Whole-body fluid distribution in humans during dehydration and recovery, before and after humid-heat acclimation induced using controlled hyperthermia.

AIM: This experiment was designed to test the hypothesis that the plasma volume is not selectively defended during exercise- and heat-induced dehydration following humid-heat acclimation. METHODS: Eight physically active males were heat acclimated (39.8 °C, relative humidity 59.2%) using 17 days of controlled hyperthermia (core temperature: 38.5 °C). Inter-compartmental fluid losses and movements were tracked (radioisotopes and Evans blue dye) during progressive dehydration (cycling) in these same conditions and also during a resting recovery without fluid replacement (28 °C), before (day 1), during (day 8) and after heat acclimation (day 22). RESULTS: On days 8 and 22, there were significant increases in total body water, interstitial fluid and plasma volume (P < 0.05), but the intracellular compartments did not change (P > 0.05). The baseline plasma volume remained expanded throughout: 43.4 [±2.6 (day 1)], 49.1 [±2.4 (day 8); P < 0.05] and 48.9 mL kg(-1) [±3.0 (day 22); P < 0.05]. During progressive dehydration, plasma reductions of 9.0% (±0.9: day 1), 12.4% (±1.6: day 8) and 13.6% (±1.2: day 22) were observed, with day 8 and 22 losses significantly exceeding day 1 (P < 0.05). During recovery, plasma volume restoration commenced, with the intracellular fluid contribution becoming more pronounced as acclimation progressed. CONCLUSION: It is concluded that the plasma volume was not defended more vigorously following humid-heat acclimation. Indeed, a greater fluid loss may well underlie the mechanisms for enhancing plasma volume recovery when heat acclimation is induced using the controlled-hyperthermia technique.

Development of predictive models for airflow obstruction in alpha-1-antitrypsin deficiency.

Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

Heritability of lung function in severe alpha-1 antitrypsin deficiency.

Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.

Effects of immersion water temperature on whole-body fluid distribution in humans.

AIM: In this study, we quantified acute changes in the intracellular and extracellular fluid compartments during upright neutral- and cold-water immersion. We hypothesized that, during short-term cold immersion, fluid shifts would be wholly restricted to the extracellular space. METHODS: Seven males were immersed 30 days apart: control (33.3 degrees SD 0.6 degrees C); and cold (18.1 degrees SD 0.3 degrees C). Posture was controlled for 4 h prior to a 60-min seated immersion. RESULTS: Significant reductions in terminal oesophageal (36.9 degrees +/- 0.1 degrees -36.3 degrees +/- 0.1 degrees C) and mean skin temperatures (30.3 degrees +/- 0.3 degrees -23.0 degrees +/- 0.3 degrees C) were observed during the cold, but not the control immersion. Both immersions elicited a reduction in intracellular fluid [20.17 +/- 6.02 mL kg(-1) (control) vs. 22.72 +/- 9.90 mL kg(-1)], while total body water (TBW) remained stable. However, significant plasma volume (PV) divergence was apparent between the trials at 60 min [12.5 +/- 1.0% (control) vs. 6.1 +/- 3.1%; P < 0.05], along with a significant haemodilution in the control state (P < 0.05). Plasma atrial natriuretic peptide concentration increased from 18.0 +/- 1.6 to 58.7 +/- 15.1 ng L(-1) (P < 0.05) during cold immersion, consistent with its role in PV regulation. We observed that, regardless of the direction of the PV change, both upright immersions elicited reductions in intracellular fluid. CONCLUSION: These observations have two implications. First, one cannot assume that PV changes reflect those of the entire extracellular compartment. Second, since immersion also increases interstitial fluid pressure, fluid leaving the interstitium must have been rapidly replaced by intracellular water.

Cold-water acclimation does not modify whole-body fluid regulation during subsequent cold-water immersion.

We investigated the impact of cold-water acclimation on whole-body fluid regulation using tracer-dilution methods to differentiate between the intracellular and extracellular fluid compartments. Seven euhydrated males [age 24.7 (8.7) years, mass 74.4 (6.4) kg, height 176.8 (7.8) cm, sum of eight skinfolds 107.4 (20.4) mm; mean (SD)] participated in a 14-day cold-water acclimation protocol, with 60-min resting cold-water stress tests [CWST; 18.1 (0.1) degrees C] on days 1, 8 and 15, and 90-min resting cold-water immersions [18.4 (0.4) degrees C] on intervening days. Subjects were immersed to the 4th intercostal space. Intracellular and extracellular fluid compartments, and plasma protein, electrolyte and hormone concentrations were investigated. During the first CWST, the intracellular fluid (5.5%) and plasma volumes were reduced (6.1%), while the interstitial fluid volume was simultaneously expanded (5.4%). This pattern was replicated on days 8 and 15, but did not differ significantly among test days. Acclimation did not produce significant changes in the pre-immersion distribution of total body water, or changes in plasma osmolality, total protein, electrolyte, atrial natriuretic peptide or aldosterone concentrations. Furthermore, a 14-day cold-water acclimation regimen did not elicit significant changes in body-fluid distribution, urine production, or the concentrations of plasma protein, electrolytes or the fluid-regulatory hormones. While acclimation trends were not evident, we have confirmed that fluid from extravascular cells is displaced into the interstitium during acute cold-water immersion, both before and after cold acclimation.

Transition to raloxifene with and without low-dose estrogen therapy in postmenopausal women: effects on serum lipids and fibrinogen - a pilot study.

OBJECTIVE: To compare the effects of transferring from low-dose transdermal estrogen to raloxifene (RLX), with a phase of alternate-day RLX therapy with or without low-dose transdermal estrogen, on serum lipids and fibrinogen in postmenopausal women previously administered estrogen plus progestogen therapy. METHODS: Sixty postmenopausal women (mean age 55 years) were randomized to one of two treatment groups: RLX + low-dose transdermal estrogen (RLX + E) or RLX + placebo. The study consisted of four 8-week phases: phase I (all subjects low-dose transdermal estrogen 25 microg/day), phase II (double-blind RLX 60 mg every 2nd day in combination with either low-dose transdermal estrogen or placebo), phase III (all subjects RLX 60 mg every 2nd day + placebo) and phase IV (all subjects RLX 60 mg/day + placebo). RESULTS: No significant differences existed between groups for baseline measurements prior to phase I. In phase I, for all subjects combined, total cholesterol and low-density lipoprotein cholesterol both showed a significant increase (median increase of 0.2 mmol/l, p = 0.008 and 0.4 mmol/l, p< 0.001, respectively), while triglycerides decreased significantly (median decrease of 0.2 mmol/l, p< 0.001). For the primary analysis (phase II to phase IV), the mean change from baseline observations showed no significant differences between the therapy groups for serum lipids, fibrinogen, vital signs or weight. In the comparison phase (phase II), changes in serum lipids, fibrinogen, vital signs and weight were not significantly different between groups. CONCLUSION: Gradual conversion to RLX from low-dose transdermal estrogen, with a phase of alternate-day RLX therapy with or without low-dose transdermal estrogen, does not have any effect on the serum lipid profile or fibrinogen level.

An evaluation of cefaclor in Pakistani children with pharyngotonsillitis.

OBJECTIVE: To assess the efficacy, safety of cefaclor for the treatment of pharyngotonsillitis in Pakistani children. METHOD: Pakistani children between the ages of two to twelve years and diagnosed with pharyngotonsillitis were eligible to participate in the study. Cefaclor was administered three times daily for a total dose of 20-40 mg/kg/day, depending on the severity of the infection, for 7 days. Patients were evaluated on the basis of symptomatic response and antibiotic susceptibility pattern as a result of bacteriological examination. RESULTS: Based on observed pre-therapy signs/symptoms of infection with pharyngotonsillitis, 99% of patients (95% CI=94.9% to 100.0%) were reported as having a symptomatic response of Cure or Improvement by end of study. Group A b-haemolytic Streptococci was the most prevalent pathogen isolated pre-therapy (occurring in 45% of patients). Of all patients for whom this pathogen was isolated, 64% had complete eradication by end of therapy, while there was persistence or superinfection in 36% of patients. Only 9 occurrences of non-serious adverse events were observed among 7 of the 107 patients, including diarrhea (5), nausea (1), vomiting (1), rash (1) and stomatitis (1). CONCLUSION: Based on the high symptomatic response rate of 99% and the positive safety data, cefaclor was found to be effective and safe in treating Pakistani children with pharyngotonsillitis.

Metabolic habituation following repeated resting cold-water immersion is not apparent during low-intensity cold-water exercise.

This project examined the effects of repeated, resting cold-water immersion on metabolic heat production and core temperature defence during subsequent rest and exercising immersions. Seven males undertook 15 days of cold-water adaptation, immersed to the fourth intercostal space, with cold-water stress tests (CWST) on days 1, 8 and 15 (18.1 SD 0.1 degree C: 60 min seated, followed by 30 min cycling (1 W.kg-1)), and 90-min resting immersions (18.4 SD 0.4 degree C) on each of the intervening days. Adaptation elicited an habituated thermogenic response during the rest phase of CWST3 beyond 20 min, compared to CWST1 (P < 0.05), with oxygen consumption averaging 11.15 (+/- 0.25) ml.kg-1.min-1 and 8.61 (+/- 0.90) ml.kg-1.min-1 by 50 min, for CWST1 and CWST3, respectively. During exercise, this metabolic blunting was only apparent over the first 10-min period (60-70 min). No significant differences were observed during either the rest or exercise phases of the CWSTs for oesophageal temperature (Tes). While repeated cold-water exposures produced an habituated-thermogenic response, for an equivalent drop in Tes during rest, neither this response, nor an elevated thermogenesis, were apparent during subsequent cold-water exercise.

Cardiorespiratory dynamics: sensitivity of the on-transition to endurance-training status.

This project investigated the sensitivity of oxygen uptake (VO(2)) dynamics to training-induced physiological changes, across a broad spectrum of endurance-training histories. Forty subjects participated: sedentary (n = 10), active healthy (n = 10), regular runners (n = 10), and competitive distance runners (n = 10). Subjects completed a cycle step-function protocol, to elicit a steady state at 60% maximal work rate. Breath-by-breath data were collected for VO(2) and cardiac frequency (f(c)), and modelled mathematically, and used to determine the average response times to attain 20%, 40%, 60%, 80% and 100% of the respective steady states. The between-group comparisons for both VO(2) and f(c) revealed significantly faster response times to 40%, 60%, 80% and 100% of the induced response, for the better trained subjects (P < 0.05). In general, this technique permitted differentiation between the VO(2) and f(c) response dynamics of non-elite subjects from a broad range of endurance-training histories, with differences becoming more pronounced as subjects approached the steady state.

Analysis of ferruginous bodies in bronchoalveolar lavage from foundry workers.

Classical ferruginous bodies in tissue samples are considered to be markers of past exposure to asbestos. Recent studies have shown that the presence of ferruginous bodies in bronchoalveolar lavage (BAL) fluid correlates with past exposure to asbestos and offers a more sensitive reference than occupational history. Lavage samples from five subjects who had worked in foundries were evaluated by light microscopy for the presence of ferruginous bodies and by transmission electron microscopy for both characterisation of the uncoated fibre burden and analysis of the cores of the ferruginous bodies. All samples at lower magnification (light microscopy (200 x)) contained ferruginous bodies that were externally consistent with asbestos bodies. At higher magnification (400 x), a separate population from this group could be identified by the presence of a thin black ribbon. Transmission electron microscopy of the core materials of ferruginous bodies and comparable uncoated particulates supported the reliability of higher magnification light microscopy for distinguishing most of those non-asbestos cores; however, a population of transparent non-asbestos cored ferruginous bodies were also shown to exist.

Characterization of the high Mr glycoprotein (gP300) of equine herpesvirus type 1 as a novel glycoprotein with extensive O-linked carbohydrate.

The high Mr glycoprotein (gp300) of equine herpesvirus type 1 was found to have an Mr, estimated by SDS-PAGE, of over 400,000 and was confirmed as being a surface glycoprotein by 125I-labelling. In contrast to [3H]glucosamine, gp300 showed very low levels of [3H]glucosamine, gp300 showed very low levels of [3H]mannose incorporation. The Mr of gp300 showed no detectable change upon treatment of purified virus with N-glycanase, and showed only a small change in virus-infected cells treated with tunicamycin. In addition, gp300 failed to bind the lectin concanavalin A. Taken together, these results indicate a lack of N-linked carbohydrate on gp300. The major carbohydrate species were found to be composed primarily of O-linked chains, as indicated by the sensitivity of the protein to monensin, to exoglycanase enzymes specific for sugars present in O-linked chains and to mild alkaline borohydride treatment, which revealed three species of carbohydrate of Mr of greater than 10,000, 2400 and 1100, respectively. Neuraminidase treatment and binding of Helix pomatia lectin indicated the presence of alpha-N-acetylglucosamine and sialic acid as terminal sugars. Immunological cross-reactivity of gp300 with a high Mr protein of equine herpesvirus type 4 was shown and it also exhibited a marked Mr variation in the vaccine strain Rhinomune.

Ofloxacin in community-acquired lower respiratory infections. A comparison with amoxicillin or erythromycin.

Ninety-one patients with community-acquired lower respiratory infections were treated orally in a comparative 10-day trial of ofloxacin versus amoxicillin or erythromycin. Approximately one-half of the patients had no major underlying disease and the other half had some form of chronic lung disease. Pneumonia was present in 31 percent of the patients and the remainder had purulent bronchitis. Bacterial pathogens were recovered from 60 percent of the patients, with Haemophilus influenzae (33 isolates) and Streptococcus pneumoniae (16 isolates) being the most common. Ofloxacin was found to be a safe, well-tolerated therapeutic agent, which was as effective clinically as amoxicillin or erythromycin and with an advantage of less frequent administration. Ofloxacin was more effective than amoxicillin (90 percent versus 75 percent; p = 0.05) in elimination of pathogenic bacteria from lower airway cultures. Caution should be exercised in the use of ofloxacin, at least in short-term treatment regimens, with anaerobic pulmonary infections; additional information is needed for S. pneumoniae given the relatively high minimal inhibitory concentrations for this species.

Identification of the gB homologues of equine herpesvirus types 1 and 4 as disulphide-linked heterodimers and their characterization using monoclonal antibodies.

Equine herpesvirus types 1 and 4 (EHV-1 and EHV-4) labelled with [14C]glucosamine were purified from infected cell culture medium and profiles of their structural proteins were obtained that enabled identification of the major glycoproteins. Nine glycosylated polypeptides were identified for each virus. Preparations of the purified viruses each contained a glycoprotein which was linked by disulphide bonds, as determined by diagonal gel electrophoresis under reducing/non-reducing conditions. High Mr forms of this glycoprotein were detected for EHV-1 when the sample was not heated. The EHV-1 protein consisted of three polypeptides of Mr 108K, 76K and 58K and the EHV-4 protein consisted of three polypeptides of Mr 112K, 74K and 61K. Western blotting and immunoprecipitation with monoclonal antibodies confirmed that the EHV-1 gB homologue migrates with an apparent Mr of 108K (140K under non-reducing conditions) but is cleaved to give glycoproteins of 76K and 58K which are held together by disulphide bonds. The EHV-4 gB homologue consists of a 112K glycoprotein which is cleaved to give glycoproteins of 74K and 61K which are also linked by disulphide bonds.