Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali.

The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.

Extended antiretroviral treatment interruption in HIV-infected patients with long-term suppression of plasma HIV RNA.

OBJECTIVES: Evaluation of extended treatment interruption (TI) in chronic HIV infection among patients successfully treated with antiretroviral therapy. METHODS: An observational analysis of 25 patients in a prospectively followed cohort with chronic HIV infection, viral loads <500 HIV-1 RNA copies/mL for at least 6 months, and an interruption in therapy of >/=28 days duration was carried out. Follow up was divided into 3-month time periods for analysis. The effects of time period, stratification group and stratification group by time period interactions on CD4 counts were tested using a mixed model. Univariate comparisons among patient characteristics and responses were performed using Fisher's exact test or the Wilcoxon rank sum test. RESULTS: At initiation of TI, the median CD4 count was 799 cells/microL. TI duration was a median of 7.1 months. HIV RNA rebounded to a median maximum level of 75 000 copies/mL. Maximum viral rebound was significantly greater in patients who were male, had lipodystrophy and had zenith HIV RNA prior to TI of >/=50 000 copies/mL. Lower CD4 cell counts were observed during TI in patients with lipodystrophy, zenith HIV RNA >/=50 000 copies/mL, history of AIDS, HIV infection >/=5 years and presuppression CD4 count

Verbal perseveration after right-unilateral ECT.

After electroconvulsive therapy (ECT), many patients experience a decrement in their mnestic capacity. We studied episodic memory in eight severely depressed patients treated with a course of right-unilateral ECT. For this purpose, a testing instrument was constructed by the authors. It was made of paper cards that held four pieces of information, namely a word, a number, a figure, and the color of the card. One of the cards was presented to the patients and the respective information was asked for on the subsequent day. Patients were tested every morning during the first two weeks of the ECT course. About half of the responses were correct. Patients did best in recalling the color; they did worst in recalling the number. Seven of the patients showed verbal perseverations. This is in accordance with the literature on perseveration in patients with neurologic deficits, especially in proactive-inhibitory tasks. Perseveration may be attributed to a deficit in selective attention, producing an arousal of irrelevant cues.

U.S. hospital care for HIV-infected persons and the role of public, private, and Veterans Administration hospitals.

Hospitals are a major provider of medical care for human immunodeficiency virus (HIV)-infected persons. Although utilization and patterns of care profiles in public and private hospitals have been evaluated for acquired immunodeficiency syndrome (AIDS)-related Pneumocystis carinii pneumonia (PCP), one of the most costly and common severe complications of AIDS, information from Veterans Administration (VA) hospitals has not been reported previously. This article reports on inpatient care for PCP patients by obtaining data from VA, private, and public hospitals. Cost and resource utilization data were obtained from reviews of medical records, claims, and provider bills from 26 non-VA hospitals and 18 VA hospitals in 10 cities in the United States. Data on severity of illness, patterns of care, and outcomes for PCP were obtained from medical record reviews from 2,174 PCP cases treated in 82 non-VA and 14 VA hospitals in five U.S. cities. Estimates were made of the average costs and the rates of use of diagnostic tests, anti-PCP medications, and intensive care units for samples of public hospital, private hospital, and VA patients with PCP. With mean charges for a single PCP episode of $14,500 to $16,060, PCP remains one of thea most costly complications of AIDS. Although the severity of PCP illness at admission was greatest at public hospitals, the intensity of care was lowest: for frequency of cytologic diagnosis (48% at public, 62% at VA, and 66% at private hospitals), bronchoscopy (45% at public, 60% at VA, and 66% at private hospitals), and intensive care unit use (11% at public, 22% at VA, and 19% at private hospitals). In-hospital mortality rates for PCP also differed in the three types of hospitals (20% at public, 24% at VA, and 18% at private hospitals). Patterns of PCP care differ among VA, public, and private hospitals. Future studies on the HIV epidemic should include data collected from uniform data sources from VA hospitals, in addition to public and private hospitals, to provide insight on the processes of care and outcomes for HIV-infected persons.

Predictors of resource utilization for hospitalized patients with Pneumocystis carinii pneumonia (PCP): a summary of effects from the multi-city study of quality of PCP care.

To determine whether patient and hospital characteristics were significantly associated with variations in Pneumocystis carinii (PCP) care and outcomes, we analyzed the use of diagnostic tests, intensive care units (ICUs), anti-PCP medications for persons hospitalized with human immunodeficiency virus (HIV)-related PCP, and hospital discharge status. We conducted retrospective chart reviews of a cohort of 2,174 patients with PCP hospitalized in 1987-1990. Outcomes included process of care for PCP and in-hospital mortality rates. Persons with PCP who were more severely ill at admission were more likely to have early medical care, to receive care in an intensive care unit, and to die in hospital. After we adjusted for differences in this severity of illness, we noted that Medicaid patients, injection drug users (IDUs), and patients treated at VA or county hospitals were significantly less likely than others to have diagnostic bronchoscopies and that persons covered by Medicaid, with a previous diagnosis of acquired immunodeficiency syndrome (AIDS), who did not receive prior zidovudine (AZT) or who received care in a VA hospital had the highest chances of in-hospital death. Insurance and risk group characteristics, severity of illness, and hospital characteristics appear to be the most important determinants of the intensity and timing of medical care and outcomes among patients hospitalized with PCP.

Resolution of ouabain-sensitive and extracellular K+-activated Na+ extrusion in cardiac tissue.

Intracellular sodium activity (aiNa) was measured in sheep cardiac Purkinje fibres exposed intermittently to calcium-free solutions containing 1.3 mM-Na+ with 0-16 mM-K+ and 0-0.2 mM ouabain. In potassium-free solution (O K+) mean maximum Na+ pump activity (i.e. excluding Na+ influx and Na+-Ca2+ exchange) was 61% of that in the 4 mM-K+ control solution; in 0.2mM-ouabain-4 mM-K+ it was still 44% of control. This high ouabain concentration abolished Na+ extrusion only in O K+ while reducing it by the same absolute amount at all other extracellular K+ concentrations. The Na+ pump may therefore have two independent components in cardiac tissue.

The response of the calcium dependent myocardial contractility to the new cardiotonic agent sulmazole.

In vitro and in vivo animal experiments to test the positive inotropism of 2-[(2-methoxy-4-methylsulfinyl)-phenyl]-1H-imidazo[4,5-b]pyridine (sulmazole, AR-L 115 BS) have shown increases of contractility of up to 220% in the mmol/l concentration range. Comparative studies designed to attribute to sulmazole mechanisms established for other positive inotropic drugs have been negative for digitalis and beta-adrenoceptor agonists but showed slight similarities to xanthine derivatives. To explore the yet unknown mode of action of sulmazole we investigated the interaction between sulmazole and non-humoral/non-drug interventions for positive inotropism in vitro. Peak tension obtained in solutions varying in calcium content between 0.36 and 7.2 mmol/l Ca2+ were normalized with respect to the tension measured at standard 1.8 mmol/l Ca2+ for control and sulmazole treated preparations (sheep interventricularis cordis muscle and guinea pig papillary muscle). Double logarithmic plots of normalized tension versus calcium concentration were linear and superimposable for control, 10(-4), and 10(-3) mol/l sulmazole. In depleted sodium solutions (choline substitution) normalized peak tension of control and 10(-4) mol/l sulmazole containing solutions did not significantly differ. In length-tension plots sulmazole behaved as did increased extracellular calcium. We assume that the positive inotropism of sulmazole is primarily due to a displacement of calcium at non-specific ligand sites within the protein matrix of the cytosol which effectively raises the apparent intracellular calcium activity.

Effects of the new cardiotonic agent sulmazole on the slow inward current of sheep cardiac Purkinje fibres.

The new cardiotonic agent 2-[(2-methoxy-4-methylsulfinyl)-phenyl]-1H-imidazo[4,5-b]pyridine (sulmazole, AR-L 115 BS) has marked positive inotropism but causes a depression in the plateau phase of the action potential of cardiac Purkinje fibres. This loss of plateau is known to occur with calcium antagonists which reduce contractility. In order to identify the mechanism underlying this possibly controversal effect the slow (calcium dependent) inward current (isi) was measured using the double microelectrode voltage clamp technique. In this current system, sulmazole was observed to have a slight effect on the inactivation parameter f infinity of isi by shifting it in hyperpolarizing direction. This increase in inactivation was considered when isi was determined. However, isi itself is reduced quite considerably and the linear instantaneous current voltage relationship is shifted to negative potentials. The kinetics of activation (d infinity) are not affected by sulmazole. From the more or less parallel shifts of isi we conclude that the reversal potential of isi is decreased which in turn strongly indicates an increase of intracellular calcium ion concentration. The reduction of isi by sulmazole is not the result of a specific membrane effect as in the case of some calcium antagonists. Sulmazole does not generate its positive inotropism by way of an increased slow inward current as do beta-adrenoceptor agonists but rather reduces the slow inward current by means of a negative shift of Eisi and a decrease in isi-driving force after it has affected intracellular calcium.

Thallium determinations in fetal tissues and maternal brain and kidney.

The transfer of T1+ cations through the placental barrier of pregnant mice and rats was studied by comparing the thallium concentrations in the maternal brain and kidney and those in fetal tissue at times of 10 min to 50 h after dosage of the animals with 10 mg/kg body wt. T1(2)SO4. The quantitative determinations were performed with field desorption mass spectrometry after dilution of the homogenised tissue samples with enriched stable isotopes of thallium. The total sample quantity required for one complete assay is 1-3 micrograms, the analysis time for one determination about 30 min.

Determination of rubidium in human serum.

Field desorption mass spectrometry (FD-MS) combined with stable isotope dilution has been used to determine rubidium concentrations from human serum. Samples obtained from 110 healthy volunteers (50 males, 60 females) were examined. The rubidium concentrations found varied from 0.96 to 3.56 mumoles/l, the average value being 1.96 mumoles/l. The precision of the measurements within a batch was 0.8%. The time for 1 analysis, including sample preparation is about 30 min, the total sample consumption is 100-200 mul. The corresponding potassium concentrations were also determined from all these serum samples; a weak trend towards higher potassium levels with increasing rubidium concentration is found.

The influence of a new cardiotonic drug, acrihellin, on sinus node and the current underlying pacemaker activity of cardiac Purkinje fibres.

The spontaneous beating frequency of guinea pig sino-atrial preparations was observed under the influence of 3 beta, 5, 14-trihydroxy-19-oxo-5 beta-bufa-20,22-dienolide-3-(3-methylcrotonate (D 12316, acrihellin), a new cardiotonic drug. There was a slight acceleration of spontaneous frequency after administering rather high doses (10(-6) mol/l) of the drug. Voltage clamp experiments were performed in sheep cardiac Purkinje fibres. AcriheLlin strongly affected the current underlying pacemaker activity, ik2. The kinetic parameter s infinity of this current system was shifted in the hyperpolarizing direction by 4-13 mV. The amplitude of the pacemaker current in Purkinje fibres was reduced by up to 25% in voltage clamp experiments, but the reversal potential and the inward going rectification were left unchanged. After exposure to adrenaline (epinephrine) the well-known depolarizing shift of s infinity was partially restored by acrihellin. This can be interpreted as an antiadrenergic effect of the drug similar to that of beta-adrenoceptor antagonists. However, beta-blockers do not affect the pacemaker kinetics of fibres untreated with adrenaline as does acrihellin. This suggests that the interplay of acrihellin and adrenaline is not that of an agonist and antagonist at a membrane receptor but rather the overlapping of two separate membrane effects.

Effects of acrihellin on cardiac contractility in comparison to various inotropic interventions.

The inotropic effects of the new cardiotonic drug 3 beta,5,14-trihydroxy-19-oxo-5 beta-bufa-20,22-dienolide-3-(3-methylcrotonate) (D 12316, acrihellin) were investigated using twitch contractions time to peak and twitch lengths did not change. Peak tension increased by 140% on an average in 12 experiments at 10(-6) mol/l (acrihellin). In the dose-response curve half maximal positive inotropism occurred at approx. 10(-7) mol/l. Experiments on length tension relationships of resting and twitch tension confirmed that resting tension does not change at any stretch length after administering acrihellin. The position Lmax of maximal twitch contraction force also was not changed but in normalized length-tension cones the positive slope region showed an increase relative to maximal tension which is a feature of positive inotropic interventions. Measurements of contractility in various external calcium solutions between 0.45 mmol/l and 7.2 mmol/l gave evidence that the response of contraction force of fibres exposed to acrihellin to variation of external calcium differs from untreated fibres which respond more strongly. This behaviour of the cardiosteroid acrihellin was very similar to that of adrenaline (epinephrine) whereas digoxin and ouabain did not affect the response of twitch force to changes in external calcium.

Voltage clamp study of the action of the new cardiotonic compound acrihellin on fast and slow inward currents in cardiac Purkinje fibres.

The action of 3 beta,5,14-trihydroxy-19-oxo-5 beta-bufa-20,22-dienolide-3-(3-methylcrotonate) (D 12316, acrihellin) on the fast and slow inward currents of sheep cardiac Purkinje fibres was analyzed by means of a conventional double microelectrode voltage clamp technique. Acrihellin diminished action potential duration and the plateau phase. Effective refractory periods were shortened in relation to the decrease in action potential duration. The upstroke velocity was slightly decreased; a systematic study of dV/dtmax, however, did not reveal any specific local anaesthetic side-effect of the drug. The decrease in the plateau phase of the action potential was due to a reduction in time-dependent slow inward current. The kinetics and the reversal potential of the slow inward current was not affected by acrihellin, but only the current voltage relationship, which was decreased.

Tl+-ions: effects on the automaticity of sinoatrial tissue and dV/dtmax and iK2 of cardiac Purkinje fibres.

The disrhythmic effects of thallium were investigated in various cardiac tissues to determine the primary site of intoxication with respect to ensuing arrhythmias. In isolated cardiac tissue Lameijer and van Zwieten [1] had contended that arrhythmias arise from the sinus node after thallium poisoning. To test this hypothesis we administered concentrations of Tl+ between 10(-7) and 10(-4) M to guinea pig sinoatrial preparations, to guinea pig papillary muscles and to sheep cardiac Purkinje fibres. In sinoartial preparations thallium provoked increases and decreases of spontaneous beat frequency which were not linked to corresponding changes in contractile force. In conductive tissue, Purkinje fibres, the inactivation kinetics of the fast sodium current and the pacemaker current iK2 were investigated by voltage clamp experiments. Here, thallium was seen to be essentially without toxic effects which could account for arrhythmias. In ventricular muscle actions potentials and contractile force were recorded simultaneously. Here again, ventricular arrhythmias are not to be expected from thallium intoxication in rather high concentrations. The findings support the view that arrhythmogenic effects of thallium are restricted to the sinus node.

Tl+-ions: influence on cardiac contractility.

Attention has recently focussed on the heavy metal thallium as an environmental contaminant of increasing importance. From accidental or suicidal ingestions of thallium it has been known for many years that cardiovascular disorders regularly emerge, and for this reason, a variety of investigations of cardiological interest have been conducted. Amongst these, the effects of thallium on the contractile force of isolated myocardial tissues have been studied. Previous experiments were all carried out at concentrations far beyond those encountered during intoxication and yielded controversal data. We therefore reinvestigated the effects of thallium on myocardial tissue at levels between l0(-8) and 10(-3) M, thus covering the range of thallium concentrations encountered after uptake from a polluted environment through those seen after unintentional or intentional ingestion to levels at which previous studies were performed. Sheep interventricular cordis muscles were used at a stimulation frequency of 0.4 Hz showing three types of responses to thallium exposure. From a total of 32 experiments in 15% of all cases thallium caused a persistent increase in contractility which tended to decrease with time and thallium concentration but always remained greater than the control value. 50% of the experiments showed a progressive loss of contractile force with time and thallium concentration, despite transient increases in contractility which lasted for only 2-5 min after the application of each new thallium concentration. A combination of these types of reaction was observed in the remaining experiments in that a low thallium concentrations myocardial contractility increased considerably but then decreased progressively with time and thallium concentration. Guinea pig papillary muscles were used to test one thallium concentration only for up to 75 min. At 10(-8) M there was no effect, at 10(-7), 10(-6), 10(-5) M Tl+ there were positive inotropic transients followed by an inotropic decay; at 10(-4) M Tl+ only a progressive decrease of contractility was observed. The relationships between time and thallium concentration at different rates of stimulation were examined in two series of experiments at 0.1, 0.2, 0.4, 1.0, and 2.0 Hz. The effects of thallium were accelerated with increased beating rate and the decay of contraction also proceeded to markedly lower levels. In the rested state, thallium was also very effectual; this was illustrated in two series of experiments in which after 10 min intervals of quiescency 15 or more test stimuli were applied at different beating rates (0.1 to 2.0 Hz). The configurations of the resulting staircase phenomena were analyzed with respect to control behavior for each frequency of the test stimuli and for each thallium concentration. These results suggested an involvement of the slow inward current. The steady state values after quiescency showed a pronounced thallium-induced decay similar to that obtained at high constant stimulation rates...

A voltage clamp study of the effects of AR-L 115 BS on the pacemaker current of cardiac Purkinje fibres.

The new cardiotonic agent AR-L 115 BS was investigated by means of the double-micro-electrode voltage clamp technique on sheep cardiac Purkinje fibres. Clinical and pharmacological studies show that AR-L 115 BS increases heart rate as a side effect at medium to high therapeutic doses. The classical analysis of the pacemaker current was therefore performed to study the possible mechanism of this effect at a cellular level. The kinetic parameter s infinity and the reversal potential of the pacemaker current were shifted in the depolarizing direction after exposure to AR-L 115 BS. Peak values of the fully activated pacemaker current were either increased or diminished, while potassium leakage was slightly increased. These results are not related to the action of AR-L 115 BS on beta-adrenergic receptors but possibly due to enhanced intracellular calcium (see third paper in this series). Despite its tendency to increase heart rate, high concentrations of AR-L 115 BS should not be expected to promote arrhythmias in the Purkinje system since the electrophysiological effects tend to counteract each other.

The action of beta-adrenoceptor antagonist penbutolol on the pacemaker current of cardiac Purkinje fibres.

The action of beta-adrenoceptor antagonist penbutolol on the current underlying pacemaker activity in cardiac Purkinje fibres was analysed using the voltage clamp technique described by DECK et al. (1964). After the application of adrenalin, beta-blockers are able to counteract the well known shift of the s-kinetics of the pacemaker current. However, without any prior application of adrenalin the beta-blocker Penbutolol has no effect on these kinetics except for a small depression of the amplitude of the pacemaker current tails. The rectifier properties of the pacemaker current and the negative slope of the fully activated current voltage relationship of iK2 are unchanged. Penbutolol is able--even after a longer period of washout (about 60-90 min was necessary)--to protect the beta-adrenoceptors from the action of adrenalin (HASHIMOTO et al., 1979). These findings suggest that beta-blockers are competitive inhibitors of beta-stimulators and further support the notion that the pacemaker current in cardiac Purkinje fibres is controlled by beta-adrenoceptors.