Adipokine secretion and lipolysis following gender-affirming treatment in transgender individuals.

BACKGROUND: The organ-specific effects of gender-affirming sex hormone treatment (GAHT) in transgender women (TW) and transgender men (TM) are insufficiently explored. This study investigated the effects of GAHT on adipose tissue function. METHODS: In a single-center interventional prospective study, 32 adults undergoing GAHT, 15 TW and 17 TM, were examined with anthropometry and abdominal subcutaneous adipose tissue biopsies obtained before initiation of treatment, 1 month after endogenous sex hormone inhibition and three and 11 months after initiated GAHT. Fat cell size, basal/stimulated lipolysis and cytokine secretion in adipose tissue were analyzed. RESULTS: TW displayed an increase in complement component 3a and retinol-binding protein 4 (RBP4) secretion after sex hormone inhibition, which returned to baseline following estradiol treatment. No changes in lipolysis were seen in TW. TM showed downregulation of RBP4 after treatment, but no changes in basal lipolysis. In TM, the estrogen suppression led to higher noradrenaline stimulated (NA) lipolysis that was normalized following testosterone treatment. At 11 months, the ratio of NA/basal lipolysis was lower compared to baseline. There were no significant changes in fat cell size in either TW or TM. CONCLUSION: In TW, gonadal hormone suppression results in transient changes in cytokines and in TM there are some changes in NA-stimulated lipolysis following testosterone treatment. However, despite the known metabolic effects of sex hormones, the overall effects of GAHT on adipose tissue function are small and likely have limited clinical relevance, but larger studies with longer follow-up are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02518009, Retrospectively registered 7 August 2015.

Genetic analyses of pathogen-specific mastitis.

The aims of this study were to investigate the presence of genetic variation for susceptibility to pathogen-specific mastitis and to examine whether haplotypes of an identified quantitative trait locus with effect on unspecific mastitis resistance had different effects on specific mastitis pathogens. Bacteriological data on mastitis pathogens were obtained from the diagnostic laboratory at the Swedish National Veterinary Institute. The data were mainly from subclinical cases of mastitis but also clinical cases were included. Variance components were estimated for incidence of the six most frequent pathogens using Markov Chain Monte Carlo methodology via Gibbs sampling. Genetic variation for susceptibility to pathogen-specific mastitis was higher compared to estimates of general resistance to clinical mastitis in most other studies. However, because of the non-random nature of data collection, comparisons to other studies should be made by caution. The effect of haplotype on the risk of being infected by a given mastitis pathogen, relative to other pathogens, was studied using an allele substitution model. Although there were no significant haplotype substitution effects on the resistance to any of the six mastitis pathogens, there was a significant difference between the effects of two of the haplotypes regarding the risk of acquiring a Streptococcus dysgalactiae infection.

Sputter deposited bioceramic coatings: surface characterisation and initial protein adsorption studies using surface-MALDI-MS.

Protein adsorption onto calcium phosphate (Ca-P) bioceramics utilised in hard tissue implant applications has been highlighted as one of the key events that influences the subsequent biological response, in vivo. This work reports on the use of surface-matrix assisted laser desorption ionisation mass spectrometry (Surface-MALDI-MS) as a technique for the direct detection of foetal bovine serum (FBS) proteins adsorbed to hybrid calcium phosphate/titanium dioxide surfaces produced by a novel radio frequency (RF) magnetron sputtering method incorporating in situ annealing between 500°C and 700°C during deposition. XRD and XPS analysis indicated that the coatings produced at 700°C were hybrid in nature, with the presence of Ca-P and titanium dioxide clearly observed in the outer surface layer. In addition to this, the Ca/P ratio was seen to increase with increasing annealing temperature, with values of between 2.0 and 2.26 obtained for the 700°C samples. After exposure to FBS solution, surface-MALDI-MS indicated that there were significant differences in the protein patterns as shown by unique peaks detected at masses below 23.1 kDa for the different surfaces. These adsorbates were assigned to a combination of growth factors and lipoproteins present in serum. From the data obtained here it is evident that surface-MALDI-MS has significant utility as a tool for studying the dynamic nature of protein adsorption onto the surfaces of bioceramic coatings, which most likely plays a significant role in subsequent bioactivity of the materials.

Fatal and mild primary dengue virus infections imported to Norway from Africa and south-east Asia, 2008-2010.

Between 2008 and 2010, eight cases of viraemic dengue fever in travellers were diagnosed in Norway. They had returned from Eritrea, Thailand and Indonesia. All cases were primary dengue infections, seven non-complicated dengue fever and one dengue shock syndrome with a fatal outcome. Four patients were infected with dengue virus serotype 1, one with type 2 and three with type 3. Two cases from Thailand, the fatal case and the two imported from Eritrea were infected with type 1.

Higher all-cause mortality in children during autumn 2009 compared with the three previous years: pooled results from eight European countries.

The paper describes weekly fluctuations of all-cause mortality observed in eight European countries during the period between week 27 and 51, 2009, in comparison with three previous years. Our preliminary data show that the mortality reported during the 2009 influenza pandemic did not reach levels normally seen during seasonal influenza epidemics. However, there was a cumulative excess mortality of 77 cases (1 per 100,000 population) in 5-14-year-olds, and possibly also among 0-4-year-olds.

A novel NGFB point mutation: a phenotype study of heterozygous patients.

OBJECTIVE: A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients. METHODS: 26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13-90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15-86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy. RESULTS: The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Adelta) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found. CONCLUSIONS: The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.

Titan's ionosphere: A survey of solar EUV influences.

Effects of solar EUV on positive ions and heavy negative charge carriers (molecular ions, aerosol, and/or dust) in Titan's ionosphere are studied over the course of almost 12 years, including 78 flybys below 1400 km altitude between TA (October 2004) and T120 (June 2016). The Radio and Plasma Wave Science/Langmuir Probe-measured ion charge densities (normalized by the solar zenith angle) show statistically significant variations with respect to the solar EUV flux. Dayside charge densities increase by a factor of ≈2 from solar minimum to maximum, while nightside charge densities are found to anticorrelate with the EUV flux and decrease by a factor of ≈3-4. The overall EUV dependence of the ion charge densities suggest inapplicability of the idealized Chapman theory below 1200 km in Titan's ionosphere. Nightside charge densities are also found to vary along Titan's orbit, with higher values in the sunward magnetosphere of Saturn compared to the magnetotail.

Quantitative trait loci affecting fertility and calving traits in Swedish dairy cattle.

Impaired fertility is the main reason for involuntary culling of dairy cows in Sweden. The objective of this study was to map quantitative trait loci (QTL) influencing fertility and calving traits in the Swedish dairy cattle population. The traits analyzed were number of inseminations, 56-d nonreturn rate, interval from calving to first insemination, fertility treatments, heat intensity score, stillbirth, and calving performance. A genome scan covering 20 bovine chromosomes was performed using 145 microsatellite markers. The mapping population consisted of 10 sires and their 417 sons in a granddaughter design. Nine of the sires were of the Swedish Red Breed, and one was a Swedish Holstein. Least squares regression was used to map loci affecting the analyzed traits, and permutation tests were used to set significance thresholds. Cofactors were used in the analyses of individual chromosomes to adjust for QTL found on other chromosomes. The use of cofactors increased both the number of QTL found and the significance level. In the initial analysis, we found 13 suggestive QTL that were mapped to chromosomes 6, 7, 9, 11, 13, 15, 20, and 29. When cofactors were included, 30 QTL were detected on chromosomes 1, 3, 4, 18, 19, 22, and 25, in addition to the 8 previously mentioned chromosomes. Some of the results from the cofactor analysis may be false positives and require further validation. In conclusion, we were able to map several QTL affecting fertility and calving traits in Swedish dairy cattle.

Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans.

Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 hours to infinity (AUC0-∞ ) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-∞ of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12 -mediated platelet aggregation 0-12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites.

The antihypertensive mechanism of clonidine in man. Evidence against a generalized reduction of sympathetic activity.

Recording of multi-unit sympathetic activity were made from muscle branches of the peroneal nerve during i.v. bolus injection of 100 to 275 micrograms clonidine in seven hypertensive patients. Blood pressure was reduced in all patients, but sympathetic activity and heart rate could either increase or decrease. When plasma levels of clonidine were low, sympathetic activity tended to increase, and when plasma levels were high, activity tended to decrease. Irrespective of whether mean level of sympathetic activity increased or decreased with the fall in blood pressure level, transient fluctuations of blood pressure continued to cause dynamic baroreflex modulation of the sympathetic outflow. It is suggested that the drug influences sympathetic outflow by a combination of central and peripheral effects.

Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia.

Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCA7 gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.

Concentration-dependent blood pressure effects of guanfacine.

Central alpha 2-adrenoceptor stimulation decreases blood pressure, whereas stimulation of postjunctional peripheral adrenoceptors induces a pressor response. The net blood pressure response during multiple dosing is the sum of these effects and is dependent on drug kinetics, receptor affinity, and receptor occupancy. Guanfacine (2 to 6 mg/day), a selective alpha 2-adrenoceptor agonist, decreased blood pressure in patients with hypertension. At a dose greater than 6 mg/day the antihypertensive response deteriorated. Steady-state kinetics were linear but there was a tendency for a decrease in clearance after the highest dose. These results have practical implications for the therapeutic handling of the drug: Low doses for maximal therapeutic effect and longer dosage intervals at high-dosage schedules are indicated.

Exercise during therapeutic beta-blockade: a two-year study in hypertensive patients.

The use of beta-adrenoceptor blocking drugs has been thought to impair physical performance. To test this statement, 12 patients with mild to moderate hypertension performed a submaximal exercise test during treatment with placebo and after 3 and 24 months of monotherapy with betaxolol, 20 to 40 mg daily. The resting heart rate and systolic and diastolic blood pressures were reduced after 3 months of treatment and the reduction was maintained 24 hours after the last dose at the 2-year visit. A 12% to 14% reduction of exercise-induced tachycardia was found, but blood pressure during exercise was reduced only in the patients with mild hypertension. However, in no patient did the working capacity decrease.

Therapeutic and metabolic effects of sotalol.

In a single-blind, randomized study, the cardiovascular and metabolic effects of sotalol, 40 to 160 mg/day, in six patients with mild essential hypertension were compared to those of placebo at rest and during submaximal dynamic exercise. Resting blood pressure was controlled by sotalol but not the pressor response to exercise, despite reduction of tachycardia. The major metabolic finding on sotalol was an approximately 40% decrease in lipid mobilization during exercise. Alterations in muscle lactate concentrations were much like those caused by other beta-blockers. Plasma concentrations of norepinephrine and epinephrine were doubled during exercise on sotalol, epinephrine disposition more so. No effects on serum lipoproteins were observed after 6 wk on sotalol in therapeutic doses. Despite its special electrophysiologic properties, sotalol appears to induce the same cardiovascular and metabolic changes during exercise as do other beta-blockers.

Metabolic effects in muscle during antihypertensive therapy with beta 1- and beta 1/beta 2-adrenoceptor blockers.

The hemodynamic and metabolic consequences of long-term antihypertensive treatment with beta 1- and beta 1/beta 2-adrenoceptor blockade was investigated in five young men with mild essential arterial hypertension (World Health Organization stages I and II) at rest and during submaximal exercise in a single-blind crossover study. The drugs (atenolol and alprenolol) were given in equipotent doses as estimated from their effects on blood pressure. Leg blood flow and oxygen uptake were the same during both treatment periods. Muscle glycogen decreased by 40% during exercise, irrespective of the drug. There was a positive relationship between muscle lactate release and concentration, but for a given muscle lactate concentration the release tended to be lower during treatment with alprenolol. A negative correlation was observed between the percentage of slow-twitch fibers versus lactate release and muscle lactate concentration. The results demonstrate that during exercise muscle glycogen breaks down despite beta blockade and is neither reduced when both beta 1- and beta 2-receptors are blocked, nor when only the beta 1-receptors are blocked. It is also shown that beta blockade impairs the translocation of lactate from the muscle cell to the blood and this is greater with alprenolol than with atenolol, probably due to a membrane effect.

Influence of alprenolol on hemodynamic and metabolic responses to prolonged exercise in subjects with hypertension.

In 7 young men with essential hypertension, central and regional hemodynamics and leg metabolism were studied at rest, during and after a prolonged exercise, and with and without long-term alprenolol treatment. Alprenolol (200 mg twice daily) lowered arterial blood pressure. Heart rate decreased in relation to plasma levels during and after exercise. Cardiac output was not significantly influenced, but leg blood flow was reduced at rest. Lipolysis was also attenuated by treatment both at rest and during exercise, and the increment in plasma insulin after exercise was decreased. A reduction in the release of leg muscle lactate was noted during exercise.

Metabolic changes in muscle on long-term alprenolol therapy.

Muscle biopsies from the vastus muscle were taken at rest and immediately after upright bicycle exercise at 50% of the individual VO2max, before and during 6 wk of alprenolol treatment (200 to 400 mg twice daily) in 6 untrained patients with essential hypertension. Resting muscle concentrations (mmole - kg-1 - wet weight) of glycogen, glucose, lactate, and high-energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] were not affected by alprenolol treatment, but after 10 min after exercise the glycogenolysis increased and depletion of ATP and CP was enhanced. The relationship between blood and muscle lactate was altered by alprenolol, indicating that alprenolol prevents lactate translocation from the muscle to the blood. The results show that during moderate exercise, leg muscle metabolism is influenced by long-term antihypertensive therapy.

Chloroquine serum concentration and side effects: evidence for dose-dependent kinetics.

Serum concentrations of chloroquine were determined fluorometrically in 100 rheumatoid patients who had been treated with 0.25 gm daily for at least 2 mo. The total dose varied between 3.7 and 400 gm. No patient received more than 75 gm annually. In 15% of the patients side effects were noted. There was a relationship between serum concentrations and side effects but not with the total dose administered. Chloroquine displayed dose-dependent kinetics, which may indicate that close monitoring of serum concentrations is an aid to the safe and rational use of the drug.