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An inability to standardize the bioinformatic data produced by whole-genome sequencing (WGS) has been a barrier to its widespread use in tuberculosis phylogenetics. The aim of this study was to carry out a phylogenetic analysis of tuberculosis in Wales, United Kingdom, using Ridom SeqSphere software for core genome multilocus sequence typing (cgMLST) analysis of whole-genome sequencing data. The phylogenetics of tuberculosis in Wales have not previously been studied. Sixty-six Mycobacterium tuberculosis isolates (including 42 outbreak-associated isolates) from south Wales were sequenced using an Illumina platform. Isolates were assigned to principal genetic groups, single nucleotide polymorphism (SNP) cluster groups, lineages, and sublineages using SNP-calling protocols. WGS data were submitted to the Ridom SeqSphere software for cgMLST analysis and analyzed alongside 179 previously lineage-defined isolates. The data set was dominated by the Euro-American lineage, with the sublineage composition being dominated by T, X, and Haarlem family strains. The cgMLST analysis successfully assigned 58 isolates to major lineages, and the results were consistent with those obtained by traditional SNP mapping methods. In addition, the cgMLST scheme was used to resolve an outbreak of tuberculosis occurring in the region. This study supports the use of a cgMLST method for standardized phylogenetic assignment of tuberculosis isolates and for outbreak resolution and provides the first insight into Welsh tuberculosis phylogenetics, identifying the presence of the Haarlem sublineage commonly associated with virulent traits.

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High rates of tuberculosis (TB) and HIV are believed to exist in Russian prisons. Prisoners with TB were studied in order to identify the following: 1) prevalence of HIV, and risk factors for HIV and other blood-borne virus infections; and 2) clinical and social factors that might compromise TB treatment effectiveness and/or patient adherence and, hence, encourage treatment failure. A 1-yr cross-sectional prevalence study of 1,345 prisoners with TB was conducted at an in-patient TB facility in Samara, Russian Federation. HIV and hepatitis B and/or C co-infection occurred in 12.2% and 24.1% of prisoners, respectively, and rates were significantly higher than in civilians. Overall, 48.6% of prisoners used drugs, of which 88.3% were intravenous users. Prisoners were more likely to be intravenous drug users and HIV positive compared with civilians with TB, and 40.2% of prisoners shared needles. Two-thirds of prisoners (68.6%) had received previous TB drug therapy (frequently multiple, interrupted courses) and were significantly more likely than civilians to have had previous therapy consistent with the high drug-resistance rates seen. Prisons are major drivers of the tuberculosis and HIV epidemics. Novel strategies are needed to reduce the spread of blood borne diseases, particularly in intravenous drug users.

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BACKGROUND: A description is given of a major outbreak of isoniazid monoresistant tuberculosis (TB) chiefly in north London, including prisons. The earliest case was diagnosed in 1995 with most cases appearing after 1999. METHODS: Confirmation of a local cluster of cases was confirmed by restriction fragment length polymorphism (RFLP IS6110) typing or "rapid epidemiological typing" (RAPET). Further cases were found by retrospective analysis of existing databases, prospective screening of new isolates, and targeted epidemiological case detection including questionnaire analysis. RESULTS: By the end of 2001, 70 confirmed cases in London had been linked with a further 13 clinical cases in contacts and nine epidemiologically linked cases outside London. The epidemic curve suggests that the peak of the outbreak has not yet been reached. Cases in the outbreak largely belong to a social group of young adults of mixed ethnic backgrounds including several individuals from professional/business backgrounds. Compared with other cases of TB reported to the enhanced surveillance scheme in London during 1999-2001, the cases are more likely to be of white (26/70 (37%) v 1308/7666 (17%)) or black Caribbean ethnicity (17/70 (24%) v 312/7666 (4%)), born in the UK (41/70 (59%) v 1335/7666 (17%)), and male (52/70 (74%) v 4195/7666 (55%)). Drug misuse and/or prison detention are factors common to many cases. CONCLUSIONS: The investigation of the outbreak revealed significant problems on an individual patient and population based level including difficulties with contact tracing, compliance, and the risk of developing multidrug resistance. This incident has demonstrated the value of molecular strain typing in investigating an extensive outbreak of TB. This is the first documented outbreak involving a UK prison.

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Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (P=0.008), ambulatory systolic blood pressure (P=0.004), and ambulatory mean arterial pressure (P=0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (P<0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (P<0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.

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Calcium channel blockers have come into worldwide use for treating hypertension and other circulatory disorders. In recent years, results of several observational studies have suggested that these drugs may not be as safe or effective as other available therapies, such as diuretics and beta-blockers, in the prevention of cardiovascular events. The Nordic Diltiazem (NORDIL) and the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) studies were the first two randomized interventional trials in hypertensive patients that directly compared the effects of therapy based on calcium antagonists with those of diuretic and beta-blocker-based treatment on major cardiovascular endpoints. Both studies found that the effectiveness of calcium antagonist therapy was similar to that of diuretic and beta-blocker therapy for preventing the composite primary endpoint of fatal and nonfatal stroke, myocardial infarction, and other cardiovascular death. The two studies shared several nonsignificant trends for cause-specific events, including greater stroke prevention and lesser coronary event prevention in the calcium antagonist groups compared with the diuretic and beta-blocker groups. There is not yet sufficient evidence to prove whether cause-specific differences exist. Results of the NORDIL and INSIGHT studies support incorporating calcium antagonist-based therapy as an additional safe and effective approach for preventing blood pressure-related illness and death.

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The principal aim of the present study was to determine the relationship of ambulatory blood pressure (BP) to urinary electrolyte excretion in normotensives. Twenty-five young adults underwent ambulatory BP and heart rate monitoring while collecting urine over 24 h. The correlations of 24 h urine sodium excretion and the ratio of sodium/potassium excretion with systolic BP in the laboratory (r = 0.12 and 0.24), ambulatory awake (r = 0.11 and 0.24), and ambulatory asleep (r = 0.24 and 0.31) settings were all in the positive direction but not significant. However, 24 h sodium excretion did correlate significantly and positively with awake and asleep ambulatory systolic (r = 0.45 and 0.41, P < .05) and diastolic (r = 0.42 and 0.43, P < .05) coefficients of variability. Thus, in normotensives on an unlimited diet, 24 h urinary sodium was more closely related to ambulatory BP variability than to BP level.

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STUDY OBJECTIVE: To compare the clinical safety and efficacy of ramipril, a new long-acting nonsulfhydryl inhibitor of angiotensin-converting enzyme (ACE), with enalapril. DESIGN: A randomized, double-blind trial. SETTING: Multicenter trial involving 4 large teaching hospitals and 12 community medical centers. PATIENTS: One hundred fifty-nine patients with mild to moderate essential hypertension were enrolled. Two patients were excluded from the efficacy analysis because they failed to return for follow-up. INTERVENTIONS: Patients were randomized to receive ramipril 2.5, 5, or 10 mg, or enalapril 5, 10, or 20 mg once/day for 3 or 4 weeks. MEASUREMENTS AND MAIN RESULTS: At baseline, supine diastolic blood pressures ranged from 98-116 mm Hg. Supine and standing systolic blood pressures were reduced by 11.8 and 10.2 mm Hg with ramipril 10 mg (p < or = 0.001) and 9.3 and 10.7 mm Hg with enalapril 20 mg (p < or = 0.001). At the end of the 4-week trial, patients in all six dosage groups had clinically and statistically significant reductions in supine diastolic blood pressure compared with baseline values. The agents did not differ significantly with respect to their blood pressure-lowering effects. Both lowered plasma ACE activity; after 4 weeks, changes from baseline were highly significant for all dosage groups (p < or = 0.001). CONCLUSION: Ramipril was as effective in reducing blood pressure and was as well tolerated as enalapril. A larger average decrease in plasma ACE activity was achieved with ramipril over all dosages (71%) compared with that for enalapril (48%), suggesting that ramipril has greater ACE inhibition in the circulation.

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In a crossover study, 12 patients with mild to moderate hypertension were given placebo, captopril (12.5 to 50 mg three times a day), and nadolol (20 to 160 mg once a day) to control the resting diastolic blood pressure to a nearly identical degree (p less than 0.0001) (106.1 +/- 4 placebo, 89.6 +/- 8 captopril, 89.8 +/- 7 nadolol). Both drugs lowered (p less than 0.0004) systolic and diastolic blood pressure at rest and during exercise. However, systolic blood pressure lowering during exercise was more pronounced (p less than 0.05) with nadolol than with captopril (difference of 6 mmHg, 16 mmHg, and 21 mmHg at 5.0, 7.0, and 9.0 metabolic equivalents (METS) respectively). Heart rate was lower (p less than 0.05) at rest and during exercise with nadolol as compared with placebo and with captopril. These data imply different mechanisms of action of the two drugs at rest and during exercise and may help in selection of drug therapy in special patient subsets.

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Enzymatically inactive renin (IR) is the predominant circulating form of renin. Sympathetic activity may influence plasma renin activity (PRA) by regulation of the conversion of IR to active renin (AR, PRA). It has been demonstrated previously that beta blockade lowers PRA at least partly through inhibition of this conversion process. The authors hypothesized that beta blockade and intrinsic sympathomimetic activity (ISA) would have opposing effects on production of AR from its inactive precursor. Eighteen primary hypertensives (12 male, 6 female, mean age 57.7 +/- 2.7) were entered in a placebo-controlled, double-blind crossover study of the effects of equipotent doses of pindolol and propranolol on mean +/- SEM systolic BP, diastolic BP, heart rate, active renin (AR), total renin (TR), inactive renin (IR), and % AR/TR. Drug dose was titrated to achieve a goal DBP of 90 mmHg or less. Active renin was defined as the rate of generation of angiotensin I in 37 degrees C plasma at pH 5.7. Total renin was determined by preincubation of plasma aliquots with 1.5 mg/mL trypsin in the presence of 5 mM benzamadine for one hour at -4 degrees C prior to assay of renin activity. Inactive renin was calculated as TR minus AR. The BP responses achieve by dose titration of propranolol and pindolol were virtually identical at rest, indicating equivalent depressor effects of the two beta blockers. Heart rate and active renin were, however, lowered to a much greater extent with propranolol as compared with pindolol. The lack of significant pindolol-induced fall in % AR/TR suggests that this drug has little net effect on the formation of AR from IR.(ABSTRACT TRUNCATED AT 250 WORDS)

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Eighty-one untreated elderly patients with clinic-defined isolated systolic hypertension (ISH) and 39 normotensive elderly subjects underwent 24-h ambulatory blood pressure monitoring. Before the ambulatory blood pressure monitoring, EDTA-anticoagulated venous blood was obtained from seated subjects for determination of plasma renin activity. Ambulatory blood pressure and heart rates were determined at 15-30-min intervals by a validated, portable non-invasive technique (Spacelabs 5200). Ambulatory blood pressure variability was defined for each subject as the standard deviation and the coefficient of variation of the ambulatory blood pressure. The mean awake systolic blood pressure was much lower than the clinic-determined value in the ISH group (P less than 0.001), but only slightly so in the normotensive group. Forty-two per cent of the clinic-defined ISH group had mean awake ambulatory systolic blood pressures below the 90th percentile of the normotensive group. A discrepancy between office and ambulatory blood pressures was not associated with blood pressure variability, heart rate or plasma renin activity.

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Clinic/office (casual), home (self), and twenty-four-hour ambulatory (ABP) blood pressure determinations were compared in 32 subjects defined by conventional office criteria as mild or borderline hypertensives. Office diastolic blood pressures (mean 93.1 +/- 5.3 mmHg) were significantly higher than either home (mean 88.9 +/- 7.1 mm Hg) or awake ABP (mean 88.4 +/- 8.4 mm Hg) readings for the total group, as well as for the mild hypertension subgroup (office mean 96.0 +/- 3.5 mm Hg, home mean 91.0 +/- 8.0, awake ABP mean 90.4 +/- 8.8) but not for the borderline subgroup. In the total study group, office diastolic blood pressure (DBP) correlated better with home DBP (r = 0.58, p = 0.0005), than with the awake ABP (r = 0.40, p = 0.02). Home DBP correlated well with awake DBP (r = 0.48, p = 0.006). In subgroup analysis, office DBPs correlated well with home (self) readings for both the mild (r = 0.53, p = 0.03) and the borderline (r = 0.62, p = 0.01) subgroups. When office DBPs were compared with awake ABP DBPs, the correlation coefficient for the mild subgroup was significant (r = 0.49, p = 0.04); this was not the case for the borderline subgroup (r = 0.10, p = NS). Comparison of home (self) DBPs with awake ABP determinations revealed a good correlation for the borderline subgroup (r = 0.63, p = 0.01) but not for the mild subgroup (r = 0.35, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

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Franz Alexander (1939) offered the hypothesis a number of years ago that hypertension can result from the inhibition of feelings of anger. Although a great deal of research has been done to test this hypothesis, the results remain equivocal. Part of the difficulty is that usually only anger was examined, making it impossible to determine the extent to which the results were specific to anger and not general for other negative emotions. A second prevalent problem has been the failure to match hypertensive and control groups on demographic variables that may be relevant to the relationship of hypertension to anger and its expression, such as education, economic level, and age. A third problem is that most studies have investigated only male hypertensives, thereby limiting the generality of the findings. The present study compares male and female hypertensives with carefully matched controls on measures of anxiety, depression, and anger and its suppression.

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A selective antagonist of S2-serotonergic receptors, ketanserin, was administered intravenously during right heart catheterization to 14 patients with pulmonary hypertension complicating systemic sclerosis. A significant reduction in pulmonary vascular resistance was noted which was accompanied by an increase in cardiac output. Paradoxical increase of pulmonary artery pressure occurred in 3 patients, whereas 2 patients with mild pulmonary hypertension normalized both pulmonary pressure and vascular resistance. Our data support the hypothesis that serotonin, released during in vivo platelet activation, influences pulmonary vascular tone in systemic sclerosis.

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Low-dose heparin has achieved wide use for the prevention of deep vein thrombosis. Full-dose heparin (20,000 U/day or more) has a well-documented suppressive effect on adrenal aldosterone production. To determine whether this effect may also occur with low-dose heparin, 5 healthy male volunteers were given heparin, 5,000 U subcutaneously every 12 h for 10 days, and their renin-aldosterone axis was studied. Plasma aldosterone fell from a mean of 17.2 ng/dl at baseline to 6.6 on day 5 and 4.3 on day 10. The 24-hour urinary aldosterone fell from 11.5 micrograms/day at baseline to 5.3 and 6.8 on days 4-5 and 9-10, respectively. After stimulation with furosemide (60 mg orally) and 4 h ambulation, plasma aldosterone remained suppressed on heparin: 22.4 ng/sl at baseline, 7.0 on day 5 and 6.2 ng/dl on day 10. Plasma renin activity, serum and urinary electrolytes, and body weight were unchanged during the study. Hence, low-dose heparin can inhibit aldosterone production. Patients receiving this treatment should be observed (during and after therapy) for impaired electrolyte homeostasis.

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Inactive renin comprises well over half the total renin in normal human plasma. There is a direct relationship between active and inactive renin levels in normal and hypertensive populations, but the proportion of inactive renin varies inversely with the active renin level; as much as 98% of plasma renin is inactive in patients with low renin, whereas the proportion is consistently lower (usually 20-60%) in high-renin states. Two hypertensive patients with proven renin-secreting carcinomas of non-renal origin (pancreas and ovary) had high plasma active renin (119 and 138 ng/h per ml) and the highest inactive renin levels we have ever observed (5,200 and 14,300 ng/h per ml; normal range 3-50). The proportion of inactive renin (98-99%) far exceeded that found in other patients with high active renin levels. A third hypertensive patient with a probable renin-secreting ovarian carcinoma exhibited a similar pattern. Inactive renins isolated from plasma and tumors of these patients were biochemically similar to semipurified inactive renins from normal plasma or cadaver kidney. All were bound by Cibacron Blue-agarose, were not retained by pepstatin-Sepharose, and had greater apparent molecular weights (Mr) than the corresponding active forms. Plasma and tumor inactive renins from the three patients were similar in size (Mr 52,000-54,000), whereas normal plasma inactive renin had a slightly larger Mr than that from kidney (56,000 vs. 50,000). Inactive renin from each source was activated irreversibly by trypsin and reversibly by dialysis to pH 3.3 at 4 degrees C; the reversal process followed the kinetics of a first-order reaction in each instance. The trypsin-activated inactive renins were all identical to semipurified active renal renin in terms of pH optimum (pH 5.5-6.0) and kinetics with homologous angiotensinogen (Michaelis constants, 0.8-1.3 microM) and inhibition by pepstatin or by serial dilutions of renin-specific antibody. These results indicate that a markedly elevated plasma inactive renin level distinguishes patients with ectopic renin production from other high-renin hypertensive states. The co-production of inactive and active renin by extrarenal neoplasms provides strong presumptive evidence that inactive renin is a biosynthetic precursor of active renin. The unusually high proportion of inactive renin in plasma and tumor extracts from such patients is consistent with ineffective precursor processing by neoplastic tissue, suggesting that if activation of "prorenin" is involved in the normal regulation of active renin levels it more likely occurs in the tissue of origin (e.g., kidney) than in the circulation.

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Prostaglandin-dependent adherent cell suppressor activity was assessed in patients with end-stage renal insufficiency. Proliferative responses of uremic peripheral blood mononuclear cells to optimal concentrations of phytohemagglutinin and concanavalin A were impaired. Responses to the galactosyl-directed lectins, soybean agglutinin and peanut agglutinin, were, however, normal or supranormal. The addition of 1 microgram/ml of indomethacin, to cell cultures resulted in relatively less potentiation of blastogenic responses to the galactosyl-directed lectins in cells from uremic patients (soybean agglutinin, p less than 0.02; peanut agglutinin, p less than 0.05). Similarly, depletion of adherent cells markedly enhanced blastogenesis induced by the galactosyl-directed lectins in normal cell cultures, whereas the effect was much less pronounced (soybean agglutinin, p less than 0.02; peanut agglutinin, p less than 0.02) in uremic cells. Reduced activity of the adherent cell suppressor system in patients with renal failure might be associated with altered sensitivity of uremic lymphocytes to soluble mediators of suppression. The lymphocytes of uremic patients, depleted of adherent cells, were relatively resistant to the inhibitory action of prostaglandin E1 (0.001 microgram/ml, p less than 0.05, and 0.01 microgram/ml, p less than 0.02) on galactosyl-directed, lectin-induced mitogenesis. In contrast, dibutyryl cyclic AMP (10(-4) M), 8-bromo cyclic AMP (10(-5) M), and 3-isobutyl-1-methyl xanthine (20 micrograms/ml) inhibited both control subject and patient cultures to the same extent. Prostaglandin E1 in combination with methyl isobutyl xanthine produced, in adherent-cell-depleted control subjects, levels of cyclic AMP that were significantly higher than in cells from uremic patients (p less than 0.05). Thus, depressed adherent cell suppressor activity in patients with renal failure may result in part from impaired generation of cyclic AMP by lymphocytes.

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