Diagnostic findings in sinonasal aspergillosis in dogs in the United Kingdom: 475 cases (2011-2021).

OBJECTIVES: To describe the diagnostic tests used and their comparative performance in dogs diagnosed with sinonasal aspergillosis in the United Kingdom. A secondary objective was to describe the signalment, clinical findings and common clinicopathologic abnormalities in sinonasal aspergillosis. MATERIALS AND METHODS: A multi-centre retrospective survey was performed involving 23 referral centres in the United Kingdom to identify dogs diagnosed with sinonasal aspergillosis from January 2011 to December 2021. Dogs were included if fungal plaques were seen during rhinoscopy or if ancillary testing (via histopathology, culture, cytology, serology or PCR) was positive and other differential diagnoses were excluded. RESULTS: A total of 662 cases were entered into the database across the 23 referral centres. Four hundred and seventy-five cases met the study inclusion criteria. Of these, 419 dogs had fungal plaques and compatible clinical signs. Fungal plaques were not seen in 56 dogs with turbinate destruction that had compatible clinical signs and a positive ancillary test result. Ancillary diagnostics were performed in 312 of 419 (74%) dogs with observed fungal plaques permitting calculation of sensitivity of cytology as 67%, fungal culture 59%, histopathology 47% and PCR 71%. CLINICAL SIGNIFICANCE: The sensitivities of ancillary diagnostics in this study were lower than previously reported challenging the clinical utility of such tests in sinonasal aspergillosis. Treatment and management decisions should be based on a combination of diagnostics including imaging findings, visual inspection, and ancillary testing, rather than ancillary tests alone.

A two-ward acute care hospital outbreak of SARS-CoV-2 delta variant including a point-source outbreak associated with the use of a mobile vital signs cart and sub-optimal doffing of personal protective equipment.

BACKGROUND: The arrival of the Delta variant of SARS-CoV-2 was associated with increased transmissibility and illness of greater severity. Reports of nosocomial outbreaks of Delta variant COVID-19 in acute care hospitals have been described but control measures varied widely. AIM: Epidemiological investigation of a linked two-ward COVID-19 Delta variant outbreak was conducted to elucidate its source, risk factors, and control measures. METHODS: Investigations included epidemiologic analysis, detailed case review serial SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) testing of patients and healthcare workers (HCWs), viral culture, environmental swabbing, HCW-unaware personal protective equipment (PPE) audits, ventilation assessments, and the use of whole genome sequencing (WGS). FINDINGS: This linked two-ward outbreak resulted in 17 patient and 12 HCW cases, despite an 83% vaccination rate. In this setting, suboptimal adherence and compliance to PPE protocols, suboptimal hand hygiene, multi-bedded rooms, and a contaminated vital signs cart with potential fomite or spread via the hands of HCWs were identified as significant risk factors for nosocomial COVID-19 infection. Sudden onset of symptoms, within 72 h, was observed in 79% of all Ward 2 patients, and 93% of all cases (patients and HCWs) on Ward 2 occurred within one incubation period, consistent with a point-source outbreak. RT-PCR assays showed low cycle threshold (CT) values, indicating high viral load from environmental swabs including the vital signs cart. WGS results with ≤3 SNP differences between specimens were observed. CONCLUSION: Outbreaks on both wards settled rapidly, within 3 weeks, using a `back-to-basics' approach without extraordinary measures or changes to standard PPE requirements. Strict adherence to recommended PPE, hand hygiene, education, co-operation from HCWs, including testing and interviews, and additional measures such as limiting movement of patients and staff temporarily were all deemed to have contributed to prompt resolution of the outbreak.

Quantification of zinc concentrations in serum, milk and faeces of dairy cattle as a measure of effective zinc supplementation for management of facial eczema.

AIMS: To investigate the relationship between Zn concentrations in serum and those in milk or faeces, and to assess the ability of the Zn concentrations in milk, serum and faeces to predict intake of ZnO in dairy cattle. METHOD: Seventy cows from one commercial farm in the Waikato region of New Zealand received one of seven dose rates (0, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5 g/100 kg bodyweight (BW)) of ZnO given by oral drench, every morning, for 7 consecutive days. Every afternoon, milk and blood samples were collected from all cows. Free-catch faecal samples were collected during the afternoon milking on 3 days throughout the trial.Linear mixed models were used to assess the relationship between the concentration of Zn in serum and that in milk, and in faeces, respectively, and the relationship between dose rate of ZnO and concentrations of Zn in serum, faeces and milk, respectively. Receiver operating characteristic curve analysis was used to determine the ability of the Zn concentration in serum, milk and faeces to predict that a cow had been treated with a dose of ZnO ≥2.5 g/100 kg, the industry-recommended dose rate needed to protect against facial eczema. RESULTS: A 1-µmol/L increase in Zn concentration in milk was associated with a 0.14 (95% CI = 0.11-0.17) µmol/L increase in Zn concentration in serum. Zn concentration in faeces was scaled by its SD; a 1 SD increase was associated with a 1.83 (95% CI = 0.54-3.12) µmol/L increase in zinc concentration in serum. Zn concentrations in serum and faeces increased with increasing dose rates of ZnO. No differences in Zn concentrations in milk were noted between animals dosed with 1.5-3.5 g ZnO/100 kg BW, inclusive. At the optimal threshold of Zn concentration in serum to predict protective ZnO intake (22 µmol/L), the sensitivity was 0.76 (95% CI = 0.69-0.82) and specificity 0.85 (95% CI = 0.80-0.89). For the concentration of Zn in faeces, the optimal threshold was 17.36 mmol/kg, with a corresponding sensitivity of 0.84 (95% CI = 0.84-0.85) and specificity of 0.85 (95% CI = 0.73-0.94). At the optimal threshold for the Zn concentration in milk (76.6 µmol/L), the sensitivity was lower than the other two sample types at 0.59 (95% CI = 0.52-0.67), but with a similar specificity of 0.84 (95% CI = 0.79-0.88). CONCLUSIONS AND CLINICAL RELEVANCE: The concentration of Zn in milk shows promise as an initial screening test to identify dairy farms that do not provide adequate zinc to provide protection against FE.

An observational study on the relationship between zinc concentrations in bulk tank milk and in serum and farmer-reported zinc supplementation of dairy cattle for facial eczema prophylaxis.

AIMS: To describe the concentration of Zn in bulk tank milk (BTM) in a sample of New Zealand dairy farms, investigate the association between the method of Zn administration for facial eczema prophylaxis and Zn concentrations in BTM and investigate the relationship between the concentration of Zn in serum and that in BTM. METHODS: Multiple BTM samples (n = 3,330) collected during milk pick-up by the milk tanker driver were stored and tested for 121 farms, in Northland (n = 50), Waikato (n = 51) and Southland (n = 20) from February to May 2017. Enrolled farms provided retrospective information on the type of Zn supplementation (if any) used for the prevention of facial eczema and the timeframe over which supplementation occurred. In addition, the concentration of Zn in serum was measured in blood samples collected from ≥15 cattle per farm for 22 farms from Northland (n = 11) and Waikato (n = 11), and compared against the concentrations of Zn in BTM on the day of blood sampling. A linear mixed model was used to model log Zn concentrations in BTM using method of Zn supplementation, region, milk fat and protein percentage, volume of milk, and frequency of milk pick-up as risk factors. A mixed logistic regression model was used to assess the relationship between Zn concentrations in BTM and the presence of cows with a concentration of Zn in serum of ≥20 µmol/L. RESULTS: The median Zn concentration in BTM was 67.9 (min 38.9, max 146.6) µmol/L. The median range of Zn concentrations for repeated samples of BTM within farm was 22.6 µmol/L. In comparison to farms that did not use any form of Zn supplementation, farms that supplemented Zn through a slow-release capsule, oral drench, in feed or a combination of in-feed and water were associated with increased concentrations of Zn in BTM (p < 0.001). There was no difference in Zn concentrations in BTM between farms that administered Zn through the water only and farms that did not administer Zn (p = 0.22). Every 15.3 µmol/L increase in Zn concentration in BTM was associated with 2.2 times (95% CI=1.7-2.9) the odds of a cow having Zn concentration in serum ≥20 µmol/L. CONCLUSION AND CLINICAL RELEVANCE: Zn concentration in BTM is highly variable between farms, days and Zn administration method. Zn concentration in BTM content has modest potential as a way to signal whether a herd has achieved the high Zn status considered to be protective against FE.

Glucocorticoid metabolism and the action of 11 beta-hydroxysteroid dehydrogenase 2 in canine congestive heart failure.

The enzyme 11-beta-hydroxysteroid dehydrogenase isoenzyme 2 (11BHSD2) is responsible for converting the active glucocorticoid cortisol to inactive cortisone and in the renal medulla protects the mineralocorticoid receptor (MR) from activation by cortisol. Derangements in 11BHSD2 activity can result in reduced conversion of cortisol to cortisone, activation of the MR by cortisol and, consequently, sodium and water retention. The objective of this study was to examine glucocorticoid metabolism in canine congestive heart failure (CHF), specifically to evaluate whether renal 11BHSD2 activity and expression were altered. Dogs were prospectively recruited into one of two phases; the first phase (n=56) utilized gas chromatography-tandem mass spectrometry to examine steroid hormone metabolites normalised to creatinine in home-caught urine samples. Total serum cortisol was also evaluated. The second phase consisted of dogs (n=18) euthanased for refractory CHF or for behavioural reasons. Tissue was collected from the renal medulla for examination by quantitative reverse transcription polymerase chain reaction, immunohistochemistry and protein immune-blotting. Heart failure did not change urinary cortisol:cortisone ratio (P=0.388), or modify renal expression (P=0.303), translation (P=0.427) or distribution of 11BHSD2 (P=0.325). However, CHF did increase excretion of 5α-tetrahydrocortisone (P=0.004), α-cortol (P=0.002) and α-cortolone (P=0.009). Congestive heart failure modifies glucocorticoid metabolism in dogs by increasing 5α-reductase and 20α-hydroxysteroid dehydrogenase activity. Differences between groups in age, sex and underlying disease processes may have influenced these results. However, 11BHSD2 does not appear to be a potential therapeutic target in canine CHF.

Glucocorticoid metabolism in critically ill dogs (Canis lupus familiaris).

Critical illness due to sepsis is a major global health concern associated with a high burden of mortality and cost. Glucocorticoid dysregulation in human sepsis is associated with poorer outcomes. This study examines glucocorticoid metabolism in septic canine patients to delineate elements of cellular dysregulation in common with critically ill humans and explore potential differences. This was a prospective case-control study conducted in the veterinary specialist critical care departments of two University teaching hospitals. Critically ill canine patients with naturally occurring sepsis or septic shock were compared with an in-hospital control population. Serum total, bound, and free cortisol concentrations were increased in septic shock (P < 0.001), and higher bound cortisol was associated with nonsurvival (P = 0.026). Urinary Gas Chromatography-Tandem Mass Spectrometry was performed to assess urinary glucocorticoid metabolites and estimate intracellular glucocorticoid metabolism. Decreased renal 11ß-hydroxysteroid dehydrogenase 2 (11ßHSD2) activity inferred from increased urinary cortisol-to-cortisone ratio was observed in critically ill dogs (P < 0.001). Decreased 11ßHSD2 activity (P = 0.019) and increased A-ring reduction of cortisone (P = 0.001) were associated with nonsurvival within the critically ill dogs. Intriguingly, two dogs were identified with low circulating total cortisol (<2 mg/dL) associated with increased A-ring reduction of cortisol, not previously described. Investigation of spontaneous canine sepsis and septic shock reveals dysregulation of cortisol to cortisone conversion similar to that observed in human patients, but with differences in A-ring reduction compared with those reported in humans. In addition, two dogs with high levels of cortisol inactivation associated with low circulating cortisol concentrations were identified.

I.CAN: health coaching provides tailored nutrition and physical activity guidance to people diagnosed with cancer in a rural region in West Gippsland, Australia.

PURPOSE: I.CAN is a program which uses health coaching to provide tailored nutrition and physical activity guidance to people diagnosed with cancer in a rural region in eastern Victoria, Australia. I.CAN builds patients' nutritional knowledge, attitudes and health literacy to healthy eating and weight maintenance and incorporates sustainable and affordable dietary changes into everyday eating patterns. While oncology care identifies patients at risk of malnutrition and weight loss, less attention has been placed on building patient's capacity for healthy lifestyles and behaviours after cancer treatment. METHODS: I.CAN is delivered by a dietitian and exercise physiologist and is offered in three streams, one-on-one consultation, one-one-one and group and group. Paired t tests and chi-square analysis were used to analyse data. RESULTS: At 3-month review, I.CAN participants (1) significantly increased exercise activity from 51 to 86% (p < 0.001) and (2) showed increased trends in positive food choices from 62 to 66%. Importantly, positive food choices for alcohol and processed snacks were maintained, and there were increases in positive food choices for fresh fruit and vegetables, low fat dairy and processed meats. CONCLUSION: I.CAN is an example of a program which can be delivered within a rural setting, with minimal resources, and achieve positive impact for patients. IMPLICATIONS FOR CANCER SURVIVORS: Key to the success of the program is promoting wellness early in the cancer trajectory and providing patients with practical tools, a person-centred and multidisciplinary team approach and a program which is adaptable to the changing needs of the patient and the health service.

Estimating Bacterial Pathogen Levels in New Zealand Bulk Tank Milk.

Zoonotic bacteria such as Campylobacter, Listeria, and Shiga toxin-producing Escherichia coli have been found in bulk tank milk in many countries, and the consumption of raw milk has been implicated in outbreaks of disease in New Zealand. Fecal contamination at milking is probably the most common source of pathogenic bacteria in bulk tank milk. Raw milk was collected from 80 New Zealand dairy farms during 2011 and 2012 and tested periodically for Campylobacter, E. coli O157, Listeria monocytogenes, and Salmonella. Milk quality data such as coliform counts, total bacterial counts, and somatic cell counts also were collected. By treating the total bacterial count as a proxy for fecal contamination of milk and utilizing farm and animal level prevalence and shedding rates of each pathogen, a predictive model for the level of pathogenic bacteria in bulk tank raw milk was developed. The model utilizes a mixture distribution to combine the low level of contamination inherent in the milking process with isolated contamination events associated with significantly higher pathogen levels. By simulating the sampling and testing process, the predictive model was validated against the observed prevalence of each pathogen in the survey. The predicted prevalence was similar to the observed prevalence for E. coli O157 and Salmonella, although the predicted prevalence was higher than that observed in samples tested for Campylobacter.

Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet.

AIMS/HYPOTHESIS: Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3. METHODS: Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3(+)) under control conditions and following an obesogenic high-fat diet (HFD) challenge. RESULTS: Ucn3(+) mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3(+) phenotype. Ucn3(+) mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3(+) muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3(+) muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed. CONCLUSIONS/INTERPRETATION: Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3(+) mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.

Simulating the influence of vernalization, photoperiod and optimum temperature on wheat developmental rates.

BACKGROUND AND AIMS: Accurately representing development is essential for applying crop simulations to investigate the effects of climate, genotypes or crop management. Development in wheat (Triticum aestivum, T. durum) is primarily driven by temperature, but affected by vernalization and photoperiod, and is often simulated by reducing thermal-time accumulation using vernalization or photoperiod factors or limiting accumulation when a lower optimum temperature (T(optl)) is exceeded. In this study T(optl) and methods for representing effects of vernalization and photoperiod on anthesis were examined using a range of planting dates and genotypes. METHODS: An examination was made of T(optl) values of 15, 20, 25 and 50 degrees C, and either the most limiting or the multiplicative value of the vernalization and photoperiod development rate factors for simulating anthesis. Field data were from replicated trials at Ludhiana, Punjab, India with July through to December planting dates and seven cultivars varying in vernalization response. KEY RESULTS: Simulations of anthesis were similar for T(optl) values of 20, 25 and 50 degrees C, but a T(optl) of 15 degrees C resulted in a consistent bias towards predicting anthesis late for early planting dates. Results for T(optl) above 15 degrees C may have occurred because mean temperatures rarely exceeded 20 degrees C before anthesis for many planting dates. For cultivars having a strong vernalization response, anthesis was more accurately simulated when vernalization and photoperiod factors were multiplied rather than using the most limiting of the two factors. CONCLUSIONS: Setting T(optl) to a high value (30 degrees C) and multiplying the vernalization and photoperiod factors resulted in accurately simulating anthesis for a wide range of planting dates and genotypes. However, for environments where average temperatures exceed 20 degrees C for much of the pre-anthesis period, a lower T(optl) (23 degrees C) might be appropriate. These results highlight the value of testing a model over a wide range of environments.

Spring wheat leaf appearance and temperature: extending the paradigm?

Extensive research shows temperature to be the primary environmental factor controlling the phyllochron, or rate of leaf appearance, of wheat (Triticum aestivum L.). Experimental results suggest that soil temperature at crown depth, rather than air temperature above the canopy, would better predict wheat leaf appearance rates. To test this hypothesis, leaf appearance in spring wheat ('Nordic') was measured in a 2-year field experiment (Nunn clay loam soil; fine, smectitic, mesic Aridic, Argiustoll) with three planting dates and two soil temperature treatments. One temperature treatment (denoted +3C) consisted of heating the soil at crown depth to 3 degrees C above the ambient soil temperature (denoted +0C). Main stem cumulative leaf number was measured at least weekly until flag leaf emergence. Leaf appearance was essentially linear with both air and soil growing degree-days (GDD), although there was a stronger linear relationship with soil GDD in the +0C plants than in +3C plants. A weak positive relationship between planting date and the phyllochron was observed. Unexpectedly, we found that heating the soil did not increase the rate of leaf appearance, as the paradigm would predict. To explain these results, we propose extending the paradigm in two ways. First, three processes are involved in leaf appearance: (1) cell division at the shoot apex forms the primordium; (2) cell division in the intercalary meristem forms the cells that then (3) expand to produce the leaf. Cell division is predominantly controlled by temperature, but cell expansion is considerably more affected by factors other than temperature, explaining the influence of other factors on the phyllochron. Secondly, the vertical distribution of the two meristems and region of cell expansion occur over a significant distance, where temperature varies considerably, and temperature at a specific point (e.g. crown depth) does not account for the entire temperature regime under which leaves are developing.

Association between anal furunculosis and colitis in the dog: preliminary observations.

Treatment of anal furunculosis in dogs is often unsatisfactory and may be associated with significant recurrence and complications. This may be compounded by the simultaneous presence of colitis in affected animals. Clinical signs associated with colitis and anal furunculosis may be similar, including faecal tenesmus, dyschezia and haematochezia. To examine the incidence of concurrent anal furunculosis and colitis, colonic biopsies were collected from 18 dogs referred for treatment of anal furunculosis. Nine dogs (50 per cent) had a histopathological diagnosis of colitis. Clinical signs more indicative of colitis than anal furunculosis (increased frequency of defecation, mucus in faeces and diarrhoea) were not observed more frequently in dogs with confirmed colitis compared with those with furunculosis alone. Therefore, while an association between colitis and anal furunculosis may exist, clinical signs alone cannot be used as an indicator of the presence of colitis in cases of anal furunculosis. The authors recommend that colonic biopsies should be undertaken in all dogs presented with anal furunculosis. Whether specific treatment of colitis in dogs with histopathological evidence of colitis improves the outcome of treatment for anal furunculosis awaits further study.

Canine dysautonomia: two clinical cases.

Two clinical cases of canine dysautonomia are described. Two young female neutered dogs were presented with clinical signs including vomiting, diarrhoea, faecal tenesmus, dysphagia and urinary retention. Decreased tear production, dry mucous membranes, bilateral Horner's syndrome, decreased anal sphincter tone and gastrointestinal hypomotility were also observed. Presumptive diagnoses of dysautonomia were made based on the clinical presentation and investigations. Postmortem histopathological examination in one of the cases demonstrated marked depletion of neuronal cell bodies in the intestinal myenteric plexuses and parasympathetic ganglia, confirming the diagnosis in this case. Criteria for aiding the antemortem diagnosis of this rare condition based on clinical observations and diagnostic testing are proposed.

Transient renal tubulopathy in a Labrador retriever.

A four-month-old male Labrador retriever was presented for polyuria, polydipsia and persistent euglycaemic glucosuria. On referral, diagnostic tests demonstrated abnormal fractional excretions of electrolytes, increased urinary excretion of selected amino acids, mild renal tubular acidosis and mild proteinuria, indicating renal tubular dysfunction. Pyelonephritis was suspected and potentiated amoxycillin was administered. On re-evaluation at six months of age, the dog was no longer polyuric or polydipsic and the metabolic abnormalities associated with the tubulopathy had resolved. Transient Fanconi's syndrome has not previously been reported in small animals. This report demonstrates the potential for recovery of function in cases presenting with renal tubulopathies.

Do adolescents appreciate the risks of smoking? Evidence from a national survey.

PURPOSE: To evaluate whether adolescents understand the risks of smoking when they decide to start. Estimates of objective risks that can be compared with epidemiologic evidence suggest that adolescents overstate the risks. Ratings of personal risk suggest the opposite. METHODS: A nationally representative telephone survey of 300 14- to 22-year-old nonsmokers and 300 14- to 22-year-old smokers was conducted. Respondents estimated both objective and personal risks of smoking, and smokers reported their plans to quit. Objective estimates were compared with both epidemiologic evidence and personal ratings of risk. Regression procedures were used to assess relationships between different estimates of risk and between risk estimates and plans to quit. RESULTS: Two of the three objective estimates of risk revealed high proportions of misunderstanding. Over 40% of smokers and 25% of nonsmokers underestimated, or did not know, the likelihood of smoking-related death, and over 40% did not know, or underestimated, the number of years of life lost owing to smoking. Although young people overestimated lung cancer risk relative to objective data, these estimates are inflated by underestimation of the fatality of lung cancer and by overlap with other illnesses not included in objective risk measures. Young smokers exhibited optimism about personal risks of smoking regardless of their perceptions of objective risk. Both objective and personal measures of risk predicted plans to quit. CONCLUSIONS: Because perceptions of both personal and objective risks are related to plans to quit, antismoking messages should include evidence about risk, particularly to the individual smoker.

Preliminary clinical observations on the use of piroxicam in the management of rectal tubulopapillary polyps.

Rectal tubulopapillary polyps were diagnosed in eight dogs following proctoscopy and mucosal pinch biopsy. Histological examination of the pinch biopsies revealed evidence of malignant transformation in three of the cases. The remaining cases were diagnosed as benign polyps. Inflammatory changes were observed in four cases. Seven dogs were treated with piroxicam suppositories and one with oral piroxicam. All dogs were re-examined after four to six weeks of piroxicam therapy and the extent of haematochezia, tenesmus and faecal mucus production was reduced in all cases. The owners of seven of the dogs considered the improvement in clinical signs to be good or excellent. Cases with and without evidence of inflammation responded equally well. This finding supports the hypothesis that piroxicam has an antineoplastic effect due to apoptosis and alteration in the cell cycle. Medical management with piroxicam may provide a non-invasive treatment option for dogs with rectal polyp formation in which surgical treatment is likely to be associated with complications such as incontinence, infection and wound breakdown, or where the owner declines such treatment.

11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver.

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1), a regulator of intrahepatocellular glucocorticoid activity, is bidirectional in homogenates but catalyses 11 beta-reduction (regenerating glucocorticoid) in intact primary hepatocytes in culture. To examine this discrepancy at the whole-organ level, we examined 11 beta-HSD-1 activity in the intact bivascularly perfused rat liver. On a single pass through male rat liver, 44+/-5% of 11-dehydrocorticosterone (11-DHC) recovered was 11 beta-reduced to corticosterone, whereas 10+/-1% of corticosterone was 11 beta-dehydrogenated to 11-DHC. 11 beta-Reduction was less in female liver (21+/-2%, P<0.01) and was significantly greater with perfusion of all substrate via the portal vein (50+/-3%) than via the hepatic artery (30+/-2%, P<0.05). 11 beta-Reductase activity was not saturated by 11-DHC (10(-)(9)-10(-)(6) M). Perfusion with carbenoxolone (CBX, 10(-)(6)-10(-)(3 )M) did not alter 11 beta-reduction of 11-DHC. In contrast, pretreatment with CBX in vivo (10 mg/day) for 7 days inhibited 11 beta-reductase (19+/-4% conversion, P<0.01). Concentrations of 11-DHC in male rat plasma were 44+/-6 nM. Thus 11 beta-HSD-1 is predominantly an 11 beta-reductase in the intact rat liver and is only inhibited by chronic administration of CBX. The substantial concentrations of plasma 11-DHC as substrate suggest that 11 beta-HSD-1 activity and its potential selective inhibition could modify glucocorticoid action in vivo.

Attitudes toward secondhand smoke, smoking, and quitting among young people.

OBJECTIVE: To assess the impact of attitudes toward secondhand smoke among young people. METHODS: Three hundred nonsmokers and 300 smokers (smoked a cigarette in last 30 days) 14 through 22 years of age in the United States were surveyed with random-digit dialing. The results of this cross-sectional survey were analyzed using logistic regression to determine predictors of nonsmoking and intent to stop among current smokers. RESULTS: Controlling for age, ethnicity, and education, nonsmokers were more likely to consider smoking risky than smokers (odds ratio [OR] = 3.46). Nonsmokers were twice as likely to consider secondhand smoke dangerous than smokers (OR = 1.47). Among the variables in our model, the only statistically significant predictor of planning to stop smoking or having actually stopped was believing that secondhand smoke harmed nonsmokers, which more than doubled the chances of planning to stop or having stopped smoking (relative risk = 2.17). CONCLUSIONS: Educating young people about the dangers of secondhand smoke and empowering nonsmokers to speak out should be a strong element of any tobacco control program.

Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats.

The role of glucocorticoids in obesity is poorly understood. Observations in obese men suggest enhanced inactivation of cortisol by 5alpha-reductase and altered reactivation of cortisone to cortisol by 11betahydroxysteroid dehydrogenase type 1 (11betaHSD1). These changes in glucocorticoid metabolism may influence corticosteroid receptor activation and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA). We have compared corticosterone metabolism in vivo and in vitro in male obese and lean Zucker rats, aged 9 weeks (n = 8/group). Steroids were measured in 72-h urine and 0900 h trunk blood samples. 5alpha-Reductase type 1 and 11betaHSD activities were assessed in dissected tissues. Obese animals were hypercorticosteronemic and excreted more total corticosterone metabolites (2264+/-623 vs. 388+/-144 ng/72 h; P = 0.003), with a greater proportion being 5alpha-reduced or 11-oxidized. 11-Dehydrocorticosterone was also elevated in plasma (73+/-9 vs. 18+/-2 nM; P = 0.001) and urine (408+/-111 vs. <28 ng/72 h; P = 0.01). In liver of obese rats, 5alpha-reductase type 1 activity was greater (20.6+/-2.7% vs. 14.1+/-1.5%; P<0.04), but 11betaHSD1 activity (maximum velocity, 3.43+/-0.56 vs. 6.57+/-1.13 nmol/min/mg protein; P = 0.01) and messenger RNA levels (0.56+/-0.08 vs. 1.03+/-0.15; P = 0.02) were lower. In contrast, in obese rats, 11betaHSD1 activity was not different in skeletal muscle and sc fat and was higher in omental fat(36.4+/-6.2 vs. 19.2+/-6.6; P = 0.01), whereas 11betaHSD2 activity was higher in kidney (16.7+/-0.6% vs. 11.3+/-1.5%; p = 0.01). We conclude that greater inactivation of glucocorticoids by 5alpha-reductase in liver and 11betaHSD2 in kidney combined with impaired reactivation of glucocorticoids by 11betaHSD1 in liver may increase the MCR of glucocorticoids and decrease local glucocorticoid concentrations at these sites. By contrast, enhanced 11betaHSD1 in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity.

Tissue- and temporal-specific regulation of 11beta-hydroxysteroid dehydrogenase type 1 by glucocorticoids in vivo.

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. Short-term glucocorticoid excess upregulates 11beta-HSD-1 in liver and hippocampus leading to suggestions that 11beta-HSD-1 ameliorates the deleterious effects of glucocorticoid excess by its 11beta-dehydrogenase activity. However the predominant activity of 11beta-HSD-1 in vivo is 11beta-reduction, thus generating active glucocorticoid. We have re-examined the time-course of glucocorticoid regulation of 11beta-HSD-1 in the liver, hippocampus and kidney of adult male rats in vivo. Sham operation markedly reduced 11beta-HSD-1 mRNA expression in all tissues, and reduced 11beta-HSD bioactivity in liver and hippocampus when compared to untouched controls. Adrenalectomy reduced 11beta-HSD-1 expression in all tissues in the short-term (7 days), followed by subsequent recovery of enzyme activity by 21 days in liver and hippocampus. Dexamethasone replacement of adrenalectomised rats attenuated the initial decrease in hepatic 11beta-HSD-1 activity, but by 21 days dexamethasone reduced activity compared to control levels. Thus glucocorticoids regulate 11beta-HSD-1 in a complex tissue- and temporal-specific manner. This pattern of regulation suggests glucocorticoids repress 11beta-HSD-1 at least in the liver, a pattern of regulation more consistent with the evidence that 11beta-HSD-1 is an 11beta-reductase in vivo. Operational stress per se down-regulates 11beta-HSD-1 which has implications for interpretation and design of in vivo studies of 11beta-HSD-1.