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.

Pressure-assisted microsyringe 3D printing of oral films based on pullulan and hydroxypropyl methylcellulose.

Oral films (OFs) continue to attract attention as drug delivery systems, particularly for pedatric and geriatric needs. However, immiscibility between different polymers limits the full potential of OFs from being explored. One example is pullulan (PUL), a novel biopolymer which often has to be blended with other polymers to reduce cost and alter its mechanical properties. In this study, the state-of-the-art in fabrication techniques, three-dimensional (3D) printing was used to produce hybrid film structures of PUL and hydroxypropyl methylcellulose (HPMC), which were loaded with caffeine as a model drug. 3D printing was used to control the spatial deposition of films. HPMC was found to increase the mean mechanical properties of PUL films, where the tensile strength, elastic modulus and elongation break increased from 8.9 to 14.5 MPa, 1.17 to 1.56 GPa and from 1.48% to 1.77%, respectively. In addition, the spatial orientation of the hybrid films was also explored to determine which orientation could maximize the mechanical properties of the hybrid films. The results revealed that 3D printing could modify the mechanical properties of PUL whilst circumventing the issues associated with immiscibility.

Circulating Interleukin-6 Is Associated with Skeletal Muscle Strength, Quality, and Functional Adaptation with Exercise Training in Mobility-Limited Older Adults.

BACKGROUND: Human aging is characterized by a chronic, low-grade inflammation suspected to contribute to reductions in skeletal muscle size, strength, and function. Inflammatory cytokines, such as interleukin-6 (IL-6), may play a role in the reduced skeletal muscle adaptive response seen in older individuals. OBJECTIVES: To investigate relationships between circulating IL-6, skeletal muscle health and exercise adaptation in mobility-limited older adults. DESIGN: Randomized controlled trial. SETTING: Exercise laboratory on the Health Sciences campus of an urban university. PARTICIPANTS: 99 mobility-limited (Short Physical Performance Battery (SPPB) ≤9) older adults. INTERVENTION: 6-month structured physical activity with or without a protein and vitamin D nutritional supplement. MEASUREMENTS: Circulating IL-6, skeletal muscle size, composition (percent normal density muscle tissue), strength, power, and specific force (strength/CSA) as well as physical function (gait speed, stair climb time, SPPB-score) were measured pre- and post-intervention. RESULTS: At baseline, Spearman's correlations demonstrated an inverse relationship (P<0.05) between circulating IL-6 and thigh muscle composition (r = -0.201), strength (r = -0.311), power (r = -0.210), and specific force (r = -0.248), and positive association between IL-6 and stair climb time (r = 0.256; P<0.05). Although the training program did not affect circulating IL-6 levels (P=0.69), reductions in IL-6 were associated with gait speed improvements (r = -0.487; P<0.05) in "higher" IL-6 individuals (>1.36 pg/ml). Moreover, baseline IL-6 was inversely associated (P<0.05) with gains in appendicular lean mass and improvements in SPPB score (r = -0.211 and -0.237, respectively). CONCLUSIONS: These findings implicate age-related increases in circulating IL-6 as an important contributor to declines in skeletal muscle strength, quality, function, and training-mediated adaptation. Given the pervasive nature of inflammation among older adults, novel therapeutic strategies to reduce IL-6 as a means of preserving skeletal muscle health are enticing.

Effect of liraglutide on anthropometric measurements, sagittal abdominal diameter and adiponectin levels in people with type 2 diabetes treated with multiple daily insulin injections: evaluations from a randomized trial (MDI-liraglutide study 5).

AIM: Use of the glucagon-like peptide 1 receptor agonist liraglutide has been shown to reduce weight. Different types of anthropometric measurements can be used to measure adiposity. This study evaluated the effect of liraglutide on sagittal abdominal diameter, waist circumference, waist-to-hip ratio and adiponectin levels in people with type 2 diabetes (T2D) treated with multiple daily insulin injections (MDI). MATERIALS AND METHODS: In the multicentre, double-blind, placebo-controlled MDI-liraglutide trial, 124 individuals with T2D treated with MDI were randomized to either liraglutide or placebo. Basal values of weight, waist circumference, waist-to-hip ratio, sagittal abdominal diameter and adiponectin were compared with measurements at 12 and 24 weeks after randomization. RESULTS: Baseline-adjusted mean weight loss was 3.8 ± 2.9 kg greater in liraglutide than placebo-treated individuals (p < 0.0001). Waist circumference was reduced by 2.9 ± 4.3 cm and 0.2 ± 3.6 cm in the liraglutide and placebo groups, respectively, after 24 weeks (baseline-adjusted mean difference: 2.6 ± 4.0 cm, p = 0.0005). Corresponding reductions in sagittal abdominal diameter were 1.1 ± 1.7 cm and 0.0 ± 1.8 cm (baseline-adjusted mean difference: 1.1 ± 1.7 cm, p = 0.0008). Hip circumference was reduced in patients randomized to liraglutide (baseline-adjusted mean difference between treatment groups: 2.8 ± 3.8 cm, p = 0.0001), but there was no significant difference between the groups in either waist-to-hip ratio (baseline-adjusted mean difference: 0.0 ± 0.04 cm, p = 0.51) or adiponectin levels (baseline-adjusted mean difference: 0.8 ± 3.3 mg L-1, p = 0.17). Lower HbA1c and mean glucose levels measured by masked continuous glucose monitoring at baseline were associated with greater effects of liraglutide on reductions in waist circumference and sagittal abdominal diameter. CONCLUSIONS: In patients with T2D, adding liraglutide to MDI may reduce abdominal and hip obesity to a similar extent, suggesting an effect on both visceral and subcutaneous fat. Liraglutide had greater effects on reducing abdominal obesity in patients with less pronounced long-term hyperglycaemia but did not affect adiponectin levels.

"Feeling More Self-Confident, Cheerful and Safe". Experiences from a Health-Promoting Intervention in Community Dwelling Older Adults - A Qualitative Study.

OBJECTIVES: Studies show that regular exercise in combination with nutritional support can be effective in managing sarcopenia, which is age-related involuntary loss of skeletal muscle mass and strength. Qualitative investigations of participants' experiences from interventions in this domain are scarce. In this study, we explored older persons' experiences from an intervention designed to prevent sarcopenia, with the aim of capturing the participants' thoughts and opinions. DESIGN: A qualitative study embedded in the multicenter randomized clinical trial The Vitality and Vigor in the Elderly study, VIVE2. Focus group interviews were conducted. Manifest and latent content analyses were performed. PARTICIPANTS: Community dwelling older adults (n=20) 71-86 years of age with minor limitations in mobility. RESULTS: The experiences from the intervention were categorized and interpreted in one overall theme "Feeling more self-confident, cheerful and safe". The theme encompasses the categories psychological effects of participating in the intervention, physical effects of participating in the intervention, the importance of social support and the importance of a tailored set-up. The participants described their motives for participating in the intervention as being based on concerns regarding the negative health effects of continuing a sedentary lifestyle, difficulties of getting started on their own and lack of confidence in accomplishing change on their own. Participants also expressed that one main objective for participating was to lose weight. CONCLUSION: In this study we have captured the experiences of older adults with minor mobility limitations who participated in a lifestyle intervention. The experiences are interpreted in one overall theme "Feeling more self-confident, cheerful and safe". The central understanding of the participants' experiences was that the intervention affected them in several ways, both psychologically and physically, and that supporting factors included the social support, which became a prerequisite for success. A noticeable finding was the discrepancy between the motive of the participants, to lose weight, and the aim of the study, to improve muscle function. The expectation to lose weight seems to reflect what is commonly known as to be healthy. To our knowledge, at least in Sweden, there are no campaigns or public information highlighting the risks of sarcopenia and the complex issue of if, and when weight loss is desirable for older individuals. This finding highlights the importance of providing such information to this target group. The findings in this study provide valuable knowledge for research teams, practitioners and decision makers when designing and setting objectives for health-promoting interventions for older individuals.

Physical Performance and Serum 25(OH)vitamin D Status in Community Dwelling Old Mobility Limited Adults: A Cross-Sectional Study.

OBJECTIVES: To examine the potential association between serum 25(OH) vitamin D and the performance on the Short Physical Performance Battery (SPPB) including the sub-components; five repeated chair stands test, 4 meters walk test and balance in older mobility-limited community-dwelling men and women. DESIGN: A cross sectional study was performed in American and Swedish subjects who were examined for potential participation in a combined exercise and nutrition intervention trial. Logistic regression analysis and linear regression analyses were performed to evaluate the association for 25(OH)D with the overall score on the SBBP, chair stand, gait speed and balance. PARTICIPANTS: Community-dwelling (mean age 77.6 ± 5.3 years) mobility limited American (n=494) and Swedish (n=116) females (59%) and males. MEASUREMENTS: The SPPB (0-12 points) includes chair stand (s), gait speed (m/s) and a balance test. Mobility limitation i.e., SPPB score ≤ 9 was an inclusion criterion. A blood sample was obtained to measure serum 25(OH)vitamin D concentrations. RESULTS: No clear association of 25(OH)D with SPPB scores was detected either when 25(OH)D was assessed as a continuous variable or when categorized according to serum concentrations of <50, 50-75 or <75 nmol/L. However, when analyzing the relationship between 25(OH)D and seconds to perform the chair stands, a significant quadratic relationship was observed. Thus, at serum levels of 25(OH)D above 74 nmol/L, higher concentrations appeared to be advantageous for the chair stand test, whereas for serum levels below 74 nmol/L this association was not observed. CONCLUSION: This cross- sectional study lacked clear association between serum 25(OH)D and physical performance in mobility limited adults. A potentially interesting observation was that at higher serum levels of 25(OH)D a better performance on the chair stand test was indicated.

High doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults.

AIMS: This study tested the hypothesis that high doses of anti-inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses. METHODS: Healthy men and women (aged 18-35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n = 15) or acetylsalicylic acid (ASA; 75 mg; n = 16) for 8 weeks. During this period, subjects completed supervised knee-extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work-matched across groups) weight-stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators. RESULTS: The increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm3 ; P = 0.029). In the WS leg, muscle strength improved similarly (11-20%) across groups. In the FW leg, increases (10-23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P < 0.05) for ASA compared with IBU. While our molecular analysis revealed several training effects, the only group interaction (P < 0.0001) arose from a downregulated mRNA expression of IL-6 in IBU. CONCLUSION: Maximal over-the-counter doses of ibuprofen attenuate strength and muscle hypertrophic adaptations to 8 weeks of resistance training in young adults. Thus, young individuals using resistance training to maximize muscle growth or strength should avoid excessive intake of anti-inflammatory drugs.

Effect of Structured Physical Activity and Nutritional Supplementation on Physical Function in Mobility-Limited Older Adults: Results from the VIVE2 Randomized Trial.

OBJECTIVES: The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). DESIGN: All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). SETTING: Participants were recruited from urban communities at 2 field centers in Boston MA USA and Stockholm SWE. PARTICIPANTS: Mobility-limited (Short Physical Performance Battery (SPPB) ≤9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. MEASUREMENTS: Primary outcome was gait speed assessed by the 400M walk. RESULTS: 149 subjects were randomized into the study (mean age=77.5±5.4; female=46.3%; mean SPPB= 7.9±1.2; mean 25(OH)D=18.7±6.4 ng/ml). Adherence across supplement and placebo groups was similar (86% and 88%, respectively), and was also similar across groups for the physical activity intervention (75% and 72%, respectively). Both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo (0.071 and 0.108 m/s, respectively (p=0.06)). Similar effects in physical function were observed using the SPPB. Serum 25(OH)D increased in supplemented group compared to placebo 7.4 ng/ml versus 1.3 ng/ml respectively. CONCLUSION: Results suggest improved gait speed following physical activity program with no further improvement with added nutritional supplementation.

Limb proportions show developmental plasticity in response to embryo movement.

Animals have evolved limb proportions adapted to different environments, but it is not yet clear to what extent these proportions are directly influenced by the environment during prenatal development. The developing skeleton experiences mechanical loading resulting from embryo movement. We tested the hypothesis that environmentally-induced changes in prenatal movement influence embryonic limb growth to alter proportions. We show that incubation temperature influences motility and limb bone growth in West African Dwarf crocodiles, producing altered limb proportions which may, influence post-hatching performance. Pharmacological immobilisation of embryonic chickens revealed that altered motility, independent of temperature, may underpin this growth regulation. Use of the chick also allowed us to merge histological, immunochemical and cell proliferation labelling studies to evaluate changes in growth plate organisation, and unbiased array profiling to identify specific cellular and transcriptional targets of embryo movement. This disclosed that movement alters limb proportions and regulates chondrocyte proliferation in only specific growth plates. This selective targeting is related to intrinsic mTOR (mechanistic target of rapamycin) pathway activity in individual growth plates. Our findings provide new insights into how environmental factors can be integrated to influence cellular activity in growing bones and ultimately gross limb morphology, to generate phenotypic variation during prenatal development.

Multivariate linear regression modelling of lung weight in 24,056 Swedish medico-legal autopsy cases.

Heavy combined lung weight at autopsy is a non-specific autopsy finding associated with certain causes of death such as intoxication. There is however no clear definition of what constitutes "heavy" lung weight. Different reference values have been suggested but previous studies have been limited by small select populations and only univariate regression has been attempted. The aim of this study was to create a model to estimate lung weight from decedent parameters. We identified all cases >18 years age autopsied at the Swedish National Board of Forensic Medicine from 2000 through 2013, excluding cases with a post-mortem interval >5 days as well as cases with extreme values, totalling 24,056 cases. We analysed body weight, body height, sex, age, BMI, BSA as well as untransformed and transformed lung weight. The analysis was stratified for sex. We evaluated the fit of the models and that the model assumptions were not violated. We set out to apply the model with the highest residual sum of squares to derive limits for heavy lungs. In univariate regression BSA and height showed best performance. The final model included height, weight and age group. After excluding large standardized residuals (>3, <-3) the final model achieved R2 of 0.132 and 0.106 for women and men respectively. While we managed to create a multivariate model its performance was poor, possibly a fact reflective of the physiological nature of the lungs and in turn its variability in fluid content. Linear regression is a poor model for estimating lung weight in an unselected population.

Dietary micronutrient intake and atherosclerosis in systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to investigate the role of dietary micronutrient intake in systemic lupus erythematosus (SLE). METHODS: This study included 111 SLE patients and 118 age and gender-matched controls. Data on diet (food frequency questionnaires) were linked with data on Systemic Lupus Activity Measure, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and carotid atherosclerotic/echolucent plaque (B-mode ultrasound). Dietary micronutrient intake were compared between SLE patients and controls and in relation to lupus activity and atherosclerosis in SLE. Associations between micronutrient intake and plaque were analyzed through logistic regression, adjusted for potential confounders. RESULTS: Micronutrient intake did not differ between patients and controls, and between lower and higher lupus activity, apart from the fact that phosphorus was associated with SLEDAI > 6. In SLE patients, some micronutrients were associated with atherosclerotic plaque, left side. Lower intake of riboflavin and phosphorus was associated with atherosclerotic plaque, left side (odds ratio (OR) 3.06, 95% confidence interval (CI) 1.12-8.40 and OR 4.36, 95% CI 1.53-12.39, respectively). Higher intake of selenium and thiamin was inversely associated with atherosclerotic plaque, left side (OR 0.28, 95% CI 0.09-0.89 and OR 0.26, 95% CI 0.08-0.80, respectively). In addition, higher intake of thiamin was inversely associated with echolucent plaque, left side (OR 0.22, 95% CI 0.06-0.84). Lower intake of folate was inversely associated with bilateral echolucent plaque (OR 0.36, 95% CI 0.13-0.99). CONCLUSIONS: SLE patients did not have different dietary micronutrient intake compared to controls. Phosphorus was associated with lupus activity. Riboflavin, phosphorus, selenium and thiamin were inversely associated with atherosclerotic plaque, left side in SLE patients, but not in controls. Dietary micronutrients may play a role in atherosclerosis in SLE.

Negative regulation of HIF in skeletal muscle of elite endurance athletes: a tentative mechanism promoting oxidative metabolism.

The transcription factor hypoxia-inducible factor (HIF) has been suggested as a candidate for mediating training adaptation in skeletal muscle. However, recent evidence rather associates HIF attenuation with a trained phenotype. For example, a muscle-specific HIF deletion increases endurance performance, partly through decreased levels of pyruvate dehydrogenase kinase 1 (PDK-1). HIF activity is regulated on multiple levels: modulation of protein stability, transactivation capacity, and target gene availability. Prolyl hydroxylases (PHD1-3) induces HIF degradation, whereas factor-inhibiting HIF (FIH) and the histone deacetylase sirtuin-6 (SIRT6) repress its transcriptional activity. Together, these negative regulators introduce a mechanism for moderating HIF activity in vivo. We hypothesized that long-term training induces their expression. Negative regulators of HIF were explored by comparing skeletal muscle tissue from moderately active individuals (MA) with elite athletes (EA). In elite athletes, expression of the negative regulators PHD2 (MA 73.54 ± 9.54, EA 98.03 ± 6.58), FIH (MA 4.31 ± 0.25, EA 30.96 ± 7.99) and SIRT6 (MA 0.24 ± 0.07, EA 11.42 ± 2.22) were all significantly higher, whereas the response gene, PDK-1 was lower (MA 0.12 ± 0.03, EA 0.04 ± 0.01). Similar results were observed in a separate 6-wk training study. In vitro, activation of HIF in human primary muscle cell culture by PHD inactivation strongly induced PDK-1 (0.84 ± 0.12 vs 4.70 ± 0.63), providing evidence of a regulatory link between PHD activity and PDK-1 levels in a relevant model system. Citrate synthase activity, closely associated with aerobic exercise adaptation, increased upon PDK-1 silencing. We suggest that training-induced negative regulation of HIF mediates the attenuation of PDK-1 and contributes to skeletal muscle adaptation to exercise.

Gold nanostar substrates for SERS-based chemical sensing in the femtomolar regime.

We report a novel approach for fabricating gold nanostar-functionalized substrates for highly sensitive surface enhanced Raman spectroscopy (SERS)-based chemical sensing. Gold nanostars immobilized on a gold substrate via a Raman silent organic tether serve as the SERS substrate, and facilitate the chemical sensing of analytes that can either be chemisorbed or physisorbed on the nanostars. Our SERS substrates are capable of detecting chemisorbed 4-mercaptobenzoic acid at a concentration as low as 10 fM with a reproducible SERS enhancement factor of 10(9), and enable the semi-quantitative multiplexed identification of analytes from mixtures in which they have been dissolved in variable stoichiometry. Most importantly, they afford the detection of physisorbed analytes, such as crystal violet, with an excellent signal-to-noise ratio, hence serving as a versatile platform for the chemical identification of in principle any molecular analyte. These characteristics make a strong case for the use of our nanostar-based SERS substrate in practical chemical sensing applications.

Truncated splice variant PGC-1α4 is not associated with exercise-induced human muscle hypertrophy.

INTRODUCTION: A truncated PGC-1α splice variant (PGC-1α4) has been implicated in the regulation of resistance exercise (RE)-induced muscle hypertrophy, and basal expression levels said to be augmented in response to concurrent aerobic (AE) and RE training. AIM: The current study investigated human muscle truncated and non-truncated PGC-1α transcripts in response to both acute and chronic RE, and with or without preceding AE (AE+RE). METHODS: Ten men performed 5 weeks of unilateral AE+RE and RE training. Before (untrained) and after (trained) this intervention, PGC-1α transcripts were assessed in vastus lateralis muscle biopsies obtained before and 3 h after acute RE, with or without preceding AE. Additionally, samples were collected 72 h after the last exercise bout of the training programme. RESULTS: The truncated splice variant increased (P < 0.05) its expression after acute exercise regardless of mode. However, the expression was greater (P < 0.05) after AE+RE than RE. Other PGC-1α transcripts showed similar response. Truncated transcripts originated from both the alternative and proximal promoter, and AE+RE increased PGC-1α expression from both promoter sites. RE induced transcripts from the alternative promoter only. PGC-1α expressions after acute exercise were comparable across isoforms in both untrained and trained muscle. Steady-state levels of isoforms were unchanged after 5-week training (P > 0.05). Exercise-induced expression of PGC-1α variants did not correlate with changes in muscle size or strength (P > 0.05). CONCLUSION: Our results do not support the view that truncated PGC-1α coordinates exercise-induced hypertrophy in human skeletal muscle. Rather, all PGC-1α isoforms appear to be regulated transiently in response to acute exercise and regardless of mode.

X-ray absorption spectroscopy and resonant inelastic scattering study of the first lithiation cycle of the Li-ion battery cathode Li(2-x)MnSiO4.

We employ soft X-ray absorption spectroscopy and resonant inelastic X-ray scattering spectroscopy to study the redox behavior in the first lithiation/delithiation cycle of Li(2-x)MnSiO4 (4.0-4.6 V). For extraction of lithium ions up to an end potential of 4.1 V, we do not detect any change in the oxidation state for the expected redox-active Mn atom, instead the electronic structure of the Si-O network is affected. Above 4.1 V, there is an abrupt change in the oxidation state of the Mn-ions, from 2+ to 4+, which is accompanied by a complete loss of long range order in the material, as detected by X-ray diffraction. Further lithium extraction leads to progressive loss of crystallinity of Li(2-x)MnSiO4, rather than formation of a new structure, explaining the measured first-cycle capacity loss of this material. Our results suggest that future improvement of the crystalline stability of the material, particularly with respect to the SiO4 network, is required to harness the full charge capacity of Li(2-x)MnSiO4.

Elevations of local intravascular pressures release vasoactive substances in humans.

The wall stiffness of arteries and arterioles adapts to the long-term demands imposed by local intravascular pressure. We investigated whether substances capable of inducing acute and long-term effects on arterial wall stiffness are released locally into the bloodstream in response to an acute marked increase in local intravascular pressure in the blood vessels of the human arm. Experiments were performed on ten subjects positioned in a pressure chamber with one arm extended through a hole in the chamber door and kept at normal atmospheric pressure. Intravascular pressure was increased in the arm, by a stepwise increase in chamber pressure up to +150 mmHg. Diameter and flow were measured in the brachial artery by Doppler ultrasonography. Blood samples were drawn simultaneously from both arms before, during, immediately after and 2 h after the release of the chamber pressure. Plasma levels of endothelin-1 (ET-1), vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and angiotensin II (Ang-II) were measured. Elevation of chamber pressure by 150 mmHg increased local arterial distending pressure to about 220-260 mmHg, resulting in an increase in brachial artery diameter of 9% and flow of 246%. The pressure stimulus increased the plasma levels of ET-1 and Ang-II, but not of VEGF-A or FGF-2 in the test arm. The local release of the vasoconstrictors ET-1 and Ang-II in response to markedly increased distending pressure may reflect one mechanism behind adaptation to acute and long-term changes in intravascular pressure.

Circulating MMP-9 during exercise in humans.

Matrix metalloproteinase 9 (MMP-9) is a member of a family of zinc-dependent endopeptidases capable of degrading extracellular matrix (ECM) proteins. A single bout of exercise increases levels of activated MMP-9 in skeletal muscle and in the circulation. However, whether the exercise-induced activation of MMP-9 is associated with ECM remodeling and the cellular source behind MMP-9 in the circulation is not known. In the present study ten healthy male subjects performed a single cycle exercise bout and arterial and venous femoral blood was collected. To test if exercise induces basal lamina degradation and if circulating levels of MMP-9 is related to a release from the exercising muscle, arteriovenous differences of collagen IV and MMP-9 were measured by ELISA and zymography, respectively. Furthermore, markers of neutrophil degranulation elastase and neutrophil gelatinase-associated lipocalin (NGAL) were measured by ELISA. Plasma levels of collagen IV increased during the exercise bout and an increased arteriovenous difference of collagen IV was noted at 27 min of exercise. Plasma levels of MMP-9 were increased at both 27 and 57 min of exercise but no arteriovenous difference was noted. No changes over time were detected for elastase and NGAL. The observed release of collagen IV from the exercising muscle indicate basal lamina turnover following a single bout of exercise. No detectable release of MMP-9 was observed, suggesting that the increase in plasma MMP-9 could come from a source other than the skeletal muscle.

Boys with undescended testes: endocrine, volumetric and morphometric studies on testicular function before and after orchidopexy at nine months or three years of age.

CONTEXT: A randomized controlled study was conducted comparing the outcome of surgery for congenital cryptorchidism at 9 months or 3 yr of age. OBJECTIVE: The aim of the study was to investigate whether surgery at 9 months is more beneficial than at 3 yr and to identify early endocrine markers of importance for testicular development. PATIENTS AND METHODS: A total of 213 biopsies were taken at orchidopexy, and the number of germ and Sertoli cells per 100 seminiferous cord cross-sections and the surface area of seminiferous tubules and interstitial tissue were analyzed. Inhibin B, FSH, LH, and testosterone were determined. Testicular volume was assessed by ultrasonography and by a ruler. RESULTS: The number of germ and Sertoli cells and testicular volume at 9 months were significantly larger than at 3 yr. The intraabdominal testes showed the largest germ cell depletion at 3 yr. At both ages, testicular volume correlated to the number of germ and Sertoli cells. None of the hormones measured during the first 6 months of life (LH, FSH, testosterone, and inhibin B) could predict the number of germ or Sertoli cells at either 9 or 36 months of age, nor could hormone levels predict whether spontaneous descent would occur or not. CONCLUSION: Morphometric and volumetric data show that orchidopexy at 9 months is more beneficial for testicular development than an operation at 3 yr of age. Testicular volume was furthermore shown to reflect germ cell numbers in early childhood, whereas endocrine parameters could not predict cellular structure of the testis or its spontaneous descent.

Diet and fatty acid pattern among patients with SLE: associations with disease activity, blood lipids and atherosclerosis.

OBJECTIVE: As atherosclerosis is increased in systemic lupus erythematosus (SLE) we compared dietary habits in patients with SLE with controls, and in the patients studied associations of diet components, especially fatty acids (FAs), with disease activity, serum lipids and carotid plaque presence. METHODS: In all 114 patients with SLE and 122 age- and sex-matched population-based controls answered a food frequency questionnaire (FFQ). Subcutaneous abdominal fat cell aspiration was analysed as to FA content and plaque occurrence was determined by B-mode ultrasound. RESULTS: The total diet energy intake did not differ between patients and controls. However, the patients with SLE reported a higher intake of carbohydrate, lower fibre intake and lower intake of omega-3 and omega-6, than controls (p < 0.05). In the patients, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in adipose tissue (AT) correlated negatively with disease activity (SLEDAI), r = -0.36, p = < 0.001 and r = -0.33, p = < 0.001, respectively. AT omega-3 was further positively associated with serum apoA1, r = 0.29, p = 0.004, whereas AT omega-6 showed a negative association, r = -0.21, p = 0.040. These FAs also had opposite associations with plaque presence, EPA and were DHA negative, r = -0.32, p = 0.002 and r = -0.33, p = 0.001, respectively, and omega-6 positive, r = 0.22, p = 0.027. The carbohydrate intake was positively correlated to AT omega-6, r = 0.38, p < 0.001, and negatively with serum apoA1, r = -0.27, p = 0.005. CONCLUSION: The macronutrient dietary pattern is different in SLE as compared with controls. The low intake of omega-3 and high intake of carbohydrate among patients with SLE appear to be associated with worse disease activity, adverse serum lipids and plaque presence.

Microcirculation as determined by iontophoresis in SLE-patients and controls.

BACKGROUND: The risk of cardiovascular disease (CVD), microangiopathy and prevalence of atherosclerotic plaques are increased in Systemic Lupus Erythematosus (SLE). As systemic endothelial dysfunction is one of the earliest signs of these vascular outcomes in the general population we assessed skin microvascular endothelial function in SLE patients. METHODS: Endothelial function in skin was tested with local application of acetylcholine (inducing endothelium-dependent vasodilatation) and any concomitant increase in skin perfusion was measured with Laser Doppler Fluxmetry (LDF) in 84 SLE-patients (83% women, mean age 47 years) and 81 age and sex matched controls. Common carotid intima-media thickness (cIMT) and plaque occurrence were also determined using B-mode ultrasound. RESULTS: There were no significant differences in skin microvascular endothelial function between SLE-patients and controls. In the SLE group, endothelial function did not vary in relation to skin manifestations, Raynaud's phenomenon, nephritis or plaque occurrence. In SLE patients with CVD, however, endothelial function was impaired. CONCLUSION: Skin microvascular endothelial function is associated with CVD but not with early signs of atherosclerosis in SLE-patients. The endothelial function is not different in SLE-patients as compared to controls.