Efficiency of work of inspiratory muscles in standing and in exercising dogs

The objective of this study was to elucidate the resistive, elastic, and total inspiratory muscle work and mainly the efficiency of the inspiratory muscle work in still standing and in exercising dogs. In 180 experiments with nine mongrel dogs, respiratory and circulatory functions were recorded at rest and during a 1.5-mph walk on a treadmill belt which was inclined by 9 degrees. Each dog had been trained and surgically prepared before the series of experiments started. An electronic pressure transducer together with a fluid-filled catheter was attached to the ribs at the midthoracic level. Airflow was monitored with a pneumotachygraph attached to a face mask. Aortic flow was monitored with an electromagnetic flow transducer. Catheters in the atria, the ventricles, and the pulmonary and systemic vessels were used to determine hemodynamic parameters and blood gas levels. All recorded and all derived functions were evaluated by a dedicated computer. At rest, resistive inspiratory work (0.98 kg cm) was smaller than elastic work (1.36 kg cm). Elastic work did not change with exercise but resistive work increased to 1.46 kg.cm. The increase of total work from 2.33 kg.cm at rest to 2.79 kg.cm during exercise did not reach significance. Inspiratory power increased with exercise. Estimated diaphragmatic oxygen consumption increased from 2.23 ml/min at rest to 3.64 ml/min during exercise. It was 1.6 percent of the total oxygen consumption at rest and 1.7 percent of the total oxygen consumption during exercise. The estimated efficiency of the work of inspiratory muscles was 15.8 percent at rest and 25.8 percent during exercise. These values did not vary substantially between different animals.     

Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS

OBJECTIVE: To assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. DESIGN: A phase I/II dose-escalation study of oral azithromycin in combination with pyrimethamine. SETTING: Eight clinical sites in the United States. PATIENTS: Forty-two adult HIV-infected patients with confirmed or presumed acute TE. METHODS: Patients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500 mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy. MAIN OUTCOME MEASURES: Patient response was evaluated clinically and radiologically. RESULTS: Of the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose. CONCLUSION: The combination of azithromycin (900-1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common.     

Myocardial and microcirculatory kinetics of BR14, a novel third-generation intravenous ultrasound contrast agent

OBJECTIVES: This study sought to investigate the myocardial and microvascular kinetics of BR14, a novel third-generation ultrasound contrast agent. BACKGROUND: BR14 produces persistent myocardial opacification after the administration of a single intravenous bolus when the left ventricular cavity contrast has considerably diminished. The mechanism of this finding is unknown. METHODS: Nine open-chest dogs with non-critical stenosis of a single coronary artery were given intravenous bolus injections of BR14 during coronary hyperemia. Time versus acoustic intensity (AI) plots were generated from the normal and stenosed beds and myocardial blood flow (MBF) was measured with radiolabeled microspheres. Intravital microscopy was performed on an exteriorized cremaster muscle in 11 wild-type mice to study the microvascular kinetics of the agent. RESULTS: At peak contrast enhancement, the ratio between AI in the stenosed and normal bed was 0.44+/-0.23, which was similar to the radiolabeled microsphere-derived MBF ratio between the two beds (0.45 +/-0.20). At 400 s after injection, the AI ratio between the two beds approximated unity (0.99+/-0.07) despite no changes in MBF, indicating redistribution of the agent. The myocardial kinetics of BR14 was best characterized by a modified lagged normal density function. Only about 3% of administered microbubbles were estimated to be retained in the myocardium. Intravital microscopy showed that most of these bubbles were retained only transiently (2 to 3 s) within capillaries. CONCLUSIONS: BR14 demonstrates redistribution because of transient retention within capillaries. Therefore, similar to (201)Tl, it could potentially be used to detect both coronary stenosis and myocardial viability after a single injection during stress.     

Rediocides B-E, potent insecticides from Trigonostemon reidioides

Four new congeners, rediocides B-E (2-5), of the previously reported rediocide A (1) were isolated from a methanol extract of the roots of the plant Trigonostemon reidioides. The structures of these minor analogues were elucidated by comparison of their NMR and mass spectral data with those of rediocide A and confirmed by extensive 2D NMR spectral analysis. They all possess potent activity against fleas (Ctenocephalides felis) in an artificial membrane feeding system and exhibited LD(90) values ranging from 0.25 to 0.5 ppm.     

Isolation, structure, absolute stereochemistry, and HIV-1 integrase inhibitory activity of integrasone, a novel fungal polyketide

HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition is one of the most promising new drug targets for anti-retroviral therapy with potentially significant advantages over existing therapies. In this Note, the isolation, structure elucidation, and absolute stereochemistry of integrasone, a novel polyketide, derived from an unidentified sterile mycelium have been described. This bicyclic dihydroxy epoxide lactone inhibited the strand transfer reaction of HIV-1 integrase with an IC(50) of 41 microM.     

Health status,health behaviour and healthcare use among migrants in the UK: Evidence from mothers in the Millennium Cohort Study

The health of migrants in the UK and their access to healthcare is of considerable policy interest. There is evidence of ethnic inequalities in health and access to and use of healthcare but insufficient consideration of the importance of birth abroad and length of residence in the UK. This study examines indicators of health status, behaviour and healthcare use among mothers of infants in the Millennium Cohort Study, according to whether born in the UK or abroad, individual ethnic grouping, and length of residence. Our findings show there are both positive and negative health indicators associated with ethnicity, birth abroad, and length of residence and presenting results on a single factor in isolation could lead to a misinterpretation of associations. For mothers ethnicity has an important relationship with most health indicators independent of country of birth, length of residence and socio-demographic circumstances. Once adjusted for ethnicity and socio-demographic variables, association with birth abroad disappears for most health outcomes suggesting that there may not be an independent migrant penalty in health. There is a linear trend in decreasing health status with increasing length of residence but no independent association between length of residence and healthcare use. This suggests that while there are continuing barriers to good health for migrants in the receiving society as shown in other studies, factors important for one health outcome may not apply to another. Our findings challenge linear acculturation models for migrants’ health in showing that a linear trend in improving socio-economic circumstances for mothers in some ethnic groups is not always associated with better health outcomes or changes in health behaviour. Our results point to a need for a comprehensive collection of information and analysis for all categories of migrants for understanding patterns of and factors underlying health and use of healthcare.     

Method for the quantitation of myocardial perfusion during myocardial contrast two-dimensional echocardiography

This article describes the hardware and software components of two systems designed for quantitative analysis of data obtained during myocardial contrast two-dimensional echocardiography. One system is meant for off-line analysis of data, whereas the other is designed for on-line analysis, especially in the operating room. The algorithms used for data transfer, selection of appropriate frames, data alignment, derivation of time-intensity plots, and curve-fitting and parameter generation are described in some detail. It is hoped that this information will be of use to others who work in the field of myocardial perfusion imaging.     

Direct effects of dobutamine on the coronary microcirculation: comparison with adenosine using myocardial contrast echocardiography.

The direct effects of dobutamine on capillary blood volume (VOL) and blood flow velocity (VEL) are not known. We hypothesized that these would be more similar to that of adenosine because of its effects on the beta(2) receptors on the coronary circulation. A total of 9 open-chest anesthetized dogs were studied after placement of 2 noncritical stenoses at rest and during separate intracoronary administrations of 5 microg/kg(-1)/min(-1) of adenosine and 2 microg/kg(-1)/min(-1) of dobutamine. VOL and VEL were measured using myocardial contrast echocardiography, wall thickening with 2-dimensional echocardiography, and myocardial blood flow (MBF) with radiolabeled microspheres. Dobutamine increased the rate-pressure product significantly, whereas adenosine had no effect on the rate-pressure product. In the normal myocardium, adenosine had no effect on VOL and increases in MBF were all a result of increases in VEL. Dobutamine also caused mostly an increase in VEL and only a 30% increase in VOL indicating modest capillary recruitment. In the bed with stenosis both drugs attenuated increase in MBF by the same amount, which was associated with an attenuation in the increase in VEL secondary to a 15% increase in capillary resistance because of capillary derecruitment. The MBF-wall thickening relation was described for both drugs by the same function: y = 1 - exp(x) with wall thickening being significantly higher for dobutamine compared with adenosine for each level of MBF. We conclude that the increase in MBF in the normal myocardium with intracoronary dobutamine occurs mostly from an increase in VEL rather than from an increase in VOL. In the bed with a noncritical stenosis, the increases in MBF and VEL are similar for both drugs. Similar to intracoronary adenosine, intracoronary dobutamine also caused capillary derecruitment distal to a noncritical coronary stenosis.