDL cholesterol, HDL cholesterol, and triglyceride (TG) levels into risk categories. The proportion of patients who had none, one, two, and three lipoprotein concentrations outside of recommended clinical targets was examined. Multiple logistical regression analyses were performed to determine the influence of sex and race on the probability of having a lipid level outside of the recommended target. RESULTS: The percentages of African-Americans with high-, borderline-, and low-risk LDL cholesterol concentrations were 58, 26, and 16%, respectively, and the percentages for Caucasians were 54, 29, and 16%, respectively (P = 0.51). For HDL cholesterol, 41, 33, and 26% of African-Americans were in the high-, borderline-, and low-risk categories, respectively, compared with 73, 18, and 9% of Caucasians, respectively (P < 0.0001). Nearly 81% of African-Americans had TG concentrations that were in the low-risk category compared with only 50% of Caucasians. More women than men had high-risk LDL and HDL cholesterol profiles. The most common pattern of dyslipidemia was an LDL cholesterol level above target combined with an HDL cholesterol level below target, which was detected in nearly 50% of African-Americans and 42% of Caucasians. African-Americans had lower odds of having an HDL cholesterol or TG level outside of target. African-American women, compared to men, had greater probabilities of having abnormal levels of LDL and HDL, but a lower likelihood of having a TG level above goal. CONCLUSIONS: In a large sample of urban type 2 diabetic patients receiving care at a diabetes treatment program, race and sex differences in serum lipid profiles were present. Because hypertriglyceridemia was rare among African-American subjects, interventions will need to focus primarily on improving their LDL and HDL cholesterol levels. Further studies are required regarding how to best adapt these observed differences into more effective strategies to optimize lipid levels for this population of diabetic patients and to determine whether similar patterns of dyslipidemia occur in other clinical settings.

The effectiveness of a point-of-decision prompt in deterring sedentary behavior.

Individuals using a university library were observed using stairs or elevators to travel up one to three floors. After a baseline assessment, a sign was posted by the elevator to discourage elevator use over a five-week period. A hierarchical log linear analysis indicated that stair use increased significantly after the intervention moderated by day of the week, sex, and age. The study suggests that point-of-decision prompts to deter sedentary activity may be effective.

Selective loss of PMA-stimulated expression of matrix metalloproteinase 1 in HaCaT keratinocytes is correlated with the inability to induce mitogen-activated protein family kinases.

Many cell types, including fibroblasts and primary keratinocytes, increase matrix metalloproteinase 1 (MMP-1) production in response to agonists such as growth factors and phorbol esters. However, the spontaneously transformed human keratinocyte cell line HaCaT, although it increases MMP-1 production in response to epidermal growth factor (EGF), does not respond similarly to stimulation with PMA. This phenomenon occurs even though HaCaT cells remain proliferatively responsive to both agonists, suggesting a HaCaT-specific defect in a PMA-mediated signal transduction pathway. Using an inside-out approach to elucidate the source of this defect, we found that EGF, but not PMA, stimulated MMP-1 promoter activity in transiently transfected HaCaT keratinocytes. In addition, an assessment of fibroblast and HaCaT c-fos and c-jun gene expression after exposure to EGF and PMA showed that although both agonists increased the expression of c-fos and c-jun mRNA in fibroblasts, only EGF did so in HaCaT keratinocytes. Finally, we looked at the activation of mitogen-activated protein (MAP) family kinases after stimulation with EGF or PMA and found that both agonists increased the phosphorylation and activation of fibroblast extracellular signal-regulated protein kinase and c-Jun N-terminal kinase, but only EGF activated the same kinase activities in HaCaT cells. Further, the EGF-mediated increase in MMP-1 gene expression was inhibited by the MAP kinase/ERK kinase (MEK)-specific inhibitor PD98059 and the p38 kinase-specific inhibitor SB203580. Our evidence indicates that although HaCaT MAP kinases are functional, they are not properly regulated in response to the activation of protein kinase C, and that the defect that bars HaCaT MMP-1 expression in response to stimulation with PMA lies before MAP kinase activation.

A comparison of the efficacy of captopril and enalapril given once daily for the treatment of hypertension: a study using 24-hour ambulatory blood pressure monitoring.

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24-hour blood pressure profiles monitored by using one of two automatic, non-invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24-hour period, with no clinically significant difference between them.