The mycobacterial cell-wall as target for antimycobacterial drugs. I--Synthesis and activity of some diphenylalkylanalogues of mycolic acids

Mycolic acids are 2-alkyl-3-hydroxyfatty acids and are essential parts of the peptidoglycan of mycobacteria. Potential antimetabolites were prepared by substituting a longchain alkylgroup by a diphenylmethylfunction. 3-Oxo esters and 3-hydroxy esters and acids were prepared. The 3-oxo esters showed a slight activity against M. tuberculosis and some atypical mycobacteria.     

Effects of epinephrine and norepinephrine on hemodynamics,oxidative metabolism,and organ energetics in endotoxemic rats

OBJECTIVE: To determine whether epinephrine increases lactate concentration in sepsis through hypoxia or through a particular thermogenic or metabolic pathway. DESIGN: Prospective, controlled experimental study in rats. SETTING: Experimental laboratory in a university teaching hospital. INTERVENTIONS: Three groups of anesthetized, mechanically ventilated male Wistar rats received an intravenous infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after 90 min by epinephrine ( n=14), norepinephrine ( n=14), or hydroxyethyl starch ( n=14). Three groups of six rats served as time-matched control groups and received saline, epinephrine, or norepinephrine from 90 to 180 degrees min. Mean arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after endotoxin challenge. At the end of experiments biopsy samples were taken from the liver, heart, muscle, kidney, and small intestine for tissue adenine nucleotide and lactate/pyruvate measurements. MEASUREMENTS AND RESULTS: Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric, and renal blood flow. Plasmatic and tissue lactate increased with a high lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs. Epinephrine and norepinephrine increased mean arterial pressure to baseline values. Epinephrine increased aortic blood flow while renal blood low decreased with both drugs. Plasmatic lactate increased with a stable L/P ratio with epinephrine and did not change with norepinephrine compared to endotoxin values. Nevertheless epinephrine and norepinephrine when compared to endotoxin values did not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or liver. In kidney both drugs decreased ATP concentration. CONCLUSIONS: Our data demonstrate in a rat model of endotoxemia that epinephrine-induced hyperlactatemia is not related to cellular hypoxia.     

Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation

OBJECTIVE: To study the factors associated with relative adrenocortical deficiency in mechanically ventilated, critically ill patients. DESIGN AND SETTING: Prospective observational study in a multidisciplinary ICU of a university-affiliated teaching hospital. PATIENTS: Sixty-two consecutive, acutely ill patients needing mechanical ventilation for more than 24 h. MEASUREMENTS AND RESULTS: A high-dose short corticotropin test 24 h after endotracheal intubation. Relative adrenocortical deficiency ("nonresponder" group of patients) was defined by a rise in cortisol less than 90 microg/l after stimulation. Twenty-seven patients were classified as nonresponders and 35 as responders. On univariate analysis nonresponders were more often men, had lower mean arterial pressure, required vasoactive agents more often, had lower creatinine clearance, higher SAPS II, higher organ dysfunction scores, and received etomidate as a single bolus for endotracheal intubation more often than responders. On multivariate analysis, only etomidate administration was related to relative adrenocortical deficiency (OR 12.21; 95% CI 2.99-49.74) while female gender was protective (OR 0.13; 95% CI 0.03-0.57). CONCLUSIONS: A single bolus infusion of etomidate could be a major risk factor for the development of relative adrenocortical deficiency in ICU patients for at least 24 h after administration. Female gender is an independent protective factor.     

Cost-effectiveness of activated protein C in real-life clinical practice

Background

Recombinant human activated protein C (rhAPC) has been reported to be cost-effective in severely ill septic patients in studies using data from a pivotal randomized trial. We evaluated the cost-effectiveness of rhAPC in patients with severe sepsis and multiple organ failure in real-life intensive care practice.

Methods

We conducted a prospective observational study involving adult patients recruited before and after licensure of rhAPC in France. Inclusion criteria were applied according to the label approved in Europe. The expected recruitment bias was controlled by building a sample of patients matched for propensity score. Complete hospitalization costs were quantified using a regression equation involving intensive care units variables. rhAPC acquisition costs were added, assuming that all costs associated with rhAPC were already included in the equation. Cost comparisons were conducted using the nonparametric bootstrap method. Cost-effectiveness quadrants and acceptability curves were used to assess uncertainty of the cost-effectiveness ratio.

Results

In the initial cohort (n = 1096), post-license patients were younger, had less co-morbid conditions and had failure of more organs than did pre-license patients (for all: P < 0.0001). In the matched sample (n = 840) the mean age was 62.4 ± 14.9 years, Simplified Acute Physiology Score II was 56.7 ± 18.5, and the number of organ failures was 3.20 ± 0.83. When rhAPC was used, 28-day mortality tended to be reduced (34.1% post-license versus 37.4% pre-license, P = 0.34), bleeding events were more frequent (21.7% versus 13.6%, P = 0.002) and hospital costs were higher (€47,870 versus €36,717, P < 0.05). The incremental cost-effectiveness ratios gained were as follows: €20,278 per life-year gained and €33,797 per quality-adjusted life-year gained. There was a 74.5% probability that rhAPC would be cost-effective if there were willingness to pay €50,000 per life-year gained. The probability was 64.3% if there were willingness to pay €50,000 per quality-adjusted life-year gained.

Conclusion

This study, conducted in matched patient populations, demonstrated that in real-life clinical practice the probability that rhAPC will be cost-effective if one is willing to pay €50,000 per life-year gained is 74.5%.     

Bayesian detection of abnormal hematological values to introduce a no-start rule for heterogeneous populations of athletes

Sports authorities exclude athletes with abnormal levels of blood parameters. Here, the consideration of longitudinal blood profiles together with heterogeneous factors such as ethnicity and age produces a model with enhanced sensitivity to detect blood doping. Sports disciplines with heterogeneous populations now have a general method to introduce the no-start rule.     

Subscapular artery Y-shaped flow-through muscle flap: a novel one-stage limb salvage procedure

OBJECTIVES: Major tissue loss caused by the critical limb ischemia requires improvement of distal perfusion and cover of large tissue defects. We propose a new method, the y-shaped subscapular artery flow-through (Y-SCAFT) muscle flap using the subscapular artery that yields an arterial graft and a free muscle flap sustained by a collateral branch of this artery. This prospective study evaluated the feasibility of this technique and analyzed wound healing, graft patency, and limb salvage. METHODS: Between 2002 and 2007, 20 patients, mean age 64 years (range, 55-79 years), were treated with this technique. All presented with critical ischemia and major tissue loss, with exposure of the tendons, bones, or joint, and were candidates for major amputation. Revascularization and cover of tissue loss with the same Y-SCAFT anatomic unit was used for all patients. The distal anastomosis was performed between the distal branch of the Y-SCAFT and the pedal artery in 9, posterior tibial artery in 4, peroneal artery in 1, lateral tarsal artery in 3, and the plantar artery in 3. In four patients, the distal part of the arterial graft, including the anastomosis, was covered with the muscle flap because the tissue loss was nearby. The proximal anastomosis was performed between a leg artery and the arterial graft in 10 patients. A venous graft was necessary in 10 patients to extend the bypass proximally. RESULTS: One patient died during the postoperative period. Duplex control evidenced patency all the Y-SCAFT muscle flaps. Healing was achieved in all patients. Mean follow-up was 31 months (range, 6-58 months). No patients died during follow-up. One patient presented occlusion of the Y-SCAFT muscle flap and underwent amputated. One patient had major amputation despite a patent graft. At 2 years, leg salvage was 85%, patency was 94%, and survival was 94%. At the end of the follow-up, 17 patients (1 death, 2 amputations) had a patent graft, a viable muscle flap, wound healing, and a functional leg. CONCLUSION: We showed the clinical feasibility of the technique of Y-SCAFT muscle flap, which allows for revascularization and cover of major tissue loss with one anatomic unit. This method is particularly useful in selected cases with poor run-off and large ischemic lesions.     

Outcome and treatment of Bartonella endocarditis

BACKGROUND: Endocarditis caused by Bartonella species is a potentially lethal infection characterized by a subacute evolution and severe valvular lesions. OBJECTIVES: To evaluate the outcome of patients with Bartonella endocarditis and to define the best antibiotic regimen using the following measures: recovery, relapse, or death. METHODS: We performed a retrospective study on 101 patients who were diagnosed in our laboratory as having Bartonella endocarditis between January 1, 1995, and April 30, 2001. Bartonella infection was diagnosed using immunofluorescence with a 1:800 cutoff, polymerase chain reaction amplification of DNA, and/or culture findings of Bartonella species from whole blood, serum, and/or valvular biopsy specimens. A standardized questionnaire was completed by investigators for each patient. RESULTS: Twelve of the 101 patients died and 2 relapsed. Patients receiving an aminoglycoside were more likely to fully recover (P =.02), and those treated with aminoglycosides for at least 14 days were more likely to survive than those with shorter therapy duration (P =.02). CONCLUSION: Effective antibiotic therapy for Bartonella endocarditis should include an aminoglycoside prescribed for a minimum of 2 weeks.