Switching tenofovir disoproxil fumarate to tenofovir alafenamide in a real life setting: what are the implications?

OBJECTIVES: Development of novel antiretrovirals aims at reducing long-term toxicities. Tenofovir disoproxil fumarate (TDF) has been associated with potential nephrotoxicity. The aim of our study was to assess the impact of switching from TDF to tenofovir alafenamide (TAF) on functional nephropathy and lipid parameters in a real-life setting. METHODS: We retrospectively analysed data from 347 HIV-infected patients switching from a TDF- to a TAF-containing regimen between April and December 2016. Sociodemographic, clinical and laboratory data were collected at TDF-to-TAF switch, and at 3 and 6 months thereafter. Proteinuria and albuminuria were classified according to Kidney Diseases Improving Global Outcomes (KDIGO) guidelines. RESULTS: At time of switch, moderately and severely increased proteinuria was detected in 32% and 8% of patients, respectively; however, urine dipstick analysis was negative in 84% and 42%, respectively. Moderately and severely increased albuminuria was found in 17% and 3% of patients, respectively. In patients with a urinary protein-to-creatinine ratio (UPCR) ≥ 150 mg/g, the mean value declined from 416 mg/g at baseline to 272 mg/g (P < 0.001) and 242 mg/g (P < 0.001) after 3 and 6 months, respectively. Patients with an albumin-to-creatinine ratio (UACR) ≥ 30 mg/g showed no significant decrease of albuminuria. Mean total cholesterol increased from 187 mg/dL at baseline to 202 (P < 0.001) and 208 mg/dL (P < 0.001) at 3 and 6 months, respectively, and mean low-density lipoprotein (LDL) cholesterol increased from 114 mg/dL at baseline to 124 (P < 0.001) and 128 mg/dL (P < 0.001), respectively. As mean high-density lipoprotein (HDL) cholesterol increased from 50 mg/dL at baseline to 54 (P < 0.001) and 57 mg/dL (P < 0.001) at 3 and 6 months, respectively, the LDL:HDL ratio remained stable. CONCLUSIONS: In an aging HIV-infected cohort, proteinuria and albuminuria were common findings and were underdiagnosed via urine dipstick. Our real-life data suggest that laboratory markers of moderately/severely increased proteinuria improved after TDF-to-TAF-switch. Lipid profiles were not aggravated. Long-term follow-up is needed to determine the clinical benefit of the TDF-to-TAF switch.

Cardiovascular magnetic resonance assessment of acute cardiovascular effects of voluntary apnoea in elite divers.

BACKGROUND: Prolonged breath holding results in hypoxemia and hypercapnia. Compensatory mechanisms help maintain adequate oxygen supply to hypoxia sensitive organs, but burden the cardiovascular system. The aim was to investigate human compensatory mechanisms and their effects on the cardiovascular system with regard to cardiac function and morphology, blood flow redistribution, serum biomarkers of the adrenergic system and myocardial injury markers following prolonged apnoea. METHODS: Seventeen elite apnoea divers performed maximal breath-hold during cardiovascular magnetic resonance imaging (CMR). Two breath-hold sessions were performed to assess (1) cardiac function, myocardial tissue properties and (2) blood flow. In between CMR sessions, a head MRI was performed for the assessment of signs of silent brain ischemia. Urine and blood samples were analysed prior to and up to 4 h after the first breath-hold. RESULTS: Mean breath-hold time was 297 ± 52 s. Left ventricular (LV) end-systolic, end-diastolic, and stroke volume increased significantly (p < 0.05). Peripheral oxygen saturation, LV ejection fraction, LV fractional shortening, and heart rate decreased significantly (p < 0.05). Blood distribution was diverted to cerebral regions with no significant changes in the descending aorta. Catecholamine levels, high-sensitivity cardiac troponin, and NT-pro-BNP levels increased significantly, but did not reach pathological levels. CONCLUSION: Compensatory effects of prolonged apnoea substantially burden the cardiovascular system. CMR tissue characterisation did not reveal acute myocardial injury, indicating that the resulting cardiovascular stress does not exceed compensatory physiological limits in healthy subjects. However, these compensatory mechanisms could overly tax those limits in subjects with pre-existing cardiac disease. For divers interested in competetive apnoea diving, a comprehensive medical exam with a special focus on the cardiovascular system may be warranted. TRIAL REGISTRATION: This prospective single-centre study was approved by the institutional ethics committee review board. It was retrospectively registered under ClinicalTrials.gov (Trial registration: NCT02280226 . Registered 29 October 2014).

Pulmonary hypertension in HIV infection: a prospective echocardiographic study.

OBJECTIVES: While idiopathic pulmonary arterial hypertension (PAH) is a rare disease, it is seen more frequently in patients with HIV infection. The aim of this study was to evaluate the prevalence of pulmonary hypertension (PH) in patients with HIV infection by echocardiographic screening. METHODS: Echocardiography and N-terminal of the prohormone brain natriuretic peptide measurement were used to examine the prevalence of PH prospectively in HIV-positive patients (n = 374) during routine follow-up visits for HIV disease. RESULTS: In echocardiographic screening, PH was detected in a total of 23 of 374 HIV-infected patients (6.1%). Of these, three patients (13%) presented with symptoms of dyspnoea and fatigue, and diagnosis of PAH was confirmed by right heart catheterization. Patients with systolic pulmonary artery pressure (sPAP) > 30 mmHg were more likely to be female, to have a history of injecting drug use and to originate from high-prevalence countries (HPCs). CONCLUSIONS: Echocardiographic screening detected PH in a substantial proportion of HIV-positive patients. Female gender, a history of injecting drug use and HPC origin were associated with a higher prevalence of HIV-associated PH. The relevance and long-term outcome of these findings need to be validated in follow-up studies, which are ongoing.

Oxygen saturation in pulse oximetry in hemoglobin anomalies.

Pulse oximetry is an essential diagnostic method in pediatric emergency medicine and pediatric intensive care. However, if undetected hemoglobin anomalies are the underlying cause measurements of low oxygen saturation can be interpreted incorrectly or may lead to unnecessary examinations. In 2 recently discovered hemoglobin anomalies, Hb Bonn and Hb Venusberg, this resulted in extensive and repeat cardiopulmonary examinations. This review aims to provide an overview of hemoglobin anomalies causing low oxygen saturation.We describe the methods required for differential diagnosis of hemoglobin anomalies, such as hemoglobin electrophoresis, High Performance Liquid Chromatography, hemoglobin gene sequencing and spectral photometry, and the difficulties with the interpretation of results. Furthermore, with a review of the literature we provide an extensive overview of hemoglobin anomalies which result in low oxygen saturation measurement in pulse oximetry. With the examples of Hb Bonn, a novel hemoglobin mutation of the proximal α1-globin, which results in false low pulse oximetry measurements of oxygen saturation, and Hb Venusberg, a low oxygen-affine hemoglobin mutation of the ß-globin, we highlight the difficulties arising from the respective case histories.In pediatric medicine, hemoglobin anomalies must be included in the diagnosis as a possible underlying cause of low oxygen saturation in case of ambiguous or conflicting pulse oximetry findings.

Changes in hormones after apneic hypoxia/hypercapnia - An investigation in voluntary apnea divers.

BACKGROUND: Prolonged apnea is characterized by hypoxia/hypercapnia. Hypoxia can be associated with hormonal dysfunction. We raised the question as to whether steroid hormonal and gonadotropin levels could be influenced by short-term hypoxia/hypercapnia in a model of dry apnea in trained apnea divers. METHODS: Adrenal, sex steroid and pituitary hormones were measured in ten trained voluntary apnea divers before, immediately after, 0.5 h and 4 h after a maximal breath-hold. Apnea was carried out under dry conditions. RESULTS: Corticosterone, progesterone, cortisol, 17-OH-progesterone, dehydroepiandrosterone and androstenedione showed a significant continuous increase with a maximum at 0.5 h after apnea, followed by a decrease back to or below baseline at 4 h after apnea. Testosterone, estradiol, cortisone and dihydrotestosterone showed a decrease 4 h after apnea. Dehydroepiandrosteronesulfate, luteinizing hormone (LH) and follicle stimulating hormone (FSH) showed no significant changes. CONCLUSION: Even a single apnea resulted in two different patterns of hormone response to apnea, with increased adrenal and reduced sex steroid levels, while LH/FSH showed no clear kinetic reaction. Apnea divers might be a suitable clinical model for hypoxic disease.

The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease.

OBJECTIVE: Plant sterols (sitosterol, campesterol, stigmasterol and brassicasterol) are solely dietary-derivable sterols that are structurally very similar to cholesterol. In contrast to peripheral cholesterol, plant sterols can cross the blood-brain barrier and accumulate within mammalian brain. As an impaired function of the cerebrospinal fluid (CSF)-blood barrier is linked to neurodegenerative disorders, i.e. Alzheimer's disease (AD), we investigated whether this results in altered plant sterol concentrations in CSF. METHOD: Applying gas chromatography/mass spectrometry analysis, plant sterol concentrations were measured in plasma and CSF of patients with AD (n = 67) and controls (n = 29). Age, gender, plasma-to-CSF albumin ratio, CSF Aß(42) , CSF pTau, APOE4 genotype, and serum creatinine were applied as covariates in the statistical analysis for individual plant sterols in order to compare plasma and CSF plant sterol concentrations between patients with AD and controls. RESULTS: Albumin quotient was a consistent predictor in CSF for cholesterol and methyl plant sterols campesterol and brassicasterol. Comparison of lipid parameters per diagnosis based on relevant predictors revealed significantly lower concentrations of brassicasterol (P < 0.001) in CSF of patients with AD. Binary logistic regression analysis revealed that brassicasterol improved the predictive value when added to pTau and Aß42 in a biomarker model. CONCLUSION: Brassicasterol might be a relevant additional biomarker in AD.

[Evaluation of folate substitution in women with epilepsy. Determination of erythrocyte folic acid concentrations]. / Folsäuresubstitution bei Frauen mit Epilepsie. Evaluation des Substitutionseffektes durch intraerythrozytäre Folsäurebestimmung.

Insufficient maternal folate concentrations appear to be a fetal risk factor for neural tube defects (NTD). Erythrocyte folate concentrations are widely accepted as an indicator of tissue folate storage. We retrospectively evaluated erythrocyte folate concentrations to examine if a recommended daily dosage of 5 mg folic acid is sufficient to balance the impact of antiepileptic drugs (AED) on folate metabolism in women with epilepsy. Data of 48 women (mean age 30.3 years) with idiopathic epilepsy with generalized seizures (n=12) or symptomatic epilepsy with focal seizures (n=36) were available, 43 women submitted to further analysis and 30 women received AED monotherapy. Duration of folic acid supplementation varied between 0.5 and 12 months. The daily dosage of folic acid ranged from 0.4 to 15 mg and 32 women received 5 mg/day. Erythrocyte folate concentrations ranged from 282 to 1596 ng/ml (mean 780 ng/ml). In 29 out of the 32 women (90.6%) on 5 mg folic acid per day, red cell folate was ≥400 ng/ml. In previous studies the risk for NTD was estimated to be 0.8‰ if red cell folate was ≥400 ng/ml. Our results suggest that 5 mg/day folic acid as preconception supplementation in women with epilepsy is effective to balance the impact of AEDs on folate metabolism in women with epilepsy.

Antihormone treatment differentially regulates PSA secretion, PSMA expression and 68Ga-PSMA uptake in LNCaP cells.

BACKGROUND: In recent years, a variety of innovative therapeutics for castration-resistant prostate cancer have been developed, including novel anti-androgenic drugs, such as abiraterone or VPC-13566. Therapeutic monitoring of these pharmaceuticals is performed either by measuring PSA levels in serum or by imaging. PET using PSMA ligands labeled with Fluor-18 or Gallium-68 is the most sensitive and specific imaging modality for detection of metastases in advanced prostate cancer. To date, it remains unclear how PSMA expression is modulated by anti-hormonal treatment and how it correlates with PSA secretion. METHODS: We analyzed modulation of PSMA-mRNA and protein expression, 68Ga-PSMA uptake and regulation of PSA secretion by abiraterone or VPC-13566 in LNCaP cells in vitro. RESULTS: We found that abiraterone and VPC-13566 upregulate PSMA protein and mRNA expression but block PSA secretion in LNCaP cells. Both anti-androgens also enhanced 68Ga-PSMA uptake normalized by the number of cells, whereas abiraterone and VPC-13566 reduced 68Ga-PSMA uptake in total LNCaP monolayers treated due to cell death. CONCLUSION: Our data indicate that PSA secretion and PSMA expression are differentially regulated upon anti-androgen treatment. This finding might be important for the interpretation of 68Ga-PSMA PET images in monitoring therapies with abiraterone and VPC-13566 in prostate cancer patients, but needs to be validated in vivo.

Beta-trace protein-based equations for calculation of GFR in renal transplant recipients.

Recently, we showed that serum beta-trace protein (BTP) is an alternative marker of glomerular filtration rate (GFR) in renal transplant recipients (RTR). We have now developed three BTP-based GFR formulae derived by multiple regression analyses from the patients who had participated in that study. Currently, we validated the diagnostic performance of these BTP-formulae in 102 consecutive RTR who underwent a technetium diethylenetriamine pentaacetic acid (DTPA) clearance for GFR measurement in comparison to the re-expressed Modification of Diet in Renal Disease (MDRD) equation and a recently proposed BTP-based equation (referred to as 'White equation'). The best-performing BTP formula was found to be: GFR = 89.85 x BTP(-0.5541)x urea(-0.3018). This equation estimated true GFR virtually without bias (+0.43 mL/min/1.73 m(2), not significant [NS]), while a small, but significant, overestimation was seen for the MDRD formula (+3.43 mL/min/1.73 m(2), p = 0.003). Precision and accuracies within 50% of true GFR (93.1% and 88.2%, respectively) tended to be higher for the BTP formula, but the differences did not reach significance. The White equation overestimated the true GFR by 9.43 mL/min/1.73 m(2)(p = 0.001), and was inferior with respect to precision and 50% accuracy (79.4%). BTP-based GFR calculations are reliable, and may serve as an alternative to the re-expressed MDRD equation.

Sampling and processing of fresh blood samples within a European multicenter nutritional study: evaluation of biomarker stability during transport and storage.

INTRODUCTION: Analysis of several biological markers improves the quality and physiologic comprehension of data obtained in epidemiological nutritional studies. AIM: To develop a methodology that guarantees the centralized analysis and quality assurance of the most relevant blood parameters from fresh blood samples in adolescents in a European multicenter study. MATERIALS AND METHODS: Stability of selected nutrients and biomarkers (vitamins, fatty acids, iron metabolism and immunological parameters) chosen with respect to time and temperature of sample transport and storage was evaluated as part of the pilot study of the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) project. RESULTS: Routine biochemistry and iron status parameters included in the HELENA Cross-Sectional Study (CSS) protocol could be analyzed within 24 h from fresh blood samples without any stability problems (coefficient of variation (CV)<5%, P<0.05). However, stability tests for lymphocyte subpopulations, vitamin C and fatty acids showed that they are very unstable at room temperature without any treatment. Therefore, a special handling for these samples was developed. Vitamin C was stabilized with metaphosphoric acid and transported under cooled conditions (CV 4.4%, recovery rate >93%, P>0.05). According to the results, a specific methodology and transport system were developed to collect blood samples at schools in 10 European cities and to send them to the centralized laboratory (IEL, Bonn, Germany). To guarantee good clinical practice, the field workers were instructed in a training workshop and a manual of operation was developed. CONCLUSION: The handling and transport system for fresh blood samples developed for the European multicenter study HELENA is adequate for the final part of the HELENA-CSS and will provide, for the first time, reference values for several biological markers in European adolescents.

Parenteral trace element provision: recent clinical research and practical conclusions.

The aim of this systematic review (PubMed, www.ncbi.nlm.nih.gov/pubmed and Cochrane, www.cochrane.org; last entry 31 December 2014) was to present data from recent clinical studies investigating parenteral trace element provision in adult patients and to draw conclusions for clinical practice. Important physiological functions in human metabolism are known for nine trace elements: selenium, zinc, copper, manganese, chromium, iron, molybdenum, iodine and fluoride. Lack of, or an insufficient supply of, these trace elements in nutrition therapy over a prolonged period is associated with trace element deprivation, which may lead to a deterioration of existing clinical symptoms and/or the development of characteristic malnutrition syndromes. Therefore, all parenteral nutrition prescriptions should include a daily dose of trace elements. To avoid trace element deprivation or imbalances, physiological doses are recommended.

Characterization of aromatase cytochrome P450 activity in the human temporal lobe.

Local aromatase-mediated conversion of androgens plays an important role in androgen action on the brain. To characterize estrogen formation in the human brain, we measured the microsomal aromatase activity of temporal lobe biopsies and compared it to that of human placenta using a highly sensitive 3H2O assay with [1beta-3H]androstenedione as substrate. Brain tissue was removed neurosurgically from 23 patients with epilepsy. Data of kinetic studies were analyzed with a computer-assisted, nonlinear, curve-fitting method using the Michaelis-Menten plus a nonspecific metabolism model. In contrast to data for placental aromatase activity, that for brain always had to be corrected for nonspecific tritium release. The mean K, values were 22.2 nmol/L in brain and 49.6 nmol/L in placenta. Inhibition experiments with atamestane, an inhibitor of aromatase cytochrome P450, revealed specific, dose-responsive, and competitive inhibition of both brain and placental aromatase activities. Placental aromatase activity was completely suppressible by atamestane, whereas in brain tissue there remained a residue of nonspecific tritium release. Subsequent experiments with cerebral cortex and subcortical white matter specimens of children and adults revealed a significantly higher aromatase activity in cerebral cortex than in subcortical white matter, but no sex or age differences were found.

Expression of 5alpha-reductase in the human temporal lobe of children and adults.

Androgens exert important biological effects on the brain, and 5alpha-reductase plays a crucial role in androgen metabolism. Therefore, we investigated the expression of the two isozymes of 5alpha-reductase in the human temporal lobe to determine the predominant isoform and to elucidate the existence of possible sex differences and differences between children and adults. We studied biopsy materials from the temporal lobe of 34 women, 32 men, and 12 children. Quantification of 5alpha-reductase 1 and 2 messenger ribonucleic acid (mRNA) was achieved by competitive RT-PCR. 5Alpha-reductase activity was determined in tissue homogenates using [1,2-3H]androstenedione as the substrate. Only 5alpha-reductase 1 mRNA was expressed in human temporal lobe tissue; 5alpha-reductase 2 mRNA was not expressed. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the cerebral cortex of women [25.9+/-7.9 arbitrary units (aU); mean +/-SEM] and men (20.4+/-2.8 aU) or in the cerebral cortex (23.3+/-4.4 aU) and the subcortical white matter of adults (32.6+/-5.6 aU), but they were significantly higher in the cerebral cortex of adults than in that of children (6.4+/-2.3 aU; P < 0.005). The apparent Km of 5alpha-reduction did not show significant differences between the two sexes. In conclusion, 5alpha-reductase 1 mRNA is expressed in the temporal lobe of children and adults, but 5alpha-reductase 2 mRNA is not. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the sexes, but they were significantly higher in specimens of adults than in those of children.

Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain.

Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We therefore investigated 5alpha-reductase and colocalized 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity in cerebral neocortex (CX) and subcortical white matter (SC) specimens neurosurgically removed from 44 patients suffering from epilepsy. We could demonstrate the presence of the 5alpha-reductase-3alpha-HSD complex in the biopsies of all patients under investigation. Inhibition experiments with specific inhibitors for 5alpha-reductase type 1 and type 2 revealed strong evidence for the exclusive activity of the type 1 isoform. We detected a significantly higher 5alpha-reductase activity in CX than in SC (P< 0.0001), but no sex-specific differences were observed. Furthermore, we found that, in contrast to liver, only 3alpha-HSD type 2 messenger RNA is expressed in the brain and that its expression is significantly higher in SC than in CX without sex-specific differences. The present study is the first to systematically characterize the 5alpha-reductase-3alpha-HSD complex in the human brain. The lack of sex-specific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g. the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.

Serum androgens return to normal after temporal lobe epilepsy surgery in men.

BACKGROUND: Epileptic discharges from the temporal lobe may influence the release of hormones from the hypothalamic-pituitary axis. If epilepsy surgery influences the underlying epileptic disorder one might expect serum hormone concentrations to return to normal following surgery. PATIENTS: Twenty-two men with epilepsy aged 25 to 48 years (mean, 34.9 years) were investigated before surgery and at 3, 6, and 12 months after surgery. Medication (all patients received carbamazepine) was maintained following surgery. METHODS: Hormone measurements included luteinizing hormone, follicle stimulating hormone, estradiol, testosterone, free testosterone, androstenedione, prolactin, dehydroepiandrosterone sulfate, cortisol, growth hormone, and sex hormone-binding globulin. These hormone levels were compared with those of 105 healthy men (mean age, 33.9 years). RESULTS: Fourteen of the 22 patients (63.6%) achieved total seizure control following epilepsy surgery. The 14 patients with successful seizure control entered further analysis. Before surgery these patients' free testosterone and androstenedione concentrations were significantly lower compared with healthy men. In seven of the 14 patients a significant increase of hormone serum concentrations could be demonstrated for testosterone, free testosterone, and androstenedione. Laterality of epileptic focus, enzyme-inducing medication, stress, and the decreasing number of patients during the follow-up did not correlate with the finding of a normalization of serum androgens. PATIENTS without complete seizure control did not show an increase in serum androgen concentrations. CONCLUSION: Successful temporal lobe epilepsy surgery may lead to a normalization of serum androgen concentrations in men with epilepsy.

Clinical significance of serum S100 in metastatic malignant melanoma.

The clinical significance of serum S100 was assessed in comparison to neuron-specific enolase (NSE) in 126 patients with malignant melanoma: 80 patients with clinical stage I/II, 23 patients with stage III and 23 patients with stage IV according to the criteria of the American Joint Committee on Cancer (AJCC). Using cut-off values of 0.15 microgram/l for S100 and 12.5 micrograms/l for NSE, the sensitivity was found to be 1.3% (1/80) for S100 and 8.75% (7/80) for NSE in patients with stage I/II, 8.7% (2/23) for S100 and 13% (8/23) for NSE in patients with stage III, and 73.9% (17/23) for S100 and 34.8% (8/23) for NSE in patients with stage IV disease (P < 0.05). In 6 patients with stage III/IV tumours, serial measurement of serum S100 and NSE was performed. A rise of serum S100 indicated progression of the disease; a decline indicated response to treatment. Our preliminary results support the value of serum S100 as an adjunct to the clinical staging and monitoring of metastatic malignant melanoma.

Clinical significance of serum S100 in metastatic malignant melanoma.

The clinical significance of serum S100 was assessed in comparison to neuron-specific enolase (NSE) in 126 patients with malignant melanoma: 80 patients with clinical stage I/II, 23 patients with stage III and 23 patients with stage IV according to the criteria of the American Joint Committee on Cancer (AJCC). Using cut-off values of 0.15 micrograms/l for S100 and 12.5 micrograms/l for NSE, the sensitivity was found to be 1.3% (1/80) for S100 and 8.75% (7/80) for NSE in patients with stage I/II, 8.7% (2/23) for S100 and 13% (8/23) for NSE in patients with stage III, and 73.9% (17/23) for S100 and 34.8% (8/23) for NSE in patients with stage IV disease (P < 0.05). In 6 patients with stage III/IV tumours, serial measurement of serum S100 and NSE was performed. A rise of serum S100 indicated progression of the disease; a decline indicated response to treatment. Our preliminary results support the value of serum S100 as an adjunct to the clinical staging and monitoring of metastatic malignant melanoma.

Expression of 17beta-hydroxysteroid dehydrogenase types 1, 2, 3 and 4 in the human temporal lobe.

Sex steroid hormones exert important biological effects on the brain. Moreover, an extensive sex steroid metabolism occurs in the brain. In sex steroid metabolism 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play essential roles in catalyzing the final steps in androgen and estrogen biosynthesis. Recently four types of human 17beta-HSDs and a pseudogene of the type 1 isoform were identified. To date, 17beta-HSD has not been extensively studied in the human brain. Therefore, we investigated the mRNA expression of the four isozymes of 17beta-HSD as well as the pseudogene of the type 1 isoform in the human temporal lobe to determine the predominant isoforms and, moreover, to elucidate the existence of possible sex and age differences. We studied biopsy materials from the temporal lobe of 34 women, 32 men and 10 children. Quantification of different mRNAs was achieved by competitive reverse transcription-PCR. 17beta-HSD 1, 17beta-HSD 3 and 17beta-HSD 4 were expressed in the human temporal lobe of children and adults, whereas 17beta-HSD 2 and the pseudogene of 17beta-HSD 1 were not expressed. In adults, 17beta-HSD 3 and 17beta-HSD 4 mRNA concentrations were significantly higher in the subcortical white matter (17beta-HSD 3: 14 591+/-3457 arbitrary units (aU), mean+/-s.e.m.; 17beta-HSD 4: 1201+/-212 aU) than in the cortex (17beta-HSD 3: 5428+/-1057 aU, P<0. 0002; 17beta-HSD 4: 675+/-74 aU, P<0.004). 17beta-HSD 1 concentrations did not differ significantly between the white matter (3860+/-1628 aU) and the cortex (2525+/-398 aU) of adults. In conclusion, the present study demonstrates the expression of 17beta-HSD 1, 3 and 4 mRNAs in the human temporal lobe. Together with CYP19AROM and 5alpha-reductase, known to be expressed in the human brain, the expression of 17beta-HSD 1, 3 and 4 mRNAs indicates the major importance of local steroid biosynthesis in the brain.

Expression of the 17beta-hydroxysteroid dehydrogenase type 5 mRNA in the human brain.

An enzyme-mediated metabolism of androgens and estrogens including 17beta-HSD activity in the brain of vertebrates was discovered approximately 30 years ago. Mainly 5alpha-reductase and aromatase have been studied in detail. Recently we could demonstrate reductive and oxidative 17beta-HSD activity as well as considerable mRNA expression of the 17beta-HSD types 3 and 4 in the human brain. In the present study, we report on 17beta-HSD type 5 mRNA expression in brain tissue of women and men. Data analysis did not reveal sex specific differences, but we determined a significantly higher mRNA concentration in the subcortical white matter (SC) than in the cerebral cortex (CX). Investigation of reductive 17beta-HSD in vitro activity with 2 microM androstenedione as the substrate revealed no sex specific differences. Testosterone formation was significantly higher in SC than in CX. Moreover, enzyme activity was significantly higher in brain tissue of adults compared to that of children.

Effect of propranolol and depot lanreotide SR on postprandial and circadian portal haemodynamics in cirrhosis.

BACKGROUND: Long-acting somatostatin analogues have been suggested as an alternative to propranolol for the prevention of variceal rebleeding. AIM: To compare the effectiveness of lanreotide SR, a new depot formulation injected once-weekly, and propranolol in reducing circadian portal blood flow (PVF) and meal-stimulated hepatic venous pressure gradient (HVPG) in patients with liver cirrhosis. METHODS: Patients were randomized to receive either lanreotide SR intramuscularly (30 mg once weekly, n=12) or propranolol (n=12) orally. Hemodynamic measurements were performed on day 0 and on day 21 after a 3-week period of drug administration, while patients received three standard oral liquid test meals. On each study day 27 PVF measurements were performed over 24 h and eight measurements of HVPG during the first postprandial period. RESULTS: Propranolol was more effective than lanreotide SR in reducing baseline HVPG (-21.9 vs. -13.6%, P=0.04) and meal-stimulated HVPG (-16.6 vs. -3.8%, P=0.04). Propranolol reduced circadian PVF significantly by 9.3% (P=0.03) but not lanreotide SR. CONCLUSIONS: Long-term treatment with propranolol reduced baseline and postprandial HVPG and circadian PVF, while lanreotide SR did not. The results of our study do not encourage clinical testing of lanreotide SR 30 mg for the prevention of variceal haemorrhage.