Staphylococcus nasal colonization in three species of non-human primates.

Bacterial nasal colonization is common in many mammals and Staphylococcus represents the main pathogen isolated. Staphylococcus nasal carriage in humans constitutes a risk factor for Staphylococcus infections pointing out the need for animal experimentation for nasal colonization studies, especially for vaccine development. A limitation in addressing this hypothesis has been a lack of appropriate animal model. Murine models do not mimic human nasal colonization studies. Non-human primates (NHP) remain the best classical models for nasal colonization studies. In this study, we analyzed nasal colonization between two species of Old World monkeys (cynomolgus and rhesus) and a New World monkey (squirrel monkey) from breeding colony at Fiocruz (Brazil). Sixty male and female NHP with the average age of 1-21 years old, comprising twenty animals of each species, were analyzed. Nine different Staphylococcus species (S. aureus, S. cohnii, S. saprophyticus, S. haemolyticus, S. xylosus, S. warneri, S. nepalensis, S. simiae, and S. kloosi) were identified by MALDI-TOF and 16S rRNA gene sequence analyses. Antibiotic resistance was not detected among the isolated bacterial population. S. aureus was the main isolate (19 strains), present in all species, predominant in cynomolgus monkeys (9/20) and squirrel monkeys (7/20). spa typing was used to examine the clonal structure and genetic profile of Staphylococcus aureus isolates. Eight (8) spa types were identified among the S. aureus strains. A major cluster was identified, corresponding to a new spa type t20455, and no spa types found in this study were seen before in Brazil.

Sex-specific fat mass ratio cutoff value identifies a high prevalence of cardio-metabolic disorders in people living with HIV.

BACKGROUND AND AIMS: HIV-associated lipodystrophy syndrome (HALS) contributes to the increased cardiovascular risk connoting people living with HIV (PLHIV). HALS recognition, based on clinical ground, may be inaccurate urging an objective instrumental diagnosis. The aim of this study is to search for the DXA-derived fat mass ratio (FMR) threshold, among those suggested for the diagnosis of HALS, able to identify PLHIV at high cardiovascular risk. METHODS AND RESULTS: In a cross-sectional analysis of 101 PLHIV (age 53 ± 11 years, men 55%) and 101 age- and sex-matched uninfected controls, DXA-derived FMR and anthropometric as well as cardio-metabolic parameters were assessed. PLHIV showed a higher FMR (1.15 ± 0.42 vs 0.95 ± 0.18, p < 0.01) together with a greater cardio-metabolic derangement than controls, in spite of lower BMI (24.3 ± 4.3 vs 26.9 ± 4.0 kg/m2, p < 0.01) and fat mass index (FMI, 6.6 ± 3.0 vs 9.2 ± 3.1 kg/m2, p < 0.01). Particularly, PLHIV with HALS (n = 28), defined as those with a FMR above 1.260 and 1.329 for men and women, respectively, had a greater prevalence of type 2 diabetes mellitus (18% vs 1%), insulin resistance (68% vs 27%), hypertriglyceridemia (50% vs 29%), hypertension (61% vs 30%) and metabolic syndrome (32% vs 10%) than those without HALS (p < 0.05 for all comparisons) and controls. At multivariate analyses, FMR in PLHIV was significantly associated (p < 0.05) with fasting glucose (ß [95%CI] = 0.5, [0.1-0.9]), insulin (44.6, [14.9-74.2]), HOMA-IR (1.6, [0.5-2.7]), triglycerides (1.0, [ 0.2-1.8]) and HDL-cholesterol (-2.1, [-3.9/-0.4]) levels. CONCLUSION: Sex-specific FMR thresholds, proposed for diagnosis of HALS, could represent new indices of cardio-metabolic derangement in PLHIV.

Effect of 1-year oral cholecalciferol on a metabolic profile and blood pressure in poor-controlled type 2 diabetes mellitus: an open-label randomized controlled pilot study.

PURPOSE: Hypovitaminosis D has been associated with many cardio-metabolic disorders, although their pathogenetic link still remains unclear. Our aim was to evaluate whether 1-year vitamin D (D) supplementation could improve glycemic control, lipid profile, systolic (SBP) and diastolic (DBP) blood pressure levels and body composition. METHODS: In an open-label randomized-controlled pilot study, thirty poor-controlled (HbA1c > 59 mmol/mol) type 2 diabetic patients (age 71.5 ± 3.2 years, M/F 21/9, BMI 29.8 ± 3.6 kg/m2) with hypovitaminosis D (25OHD 22.0 ± 11.3 nmol/l) were randomized to cholecalciferol supplementation (500 UI/kg p.o. weekly, + D) or observation (- D) for one year. Changes in parameters of glucose, lipid and blood pressure control at 3, 6, 9 and 12 months vs. baseline were assessed. RESULTS: One-year D supplementation restored D status and had a beneficial effect on fasting glucose (FG, mean percentage changes ± SD, - 1.8% ± 23.1 vs. + 18.8% ± 30.0), glycosylated haemoglobin (HbA1c, - 13.7% ± 14.5 vs. - 4.2% ± 14.1), SBP (- 13.4% ± 8.5 vs. - 2.4% ± 12.6) and HDL-cholesterol levels (- 2.1% ± 14.0 vs. - 10.9% ± 12.9; p < 0.05 for all comparisons) in + D vs. - D patients, respectively. In the former, a reduction in HBA1c, SBP and DBP levels, BMI, fat mass index (FMI) and ratio (FMR) was observed after 1 year (p < 0.05 for all comparisons vs. baseline). We noticed a relationship between 1-year mean percentage changes of serum 25OHD and SBP levels (R = - 0.36, p < 0.05). CONCLUSION: One-year cholecalciferol supplementation, able to restore D status, significantly improves FG, HbA1c, SBP and HDL-cholesterol levels in patients with poor-controlled type 2 diabetes mellitus and D deficiency.

Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial.

AIMS: The anti-inflammatory effects of the polyphenol resveratrol in patients with type 2 diabetes mellitus (T2DM) are controversial. Its role on pentraxin 3 (PTX3) concentrations, a human acute phase protein, has never been evaluated. Our aim was to determine whether a two-dosage resveratrol supplementation (500 and 40 mg/day) has an impact on PTX3 values in T2DM patients from a double-blind randomized placebo-controlled trial. Variations in total antioxidant status (TAS) were evaluated too. METHODS: A total of 192 T2DM patients were randomized to receive resveratrol 500 mg/day (Resv 500 arm), resveratrol 40 mg/day (Resv 40 arm) or placebo for 6 months. At baseline and at the trial end, PTX3 and TAS values were determined. RESULTS: A dose-dependent increase in PTX3 concentrations of 4.7% (Resv 40 arm) and 26.3% (Resv 500 arm), and 8.0% reduction after placebo were found. Adjusted mean differences of change versus placebo were 0.16 (95% CI 0.01-0.32) and 0.25 (0.09-0.42) in the Resv 40 and Resv 500 arms, respectively. At subgroup analyses, lower diabetes duration, aspirin, alcohol use, younger age, female gender, smoking (Resv 500 arm) and female gender and aspirin use (Resv 40 arm) were associated with higher PTX3 increments. A dose-dependent increment in TAS values in the resveratrol arms (1.4 and 6.4% for Resv 40 and Resv 500, respectively), and a reduction in placebo arm (-8.9%) were observed. Adjusted mean differences of change were 28.5 (95% CI 10.1-46.8) and 44.8 (25.4-64.1) in the Resv 40 and Resv 500 arms, respectively. CONCLUSION: Resveratrol supplementation increased PTX3 and TAS levels in a dose-dependent manner in T2DM patients. At present, potential clinical implications of these results remain unclear. CLINICALTRIALS. GOV IDENTIFIER: NCT02244879.

Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial.

The polyphenol resveratrol is considered to exert many beneficial actions, such as antioxidant, anti-inflammatory, insulin-sensitizer and anticancer effects. Its benefits in patients with type 2 diabetes mellitus (T2DM) are controversial. Our aims were to determine whether resveratrol supplementation at two different dosages (500 and 40mg/day) for 6 months i) reduced the concentrations of C-reactive-protein (CRP) and ii) ameliorated the metabolic pattern of T2DM patients. In the present double-blind, randomized, placebo-controlled trial, 192 T2DM patients were randomized to receive resveratrol 500mg/day (Resv500arm), resveratrol 40mg/day (Resv40arm) or placebo for 6-months. At baseline and at the trial end, CRP values, anthropometric, metabolic and liver parameters were determined. No serious adverse event occurred. A dose-dependent, though not significant, CRP decrease of 5.6% (Resv40arm) and 15.9% (Resv500arm) was observed vs placebo. We failed to detect significant differences in weight, BMI, waist circumference, and values of arterial blood pressure, fasting glucose, glycated hemoglobin, insulin, C-peptide, free fatty acids, liver transaminases, uric acid, adiponectin, interleukin-6, in both the Resv500 and Resv40 arms vs placebo. Total cholesterol and triglycerides slightly increased in the Resv500arm. Subgroup analyses revealed that lower diabetes duration (in both Resv500 and Resv40arms), and, in the Resv500arm, younger age, aspirin use and being a smoker were associated with a significantly higher CRP reduction vs placebo. The supplementations with 40mg/day or 500mg/day resveratrol did neither reduce CRP concentrations, nor improve the metabolic pattern of T2DM patients.

Generation and Characterization of Murine Monoclonal Antibodies anti-PBP2a of Methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant bacterium that causes serious infections worldwide. This pathogen is resistant to all beta lactam antibiotics due the presence of PBP2a, a transpeptidase enzyme that presents very low beta-lactam affinity. Here we report the generation and characterization of mouse monoclonal antibodies to PBP2a of MRSA strains. Two clones were obtained and characterized by immunoassays (ELISA, avidity index determination, and immunoblotting), isotyping, association/dissociation rate constants by surface plasmon resonance (SPR), and flow cytometry. Clone 38, which showed the best avidity and affinity, bound to PBP2a located on the bacterial surface by flow cytometry. Further studies are warranted in order to evaluate if these antibodies may help inhibit bacterial growth and be used to treat infections by MRSA.

Cardiovascular risk and metabolic syndrome in primary hyperparathyroidism and their correlation to different clinical forms.

Cardiometabolic disorders have been associated with primary hyperparathyroidism (PHPT), while the relationship of cardiovascular risk score (CRS) and metabolic syndrome (MS) with different clinical presentation of PHPT remains undefined. Our aim was to evaluate CRS, MS and its components in PHPT looking for their correlation to different clinical forms. In 68 consecutive PHPT patients and 68 matched controls, CRS, MS and its components were assessed to perform an observational case-control study at an ambulatory referral center for Bone Metabolism Diseases. Patients were stratified in symptomatic and asymptomatic PHPT; these latter were divided in high-risk and low-risk subgroups for end-organ damage. An increased proportion of PHPT patients had intermediate-high CRS and MS (mean, 95 % Confidence Interval (CI) 51.5 %, 39.6-63.3 and 20.6 %, 11.0-30.2, respectively, p < 0.02 vs. controls). Intermediate-high CRS was prevalent both in symptomatic and low-risk asymptomatic PHPT while MS resulted prevalent in low-risk asymptomatic but not in symptomatic PHPT. Type 2 DM, IFG, mixed dyslipidemia, hypertriglyceridemia, HDL-hypocholesterolemia, and LDL-hypercholesterolemia predominated in low-risk asymptomatic, while only LDL-hypercholesterolemia prevailed also in symptomatic PHPT. In patients and controls without cardiometabolic risk factors, HOMA-IR index was significantly increased in PHPT vs. controls (p < 0.03) and associated to total calcium (R = 0.73; p < 0.001). By multivariate analysis low-risk asymptomatic PHPT predicted MS after adjusting for age, sex, and BMI. Our data show an increased frequency of intermediate-high CRS both in symptomatic and low-risk asymptomatic PHPT while MS prevails in low-risk asymptomatic PHPT, supporting the potential for cardiovascular morbidity and mortality also in this form.

Functional dissimilarity of melanomacrophage centres in the liver and spleen from females of the teleost fish Prochilodus argenteus.

Melanomacrophage centres (MMCs) are formed by macrophage aggregates containing pigments such as hemosiderin, melanin and lipofuscin. MMCs are found in animals such as reptiles, amphibians and, mainly, fishes, in organs such as the kidney, spleen, thymus and liver. In teleost fish, several functions have been attributed to MMCs, including the capture and storage of cations, the phagocytosis of cellular debris and immunological reactions. As the use of MMCs has been suggested as a tool for the assessment of environmental impacts, our aim has been to describe the various metabolic processes performed by MMCs in diverse organs (liver and spleen) by using the teleost Prochilodus argenteus as an animal model. MMCs from the liver and spleen were assessed by histochemistry, transmission electron microscopy, scanning electron microscopy, X-ray microanalysis techniques and biochemical assay for N-acetylglucosaminidase activity. The data showed metabolic differences in MMCs between the liver and spleen of P. argenteus in their morphometric characteristics and biochemical and elemental composition. The implications of these findings are discussed, focusing on their role in organ metabolism.

Insulin resistance is not coupled with defective insulin secretion in primary hyperparathyroidism.

AIMS: An increased frequency of both impaired glucose tolerance and Type 2 diabetes mellitus (DM) has been reported in primary hyperparathyroidism (pHPT), thus we sought to investigate insulin sensitivity and insulin secretion in a large series of pHPT patients. SUBJECTS AND METHODS: One hundred and twenty-two consecutive pHPT patients without known DM were investigated [age (mean +/- sd) 59.3 +/- 13.6 years, body mass index (BMI) 25.7 +/- 4.2 kg/m(2); serum calcium 2.8 +/- 0.25 mmol/l; PTH 203.2 +/- 145.4 ng/l]. Sixty-one control subjects were matched, according to the degree of glucose tolerance, in a 2 : 1 patient:control ratio. Fasting- and oral glucose tolerance test-derived estimates of insulin sensitivity and secretion were determined by means of the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) composite. RESULTS: Both the QUICKI and ISI composite were lower in pHPT patients than control subjects (P < 0.03 and P < 0.05, respectively) after adjusting for age, systolic blood pressure and BMI. Conversely, all insulin secretion estimates were significantly increased in pHPT patients than in control subjects (P < 0.04 and P < 0.03, respectively) and after adjusting for age, systolic blood pressure and BMI. Log serum calcium levels were negatively associated with the QUICKI and log ISI composite (R = -0.30, P = 0.001; R = -0.23, P = 0.020, respectively) in pHPT patients. Serum calcium levels significantly and independently contributed to impaired insulin sensitivity in multivariate analysis (QUICKI as dependent variable: beta = -0.31, P = 0.004, R(2) = 0.15; log ISI composite as dependent variable: beta = -0.29, P = 0.005, R(2) = 0.16). CONCLUSIONS: Our study confirms a reduction in both basal and stimulated insulin sensitivity in primary hyperparathyroidism, in spite of increased insulin secretion. Moreover, our data show for the first time a significant relationship between hypercalcaemia and insulin sensitivity in this condition.

Screening for tuberculosis on admission to highly endemic prisons? The case of Rio de Janeiro State prisons.

SETTING: Rio de Janeiro (RJ) State prisons, where tuberculosis (TB) is highly endemic. OBJECTIVE: To measure TB prevalence, identify risk factors and ascertain the most appropriate screening method among inmates of the RJ prisons. DESIGN: Systematic chest X-rays (CXRs) were performed in 1696 male inmates of three RJ prisons. Inmates were selected for sputum examination and culture if their CXRs showed evidence of any pulmonary, pleural or mediastinal abnormality. TB diagnosis was based on bacteriological results or, if bacteriological results were negative, on response to TB treatment. RESULTS: TB prevalence was 2.7% (46/1696), and 32/46 cases (69%) were bacteriologically confirmed, including 19 smear-positive cases. CXR lesions were extensive in 43% of cases. In the logistic regression model, TB-associated variables were being illiterate (adjusted OR 2.10, 95%CI 1.02-4.34), cough >or=3 weeks (aOR 2.85, 95%CI 1.54-5.27), history of TB treatment (aOR 3.61, 95%CI 1.76-7.39), and living in Rio City suburbs (aOR 4.54, 95%CI 1.02-20.07) and in Rio City (aOR 5.48, 95%CI 1.29-23.33). A screening based on cough >or=3 weeks followed by sputum smear examination would have identified only 9 of the 46 cases. CONCLUSION: These results call for screening on admission to prison based, if feasible, on CXR, and demonstrate the urgent need to improve detention conditions and medical assistance in police remand cells.

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin.

BACKGROUND: Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level. OBJECTIVE: To evaluate secretory response of GH to ghrelin in PHP patients. PATIENTS: Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2)). METHODS: A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. RESULTS: Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P < 0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P < 0.001). Using ROC curves, a serum GH peak > 22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations. CONCLUSIONS: The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Growth hormone secretion in primary and secondary hyperparathyroidism.

Primary hyperparathyroidism (PHP) is associated with impaired GH secretion. Whether this effect is due to hypercalcemia or to increased serum PTH concentration is unclear. However, patients with familial hypocalciuric hypercalcemia (FHH), who have normal PTH and increased serum calcium concentrations, also have an impaired GH secretion, suggesting that calcium rather than PTH is responsable for this effect on GH secretion. To further investigate this issue, 10 consecutive patients with secondary hyperparathyroidism (SHP) due to vitamin D deficiency were evaluated by the GH response to GHRH+arginine (Arg) test. A group of 60 consecutive untreated PHP patients served as controls. Mean GH response to GHRH+Arg test was 15.8+/-14 microg/l and 37.5+/-16 microg/l (p<0.001) in PHP and in SHP patients, respectively. Forty-two out of 60 (70%) PHP patients had a suppressed or blunted GH response, whereas all SHP patients had normal GH response. The results of the present study confirm and extend our previous observations that PHP is associated with an impaired GH secretion in the majority of cases, and indicate that SHP patients have no abnormality of GH secretion. Thus, hypercalcemia rather than increased serum PTH is responsible for the abnormality of GH secretion.

Is GH therapy useful to preserve bone mass in transition-phase patients with GH deficiency?

GH deficient (GHD) adult patients, either from child- or adulthood onset, have impaired health (impairment in body composition and structure functions as well as derangement in lipoprotein and in carbohydrate metabolism leading to increased cardiovascular morbidity), which improves with GH replacement. For patients with childhood-onset GHD, the so called "transition phase", defined as the period between reaching the final height and the completion of the development of such organs, can be considered as the most important phase of life for the development of important target organs: heart, bones and muscles. Particularly, children with GHD may not attain the peak bone mass (PBM) at the time of discontinuation of GH therapy, as the complete achievement of PBM is likely reached later on, during the transition phase to adulthood. In addition, patients with GHD generally have a delayed timing of PBM compared to normal individuals. GH treatment should be continued until the attainment of PBM, independently of the final height achieved. Individual titration of the recombinant human GH (rhGH) dose is recommended, and measurement of IGF-I levels is needed for monitoring the adequacy of replacement. The GH dose for replacement in the transition adolescent is still higher than in adulthood; after puberty, the rhGH dose should be progressively decreased in the following years (probably up to 25 yr of age) in order to obtain the achievement of optimal PBM.

Derangement of glucose metabolism in hyperparathyroidism.

The derangement of glucose metabolism is found frequently in all forms of hyperparathyroidism. Both in primary (PHPT) and secondary hyperparathyroidism (SHPT) PTH excess is thought to be involved in deteriorating insulin sensitivity and secretion though their different clinical and pathophysiological conditions. In PHPT these abnormalities are related to a high frequency of Type 2 diabetes mellitus and also impaired glucose tolerance according to recent clinical studies, without differences between symptomatic and asymptomatic clinical presentation. In chronic renal failure (CRF), the disorders of glucose metabolism due to SHPT do not bear an increased risk for diabetes whereas they seem to be involved in the progression of atherosclerotic vascular damage which connotes CRF. Moreover, clinical and experimental studies have shown that vitamin D deficiency associated with glucose metabolism abnormalities favors the development of the metabolic syndrome. The potential for metabolic and cardiovascular harm related to hyperparathyroidism, especially PHPT, is the most interesting issue for clinical endocrinologists. This short review of the clinical and pathophysiological data of literature on glucose homeostasis disorders in hyperparathyroidism focuses on its potential clinical and therapeutic impact, particularly in the management of PHPT.

The oral glucose tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed Type 2 diabetes mellitus in primary hyperparathyroidism.

AIMS: To evaluate the frequency of impaired glucose tolerance (IGT)and undiagnosed diabetes mellitus together with the indices of insulin resistance (IR) in primary hyperparathyroidism (pHPT). METHODS: Out of 105 consecutive pHPT patients (F/M 78/27, asymptomatic/symptomatic 68/37, age (mean +/- s.d.) 60.7 +/- 12.7 years,body mass index 25.2 +/- 3.8 kg/m2, ionized calcium (iCa) 1.49 +/- 0.16 mmol/l,parathormone 200.4 +/- 233.9 pg/ml),59 without known diabetes mellitus and controls (n = 60) underwent an oral glucose tolerance test (OGTT, 75 g os). As indices of IR, homeostasis model assessment (HOMAIR)or OGTT data (insulin sensitivity index composite (ISI comp)) were evaluated. RESULTS: In pHPT the prevalence of IGT (mean, 95% confidence intervals (CI), 40.7%, 27.8-53.6) was higher than in controls (25.0%, 13.7-36.3, P < 0.03). Similarly,the prevalence of undiagnosed diabetes mellitus was higher in pHPT(15.3%, 5.8-24.7) than in controls (5.0%, 0-10.7, P < 0.05). Moreover,the prevalence of IGT and undiagnosed diabetes was higher in pHPT than that previously reported in the general population of Northern Italy(8.5% and 3.2%, respectively). The indices showed that insulin resistance was higher in pHPT than in controls: HOMAIR (median, 95% CI,2.6, 2.5-3.9 vs. 1.7, 1.6-2.5, respectively; P < 0.003); ISI comp (3.5, 3.4-4.6 vs. 5.1, 4.9-7.2, respectively; P < 0.002). CONCLUSIONS: Our data in a large and modern day pHPT series, with a preponderance of asymptomatic patients, confirm increased insulin resistance and pre-valence of IGT and undiagnosed diabetes.

A model for recognition of polychlorinated dibenzo-p-dioxins by the aryl hydrocarbon receptor.

Ligand binding by the aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcriptional regulatory proteins, has been mapped to a region within the second 'PAS' domain, a conserved sequence motif first discovered in the Per-ARNT-Sim family of proteins. In addition to the bacterial photoactive yellow protein (PYP), which had been proposed as a structural prototype for the three dimensional fold of PAS domains, two crystal structures of the PAS domain have recently been determined: the human potassium channel HERG and the heme binding domain of the bacterial O(2) sensing FixL protein. The three structures reveal a highly conserved structural framework in evolutionary rather distant PAS domains, provide a more general view of how these domains can recognize their ligands and suggest a structure-function relationship that we exploited to build a three-dimensional model of the ligand binding domain (LBD) of the mouse aryl hydrocarbon receptor (mAhR). The model allowed us to putatively identify the residues responsible for the recognition of polychlorinated dibenzo-p-dioxins (PCDDs) by AhR receptors and to formulate an hypothesis on the signal transduction mechanism.

The in vivo effects of general and epidural anesthesia on human immune function.

UNLABELLED: Impaired in vivo immunity is often observed after major surgery and is multifactorial. We conducted a randomized clinical study to determine the independent effects of general anesthesia (GA) and of lumbar epidural anesthesia (LEA) on human immune function in the absence of surgical trauma. Nineteen healthy volunteers were randomized to receive GA with thiopental and isoflurane, LEA with lidocaine, or no anesthesia (Control). Serial blood samples were tested for antibody responses to antigen inoculation, neutrophil and mononuclear cell antibody-dependent cell cytotoxicity (ADCC), natural killer cell cytotoxicity, and neutrophil phagocytic activity. Antibody responses were similar in the three groups. Mononuclear cell ADCC increased in the LEA group at the end of the anesthetic (P < 0.05 at effector/target [E/T] ratios of 10:1, 25:1, and 50:1). Natural killer cell cytotoxicity increased at the end of the anesthetic in both the LEA group (P < 0.05 at all E/T ratios) and the GA group (P < 0.05 at an E/T ratio of 5:1 and 10:1). No significant changes were observed for neutrophil ADCC or phagocytosis. General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function. IMPLICATIONS: General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function.