Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement.

The emergence of drug-resistant strains of Mycobacterium tuberculosis is a challenge to global tuberculosis (TB) control. Although culture-based methods have been regarded as the gold standard for drug susceptibility testing (DST), molecular methods provide rapid information on mutations in the M. tuberculosis genome associated with resistance to anti-tuberculosis drugs. We ascertained consensus on the use of the results of molecular DST for clinical treatment decisions in TB patients. This document has been developed by TBNET and RESIST-TB groups to reach a consensus about reporting standards in the clinical use of molecular DST results. Review of the available literature and the search for evidence included hand-searching journals and searching electronic databases. The panel identified single nucleotide mutations in genomic regions of M. tuberculosis coding for katG, inhA, rpoB, embB, rrs, rpsL and gyrA that are likely related to drug resistance in vivo. Identification of any of these mutations in clinical isolates of M. tuberculosis has implications for the management of TB patients, pending the results of in vitro DST. However, false-positive and false-negative results in detecting resistance-associated mutations in drugs for which there is poor or unproven correlation between phenotypic and clinical drug resistance complicate the interpretation. Reports of molecular DST results should therefore include specific information on the mutations identified and provide guidance for clinicians on interpretation and on the choice of the appropriate initial drug regimen.

Angiotensin converting enzyme inhibition in chronic stable angina: effects on myocardial ischaemia and comparison with nifedipine.

OBJECTIVES: To determine the anti-ischaemic effects of a new angiotensin converting enzyme inhibitor, benazepril, compared with nifedipine, alone and in combination, in chronic stable angina caused by coronary artery disease. DESIGN: Placebo controlled, double blind, latin square design. SETTING: Regional cardiology service for a mixed urban and rural population. SUBJECTS: 40 patients with stable exertional angina producing at least 1 mm ST segment depression on exercise test with the Bruce protocol. 34 patients completed all four phases of the trial. INTERVENTIONS: Each patient was treated with placebo, benazepril (10 mg twice daily), nifedipine retard (20 mg twice daily), and a combination of benazepril and nifedipine in the same doses, in random order for periods of two weeks. MAIN OUTCOME MEASURES AND RESULTS: Total duration of exercise was not increased by any treatment. Exercise time to the development of 1 mm ST segment depression was not significantly changed with benazepril alone or in combination with nifedipine but was increased with nifedipine from 4.18 (1.8) min to 4.99 (1.6) min (95% confidence interval (95% CI) 0.28 to 1.34; p < 0.05). There was a significant relation between increase in duration of exercise and resting renin concentration (r = 0.498; p < 0.01). Myocardial ischaemia during daily activity, as assessed by ambulatory electrocardiographic monitoring, was reduced by benazepril and by the benazepril and nifedipine combination. This was significant for total ischaemic burden (451(628) min v 231(408) min; 95% CI -398 to -41 min; p < 0.05) and maximal depth of ST segment depression (-2.47(1.2) mm v -2.16 mm; 95% CI 0.04 to 0.57; p < 0.05) for the combination and for maximal ST segment depth for benazepril monotherapy (-2.47 (1.2) mm v -1.96(1.2) mm; 95% CI 0.18 to 0.91; p < 0.05). Benazepril significantly altered the circadian rhythm of cardiac ischaemia, abolishing the peak ischaemic periods at 0700 to 1200 and 1700 to 2300 (p < 0.05). CONCLUSIONS: Benazepril, an angiotensin converting enzyme inhibitor, had a modest anti-ischaemic effect in effort angina, but this effect was not as pronounced as with nifedipine. The anti-ischaemic action was more noticeable in asymptomatic ischaemia during daily activity, whereas nifedipine had little effect on this aspect of myocardial ischaemia. The combination of benazepril and nifedipine reduced ischaemia of daily activity.

Validity of urinary urea nitrogen as a measure of total urinary nitrogen in adult patients requiring parenteral nutrition.

The validity of the urinary urea nitrogen (UUN) estimate of total urinary nitrogen (TUN) was tested in patients who required iv nutrition. UUN and TUN were determined in 120 urine collections from ten preoperative, 13 postoperative, and 11 stressed patients. The relationship between TUN and UUN was examined by linear regression, and analysis of covariance was used on log-transformed data to assess differences between the patient groups. Although there was a close relationship between UUN and TUN for the preoperative patients (r2 = .94, total range of differences = 3.85 g N), this was not as accurate in postoperative and stressed patients (r2 = .69 and .76, respectively, total range of differences = 16.8 and 10.7 g N, respectively). There was no significant difference between the slopes of the regression lines for the relationship between UUN and TUN for three groups (f = 1.1, df = 2114, p less than .3), but the intercepts of the regression lines differed between the preoperative and stressed patient groups (t = 3.47, v = 114, p less than .001). The relationship between TUN and UUN for the whole group was improved by the inclusion of the independent variables of both the patient's clinical state and the urinary creatinine excretion. Arm muscle circumference, which is an estimate of muscle mass, may replace creatinine excretion with little loss in prediction accuracy.

A survey of computer usage amongst Auckland general practitioners.

Auckland general practitioners were surveyed to assess their use of computers. Forty-eight practitioners (9.6%) had computers which were primarily used for practice administration. The main benefit offered by the computer was an improvement in quality of work rather than a reduction in quantity. Areas of dissatisfaction revealed by the survey included cost, limited flexibility, and the consequences of computer failure. Although most respondents suggested improvements in specific areas, many felt that the age of computerised general practice had arrived.

Effect of nomifensine on the toxicity of 6-hydroxydopamine for mesotelencephalic dopamine neurons.

The ability of nomifensine to protect the dopaminergic cells of the substantia nigra and ventral tegmental areas against 6-hydroxydopamine-induced destruction was evaluated. Nomifensine at high doses (20 mg/kg, i.p.) protected the cells from the effects of low amounts of 6-hydroxydopamine (2 micrograms) injected intracerebrally. This protective effect was markedly decreased with an increased amount of 6-hydroxydopamine (8 micrograms), or by lower doses of nomifensine (6.7 mg/kg). These doses of nomifensine are higher than those required to protect dopaminergic nerve terminals.

Retrograde transport of dopamine beta-hydroxylase antibodies in sympathetic neurons: effects of drugs modifying noradrenergic transmission.

Antibodies to dopamine beta-hydroxylase (anti-D beta H) were taken up by noradrenergic nerve terminals in the iris following attachment to D beta H, and were transported back to, and accumulated in, the superior cervical ganglion (SCG). Concurrent, or prior destruction of noradrenergic terminals with 6-hydroxydopamine, injected intraocularly, blocked the retrograde transport of anti-D beta H. However, recovery was rapid, reaching 50% of control values within 1 day. Such transport was characterized by a shorter time period before accumulation could be detected in the SCG and by a slower rate of accumulation. These results suggest that noradrenergic neurons recover their ability to turn over synaptic vesicles by exocytosis and transport these back to the ganglion early during the period of axonal regeneration when the axonal length is shorter than normal. The uptake and transport of anti-D beta H was regulated by alpha-adrenergic agents administered locally in the vicinity of noradrenergic nerve terminals. Thus intraocular injection of phentolamine resulted in an increased accumulation of anti-D beta H in the SCG, while amphetamine and the postsynaptic alpha-receptor antagonist, phenylephrine, decreased accumulation. Clonidine and desipramine, which have a predominant presynaptic action, failed to influence the transport of anti-D beta H. These results suggest that in vivo the uptake of anti-D beta H can be increased more by local postsynaptic reflex actions than by a mechanism depending on the inhibition of presynaptic alpha-receptors.

Increases in skin resistance of white rats following scopolamine injection.

Thirty-six male albino rats were injected with either saline or 0.6 mg/kg scopolamine and placed on a metal grid. The grid was wired to a transistor-biased detector which determined, every second, whether the subject's resistance was above or below a preset threshold value. Over test sessions of five minutes, drug subject's resistances were above each of the three threshold values used (5, 10, 15 megohms) for significantly longer than those of control subjects. Scopolamine treated rats would therefore receive lower shock levels than control subjects in a shock experiment.

Modification of novelty preferences in rats by current and prior treatment with scopolamine and methylscopolamine.

Two experimental paradigms were adopted to compare effects of scopolamine and its quaternary derivative, methylscopolamine, on the behaviour of albino rats in an exploration box comprising novel and familiar halves. Subjects tested with the first paradigm were exposed to one of the halves, injected and then observed 20 min later. Although both drugs reduced preferences for the previously inaccessible novel half, only scopolamine decreased rearing and increased ambulation. With the second paradigm, behaviour was assessed without any current drug influence. On the 2 days prior to testing the rats had been exposed to one half of the apparatus while drugged. Prior treatment with both scopolamine and methylscopolamine reduced novelty preference to the extent that the familiar half of the apparatus was preferred. Both drugs also reduced rearing (for females only) and ambulation. It was concluded that the results with both paradigms provided some support for the view that reductions in novelty preference by anticholinergic drugs arise from their aversive peripheral actions.