Salivary but not plasma cortisone tracks the plasma cortisol response to exercise: effect of time of day.

INTRODUCTION: The cortisol, cortisone, corticosterone, and CBG responses to exercise in the AM and PM have not been described. This study examined the response of these glucocorticoids and CBG to intense exercise in 12 endurance-trained men in plasma (Pl) and saliva (Sa). METHODS: Each subject completed treadmill exercise in the morning and evening. Paired blood and Sa samples were obtained at rest before and after exercise. RESULTS: Significant time effect existed for Pl-cortisol and Sa-cortisol from baseline in the AM and PM (p < 0.01). Pl-cortisone and CBG significantly increased in the PM (p < 0.01). Pl-corticosterone increased in the AM and PM (p < 0.01). Unlike Pl-cortisone, Sa-cortisone was significantly higher in the AM compared to the PM, increasing in the AM and PM (All p < 0.01). Strong associations were found between Pl-cortisol and Sa-cortisol (r = 0.81, p < 0.0001), Pl-cortisol and Sa-cortisone (r = 0.81, p < 0.0001). CONCLUSIONS: (1) Intense EX induces a similar increase in Pl-cortisone (~90 %) and corticosterone (~200 %) in the AM and PM, whereas exercise increases CBG in the PM, but not in the AM; (2) vigorous exercise increases Sa-cortisone; (3) Sa-cortisone and cortisol are equally strongly correlated to Pl-cortisol, suggesting a significant role for Sa-cortisone as a novel marker of free cortisol during exercise.

Extensive volcanism associated with the separation of australia and antarctica.

Alternating hard and soft layers characterize the Gull Rock and Tuit Members of the late Eocene Blanche Point Formation, South Australia. Originally the formation was mainly a mixture of volcanic ash, sponge spicules, and calcareous fossil remains, with hard layers produced later by selective silicification. It resembles Cretaceous sediments from western Europe and the eastern coast of the United States, and in each case it appears that alteration of volcanic ash produced smectite and clinoptilolite with release of silica that subsequently crystallized as opal-CT. The occurrence of similar deposits from New Zealand to as far west as Albany, Western Australia, indicates extensive volcanic activity south of Australia in the late Eocene resulting from rifting and separation from Antarctica.

Risk factors for clustering of tuberculosis cases: a systematic review of population-based molecular epidemiology studies.

BACKGROUND: Many molecular epidemiology studies have been conducted to identify risk factors for clustering of tuberculosis (TB) cases in the population. OBJECTIVE: To estimate the impact of commonly investigated risk factors on TB clustering. METHODS: Ten electronic databases were searched up to January 2006 along with a hand search of the International Journal of Tuberculosis and Lung Disease and bibliographies of review articles. Meta-analyses of odds ratios (ORs) for various risk factors were conducted using random effect models, stratified by TB incidence. Meta-regressions were employed to account for the heterogeneity in clustering proportions and the magnitudes of risk. FINDINGS: The TB clustering proportion varied greatly (7.0-72.3%) among 36 studies in 17 countries. In multiple meta-regression analyses, high TB incidence, mean cluster size and conventional contact tracing were significantly associated with higher clustering. The pooled ORs (95%CIs) for low and high/intermediate TB incidence studies, using a cut off of 25/100000 per year, were 3.4 (2.7- 4.2) and 1.6 (1.3-2.1) for local-born status, 1.6 (1.5-1.7) and 1.7 (1.3-2.2) for pulmonary TB and 1.2 (1.1-1.3) and 1.3 (1.1-1.7) for smear-positive cases, respectively. Male sex, local birth, alcohol abuse and injection drug use were significantly higher risks in low TB incidence studies than in the high/intermediate ones. INTERPRETATION: Meta-analyses yielded significant estimates of ORs for several risk factors across both levels of TB incidence. Alcohol abuse, injection drug use and homelessness--all characteristics of marginalized populations--were found to be consistently significant in populations of low TB incidence. More research is needed to better understand TB transmission dynamics in high-burden countries.

c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H-2K/c-myc transgenic mice.

We investigated the mechanisms of regulation of c-myc, c-fos, and c-jun at the early stages of liver regeneration in mice. We show that the transient increase in steady-state levels of c-myc mRNA at the start of liver regeneration is most probably regulated by posttranscriptional mechanisms. Although there was a marked increase in c-myc transcriptional initiation shortly after partial hepatectomy, a block in elongation prevented the completion of most transcripts. To gain further information on the mechanism of regulation of c-myc expression during liver regeneration, we used transgenic mice harboring the human c-myc gene driven by the H-2K promoter. In these animals, the murine c-myc responded to the growth stimulus generated by partial hepatectomy, whereas the expression of the transgene was constitutive and did not change in the regenerating liver. However, the mRNA from both genes increased markedly after cycloheximide injection, suggesting that the regulation of c-myc mRNA abundance in the regenerating liver differs from that occurring after protein synthesis inhibition. Furthermore, we show that in normal mice c-fos and c-jun mRNA levels and transcriptional rates increase within 30 min after partial hepatectomy. c-fos transcriptional elongation was restricted in nongrowing liver, but the block was partially relieved in the regenerating liver. Nevertheless, for both c-fos and c-jun, changes in steady-state mRNA detected after partial hepatectomy were much greater than the transcriptional increase. In the regenerating liver of H-2K/c-myc mice, c-fos and c-jun expression was diminished, whereas mouse c-myc expression was enhanced in comparison with that in nontransgenic animals.

Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells.

Treatment of WEHI 231 immature B-lymphoma cells with an antibody against their surface immunoglobulin (anti-Ig) induces apoptosis and has been studied extensively as a model of B-cell tolerance. Anti-Ig treatment of exponentially growing WEHI 231 cells results in an early transient increase in c-myc expression that is followed by a decline to below basal levels; this decrease in c-myc expression immediately precedes the induction of cell death. Here we have modulated NF-kappaB/Rel factor activity, which regulates the rate of c-myc gene transcription, to determine whether the increase or decrease in c-Myc-levels mediates apoptosis in WEHI 231 cells. Addition of the serine/threonine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), which blocks the normally rapid turnover of the specific inhibitor of NF-kappaB/Rel IkappaBalpha in these cells, caused a drop in Rel-related factor binding. TPCK treatment resulted in decreased c-myc expression, preventing the usual increase seen following anti-Ig treatment. Whereas inhibition of the induction of c-myc expression mediated by anti-Ig failed to block apoptosis, reduction of c-myc expression in exponentially growing WEHI 231 cells induced apoptosis even in the absence of anti-Ig treatment. In WEHI 231 clones ectopically expressing c-Myc, apoptosis induced by treatment with TPCK or anti-Ig was significantly diminished and cells continued to proliferate. Furthermore, apoptosis of WEHI 231 cells ensued following enhanced expression of Mad1, which has been found to reduce functional c-Myc levels. These results indicate that the decline in c-myc expression resulting from the drop in NF-kappaB/Rel binding leads to activation of apoptosis of WEHI 231 B cells.

Differential effects of the widely expressed dMax splice variant of Max on E-box vs initiator element-mediated regulation by c-Myc.

dMax, a naturally occurring splice variant of the Myc binding protein Max, lacks the DNA binding basic region and helix 1 of the Helix-Loop-Helix domain; dMax interacts with c-Myc in vitro and in vivo, and inhibits E-box Myc site driven transcription in transient transfection assays. Here we have investigated the expression, function and interactions of dMax. RT/PCR analyses detected dmax mRNA in multiple tissues of the developing, newborn and adult mouse. Functionally, dMax reduced the ability of c-Myc to cooperate with the progression factor A-Myb to promote S phase entry of quiescent smooth muscle cells. In contrast, dMax failed to ablate inhibition of initiator element (Inr)-mediated transcription by c-Myc in Jurkat T cells. In in vitro protein:protein association assays, dMax interacted with c-Myc, N-Myc, L-Myc, Mad1, Mxi1, Mad3 and Mad4, but not with itself or wild-type Max. These interactions required an intact leucine zipper. Inhibition of E-box-mediated transactivation by induction of dMax overexpression resulted in apoptosis of WEHI 231 B cells. Thus, dMax is a widely expressed, naturally occurring protein, with the capacity to bind most members of the Myc/Max superfamily; dMax has little effect on Inr-mediated repression by c-Myc, but can significantly decrease E-box-mediated events promoting proliferation and cell survival.

The innervation of hyperplastic epidermis in the mouse: a light microscopic study.

The innervation of the skin of hairless mice has been studied following induction of epidermal hyperplasia by physical and chemical methods. Physical stimuli comprised ultraviolet irradiation, heat, wounding, and friction. Effective chemicals included benzene, carbon tetrachloride, chloroform, creosote, formaldehyde, hexadecane, hydrobromic acid, sodium lauryl sulfate, and turpentine. Epidermal hyperplasia, however produced, was associated with growth of sensory nerve fibers into the outer part of the epidermis. Following a single 10-min exposure to an ultraviolet sunalmp at 40 cm, the nerves extended into the epidermis within 24 hr and disappeared during the second week as the epidermis reverted to its normal thickness. Repeated irradiation (until tumors appeared) was accompanied by persistent hyperplasia and neural invasion. Of 32 papillomas examined, intraepithelial nerves were found in 28. The presence and location of nerves in the tumor epithelium were related to the incorporation of tactile hair disc epithelium. The hyperplastic regenerative epithelium at the margins of skin ulcers were also invaded by nerves which sometimes followed the migrating epithelium across the ulcer floor. Since the regenerative epithelium was not directly treated, it was concluded that the proliferation of nervous tissue in response to skin injury was the result of the hyperplasia per se, regardless of the method used to produce it.

A method of staining basal-cell plasma membranes in epidermal sheets.

An adenosine triphosphatase method was devised to stain basal epidermal cell plasma membranes in sheet preparations of humans, rat, mouse and guinea pig epidermis. The method is useful for direct observation of sizes, shapes, and numbers of basal epidermal cells.

Spontaneous complete clefting of the palates in a mouse fetus: a study by scanning electron microscopy and serial section reconstruction.

A 15 day mouse fetus having spontaneous complete clefting of the primary and secondary palates was studied in comparison with its normal litter mates and with normal 14 day fetuses. Specimens were studied by scanning electron microscopy at various stages of microdissection, by light microscopy of thin serial sections and by serial section reconstruction of the anterior chondrocranium of the clefted specimen and one of its normal litter mates. Differentiation of tooth and bone tissue was slightly retarded in the clefted fetus but paranasal and oral landmarks, though distorted, were present. The clefted fetus had a smaller angle between cranial base and nasal capsule and a marked discontinuity between the primary and secondary palates. Cell surfaces on the medial edge of the secondary palate in the clefted fetus resembled cell surfaces of oral areas that do not normally fuse, i.e. they are polygonial, flat and bear few surface projections in contrast to the normal 14 day condition where these cells are spindle shaped, convex and have many microvilli. The observations support the concepts that clefting of the secondary palate is consequential to clefting of the primary palate, that maldevelopment of neural crest mesenchyme is not necessarily a contributing factor, that clefting of the primary and secondary palates is associated with a shorter anterior-posterior dimension of the head and that when fusion of palatal shelves fails to occur the cells of the medial edges modulate in the direction of a generalized type of surface epithelium.

The effect of increasing doses of beta-agonists on airflow in patients with chronic airflow limitation.

OBJECTIVE: To determine the increase in FEV1 associated with increasing doses of inhaled terbutaline and salbutamol, the reproducibility of the increase in FEV1, and the reproducibility of the associated optimal bronchodilator dose, in patients with chronic airflow limitation (CAL). DESIGN: Double-blind, randomized, controlled trial examining spirometric response to cumulative doses of bronchodilators. PATIENTS AND SETTING: Patients with clinical diagnosis of CAL, FEV1 below 70% predicted, and FEV1 to FVC ratio less than 0.7 after administration of bronchodilator recruited from secondary care respirology practices. MEASURES OF OUTCOME: The estimates of maximum and optimal bronchodilation, as well as the associated drug dosages, were established in each patient on three occasions (twice on terbutaline and once on salbutamol). The 'optimal' drug dose was defined as the lowest dose associated with an FEV1 not exceeded by 50 ml on any other dose. MAIN RESULTS: Thirty-five patients completed the trial. FEV1 improved from 0.93 to a maximum of 1.191 with terbutaline (average of the two administrations) and from 0.951 to 1.141 with inhaled salbutamol (difference in increase in FEV1 between terbutaline and salbutamol P = 0.006). In less than 50% of cases administration of more than four puffs of bronchodilator resulted in FEV1 increase by more than 50 ml. The average dose of salbutamol and terbutaline associated with optimal bronchodilation were 430 micrograms and 1160 micrograms respectively. Patients varied widely in the optimal dose. Estimates of optimal dose were not reproducible (intraclass correlation coefficient < 0.5). CONCLUSION: Substantial incremental increase in FEV1 in response to increasing doses of beta-agonists beyond those commonly used in clinical practice is restricted to a minority of patients. Lack of reproducibility limits the clinical usefulness of establishing the optimal dose of beta-agonist for a given patient.

Experimental histological evidence for a dual motor pathway from the hypoglossal nucleus to lingual muscles in the guinea pig.

By combining the results of retrograde cell labelling with those of anterograde degeneration after nerve sectioning, it was shown that some axons from the most caudal neurones of the hypoglossal nucleus emerge in the first cervical nerve and join the hypoglossal nerve in the neck. These indirect hypoglossal axons are distributed to the intrinsic muscles of the tongue. The observed collaboration between the hypoglossal and first cervical nerves in supplying the lingual muscles has a plausible basis of explanation in phylogeny.

Temporal indication of marijuana use can be estimated from plasma and urine concentrations of delta9-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol, and 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid.

Current technology establishes marijuana use based upon detection of the pharmacologically inactive cannabinoid metabolite (11-nor-delta9-carboxy-tetrahydrocannabinol-9-carboxylic acid, THC-COOH) in urine. No accurate prediction of time of use is possible because THC-COOH has a half-life of 6 days. To determine if a temporal relationship between marijuana use and metabolite excretion patterns could be established, eight healthy user-volunteers (18-35 years old) smoked marijuana cigarettes containing 0% (placebo), 1.77%, and 3.58% delta9-tetrahydrocannabinol (THC). Plasma and urine were collected prior to smoking, 5 min after smoking, and hourly thereafter for 8 h for measurement of cannabinoid concentrations by gas chromatography-mass spectrometry. Mathematical models proposed for determination of recent marijuana use were applied to data from this study and verified the temporal use of marijuana. One subject, who later admitted chronic marijuana use (urine baseline THCCOOH, 529.2 ng/mL; plasma, 75.5 ng/mL), excreted 8beta-dihydroxy-THC, peaking 2 h postsmoking (92.3 ng/mL). Urinary THC, the psychoactive component of marijuana, concentrations peaked 2 h after smoking and declined to assay limit of detection (LOD) (1.5 ng/mL) by 6 h. 11-Hydroxy-delta9-tetrahydrocannabinol (11-OH-THC) and THCCOOH were detectable for the entire 8-h testing period but continued to decrease. Urinary concentrations of THC greater than 1.5 ng/mL suggests marijuana use during the previous 8-h time period.

Cannabinoids in humans. II. The influence of three methods of hydrolysis on the concentration of THC and two metabolites in urine.

Glucuronide conjugates of cannabinoids were previously identified in humans. For gas chromatographic-mass spectrometric (GC-MS) analysis of the unconjugated compounds in human urine, it is necessary to cleave the glucuronide moiety. Base hydrolysis and two forms of enzymatic hydrolysis were compared in this study to examine any quantitative differences between the hydrolysis methods. Human volunteers (n = 8) each smoked one marijuana cigarette containing 3.58% delta 9-tetrahydrocannabinol (THC) and submitted urine samples prior to smoking, 5 min after smoking, and hourly for 8 h thereafter. Urine (1 mL) was buffered to the optimum pH for each form of enzyme tested. beta-Glucuronidase from Escherichia coli (bacteria) or Helix pomatia (mollusk) was added to the specimens, followed by overnight incubation at 37 degrees C. Following hydrolysis, the samples were extracted using hexane-ethyl acetate (7:1) and derivatized with N,O-bis(trimethylsilyl)-trifluoroacetamide plus 1% trimethylchlorosilane, which converted the cannabinoids to their trimethylsilyl derivatives. GC-MS analysis revealed striking differences between the hydrolysis methods. Concentrations of unconjugated THC and 11-hydroxy-THC (11-OH-THC) using E. coli were significantly increased over all other methods tested (p < .05). These results demonstrate the species-dependent nature of glucuronidase activity in hydrolyzing THC and 11-OH-THC glucuronides and the ineffectiveness of base hydrolysis on these hydroxylated compounds. The need for further study to find the optimum conditions necessary for the complete hydrolysis of cannabinoid conjugates is suggested.

Inadequacies of self-report data for exclusion criteria detection in marihuana research: an empirical case for multi-method direct examination screening.

Stringent exclusion criteria in drug abuse research are necessary to protect against methodological confounds compromising the interpretation of findings. However, reliance on self-report screening may fail to detect important exclusion variables. We compared three levels of exclusion criteria screening in a study of neurophysiological/neurocognitive sequelae of chronic marihuana use in normals. LEVEL 1 (self-report) consisted of telephone pre-screening. LEVEL 2 (also self-report) involved in-depth personal interviews. LEVEL 3 consisted of several direct examination assessments including a medical/psychiatric examination by a board certified psychiatrist, eight weeks of twice per week urine drug screens, an EEG exam and eight hours of neuropsychological testing. Results indicated that 39.0% of subjects passing self-report screening had significant exclusion criteria findings that were only detected through LEVEL 3 direct examination procedures. Of all subjects found to have exclusion criteria after being provisionally accepted following LEVEL 1 telephone pre-screening, 55.7% were detected only through more rigorous LEVEL 3 direct examination screening methods.

Student self-instruction in anatomy.

Self-instruction programmes comprise audio tapes and a variety of visual materials ranging from photographs to models. The use of such programmes in an anatomy course is described and illustrated. They are an effective ancillary in teaching and are applicable to other medical teaching disciplines.

Canadian prediction equations of spirometric lung function for Caucasian adults 20 to 90 years of age: results from the Canadian Obstructive Lung Disease (COLD) study and the Lung Health Canadian Environment (LHCE) study.

BACKGROUND: Currently, no reference or normative values for spirometry based on a randomly selected Canadian population exist. OBJECTIVE: The aim of the present analysis was to construct spirometric reference values for Canadian adults 20 to 90 years of age by combining data collected from healthy lifelong nonsmokers in two population-based studies. METHOD: Both studies similarly used random population sampling, conducted using validated epidemiological protocols in the Canadian Obstructive Lung Disease study, and the Lung Health Canadian Environment study. Spirometric lung function data were available from 3042 subjects in the COLD study, which was completed in 2009, and from 2571 subjects in the LHCE study completed in 1995. A total of 844 subjects 40 to 90 years of age, and 812 subjects 20 to 44 years of age, were identified as healthy, asymptomatic, lifelong nonsmokers, and provided normative reference values for spirometry. Multiple regression models were constructed separately for Caucasian men and women for the following spirometric parameters: forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC ratio, with covariates of height, sex and age. Comparison with published regression equations showed that the best agreement was obtained from data derived from random populations. RESULTS: The best-fitting regression models for healthy, never-smoking, asymptomatic European-Canadian men and women 20 to 90 years of age were constructed. When age- and height-corrected FEV(1), FVC and FEV(1)/FVC ratio were compared with other spirometry reference studies, mean values were similar, with the closest being derived from population-based studies. CONCLUSION: These spirometry reference equations, derived from randomly selected population-based cohorts with stringently monitored lung function measurements, provide data currently lacking in Canada.