Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli

OBJECTIVES: 1-(1-Naphthylmethyl)-piperazine (NMP) has been shown to reverse multidrug resistance (MDR) in Escherichia coli overexpressing resistance-nodulation-cell division type efflux pumps, but there is no data on its activity in clinical isolates of E. coli. METHODS: The antimicrobial susceptibility of 60 clinical isolates of E. coli to a variety of antimicrobial agents was determined in the absence and presence of NMP and, for comparison, of Phe-Arg-beta-naphthylamide (PAbetaN), another putative efflux pump inhibitor (EPI). The intracellular accumulation of ethidium bromide was measured to confirm efflux pump inhibition as the likely mechanism of action of NMP. RESULTS: Based on a 4-fold or greater reduction of the MIC after the addition of NMP in >50% of the isolates, significant effects of NMP at a concentration of 100 mg/L were seen for levofloxacin, linezolid and ethidium bromide. The ethidium bromide MIC changes after NMP addition correlated with differences in the ethidium bromide intracellular accumulation as measured by fluorometry in whole cell accumulation experiments. The activity of PAbetaN was different from that of NMP, in particular regarding macrolide resistance reversal, suggesting different modes of action of the two putative EPIs. CONCLUSIONS: NMP is moderately active in reversing MDR in clinical isolates of E. coli and can partially restore fluoroquinolone susceptibility through inhibition of efflux pumps.     

The epidemiology of liver disease in Tayside database: a population-based record-linkage study

BACKGROUND: The true incidence and prevalence of liver disease is difficult to ascertain because there are few, if any, population-based registers of liver disease available to ensure proper case and comparator selection. The epidemiology of liver disease in Tayside (ELDIT) is a specially built register of liver disease for a well-defined geographical area of Scotland. AIMS: This paper describes the electronic linkage of multiple data sources to form ELDIT and provides initial results from the database. PATIENTS: All subjects resident in Tayside and registered with a general practitioner in the study period 1980-1999, approximately 400,000 people. METHODS: Electronic record-linkage techniques were employed to include anonymised data from primary and secondary sources. Hospital admissions, dispensed medication, and laboratory results from immunology, virology, and biochemistry were used to identify cases of liver disease. Diagnostic algorithms were used to verify and classify subjects with liver disease. A validation of the algorithms against the clinical diagnosis was used to determine the measure of agreement (true positive rate) of ELDIT. RESULTS: At present approximately 10,000 subjects have been identified with liver disease or abnormal liver function. The data set is nearing completion with cases of rarer liver disease being identified last. Incidence densities for the population were calculated. From the validation study, agreement between electronic and clinical diagnosis was 0.98 and positive predictive value was 0.83 showing electronic diagnostic algorithms are sensitive enough to identify liver disease using para-clinical data. CONCLUSIONS: ELDIT demonstrates how clinical information can be harnessed electronically to provide a better understanding of liver disease in a population.     

Relationship of physical performance to maturation in perimenarchal girls

The relationship of physical performance to maturation, characterized by the onset of menarche, was examined annually from 1989 to 1992 among 61 healthy, active perimenarchal girls from 10 to 14 years. Within each age group, differences in selected physical performance variables between and among three maturity groups, early, average, and late, were compared. Subjects categorized as having early or late maturation were those whose age at menarche was minus or plus, respectively, one standard deviation from the mean age at menarche 12.70 + 0.99 yr (range 10.29–14.65). Subjects demonstrated steady progression with age in breast and pubic hair development. Weight, estimated lean body weight and fat weights, and stature increased significantly with age and maturation. With the exceptions of flexibility, bent arm hang, standing vertical jump, and relative maximum oxygen uptake, the performance measures of running speed, functional strength, explosive strength, static strength, upper body power, and aerobic power improved significantly with age and maturation. Generally more mature subjects tended to perform significantly better than the less mature, but there are fewer significant performance differences between and among maturation groups within specific age groups. Therefore, whereas more mature 10- and 14-year-old females may, within the same age group, have only a very slight advantage in some physical performance abilities over their less mature age mates, more mature females aged 11, 12, and 13 years have a greater physical performance advantage. Am. J. Hum. Biol. 9:163–171, 1997. © 1997 Wiley-Liss, Inc.     

Coinfection with hepatitis C virus,oxidative stress and antioxidant status in HIV‐positive drug users in Miami*

Background

The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV‐coinfected and HIV‐monoinfected adults.

Methods

Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB‐4) markers were calculated.

Results

Significant differences were found between HIV/HCV‐coinfected and HIV‐monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB‐4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV‐coinfected participants than in the HIV‐monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB‐4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=?0.00581; P=0.0417) as APRI increased.

Conclusion

HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.

     

Akutes Nierenversagen und Sepsis

Acute renal failure (ARF) is clinically defined as an abrupt, but in principle reversible deterioration of glomerular and tubular function. Regarding pathophysiology, ARF is caused by ischemic renal conditions and toxic mediators. Sepsis is the most common cause of ARF in the intensive care unit and ARF is an independent risk factor for lethality of septic patients. Interventions to protect the kidneys against ARF include preliminary optimization of renal perfusion by volume load with cristalloid solutions and the administration of vasopressors. Daily maximum permissible dosages for colloids should not be exceeded and hyperoncotic colloid solutions should be generally avoided. Dopamine in “renal dosage” is nowadays obsolete. Loop diuretics produce diuresis and can be beneficial to extrarenal organs by improving fluid homeostasis, however diuretics do not improve kidney function and outcome. Therefore, diuretics are not indicated for patients with imminent or existing ARF. Septic patients with ARF can be treated by intermittent and continuous forms of renal replacement therapy, whereas continuous convective and intermittent diffusive methods are equivalent when utilizing an ultrafiltration rate ≥20 ml/h?kg body weight or a therapeutic interval ≥3 times/week.