Comparison of loop diuretics in patients with chronic renal insufficiency

Furosemide and bumetanide share a number of characteristics including reduced natriuretic effects in azotemic patients. It has been presumed that this condition affects each drug equally. Previous studies, however, suggest dissimilar pathways of delivery to their sites of action. Though not rigorously tested, this potential disparity might cause them to differ when used in azotemia. We, therefore, assessed the pharmacokinetic and pharmacodynamic characteristics of intravenously administered furosemide and bumetanide in ten adult patients with stable, chronic renal insufficiency (mean creatinine clearance = 14.1 +/- 2.0 ml/min/1.73 m2) in a randomized, cross-over study during controlled sodium intake. Our goals were to assess differences in diuretic effectiveness and in so doing to determine the dose required to produce a maximal response. The mean diuretic doses of 172 and 4.3 mg for furosemide and bumetanide, respectively (ratio = 40:1) were sufficient to produce a maximum response. Despite similarities in maximal fractional excretion of sodium (18.2 +/- 2.6% with furosemide vs. 19.4 +/- 4.5% with bumetanide, P = 0.687) demonstrating an equal tubular responsiveness to both drugs, overall response as quantified by cumulative natriuresis in the initial eight hour period was 52% greater with furosemide (108 +/- 17 vs. 71 +/- 7 mEq; P = 0.042). The difference in total excreted sodium was accounted for by a preserved nonrenal clearance of bumetanide (113 +/- 12 compared to 53 +/- 5 ml/min for furosemide, P = 0.001) which resulted in relatively less bumetanide in serum available to be delivered into the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressure distribution and perceived comfort in casual footwear

The aim of this investigation was to establish the relationship between short-term perceived comfort and pressure distribution on the dorsal and plantar surfaces of the foot, while walking in a range of commercially available casual footwear. The study was carried out in the biomechanics laboratory of Manchester Metropolitan University using 15 male subjects without foot pathology. Perceived upper and plantar comfort were measured using a specially designed questionnaire, while dorsal and plantar pressure distributions were measured using a rectangular sensor pad recording at 30 Hz and a Mikro-EMED insole recording at 100 Hz respectively. Analysis of variance tests were used to determine differences in perceived comfort and pressure distribution between three pairs of shoes. The findings of this study suggest that an increase in total plantar force and force-time integral may relate to a decrease in perceived plantar comfort. For the three shoes examined in this study, overall peak plantar pressure, the pressure-time integral, and total plantar area did not appear to be linked to perceived plantar comfort. Findings for the shoe upper indicate that decreased dorsal forces and pressures may be related to decreased upper comfort. These findings suggest that the measurement of pressure distribution at the foot-shoe interface could be a useful tool in identifying the causes of discomfort in footwear.     

Trends and district variations in the hospital care of childhood asthma: results of a regional study 1970-85.

Trends and district variations in the pre-hospital and hospital care of children aged 0-14 years admitted with acute asthma were surveyed in all 13 districts of a health region by examining case notes for 1970, 1978, and 1985. From 1970 to 1985 there was a substantial increase in admissions and some reduction of hospital stay. Over this time adrenergic drugs remained the most frequently used treatment with a large shift towards selective beta2 agonists administered by nebulisation. Use of corticosteroids fell in the under 5s with a decrease in the parenteral route of administration but rose in the 5-14 age group with an increase in the oral route of administration. There was an increase the use of oral xanthines but this was outweighed by falls in the use of suppositories and in parenteral administration. The use of antibiotics became less frequent and that of sedatives and antihistamines fell to almost nil. There were also important changes in other aspects of management, notably an increase in the use of lung function tests (from 3% to 70%) and falls in the use of chest radiographs, blood tests, bacteriology, and physiotherapy. In nearly all aspects of management there were significant and often very extreme variations in practice between districts, which were unlikely to be explained by differences in morbidity. These variations would be a suitable focus for medical audit, with the aim of establishing which treatment regimens have the best outcome and avoiding unnecessary cost and discomfort. Because early hospital drug treatment is closely related to the type of treatment given before admission such audit activities would need to include general practitioners.     

Measles in developing countries. Part II. The predicted impact of mass vaccination

A mathematical model is developed to mimic the transmission dynamics of the measles virus in communities in the developing world with high population growth rates and high case fatality rates. The model is used to compare the impacts of different mass vaccination programmes upon morbidity and mortality arising from infection by measles virus. Analyses identify three conclusions of practical significance to the design of optimal vaccination programmes. First, there is no single optimum age at which to vaccinate children for all urban and rural communities in developing countries. For a given community the best age at which to vaccinate depends critically on the age distribution of cases of infection prior to the introduction of control measures. Second, numerical studies predict that the introduction of mass vaccination will induce a temporary phase of very low incidence of infection before the system settles to a new pattern of recurrent epidemics. Mass vaccination acts to lengthen the inter-epidemic period in the post-vaccination period when compared with that prevailing prior to control. Third, numerical simulations suggest that two-phase and two-stage vaccination programmes are of less benefit than one-stage programmes (achieving comparable coverage) aimed at young children. The paper ends with a discussion of the needs for: improved programmes of data collection; monitoring of the impact of current vaccination programmes; and the development of models that take account of viral transmission dynamics, host demography and economic factors.     

FACTORS RELATED TO PERINEAL TRAUMA IN CHILDBIRTH

We conducted an observational cohort study in three nurse-midwifery services to identify patient characteristics and clinical care measures related to perineal trauma at birth. Data were collected on all women who began care with a nurse-midwife in labor, using an adaptation of the Nurse-Midwifery Clinical Data Set (n = 3,049). Study variables included demographics, perineal management techniques and position for birth, and other intrapartum care and events. Univariate and multivariate analyses showed that episiotomy was strongly related to fetal bradycardia, prolonged second stage, ethnic status, and maternal education level. Warm compresses and flexion/counterpressure to slow delivery were protective. Spontaneous lacerations were influenced by these factors as well. The lateral position for birth was protective, and use of oils or lubricants and the lithotomy position increased lacerations. Multisite studies in nurse-midwifery practices may provide an ideal means of determining effective care measures in healthy populations.     

Elevation of plasma thioredoxin levels in HIV-infected individuals

Thioredoxin (Trx), a ubiquitous protein intimately involvedin redox and protein disulfide reductions, has been shown tobe released from cells and to have cytokine-like activities.In addition, Trx has been implicated in the redox regulationof immunological responses and shown to be deficient in tissuesfrom AIDS patients. In studies presented here, plasma Trx levelswere measured by ELISA in plasma samples from HIV-infected individuals(n = 136) and HIV-negative controls (n = 47). To account forthe release of Trx into plasma due to hemolysis, the Trx measurementswere corrected according to the level of hemoglobin in the plasmasample. Data presented show that, in contrast to tissue Trxlevels, corrected plasma Trx levels are significantly higherin HIV-infected individuals than in controls (P < 0.0001).Furthermore, {small tilde}25% of the HIV-infected individualsstudied have plasma Trx levels greater than the highest levelfound in controls (37 ng/ml). Detailed multiparameter FACS analysisof peripheral blood mononuclear cells (PBMC) from the infectedindividuals demonstrates that those with higher plasma Trx levels(37 ng/ml or greater) tend to have lower overall CD4 counts.In addition, increases in plasma Trx levels correlate with decreasesin monochlorobimane staining (indicative of lower intracellularglutathione levels in PBMC) and with changes in surface antigenexpression (CD62L, CD38 and CD20) that occur in the later stagesof HIV infection. These correlations suggest that elevationof plasma Trx levels may be an important component of advancedHIV disease, perhaps related to the oxidative stress that oftenoccurs at this stage.     

Synthesis and pharmacological evaluation of a series of dibenzo[a,d]cycloalkenimines as N-methyl-D-aspartate antagonists.

A series of 73 dibenzo[a,d]cycloalkenimines were synthesized and evaluated for their ability to displace (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]-(+)-10) from its specific binding site on rat cortical membranes. A number of the more active compounds (Ki ranging from 0.006 to 0.21 microM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (Kb ranging from 0.08 to 0.9 microM) and anticonvulsant activity in the mouse against NMDA induced convulsions. The ED50 values ranged from 0.22 to 7.76 mg/kg and correlated reasonably well with the Kb determination. In the dibenzo[a,d]cyclohepten-5,10-imine series, the (+)-5S,10R enantiomer displayed consistently higher levels of biological activity. While substitution at the 3-position of (+)-10 with electronegative atoms generally increased in vitro activity, a loss of potency relative to (+)-10 (MK-801) was observed in vivo for all of the compounds tested.     

The use of mathematical models in the epidemiological study of infectious diseases and in the design of mass immunization programmes

The relationship between the number of people vaccinated for an infectious disease and the resulting decrease in incidence of the disease is not straightforward and linear because many independent variables determine the course of infection. However, these variables are quantifiable and can therefore by used to model the course of an infectious disease and impact of mass vaccination. Before one can construct a model, one must know for any specific infectious disease the number of individuals in the community protected by maternally derived antibodies, the number susceptible to infectious the number infected but not yet infectious (i.e., with latent infection), the number of infectious individuals, and the number of recovered (i.e., immune) individuals. Compartmental models are sets of differential equations which describe the rates of flow of individuals between these categories. Several major epidemiologic concepts comprise the ingredients of the model: the net rate of infection (i.e., incidence), the per capita rate of infection, the Force of Infection, and the basic reproductive rate of infection. When a community attains a high level of vaccination coverage, it is no longer necessary to vaccinate everyone because the herd immunity of the population protects the unvaccinated because it lowers the likelihood of their coming into contact with an infectious individual. Many infections that confer lasting immunity tend to have interepidemic periods when the number of susceptibles is too low to sustain an epidemic. Mass vacination programs reduce the net rate of transmission of the infective organism; they also increase the length of the interepidemic period. Many diseases primawrily associated with children have much more serious consequences in older people and the question arises as to at what point childhood immunization will successfully prevent the more dangerous incidence of the disease in older cohorts. Mathematical models of disease transmission enable one to predict the course of epidemics, design mass vaccination programs, and be guided as to what are the relevant data that should be collected.