Search

Objective: To investigate associations between the prevalence of sexual difficulties reported in published studies and design features of those studies to determine if differences in design contribute to variation in prevalence estimates., Design: Systematic review, multivariate analysis., Setting: Studies published internationally in English., Patient(s): Not applicable., Intervention(s): None., Main Outcome Measure(s): Prevalence estimates of difficulty with desire, arousal, orgasm, and sexual pain reported in published studies., Result(s): Our systematic literature search identified 1,380 publications. Fifty-five studies met our inclusion criteria (reporting prevalence, sample size and response rate, sample size greater than 100, not clinic based). Reported prevalence of sexual difficulty varied across studies (up to tenfold). Eleven aspects of research conduct in these studies were included in our multivariate analysis as explanatory variables. Five aspects of study design and conduct (data collection procedures, inclusion criteria, duration of sexual difficulty recorded, sample size, and response rate) were associated with the reported prevalence of at least one type of sexual difficulty independently of likely predictors of true variation in prevalence: study location, study year, and age range of participants., Conclusion(s): This review provides evidence that study design may influence reported prevalence estimates of female sexual difficulties and contribute to the wide variation in published estimates.

Introduction: No previous population-based studies have used validated instruments to measure female sexual dysfunction (FSD) in Australian women across a broad age range., Aim: To estimate prevalence and explore factors associated with the components of FSD., Main Outcome Measures: Sexual Function Questionnaire measured low sexual function. Female Sexual Distress Scale measured sexual distress. Methods. Multivariate analysis of postal survey data from a random sample of 356 women aged 20-70 years., Results: Low desire was more likely to occur in women in relationships for 20-29 years (odds ratio 3.7, 95% confidence intervals 1.1-12.8) and less likely in women reporting greater satisfaction with their partner as a lover (0.3, 0.1-0.9) or who placed greater importance on sex (0.1, 0.03-0.3). Low genital arousal was more likely among women who were perimenopausal (4.4, 1.2-15.7), postmenopausal (5.3, 1.6-17.7), or depressed (2.5, 1.1-5.3), and was less likely in women taking hormone therapy (0.2, 0.04-0.7), more educated (0.5, 0.3-0.96), in their 30s (0.2, 0.1-0.7) or 40s (0.2, 0.1-0.7), or placed greater importance on sex (0.2, 0.05-0.5). Low orgasmic function was less likely in women who were in their 30s (0.3, 0.1-0.8) or who placed greater importance on sex (0.3, 0.1-0.7). Sexual distress was positively associated with depression (3.1, 1.2-7.8) and was inversely associated with better communication of sexual needs (0.2, 0.05-0.5). Results were adjusted for other covariates including age, psychological, socioeconomic, physiological, and relationship factors., Conclusions: Relationship factors were more important to low desire than age or menopause, whereas physiological and psychological factors were more important to low genital arousal and low orgasmic function than relationship factors. Sexual distress was associated with both psychological and relationship factors.

Background: The atopic march hypothesis suggests that infants with eczema are at increased risk of asthma. Others argue that eczema is not a risk factor for asthma unless there is also sensitization or early wheezing., Objective: To examine the role of infantile eczema as a predictor of risk of childhood asthma, while allowing for the effects of early wheeze, sensitization, and sex, both as independent effects and possible effect modifiers., Methods: A total of 620 infants with a family history of allergic disease was recruited. Eczema and wheeze was prospectively documented to 2 years of age. Sensitization was determined by skin prick tests at 6, 12, and 24 months to 6 common food and inhalant allergens. Interviews were conducted at 6 and 7 years to ascertain current asthma., Results: Sufficiently complete data were available for 403 children. Eczema within the first 2 years of life was clearly associated with an increased risk of childhood asthma in boys (adjusted odds ratio, 2.45; 95% CI, 1.31-4.46) but not in girls (odds ratio, 0.88; 95% CI, 0.43-1.77; P for interaction = .031) even with adjustment for the effects of early allergic sensitization and wheeze. If these relationships are causal, an intervention to prevent eczema in boys might reduce the incidence of childhood asthma by as much as 28%., Conclusion: Eczema in the first 2 years of life is associated with an increased risk of childhood asthma in boys, but there is no evidence of this in girls.

Introduction: A wide range of prevalence estimates of female sexual dysfunctions (FSD) have been reported., Aim: Compare instruments used to assess FSD to determine if differences between instruments contribute to variation in reported prevalence., Main Outcome Measures: Sexual Function Questionnaire combined with Female Sexual Distress Scale (SFQ-FSDS) was our gold standard, validated instrument for assessing FSD. Alternatives were SFQ alone and two sets of simple questions adapted from Laumann et al. 1994. Methods. A postal survey was administered to a random sample of 356 Australian women aged 20 to 70 years., Results: When assessed by SFQ-FSDS, prevalence estimates (95% confidence intervals) of hypoactive sexual desire disorder, sexual arousal disorder (lubrication), orgasmic disorder, and dyspareunia were 16% (12% to 20%), 7% (5% to 11%), 8% (6% to 12%), and 1% (0.5% to 3%), respectively. Prevalence estimates varied across alternative instruments for these disorders: 32% to 58%, 16% to 32%, 16% to 33%, and 3% to 23%, respectively. Compared with SFQ-FSDS alternative instruments produced higher estimates of desire, arousal and orgasm disorders and displayed a range of sensitivities (0.25 to 1.0), specificities (0.48 to 0.99), positive predictive values (0.01 to 0.56), and negative predictive values (0.95 to 1.0) across the disorders investigated. Kappa statistics comparing SFQ-FSDS and alternative instruments ranged from 0 to 0.71 but were predominantly 0.44 or less. Changing recall from previous month to 1 month or more in the previous year produced higher estimates for all disorders investigated. Including sexual distress produced lower estimates for desire, arousal, and orgasm disorders., Conclusions: Prevalence estimates of FSD varied substantially across instruments. Relatively low positive predictive values and kappa statistics combined with a broad range of sensitivities and specificities indicated that different instruments identified different subgroups. Consequently, the instruments researchers choose when assessing FSD may affect prevalence estimates and risk factors they report.

Background: Assessment of allergic sensitization is not routinely performed in infants and young children with eczema., Objective: To determine whether infants who have atopic eczema (with sensitization) are at a greater risk of developing asthma and allergic rhinitis (AR) than those with non-atopic eczema (without concurrent sensitization)., Methods: The presence of eczema was prospectively documented until 2 years of age in a birth cohort of 620 infants with a family history of atopic disease. Sensitization status was determined by skin prick tests (SPTs) at 6, 12, and 24 months using six common allergens. Interviews were conducted at 6 and 7 years to determine the presence of asthma and AR., Results: Within the first 2 years of life, 28.7% of the 443 children who could be classified had atopic eczema: 20.5% had non-atopic eczema, 19.0% were asymptomatic but sensitized and 31.8% were asymptomatic and not sensitized. When compared with children with non-atopic eczema in the first 2 years of life, children with atopic eczema had a substantially greater risk of asthma [odds ratio (OR)=3.52, 95% confidence interval=1.88-6.59] and AR (OR=2.91, 1.48-5.71). The increased risk of asthma was even greater if the infant had a large SPT (OR=4.61, 2.34-9.09) indicative of food allergy. There was no strong evidence that children with non-atopic eczema had an increased risk of asthma or AR compared with asymptomatic children., Conclusion: In children with eczema within the first 2 years of life, SPT can provide valuable information on the risk of childhood asthma and AR.

Particulate matter (PM) has been widely associated with adverse effects on respiratory health, both overseas and in Australia. This study aimed to investigate the impacts of ambient particles of <2.5 microm diameter (PM2.5) in Melbourne on adverse respiratory symptoms. Two cohorts of adults were recruited in 1992-1998, and completed detailed respiratory questionnaires in 1998-1999 and 2004-2005. The mean age at baseline was 37.2 years, 55% were female, and the mean time lapsed between the baseline and follow-up questionnaires was 5.2 years. PM2.5 exposure was assessed from gravimetric data and routine nephelometry at monitoring stations located centrally with respect to the residence of most participants. Daily exposures to PM2.5 were averaged over the previous 12 months and mean daily exposure was 6.8 microg/m3. Logistic regression models were used to examine associations between PM2.5 exposure and adverse respiratory symptoms. Adjustment was made for age, gender, current smoking status, and medication use, but further adjustment for atopy did not alter the results. There was insufficient variability in PM2.5 exposure among participants over the study period to provide convincing evidence for or against associations between PM2.5 and adverse respiratory symptoms.

Background: Eczema is commonly associated with sensitization in infants, but the causative role of sensitization in the development of eczema has been questioned., Objective: To determine if allergic sensitization increases the risk of developing eczema, or alternatively, if eczema increases the risk of developing allergic sensitization., Methods: We used data from the Melbourne Atopy Cohort Study, a prospective birth cohort of 552 infants with a family history of atopic disease. The main outcomes were risk of developing eczema from 6 months to 7 years of age in asymptomatic infants; and risk of developing sensitization, as measured by skin prick tests to milk, egg white, peanut, house dust mite, rye grass pollen and cat extracts, in previously unsensitized infants., Results: Sensitization to food extracts at 6 months was associated with an increased risk of developing eczema [hazard ratio (HR) 1.63, 95% confidence interval 1.13-2.35] up to 7 years of age, after excluding infants with eczema in the first 6 months. However, eczema in the first 6 months was also associated with increased risk of new sensitization at both 1 year (HR 2.34, 1.38-3.98) and 2 years (HR 3.47, 1.65-7.32)., Conclusion: In some infants, sensitization precedes and predicts the development of eczema, while in others eczema precedes and predicts the development of sensitization. This indicates that there are multiple pathways to atopic eczema.

Objective: To evaluate the safety, tolerability, and clinical effects of rituximab, an anti-CD20 monoclonal antibody, in the treatment of severe pediatric autoimmune diseases., Study Design: We reviewed the records of 10 patients treated with rituximab for severe, refractory autoimmune diseases at a single tertiary care children's hospital. Adverse events as well as treatment effects were recorded., Results: All patients received 4 weekly doses of rituximab at 375 mg/m2 per dose. One patient died as the result of complications of her underlying systemic lupus erythematosus 7 weeks after rituximab therapy. Three patients had serious infections, all of which resolved with standard therapy. Rituximab led to transient or sustained improvement in clinical and laboratory parameters in nine subjects. At a median follow-up of 9 months, the median prednisone dose was reduced in the responders by 0.75 mg/kg per day (mean decrease of 63%), and four patients were able to discontinue corticosteroids entirely. With longer follow-up (median, 22 months), we found that 5 of 9 patients remained clinically stable after rituximab therapy, whereas 4 patients had recurrent or new features of their underlying autoimmune disorders requiring additional corticosteroids or other immunosuppressive medications., Conclusions: Rituximab had an acceptable toxicity profile in this group of patients with severe, refractory autoimmune diseases, although there were three serious infections and one patient death. Rituximab appears to be beneficial for patients with refractory autoimmune diseases and may reduce corticosteroid exposure. Although rituximab therapy provided a durable clinical benefit for some patients in this population, other patients had reemergence of their underlying autoimmune disease.

Objective: Explore the association between Hypoactive Sexual Desire Disorder (HSDD) and aging. The American Foundation of Urologic Disease and the American Psychiatric Association stipulate that HSDD is only diagnosed when both low sexual desire and sexually related personal distress are present., Design: Community-based, cross-sectional study., Setting: Europe (UK, Germany, France, Italy) and the USA., Patient(s): Women aged 20-70 in sexual relationships participating in the Women's International Study of Health and Sexuality (n=1998 Europe, n=1591 USA)., Intervention(s): No interventions were administered., Main Outcome Measures: Self-administered questionnaire that included two validated instruments: Profile of Female Sexual Function(c) measured sexual desire; Personal Distress Scale(c) measured sexual distress. Women with low desire and distress were considered to have HSDD., Results: The proportion of European women with low desire increased from 11% amongst women aged 20-29 years to 53% amongst women aged 60-70 years. The proportion of American women with low desire displayed a trend towards an increase with age. In the 20-29 year age group 65% of European women and 67% of American women with low sexual desire were distressed by it. This decreased to 22% and 37%, respectively, in the 60-70 year age group. In Europe and the USA the prevalence of HSDD in the population did not change significantly with age (6-13% in Europe, 12-19% in the USA)., Conclusions: The proportion of women with low desire increased with age while the proportion of women distressed about their low desire decreased with age. Consequently, the prevalence of HSDD remained essentially constant with age. This may explain why no association between HSDD and age is often reported in the literature.

An elusive goal in hematology is a detailed understanding of autoimmune blood disorders including idiopathic (immune) thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and Evans Syndrome. While it is clear that these disorders have an autoimmune pathophysiology, the exact mechanisms are not clear. Agents that target the immune system specifically, such as rituximab and tacrolimus, are currently being used clinically with favorable results. Targeted therapy may be useful not only in treating these difficult diseases, but also may provide clues to the underlying disease pathophysiology. Carefully designed studies using targeted therapy may provide biologic predictors of disease severity, as well as predictors of response to therapy., (Copyright (c) 2006 Wiley-Liss, Inc.)

Research has consistently confirmed changes occur in brain morphometry between adolescence and adulthood. The purpose of the present study was to explore anatomical change during a specific environmental transition. High-resolution T1-weighted structural magnetic resonance imaging (MRI) scans were acquired from 19 participants (mean age at initial scan = 18.6 years) during their freshman year. Scans were completed during the fall term and 6 months later before the conclusion of the school year. Voxel-based morphometry was used to assess within-subject change. Significant intensity increases were observed along the right midcingulate, inferior anterior cingulate gyrus, right caudate head, right posterior insula, and bilateral claustrum. Regional changes were not observed in two control groups; one controlling for method and another controlling for age-specific change over time. The results suggest that significant age-related changes in brain structure continue after the age of 18 and may represent dynamic changes related to new environmental challenges. Findings from the regions of change are discussed in the context of specific environmental demands during a period of normative maturation., ((c) 2006 Wiley-Liss, Inc.)

The adverse public health impacts of anthropogenically derived particulate matter have been well documented, with measurable increases in both morbidity and mortality rates associated with high particulate matter pollution events. Most current research has focussed on the health impacts of anthropogenically derived particulate matter, and there is a distinct scarcity of literature that examines the role of naturally derived particulate matter and adverse health impacts in the urban context. This study of a Gobi desert dust event in the Greater Vancouver region of British Columbia, Canada, in spring of 1998 provided a unique opportunity to identify the adverse health effects related to naturally derived particulate matter in a large urban setting. Respiratory and cardiac hospitalizations were examined for a three-year period (January 1997 to December 1999), with the Gobi dust event occurring in late April 1998. A meteorological analogue was identified for spring 1997 in order to identify the public health impacts associated with anthropogenically derived particulate matter and those impacts associated with the presence of the Gobi desert dust. Results indicate that this Gobi dust event was not associated with an excess of hospitalizations in the Greater Vancouver region. Peak particulate matter concentrations of Gobi desert dust in the airshed were only associated with an additional one or two hospitalizations per 100,000 population for respiratory and cardiac illnesses, and these increases were not distinguishable from the 'normal' variability in hospitalization rates. Despite high particulate matter concentrations, fine particle size, presence of heavy metals in the dust and extended exposure periods, it appears that the Gobi desert dust event was not associated with significant risk to public health in Greater Vancouver, British Columbia. Therefore it is concluded that naturally derived particulate matter is more benign than particulate matter of anthropogenic origin, and thus poses a low risk to health for the general public.

Introduction: Many recent studies have investigated the prevalence of female sexual difficulty/dysfunction., Aim: Investigate female sexual difficulty/dysfunction using data from prevalence studies., Methods: We reviewed published prevalence studies excluding those that had not included each category of sexual difficulty (desire, arousal, orgasm, and pain), were based on convenience sampling, or had a response rate <50% or a sample size <100. Main Outcome Measures. For each study we used the prevalence of any sexual difficulty as the denominator and calculated the proportion of women reporting each type of difficulty. For each category of sexual difficulty we used the prevalence of that difficulty lasting 1 month or more as the denominator and calculated the proportion of difficulties lasting several months or more and 6 months or more., Results: Only 11 of 1,248 studies identified met our inclusion criteria. These studies used different measures of sexual dysfunction, so generating a simple summary prevalence was not possible. However, we observed consistent patterns in the published data. Among women with any sexual difficulty, on average, 64% (range 16-75%) experienced desire difficulty, 35% (range 16- 48%) experienced orgasm difficulty, 31% (range 12-64%) experienced arousal difficulty, and 26% (range 7-58%) experienced sexual pain. Of the sexual difficulties that occurred for 1 month or more in the previous year, 62-89% persisted for at least several months and 25-28% persisted for 6 months or more. Two studies investigated distress. Only a proportion of women with sexual difficulty were distressed by it (21-67%)., Conclusions: Desire difficulty is the most common sexual difficulty experienced by women. While the majority of difficulties last for less than 6 months, up to a third persist for 6 months or more. Sexual difficulties do not always cause distress. Consequently, prevalence estimates will vary depending on the time frame specified by researchers and whether distress is included in these estimates.

Intestinal parasite infections are a major cause of ill health in many resource-poor countries. This study compares the types and rates of these infections and their risk factors in recently arrived and long-term immigrants in Australia. Cross-sectional surveys of 127 East African and 234 Cambodian immigrants and refugees were undertaken in 2000 and 2002, respectively, to assess the burden of intestinal parasites and collect demographic information. Serum samples were assessed for eosinophilia and Strongyloides stercoralis and Schistosoma antibodies, and feces examined for ova, cysts, and parasites. Intestinal parasites were identified in 77/117 fecal samples from East African and in 25/204 samples collected from Cambodian participants. Eleven percent (14/124) of East Africans and 42% (97/230) of Cambodians had positive or equivocal serology for S stercoralis. Schistosoma serology was positive or equivocal in 15% (19/124) of East African participants. Potentially serious intestinal parasite infections are common among recent and longer term immigrants despite multiple visits to health care providers. Immigrants and refugees from high-risk countries would benefit from comprehensive health checks soon after resettlement.

Neutralizing alloantibodies (inhibitors) to factor VIII or factor IX develop in approximately 25% of patients with haemophilia A and <3% of patients with haemophilia B treated with factor concentrate. Patients with high titre inhibitors, in whom immune tolerance therapy fails, have few treatment options. Targeted anti-B-cell therapy with rituximab (chimeric anti-CD20) has been useful in several antibody-mediated autoimmune states. Case reports of rituximab treatment in small numbers of haemophilia patients with inhibitors have been inconclusive. We describe three adolescent patients with severe haemophilia and inhibitors treated with four weekly doses of rituximab, 375 mg m(-2). Treatment with rituximab was effective in reducing the inhibitor titre in two of three patients. Rituximab may be beneficial for patients with severe haemophilia and inhibitors in whom standard therapies have failed, but larger prospective studies are required to determine safety, efficacy and predictors of success.

We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.

Background: A number of studies have observed an association between breast-feeding and increased risk of development of asthma and eczema. It has been proposed that these results might be due to early signs of atopic disease in the infant causing mothers to prolong breast-feeding., Objective: We sought to determine whether early symptoms of atopic disease (eczema, food reaction, or asthma) or positive skin prick test responses reduce the likelihood of ceasing breast-feeding., Methods: A prospective birth cohort of 620 infants from Melbourne, Australia, was used. Telephone interviews every 4 weeks were conducted until 64 weeks and then again at 78 and 104 weeks to determine duration of breast-feeding (both exclusive and total) and evidence of atopic disease. Because of the varying time of onset of atopic symptoms, they were modeled as time-varying covariates in Cox models., Results: Only 52 (8.4%) infants did not establish breast-feeding, whereas an additional 103 (25.0%) did not establish exclusive breast-feeding. Early signs of atopic disease or sensitization were independently associated with an approximately 28% reduction in risk of ceasing exclusive breast-feeding (adjusted hazard ratio, 0.72; 95% CI, 0.53-0.97); P=.029), but there was no evidence for a relationship with risk of ceasing breast-feeding completely (adjusted hazard ratio, 1.12; 95% CI, 0.92-1.37; P=.262)., Conclusion: Early signs of atopic disease might prolong the duration of exclusive breast-feeding. This could mask a protective effect of breast-feeding or even result in breast-feeding appearing to be a risk factor for the development of atopic diseases. Future investigation of the relationship between breast-feeding and atopic diseases should consider this possibility.

Objective: This study examined outcomes after traumatic brain injury in adults salient to occupational therapy., Method: Demographic data and Functional Independence Measure (FIM) scores from the inpatient rehabilitation stay were first gathered from a retrospective chart review. At follow-up, 25 adults, on average 21 months post-injury, completed measures of disability, community participation, quality of life, and satisfaction with occupational therapy during a telephone interview. Analysis of covariance was used to test the differences between pretest and posttest scores on the FIM; regression analysis and correlations were used to analyze predictions and relationships., Results: Statistically significant improvements in FIM scores during rehabilitation were predictive of the level of long-term disability and community participation among participants. At follow-up, participants were often unemployed, depressed and withdrawn, and experienced limitations in decision making, hand use, bladder control, and community integration. Less disability and more community participation were related to higher quality of life. Satisfaction with occupational therapy, although high, was unrelated to most outcomes., Conclusion: Results support the premise that participation is associated with a high quality of life, yet persons with brain injury have significant needs for long-term occupational therapy.

Genome-wide chemical mutagenesis screens in the zebrafish (Danio rerio) have led to the identification of novel genes affecting vertebrate erythropoiesis. In determining if this approach could also be used to clarify the molecular genetics of myelopoiesis, it was found that the developmental hierarchy of myeloid precursors in the zebrafish kidney is similar to that in human bone marrow. Zebrafish neutrophils resembled human neutrophils, possessing segmented nuclei and myeloperoxidase-positive cytoplasmic granules. The zebrafish homologue of the human myeloperoxidase (MPO) gene, which is specific to cells of the neutrophil lineage, was cloned and used to synthesize antisense RNA probes for in situ hybridization analyses of zebrafish embryos. Granulocytic cells expressing zebrafish mpo were first evident at 18 hours after fertilization (hpf) in the posterior intermediate cell mass (ICM) and on the anterior yolk sac by 20 hpf. By 24 hpf, mpo-expressing cells were observed along the ICM and within the developing vascular system. Thus, the mpo gene should provide a useful molecular probe for identifying zebrafish mutants with defects in granulopoiesis. The expression of zebrafish homologues was also examined in 2 other mammalian hematopoietic genes, Pu.1, which appears to initiate a commitment step in normal mammalian myeloid development, and L-Plastin, a gene expressed by human monocytes and macrophages. The results demonstrate a high level of conservation of the spatio-temporal expression patterns of these genes between zebrafish and mammals. The morphologic and molecular genetic evidence presented here supports the zebrafish as an informative model system for the study of normal and aberrant human myelopoiesis. (Blood. 2001;98:643-651)

Aims: A systematic review of the literature was carried out to examine whether published evidence suggests a difference in the frequency and awareness of hypoglycaemia induced by 'human' and animal insulin., Methods: The review identified randomized controlled trials and studies of other designs including observational comparisons, case series and case reports in which the use of 'human' insulin was compared to animal insulin in people with diabetes. These were identified from bibliographic databases and hand-searches of key journals. The main outcome measures were frequency, severity, awareness and symptoms of insulin induced hypoglycaemia., Results: Fifty-two randomized controlled trials, 37 of double-blind design, were identified which included one or more of the relevant outcome measures. Of these, 21 specifically investigated hypoglycaemic frequency and awareness as primary outcomes (six in people with previously reported reduced hypoglycaemic awareness). The remainder of the identified trials reported hypoglycaemic outcomes as a secondary or incidental outcome during comparative investigations of efficacy or immunogenicity. Seven of the double-blind studies reported differences in frequency of hypoglycaemia or awareness of symptoms, although none of the studies which selected subjects on the basis of previously reported impaired awareness demonstrated significant differences between insulin species. Four of the unblinded trials reported differences in hypoglycaemia. This reached statistical significance in two of the studies. A further 56 studies of other designs and case reports were considered. In addition to the 10 case reports describing individuals with impaired hypoglycaemic awareness, nine studies reported differences in the incidence and manifestation of hypoglycaemia during 'human' insulin treatment. Notably, none of the four population time trend studies found any relationship between the increasing use of 'human' insulin and hospital admission for hypoglycaemia or unexplained death among those with diabetes. The largest case series could find no support for the hypothesis that an influence of treatment with 'human' insulin on hypoglycaemia had contributed to any of the 50 deaths investigated. When all types of studies considered are ranked in order of rigour (according to the accepted 'hierarchy of evidence'), it is the least rigorous which lend most support to the notion that treatment with 'human' insulin has an effect on the frequency, severity or symptoms of hypoglycaemia., Conclusions: Evidence does not support the contention that treatment with 'human' insulin per se affects the frequency, severity or symptoms of hypoglycaemia. However, a number of studies, mainly those of less rigorous design, describe an effect when people are transferred from animal insulin to 'human' insulin. It is not possible to state how common this is or whether the phenomenon is specific to 'human' insulin or an effect resulting from stricter glycaemic control (perhaps compounded, in some cases, by neurological complications in long-standing diabetes). This remaining uncertainty makes it essential that insulin from animal sources continues to be available so that clinicians and patients may retain this choice of treatment.

Objective: Examination of the relation between respiratory symptoms and time since arrival in Australia in immigrant teenagers living in Melbourne., Design: Two stage, stratified, cross sectional survey., Setting: High schools (n = 51)., Subjects: 9794 people aged 13-19 years., Main Outcome Measures: Prevalence of wheeze during a 12 month period, region of birth, duration of residence in Australia., Results: The estimated population 12 month period prevalence of wheeze was 18.9% (95% confidence interval (CI), 18.0 to 19.9). In subjects born outside Australia, residence for five to nine years in Australia was associated with a 2.1-fold (CI, 1.1 to 4.0) increase in the odds of self reported wheeze; after 10-14 years, this risk increased 3.4-fold (CI, 1.8 to 6.7). There was no difference in severity of wheeze, measured by reported frequency of attacks, between Australian born and non-Australian born subjects., Conclusions: The notion of a continued secular increase in the prevalence of wheezing is not supported. There is a time dose effect on the prevalence of symptoms in subjects born outside Australia and now living in Melbourne, which is independent of age and country of birth.

Objective: To estimate the prevalence of asymptomatic Mycobacterium tuberculosis infection in Melbourne secondary school students., Design: Cross-sectional Mantoux testing of a partly random and partly targeted sample of secondary school students, designed to enable estimation of prevalence by region of birth., Setting: Fifty-one State and Catholic secondary schools in metropolitan Melbourne during 1995., Participants: Australian and overseas-born students in Years 9 and 10., Outcome Measures: Proportions of students with positive Mantoux reactions (defined as induration at 48 hours of > or = 5 mm with a history of recent exposure; > or = 10 mm and no prior BCG vaccination; > or = 15 mm and prior BCG vaccination)., Results: Of 2586 students potentially eligible for testing, evaluable results were obtained from 1274 (49%). The overall prevalence of infection for Melbourne students in Years 9 and 10 was 2.5% (95% CI, 1.1-3.9%). Main predictors of a positive test were birth overseas and number of years residing overseas. Prevalence varied considerably by region of birth, and was very low in students born in Australia (0.7%), "other developed countries" (0.7%), and Southern Europe (0). The highest rates were observed in students born in Indochina (15.9%), other countries in South East Asia (10.2%), and Eastern Europe (10.2%)., Conclusions: The risk of a young person becoming infected with M. tuberculosis while living in Melbourne is very low. Our results do not indicate a need for the reintroduction of mass screening in Victorian schools. If targeted screening were to be considered, the group most likely to benefit would be recently arrived migrants from Indochina.

Daily patterns of pedestrian activity in young children have important health implications, primarily because of the risk of road traffic injury, but also because they may reflect the commencement of exercise habits with long-term consequences. A cross-sectional survey in two Australian cities, Melbourne and Perth, aimed to collect, by parent self-administered questionnaire, population-based data on modes of travel, numbers of street crossings (both accompanied and unaccompanied by an adult), and sociodemographic factors for six- and nine-year-old children. Results indicate that 35 per cent (95 per cent confidence interval (CI) 31 to 39 per cent) and 31 per cent (CI 28 to 34 per cent) walk to school in Melbourne and Perth respectively, while over 60 per cent are driven to school by car, with very small proportions riding bicycles or taking public transport. A higher level of walking was associated with lower levels of several indicators of socioeconomic status. Logistic regression analysis showed that the strongest predictor of walking activity was school type (government versus independent), and after adjusting for this, lesser car ownership, non-English-speaking background and lower occupational category were associated with walking to school, while a different set of predictors--age, sex and maternal education--was associated with the unaccompanied crossing of streets. There was little difference in overall walking levels between boys and girls, but boys were significantly more likely to cross streets unaccompanied (adjusted odds ratio 1.41, CI 1.14 to 1.72), providing a partial explanation of documented sex differences in injury rates.

Objective: To ascertain the incidence, severity, risk factors, and outcomes of injuries in children and adolescents playing Australian Rules football., Setting and Subjects: A prospective cohort study of football injuries in children and adolescents playing community football. We studied a stratified random sample of 54 teams and clinics (18 under-15 teams, 18 under-10 teams and 18 Vickick clinics for children under 10 years) from the Melbourne metropolitan area. Football exposure, injuries and associated risk factors were recorded for 1253 players during the 1992 football season., Results: Vickick, a modified form of the game, had the lowest rates of injury for all levels of injury severity, with an overall rate of 3.49 injuries per 1000 player-hours. The rate in the under-10 age group was 2.4 times higher (95% confidence interval [CI], 1.5-3.8) than that in Vickick, and the under-15 rate was 1.2 times (95% CI, 0.9-1.6) that of the under-10s. The under-15 age group had significantly more injuries that led to use of health services than the under-10 and Vickick groups, with rates of 3.93 (95% CI, 2.9-4.9), 0.64 (95% CI, 0.2-1.4), and 0.33 (95% CI, 0.1-0.8) injuries per 1000 players-hours respectively. Injuries were largely to soft tissues (sprains 26%, haematomas 25%) and to the lower limb (43%). Very few serious injuries occurred (19 fractures and three injuries with loss of consciousness); nearly all of these were in the under-15s. Rule modifications in under-10 teams and clinics were associated with an injury rate of 5.8 injuries per 1000 player-hours (95% CI, 4.4-7.3) compared with 7.5 injuries per 1000 player-hours (95% CI, 5.2-9.8) when no modification was used. Alterations to the ruck contest, decreased contact, field size and player numbers were significantly associated with lower injury rates, while body size was not. Of the 30% of injuries resulting in a health service consultation, the most common health provider was a medical practitioner. Very few required expensive investigation or treatment., Conclusion: Injury rates were low in children under age 10, but higher in adolescents. Most injuries were minor, and did not result in a health professional consultation. Rule modifications were associated with substantially lower injury rates at the under-10 level, and should be promoted as a safe way to learn football skills.

A 15-year-old female with primary reninism presented with benign hypertension, normokalemia, normal aortagram and normal intravenous pyelogram. The diagnosis was suggested only by a remarkably elevated plasma renin activity (PRA). Selective catheterization of renal vein branches was necessary to make the diagnosis of a tumor. A local resection of the tumor resulted in normalization of blood pressure and PRA. Prior to the definitive surgery, oral propranolol was effective in lowering PRA and blood pressure.

Previous studies of the early autologous phase of bilateral nephrotoxic serum nephritis (NSN) in rats showed that whole kidney and single nephron glomerular filtration rate (GFR) were maintained at normal levels despite a 60% reduction in the product of surface area and hydraulic permeability (Kf). Factors responsible for this compensation were an increase of net ultrafiltration pressure, due primarily to an increased glomerular capillary pressure (PGC). This study was designed to investigate some possible causes of the compensation. Rats with bilateral NSN and normal GFR had an increased extracellular fluid volume (ECFV) 2 weeks after induction of NSN; control subjects did not change. To determine whether this ECFV expansion was responsible for triggering the compensation, we developed a unilateral NSN model with one diseased and one normal kidney. Unilaterally diseased rats did not experience an increase of ECFV. Values of Kf were 0.069 +/- 0.012 nl sec-1 mm Hg-1 in control subjects, 0.037 +/- 0.005 in bilateral NSN, and 0.043 +/- 0.006 in unilateral NSN. The elevation in PGC was the same in unilateral NSN as in bilateral NSN subjects and the same was true for the hydrostatic pressure difference across glomerular capillaries (delta P). Furthermore, in paired measurements on both kidneys of rats with unilateral NSN, PGC was significantly higher in the unilaterally diseased kidney than in the nondiseased kidney; sham control subjects had no difference. These results are interpreted to indicate that the signal that causes elevation of net ultrafiltration pressure is not a consequence of a systemic effect of NSN, but arises within the diseased kidney itself. To determine whether that signal involved some change in the mechanisms mediating autoregulation measurements were made of the response of whole kidney GFR and RBF to acute changes in arterial BP. Control rats and rats with NSN autoregulated both GFR and blood flow equally well. Tubuloglomerular feedback was studied by microperfusing loops of Henle and measuring proximal stop-flow pressure and early proximal flow rate. Stop-flow pressure was 4.0 mm Hg higher in rats with NSN at a loop perfusion rate of 10 nl/min, approximately the same difference that was found by direct measurement of PGC, but the sensitivity of response to changes in perfusion rate was the same in NSN as in control subjects. Finally, end proximal tubule flow rate was higher in NSN than in control subjects reflecting decreased proximal reabsorption. Thus, a normal feedback mechanism receives a signal that should cause afferent arteriolar constriction in NSN rats.(ABSTRACT TRUNCATED AT 400 WORDS)

The quantity of antiglomerular baSEMent membrane antibodies (antiGBM) binding to the glomeruli of rats 4 hr after i.v. injection of 660 microgram of antiGBM was used as a measure of relative glomerular capillary surface area (Sr). Intact immature and adult rats (N = 27) weighing 46 to 440 g were studied to assess the effect of normal growth on Sr. Young adult rats (N = 36) were studied at 0, 8, 15, and 22 days following uninephrectomy or sham operation to assess the effect of hypertrophic kidney growth on Sr. Bound antiGBM increased from 95 microgram to approximately 350 microgram as rats grew from 46 to 200 g; further growth was associated with no further growth was associated with no further increases in bound antiGBM. In contrast, there was no progressive increase in Sr following uninephrectomy or sham operation despite as 45% increase in kidney weight at 22 days over the comparable kidney in the sham-operated rats (1.32 +/- SEM 0.06 g vs. 0.91 +/- SEM 0.01 g, P less than 0.0001). Thus, increases in GFR during early normal kidney growth parallel anatomic increases in Sr, but increases in GFR with later growth or with compensatory hypertrophy in young adult rats are not accompanied by changes in Sr.

We recently showed in dogs that there is a close relationship between bicarbonate reabsorption and glomerular filtration rate (GFR). The present studies were designed to confirm these findings in five normal men. Bicarbonate titrations were done after ingesting a low protein diet for one week and were repeated following elevation of GFR 11-29 per cent by high protein diet and dexamethazone ingestion. In every casetubular reabsorption of bicarbonate increased in proportion to the increases in GFR. We conclude that glomerular-tubular balance for bicarbonate reabsorption is a characteristic of human, as well as canine kidneys.

The plasma arginine vasopressin (pAVP) response to osmotic stimulation was studied in dogs and sheep by sampling at frequent intervals during steady-state dehydration and during water diuresis. Frequent sampling also was conducted after continuous infusion or bolus injection of 5 or 20 g/100 ml NaCl. A pulsatile pattern of pAVP was observed after such infusions or injections and in some animals after water deprivation. This pattern was not seen after water loading or in mildly dehydrated animals. The short term changes in pAVP during continuous infusion of 5 g/100 ml NaCl could not be correlated with variations in plasma tonicity. Rather, they appeared to reflect discontinuous hypothalamic posterior pituitary release of AVP. Thirst was evoked by a lower dose of 5 g/100 ml NaCl than was required for consistent stimulation of pAVP release, and the thirst response frequently was observed prior to the peak AVP response after bolus injection of 5 and 20 g/100 ml NaCl.

Renal arterial thrombosis from blunt trauma causes delayed hypertension in many patients, but few reports have been well documented. This first report of immediate onset of malignant hypertension in a patient following blunt renal trauma, with documented histologic and renal vein renin data, stresses the pitfalls associated with the diagnosis and treatment of this condition.

The influence of pindolol, other antihypertensive agents, or placebo upon plasma renin activity (PRA) was examined in five separate studies involving 249 subjects (pindolol), n = 149; propranolol, n = 43; methyldopa, n = 13; chlorthalidone, n = 16; placebo, n = 28). In addition, the subjects were stratified in for studies into low (n = 104), medium (n = 96), or high (n = 15) PRA categories according to baseline PRA and sodium excretion measurements. The response to antihypertensive therapy was analyzed in each PRA category. Pindolol and propranolol lowered PRA comparably at equivalent dosages, although this effect was not consistently observed in all studies or at all dosage levels. Methyldopa therapy was not associated with a decline in PRA and chlorthalidone elevated PRA. Pindolol and propranolol lowered both supine and erect diastolic blood pressure (BP) comparably. This effect was similar in subjects categorized as having low or medium PRA. Too few patients were studied with high PRA to derive statistically meaningful data. Pindolol lowered standing systolic BP to a greater extent than did propranolol, especially in the medium PRA category. It was concluded that pindolol, like other beta-adrenergic blockers, lowers PRA, that the effect of pindolol on diastolic BP is independent of the baseline PRA category, and that pindolol is more effective than propranolol in lowering standing systolic BP, at least in the medium PRA category.

A 15-year-old girl with hypertension, markedly elevated plasma renin activity, and normal aortogram had a well encapsulated tumor nodule removed from the right kidney. Following surgery, the plasma renin activity and blood pressure became normal and have remained so for the past 12 months. The tumor consisted of juxtaglomerular cells filling the interstitium between endothelium-lined vascular spaces. Electron microscopy disclosed the presence in the interior of the tumor, of unmyelinated nerve bundles with varicosities containing the small, densely cored vesicles characteristic of adrenergic nerves. Nerve terminals were in contact with the juxtaglomerular tumor cells. No basement membrane material was interposed between the nerve endings and the tumor cell; the width of the gap between the two plasma membranes was approximately 150 A. The presence of sympathetic fibers in the juxtaglomerular cell tumor underscores the close biologic relationship between the sympathetic and renin systems.

1. Thirty moderately severely hypertensive patients were studied in a double-blind comparison of minoxidil and hydrallazine in combination with frusemide and propranolol. 2. Blood pressure control in both groups of patients was satisfactory but long-term control appeared to be better in the minoxidil group. 3. Renal function was well preserved in both groups. Evidence of cardiac hypertrophy was slow to resolve despite good control of blood pressure. Side effects were negligible, and patient acceptance and rehabilitation was excellent.

Pressures and flows were measured in surface glomerular capillaries, efferent arterioles, and proximal tubules of 22 Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN). Linear deposits of rabbit and rat IgG and C3 component of complement were demonstrated in glomerular capillary walls by immunofluorescence microscopy. Light microscopy revealed diffuse proliferative glomerulonephritis, and proteinuria was present. Although whole kidney and single nephron glomerular filtration rate (GFR) in NSN (0.8 plus or minus 0.04 SE2 ml/min and 2 plus or minus 2 nl/min, respectively) remained unchanged from values in 16 weight-matched NORMAL HYDROPENIC control rats (0.8 plus or minus 0.08 and 28 plus or minus 2), important alterations in glomerular dynamics were noted. Mean transcapillary hydraulic pressure difference (deltaP) averaged 41 plus or minus 1 mm Hg in NSN versus 32 plus or minus 1 in controls (P LESS THAN 0.005). Oncotic pressures at the afferent (piA) end of the glomerular capillary were similar in both groups ( 16 mm /g) but increased much less by the efferent end (piE) in NSN (to 29 plus or minus 1 mm Hg) than in controls (33 plus or minus 1, P less than 0.025). Hence, equality between deltaP and piE, denoting filtration pressure equilibrium, obtained in control but not in NSN rats. While glomerular plasma flow rate was slightly higher in NSN (88 plus or minus 8 nl/min) than in controls (76 plus or minus 6, P greater than 0.2), the failure to achieve filtration equilibrium in NSN rats was primarily the consequence of a marked fall in the glomerular capillary ultrafiltration coefficient, Kf, to a mean value of 0.03 nl/(s times mm Hg), considerably lower than that found recently for the normal rat, 0.08 nl/(s times mm Hg). Thus, despite extensive glomerular injury, evidenced morphologically and by the low Kf, GFR remained normal. This maintenance of GFR resulted primarily from increases in deltaP, which tended to increase the net driving force for filtration, and thereby compensate for the reduction in Kf.

Marked reduction of the monoaminergic nerve fluorescence and catecholamine tissue content were demonstrated in the ischemic kidney of rats made hypertensive by unilateral renal artery stenosis (two-kidney Goldblatt hypertension). The nonischemic kidney showed a normal degree of fluorescence and catecholamine content. The electron microscope failed to demonstrate recognizable nerves around most of the glomerular arterioles of the ischemic kidney, whereas a normal rich innervation was observed in the nonischemic side. The juxtaglomerular index and renal renin content were elevated in the ischemic kidney and markedly reduced in the nonischemic kidney. Juxtaglomerular cells were present in the glomerular mesangium and ultrastructurally showed changes consistent with increased renin synthesis. The extent of disruption of the sympathetic system in renal hypertension might play a role in the degree of hypersecretory response of the juxtaglomerular cells to renal artery constriction.

Micropuncture studies have disclosed that extracellular fluid (ECF) volume expansion inhibits sodium reabsorption in the proximal tubule. The diuresis that ensues represents only a portion of the increment in sodium and water escaping proximal reabsorption, since a large and variable fraction of the increment is reabsorbed distally. In certain experimental models proximal reabsorption may be depressed by ECF volume expansion, yet only a negligible amount of sodium appears in the final urine. This suggests that saline diuresis is the consequence of depressed distal sodium reabsorption. Previous clearance and micropuncture studies have not conclusively proven this. Eight dogs were studied repeatedly: in some studies glomerular filtration rate and distal delivery were increased markedly without sodium administration; in others comparably high distal sodium loads were achieved by progressive 1/2 isotonic saline infusion. C(H2O) at high distal sodium loads was depressed by expansion of the ECF volume with hypotonic saline. The difference in free water formation between dogs which did and did not receive hypotonic saline was accounted for by the difference in sodium excretion. In one dog hypotonic saline expansion failed to depress free water formation; likewise the level of natriuresis in this dog was severely attenuated. The results of these experiments provide strong evidence that the natriuresis that occurs following ECF volume expansion with saline is a consequence of alteration in function of the distal nephron.

To determine whether the increased filtration of serum proteins after glomerular injury is the consequence of altered electrostatic properties of the glomerular capillary wall, we measured fractional clearances of the anionic polymer, dextran sulfate, in nine Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN). In agreement with previous studied from this laboratory, whole kidney and single nephron glomerular filtration rates were normal in NSN rats despite histological evidence of glomerular injury, and despite a marked reduction in the glomerular capillary ultrafiltration coefficient to approximately one-third of normal. In the companion study (9), it was shown that in NSN rats the mean fractional clearances of neutral dextrans over the range of effective molecular radii from 18 to 42 A were reduced, compared to normla. In contrast, in the present study the mean fractional clearances for dextran sulfate over the same range of molecular radii were significantly greater than those found previously for normal Munich-Wistar rats. The fractional clearance of dextran sulfate molecules of the same molecular radius as serum albumin (approximately 36 A) was increased markedly, from 0.015 +/- 0.005 (SEM) in nonnephritic controls to 0.24 +/- 0.03 in NSN (P less than 0.001). The sialoprotein content of glomeruli, estimated by the colloidal iron reaction, was reduced in NSN rats as compared to normal controls. It is concluded that the abnormal filtration of anionic serum proteins, such as albumin, seen in glomerulopathies is, at least in part, the consequence of loss of fixed negative charges from the glomerular capillary wall.

Segmental renal vein blood was collected in 9 hypertensive patients who had a focal renal lesion on excretory urography and/or a high peripheral plasma renin activity. The main renal vein catheterization was normal in all patients. Segmental renal vein catheterization demonstrated a renin-producing lesion in 3 patients, all of whom were cured of the hypertension postoperatively. Segmental renal vein catheterization is safe and allows the recognition of increased renin production from focal lesions of the kidney that may not be demonstrated radiographically or by main vein catheterization.

Polydisperse [3h] dextran was infused into eight Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN), thereby permitting direct measurements of pressures and flows in surface glomeruli and fractional clearances for dextrans [(U/P) dextran/(U/P) inulin] ranging in radius from 18 to 42 A. Despite glomerular injury, evidenced morphologically and by a marked reduction in the glomerular capillary ultrafiltration coefficient, the glomerular filtration rate remained normal because of a compensating increase in the mean net ultrafiltration pressure. In NSN rats, as in normal controls, inulin was found to permeate the glomerular capillary wall without measurable restriction, and dextrans were shown to be neither secreted nor reabsorbed. For dextran radii of 18, 22, 26, 30, 34, 38, and 42 A, (U/P) dextran/(U/P) inulin in NSN and control rats, respectively, averaged 0.90 vs. 0.99, 0.81 vs. 0.97, 0.63 vs. 0.83, 0.38 vs 0.55, 0.20 vs. 0.30, 0.08 vs. 0.11, and 0.02 vs. 0.03. Using a theory based on macromolecular transport through pores, the results indicate that in NSN rats, effective pore radius is the same as in controls, approximately 50 A. In NSN, however, the ratio of total pore surface area to pore length, a measure of the number of pores, is reduced to approximately 1/3 that of control, probably due to a reduction in capillary surface area. These results suggest that proteinuria in glomerular disease is not due simply to increases in effective pore radius or number of pores, as previously believed. Using a second theoretical approach, based on the Kedem-Katchalsky flux equations, dextran permeability across glomerular capillaries was found to be slightly lower, and reflection coefficient slightly higher in NSN than in control rats.

We have recently shown that in the early autologous phase of nephrotoxic serum nephritis (NSN) single nephron glomerular filtration rate is unchanged from values in normal hydropenic control rats, but that single nephron filtration fraction and efferent arteriolar oncotic pressure (piE) are reduced because of a marked reduction in the glomerular capillary ultrafiltration coefficient. The present study was undertaken to examine the influence of this decline in piE as well as the other known determinants of peritubular capillary fluid exchange on absolute proximal fluid reabsorption (APR) in NSN. The findings indicate that APR and proximal fractional reabsorption are reduced significantly in NSN, relative to values in a separate group of age and weight-matched normal hydropenic control rats studied concurrently. In addition to the measured decline in piE, efferent arteriolar plasma flow (Qe) and peritubular capillary hydraulic pressure (Pc) were found to increase significantly, while interstitial oncotic pressure, estimated from hilar lymph, was not significantly different from values in control rats. Using a mathematical model of peritubular capillary fluid uptake we found that, assuming that the capillary permeability-surface area product and interstitial hydraulic pressure are unchanged in NSN, the observed changes in piE and Pc are sufficient to offset the effect of the increase in QE, yielding a calculated reduction in APR of approximately 4 nl/min, in excellent agreement with the observed mean decline of 4.1 nl/min. These findings suggest that control of APR in NSN is mediated by the same factors that regulate APR under normal physiological conditions, namely, the imbalance of forces governing peritubular capillary uptake of isotonic reabsorbate.

The urine-concentrating mechanism was studied in chronic hypokalemia (seven dogs given a low K(+), high NaCl diet plus injections of deoxycorticosterone acetate [DOCA]) and chronic hypercalcemia (seven dogs given vitamin D). In the potassium-depleted dogs, muscle, serum, and urine K(+) fell markedly, but glomerular filtration rate (GFR) and body weight varied little. Maximum urine osmolality fell in all dogs (mean decrease = 45%); however, solute-free water reabsorption (T(CH2O)) at high rates of solute excretion remained normal in three of four dogs. Free water excretion (C(H2O)) increased normally or supranormally as a function of increasing Na(+) delivery to Henle's loop in six dogs so tested. Hypercalcemia of several weeks duration caused a decrease in both GFR (mean 36%) as well as in maximum urine osmolality (mean 57%). Maximum T(CH2O) was not invariably depressed; in fact, when the values were adjusted for the reduced number of functioning nephrons (T(CH2O)/C(In)), four of seven studies were normal. C(H20)/C(In) increased normally (or supranormally) with increasing fractional Na delivery to Henle's loop in four of five dogs.I conclude that the lowered maximum urine osmolality in these hypokalemic and hypercalcemic dogs was not related to abnormal water reabsorption from the collecting ducts. Although not specifically measured in this study, it is very likely that solute accumulation in the renal medulla was reduced. This probably was not caused by abnormal delivery of sodium to, nor reabsorption of sodium from Henle's loop. It is likely that a more subtle defect exists in the countercurrent mechanisms for establishing a steep concentration gradient in the renal medulla. In the few hypercalcemic dogs in whom GFR was very low, I believe that injury to, and blockage of medullary tubules could account for most of the reduction in maximum U(Osm). Although not specifically ruled out, there is no evidence here to suggest that high serum Ca(+) or low serum K(+) per se causes a defect in sodium and water reabsorption in the mammalian nephron.

We have tested two of the hypotheses proposed to explain the adjustment in sodium reabsorption in the proximal tubule that follows a change in the rate of glomerular filtration (glomerulotubular balance). Using the recollection micropuncture technique, we were able to measure the immediate and late changes in reabsorptive rate after an acute alteration in filtration rate produced by aortic constriction and release of constriction. It was found that fractional reabsorption, as measured by the inulin tubule fluid to plasma (TF/P) ratio, increased after aortic constriction and decreased after release, but that in most instances, absolute reabsorptive rate changed in parallel to glomerular filtration rate. The change was similar whether the collections were made less than 1 or more than 5 min after the change in blood pressure. The rapid time course of this adjustment in reabsorptive rate is viewed as evidence against an intrarenal humoral feedback mechanism. In the same experiments we measured the (TF/P)(In), transit time, and flow rate of fluid in single nephrons before and during aortic constriction or release of aortic constriction. The change in reabsorptive rate and the simultaneous change in calculated cross-sectional area of the tubule lumen were rarely proportional, i.e., C/pir(2) was not constant. In other experiments, these same measurements were made before and during periods of increased ureteral pressure. Despite large increments in calculated cross-sectional area, the absolute rate of reabsorption either remained relatively unchanged or fell in proportion to the change in filtration rate. It is concluded that under these conditions, reabsorptive rate is governed by some factor other than tubule geometry.

The function of the proximal and distal tubule was studied in the rhesus monkey during antidiuresis and during the diuresis after furosemide administration (during which extracellular fluid volume was maintained).In the proximal tubule, fluid to plasma ratios for sodium, potassium, and osmolality approximated unity. During antidiuresis, about 30% of the filtered water remained at the end of the accessible portion of this segment (92% of length). Fluid was hypotonic to plasma throughout the distal tubule. 25% of the filtered water was present in the early distal tubule. Small but significant water reabsorption (about 8% of filtered) occurred in remainder of this segment. Tubule fluid to plasma potassium concentration ratios tended to increase along the distal tubule, and the amount of potassium, relative to the amount filtered, increased from 13% in the early portion of this segment to 26% in the late portion.After furosemide was administered animals excreted about one-third of the filtered sodium and water. Despite this diuresis, electrolyte and water reabsorption along the proximal tubule did not differ from values obtained in control animals. Osmolality and sodium concentration of fluid from the distal tubule approached those of plasma. 22% of the filtered sodium (twice the control values) reached the distal tubule, whereas the fraction of filtered water remaining was only slightly increased. These findings indicate that, after the administration of this drug, inhibition of sodium reabsorption occurred in the water-impermeable segment of the nephron, rather than in the proximal tubule. After furosemide administration, all tubule fluid to plasma potassium concentration ratios in the distal tubule were equal to or greater than one, suggesting inhibition of active potassium reabsorption at or prior to this site.Fluid to plasma bicarbonate concentration ratios from the midportion of the proximal tubule were consistently less than one in normal monkeys. After acetazolamide was administered, the bicarbonate concentration of samples of tubule fluid recollected from these same sites was the same as, or higher than in plasma. This fact demonstrates the inhibition of bicarbonate reabsorption in this portion of the tubule.