Corrigendum to "Are steroid hormones and autistic traits affected by metformin? First insights from a pilot" [Compr. Psychneuroendocrinology 16C 100196].

[This corrects the article DOI: 10.1016/j.cpnec.2023.100196.].

Are steroid hormones and autistic traits affected by metformin? First insights from a pilot.

Background: Different lines of evidence imply that metformin could alter steroid hormone homeostasis and thereby improve social impairment. Here, we tried to correlate the impact of metformin treatment on alterations in steroid hormones and autism spectrum traits before versus after treatment with metformin. Material & methods: Urine steroid hormones were measured using gas chromatography mass spectrometry in 12 male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and 7 female subjects (64.14 ± 18.0 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg). Furthermore, a questionnaire on autism spectrum traits (Autism Spectrum Questionnaire]) was administered prior to and after metformin treatment. Results: Overall, a decrease of steroid hormones were detected, which were most pronounced in the metabolites of corticosterone, deoxycortisol, cortisol, as well as androgens. These remained after Bonferroni correction (three classes: glucocorticoid, mineralocorticoid, androgens). No effect on autism spectrum traits (social skills, attention switching skills, attention to detail skills, communication skills, imagination skills), was identified pre versus post metformin treatment. Discussion: The decreased steroid hormone levels are based on different mechanisms; one effect is likely via mitochondria, another effect via activated protein kinase prior to post treatment. The finding on autistic traits must be taxed as negative and do not directly provide an argument for using metformin in the treatment of autism.

Skeletal muscle and heart failure - What is the relationship between central versus peripheral affections?

BACKGROUND AND AIM: Heart failure is considered as a systemic disease as beside the heart, skeletal muscle is affected. METHODS AND RESULTS: In this retrospective case-control study 64 men and 15 women with heart failure as well as an individually pairwise matched sample by sex, age and body mass index of healthy individuals from the COmPLETE cohort study performed an exhaustive cardiopulmonary exercise test, strength tests and anthropometric measurements. V̇O2peak was 28.6% lower in male and 24.6% lower in female patients with heart failure as compared to healthy controls. Strength parameters are significantly higher for counter movement jump in male subjects. In females, significant differences were detected for mid-thigh pull in healthy versus patients with heart failure. Skeletal muscle mass of patients was in male as well as female 3.7% lower than in controls. Furthermore, the function of skeletal muscle seems impaired as the ability to accelerate is significantly lower in affected male with a heart pathology. CONCLUSION: It seems that severe affections (approx. 25 to 30%) on cardiocirculatory level are associated with moderate to low affections on functional and structural capacity on skeletal muscle level. Further, as in the male cohort with a heart pathology acceleration meaning 'fast' contracting is impaired, it is suggested, that the central limitations respectively the low perfusion of skeletal muscle over years yield to adaptions on muscle cell level ingoing with a decreased ability of fast contracting. It is therefore suggested, that the central circulatory limitations in patients with heart failure, respectively the low perfusion of skeletal muscle over years, promote maladaptation's in the periphery.

Association of Gene Variants with Seasonal Variation in Muscle Strength and Aerobic Capacity in Elite Skiers.

Background: The training of elite skiers follows a systematic seasonal periodization with a preparation period, when anaerobic muscle strength, aerobic capacity, and cardio-metabolic recovery are specifically conditioned to provide extra capacity for developing ski-specific physical fitness in the subsequent competition period. We hypothesized that periodization-induced alterations in muscle and metabolic performance demonstrate important variability, which in part is explained by gene-associated factors in association with sex and age. Methods: A total of 34 elite skiers (20.4 ± 3.1 years, 19 women, 15 men) underwent exhaustive cardiopulmonary exercise and isokinetic strength testing before and after the preparation and subsequent competition periods of the World Cup skiing seasons 2015-2018. Biometric data were recorded, and frequent polymorphisms in five fitness genes, ACE-I/D (rs1799752), TNC (rs2104772), ACTN3 (rs1815739), and PTK2 (rs7460, rs7843014), were determined with specific PCR reactions on collected DNA. Relative percentage changes of cardio-pulmonary and skeletal muscle metabolism and performance over the two seasonal periods were calculated for 160 data points and subjected to analysis of variance (ANOVA) to identify hypothesized and novel associations between performance alterations and the five respective genotypes and determine the influence of age × sex. A threshold of 0.1 for the effect size (h2) was deemed appropriate to identify relevant associations and motivate a post hoc test to localize effects. Results: The preparation and competition periods produced antidromic functional changes, the extent of which varied with increasing importance for anaerobic strength, aerobic performance, cardio-metabolic efficiency, and cardio-metabolic/muscle recovery. Only peak RER (-14%), but not anaerobic strength and peak aerobic performance, and parameters characterizing cardio-metabolic efficiency, differed between the first and last studied skiing seasons because improvements over the preparation period were mostly lost over the competition period. A number of functional parameters demonstrated associations of variability in periodic changes with a given genotype, and this was considerably influenced by athlete "age", but not "sex". This concerned age-dependent associations between periodic changes in muscle-related parameters, such as anaerobic strength for low and high angular velocities of extension and flexion and blood lactate concentration, with rs1799752 and rs2104772, whose gene products relate to sarcopenia. By contrast, the variance in period-dependent changes in body mass and peak VO2 with rs1799752 and rs2104772, respectively, was independent of age. Likely, the variance in periodic changes in the reliance of aerobic performance on lactate, oxygen uptake, and heart rate was associated with rs1815739 independent of age. These associations manifested at the post hoc level in genotype-associated differences in critical performance parameters. ACTN3 T-allele carriers demonstrated, compared to non-carriers, largely different periodic changes in the muscle-associated parameters of aerobic metabolism during exhaustive exercise, including blood lactate and respiration exchange ratio. The homozygous T-allele carriers of rs2104772 demonstrated the largest changes in extension strength at low angular velocity during the preparation period. Conclusions: Physiological characteristics of performance in skiing athletes undergo training period-dependent seasonal alterations the extent of which is largest for muscle metabolism-related parameters. Genotype associations for the variability in changes of aerobic metabolism-associated power output during exhaustive exercise and anaerobic peak power over the preparation and competition period motivate personalized training regimes. This may help to predict and maximize the benefit of physical conditioning of elite skiers based on chronological characteristics and the polymorphisms of the ACTN3, ACE, and TNC genes investigated here.

ACE-I/D Allele Modulates Improvements of Cardiorespiratory Function and Muscle Performance with Interval-Type Exercise.

Background: The prominent insertion/deletion polymorphism in the gene for the major modulator of tissue perfusion, angiotensin-converting enzyme (ACE-I/D) is associated with variability in adjustments in cardiac and skeletal muscle performance with standard forms of endurance and strength type training. Here, we tested whether the ACE-I/D genotype would be associated with variability in the effects of interval-type training on peak and aerobic performance of peripheral muscle and cardio-vasculature and post-exercise recovery. Methods: Nine healthy subjects (39.0 ± 14.7 years of age; 64.6 ± 16.1 kg, 173.6 ± 9.9) completed eight weeks of interval training on a soft robotic device based on repeated sets of a pedaling exercise at a matched intensity relative to their peak aerobic power output. Prior to and post-training, peak anaerobic and aerobic power output was assessed, mechanical work and metabolic stress (oxygen saturation and hemoglobin concentrations of Musculus vastus lateralis (VAS) and Musculus gastrocnemius (GAS), blood lactate and factors setting cardiac output such as heart rate, systolic and diastolic blood pressure were monitored during ramp-incremental exercise and interval exercise with the calculation of areas under the curve (AUC), which were put in relation to the produced muscle work. Genotyping was performed based on I- and D-allele-specific polymerase chain reactions on genomic DNA from mucosal swaps. The significance of interaction effects between training and ACE I-allele on absolute and work-related values was assessed with repeated measures ANOVA. Results: Subjects delivered 87% more muscle work/power, 106% more cardiac output, and muscles experienced ~72% more of a deficit in oxygen saturation and a ~35% higher passage of total hemoglobin during single interval exercise after the eight weeks of training. Interval training affected aspects of skeletal muscle metabolism and performance, whose variability was associated with the ACE I-allele. This concerned the economically favorable alterations in the work-related AUC for the deficit of SmO2 in the VAS and GAS muscles during the ramp exercise for the I-allele carriers and opposing deteriorations in non-carriers. Conversely, oxygen saturation in the VAS and GAS at rest and during interval exercise was selectively improved after training for the non-carriers of the I-allele when the AUC of tHb per work during interval exercise deteriorated in the carriers. Training also improved aerobic peak power output by 4% in the carriers but not the non-carriers (p = 0.772) of the ACE I-allele while reducing negative peak power (-27.0%) to a lesser extent in the ACE I-allele carriers than the non-carriers. Variability in cardiac parameters (i.e., the AUC of heart rate and glucose during ramp exercise, was similar to the time to recovery of maximal tHb in both muscles after cessation of ramp exercise, only associated with the ACE I-allele but not training per se. Diastolic blood pressure and cardiac output during recovery from exhaustive ramp exercise demonstrated a trend for training-associated differences in association with the ACE I-allele. Discussion: The exercise-type dependent manifestation of antidromic adjustments in leg muscle perfusion and associated local aerobic metabolism between carriers and non-carriers of the ACE I-allele with the interval-training highlight that non-carriers of the I-allele do not present an essential handicap to improve perfusion-related aerobic muscle metabolism but that the manifestation of responsiveness depends on the produced work. Conclusions: The deployed interval-type of exercise produced ACE I-allele-related differences in the alterations of negative anaerobic performance and perfusion-related aerobic muscle metabolism, which manifestation is exercise specific. The training-invariant ACE I-allele-associated differences in heart rate and blood glucose concentration emphasize that the repeated impact of the interval stimulus, despite a near doubling of the initial metabolic load, was insufficient to overturn ACE-related genetic influences on cardiovascular function.

Prior to versus after Metformin Treatment-Effects on Steroid Enzymatic Activities.

Background: We recently reported that metformin administration has substantial effects on steroid hormone concentrations. In this study, we specifically explored which enzymatic activities were affected before a first treatment versus after a time of metformin treatment. Material and Methods: Twelve male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and seven female subjects (57.2 ± 18.9 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg) were recruited based on an indication of metformin. Prior to the first intake of metformin and after 24 h, urine collections were performed. Urine steroid analysis was completed using gas chromatography-mass spectrometry. Results: The average reduction in steroid hormone concentrations after the metformin treatment was substantial and relatively equally distributed in all metabolites and the sum of all metabolites with 35.4%. An exception was dehydroepiandrosterone, with a decrease of almost three hundred percent of average concentration. In addition, the sum of all cortisol metabolites and 18-OH cortisol (indicative of oxidative stress) were lower after the metformin treatment. Furthermore, significant inhibition of 3ß-HSD activity was detectable. Discussion: Effects prior to and after the metformin treatment on inhibiting 3ß-HSD activity were detected in line with findings from others. Furthermore, the pattern of a reduction, for example, in the sum of all glucocorticoids following the metformin treatment supported an effect on oxidative stress, which was further supported by the reduction in 18-OH cortisol. Nevertheless, we do not understand all steps in the complex pattern of the enzymes that affect steroid hormone metabolism and, consequently, further studies are necessary to improve our understanding.

Light in the Rational Treatment of Autism? Effects of Metformin on Steroid Hormones in a Patient with Polycystic Ovarian Syndrome (PCOS).

Background: Metformin is an effective treatment option for type 2 diabetes mellitus, and it is, to this day, the most prescribed oral antiglycaemic drug. Besides its effects mainly on mitochondrial activity, an off-label use came up as a pharmaceutical for subjects with a diagnosis of polycystic ovarian syndrome (PCOS) along with altered steroid hormone homeostasis. Besides these effects, even an influence on mood and social behavior was described, leading to the aim of this case report to elucidate the effects before versus after treatment with metformin on steroid hormones and social behavior. Methods: A female patient with diagnosed PCOS was analyzed three times for steroid hormone levels. The first analysis was performed before treatment; the second, after a period of 71 days with metformin at 2 × 500 mg; and the third, after a total of 144 days with metformin at 2 × 500 mg. Spot urine probes were taken in the morning for a combined gas chromatography−mass spectrometry (GC-MS), and the steroid levels were adjusted for creatinine excretion. A questionnaire on social behavior (Autism Spectrum Questionnaire) was administered before treatment and after 71 days. Results: A decrease in all the steroid hormones measured was detected after 71 and 144 days of treatment with metformin, being more pronounced after 144 days of treatment and highly significant (p < 0.001). Furthermore, in the untreated state, the class of corticosterone metabolites showed increased values compared to the female reference values for TH-11-DH-corticosterone, TH-corticosterone, and 5a-TH-corticosterone. In the class of estrogen metabolites, increased values compared to the reference values were detected for 17b-estradiol; in the class of 11-deoxycortisol metabolites, an increase in TH-11-deoxycortisol was detected. For the class of cortisol metabolites, increased values compared to the reference values were detected for cortisone, TH-cortisone, a-cortolone, b-cortolone, 20b-dihydrocortisone, cortisol, TH-cortisol, 5a-TH-cortisol, a-cortol, 20b-dihydrocortisol, and 6b-OH-cortisol. No increases in androgen metabolites were detected. Interestingly, weight decreased from 93.4 kg to 91.3 kg after 71 days and fell to 82.7 kg after 144 days of treatment. The skeletal muscle mass was 30.1 kg at the first visit, decreasing to 29.9 kg and to 27.5 kg. No significant difference in the social behavior score from baseline to after 71 days of treatment was detected. Discussion: Metformin improved the steroid hormone profiles from levels above the upper reference values to the middle of the reference values after 71 days and to the lower ends of the reference values after 144 days of treatment. This implies not only that metformin has an effect on steroid hormone levels, but in addition that the efficacy of the pharmaceutical seems to depend on the time interval from intake. To summarize, in this patient, steroid hormones were affected but social behavior was not. If no effect of metformin on social behavior exists, this must be supported by further cases.

Deathly Accidents While High-Altitude Mountaineering in the Swiss Alps-An Observational Analysis from 2009 to 2021.

BACKGROUND: High-altitude mountaineering has become more and more popular. While many enjoy the beauty of the highest parts of Switzerland, there are considerable risks, which can even result in death. This study analyzed fatal events while high-altitude mountaineering in the Swiss Alps. MATERIALS AND METHODS: In this study, cases of emergencies while high-altitude mountaineering in the Swiss Alps were analyzed in the period from 2009 to 2021 from the Swiss Alpine Club (SAC) emergency registry. Fatal emergencies were identified and analyzed in detail. RESULTS: In total, 5020 emergency cases were analyzed, and among them 303 deathly events where detected. Of the fatal emergencies, 261 cases (86.1%) were male and 42 (13.9%) were female. The average age was 53.2 ± 19.1 years. More than half of the emergencies were on a route to a classic four-thousander. Fatal events were most common on the Matterhorn, with 40 cases (13.2%); on the Mönch, with 18 cases (5.9%); and on the Piz Bernina, with 10 cases (3.3%). In 245 of the fatal emergencies (80.9%), a fall was the cause. The second most prominent cause was rockfalls, with 16 cases (5.3%), followed by stranding, with 10 cases (3.3%), and avalanches, with 9 cases (3%). Illnesses and crevasse accidents counted together for less than 5% of the fatal cases. Almost two-thirds of fatal falls occurred while descending. Concerning nationality, 30% were from Switzerland and more than three-fourths of victims were from the countries of the Alps. DISCUSSION: We found that falls were the most common cause of fatal emergencies in the Swiss Alps. Concerning the fact that most of these emergencies occurred during descents, fatigue and inadequate focus (forgetting the risks of the descent after successfully reaching the peak) are potential reasons for the fatal events. This potentially resulted from a lack of acclimatization, insufficient physical fitness, and inadequate tour planning. Since most victims were from the countries of the Alps, training tours may be possible as a recommended preparation for more difficult four-thousander peaks.

Association of Gene Variants for Mechanical and Metabolic Muscle Quality with Cardiorespiratory and Muscular Variables Related to Performance in Skiing Athletes.

BACKGROUND: Skiing is a popular outdoor sport posing different requirements on musculoskeletal and cardiorespiratory function to excel in competition. The extent to which genotypic features contribute to the development of performance with years of ski-specific training remains to be elucidated. We therefore tested whether prominent polymorphisms in genes for angiotensin converting enzyme (ACE-I/D, rs1799752), tenascin-C (TNC, rs2104772), actinin-3 (ACTN3, rs1815739) and PTK2 (rs7460 and rs7843014) are associated with the differentiation of cellular hallmarks of muscle metabolism and contraction in high level skiers. MATERIAL & METHODS: Forty-three skiers of a world-leading national ski team performed exhaustive cardiopulmonary exercise testing as well as isokinetic strength testing for single contractions, whereby 230 cardiopulmonary measurements were performed in the period from 2015-2018. A total of 168 and 62 data measurements were from the Alpine and Nordic skiing squads, respectively. Ninety-five and one hundred thirty-five measurements, respectively, were from male and female athletes. The average (±SD) age was 21.5 ± 3.0 years, height 174.0 ± 8.7 cm, and weight 71.0 ± 10.9 kg for the analysed skiers. Furthermore, all skiers were analysed concerning their genotype ACE-I/D, Tenascin C, ACTN3, PTK2. RESULTS: The genotype distribution deviated from Hardy-Weinberg equilibrium for the ACTN3 genotype, where rs1815739-TT genotypes (corresponding to the nonsense mutation) were overrepresented in world-class skiers, indicating a slow muscle fibre phenotype. Furthermore, the heterozygous rs2104772-AT genotypes of TNC also demonstrated the best scaled peak power output values during ramp exercise to exhaustion. The highest values under maximum performance for heart rate were associated with the rs1799752-II and rs1815739-CC genotypes. The lowest values for peak power of single contractions were achieved for rs1815739-CC, rs1799752-II and rs7843014-CT genotypes. The skiing discipline demonstrated a main influence on cardiorespiratory parameters but did not further interact with genotype-associated variability in performance. DISCUSSION: Classically, it is pointed out that muscles of, for example, alpine skiers do not possess a distinct fibre type composition, but that skiers tend to have a preponderance of slow-twitch fibres. Consequently, our findings of an overrepresentation of ACTN3-TT genotypes in a highly selective sample of elite world class skiers support the potential superiority of a slow fibre type distribution. CONCLUSIONS: We suggest that one competitive advantage that results from a slow, typically fatigue-resistant fibre type distribution might be that performance during intense training days is better preserved, whereby simply a higher technical training volume can be performed, yielding to a competitive advantage.

Metformin-Treatment Option for Social Impairment? An Open Clinical Trial to Elucidate the Effects of Metformin Treatment on Steroid Hormones and Social Behavior.

BACKGROUND: Social behavior is mediated by steroid hormones, whereby various lines of evidence indicate that metformin might improve the symptoms of social withdrawal. This directly yields to the aim of the study to correlate the impact of metformin treatment on the potential alterations in steroid hormone homeostasis, which is ultimately impacting social behavior. Therefore, urinary samples of patients before and after treatment with metformin will be correlated to social behavior to elucidate potential changes in steroid hormone profiles and social behavior. MATERIAL AND METHODS: An observational study in healthy adults with a new indication for metformin. Steroid hormone analysis, including the most prominent androgen, estrogen, progesterone, aldosterone, corticosterone, cortisone and cortisol metabolites analyzed with gas chromatography-mass spectrometry and a questionnaire on social behavior (Autism Spectrum Questionnaire (AQ)) will be administered prior to and after around a 12-week phase of metformin treatment. DISCUSSION: It is likely that due to different pathophysiological mechanisms such as an effect on the respiratory chain in mitochondria or via AMP-activated protein kinase, a general alteration of steroid hormone levels can be detected prior to post treatment. The encompassing measurement of steroid hormones shall give hints concerning the involvement of specific cascades yielding potential pharmacological targets for future research.

Androgens Tend to Be Higher, but What about Altered Progesterone Metabolites in Boys and Girls with Autism?

Background: Evidence exists that steroid hormones are altered in individuals with autism, especially androgens. Despite lower prevalence in girls than boys, evidence of potential alterations in progesterone metabolites is sparse, so the aim of this study was to elucidate different progesterone metabolites in affected children with autism versus healthy controls. Material and Methods: Circadian urine samples from 48 boys and 16 girls with autism spectrum disorders and a matched case−control group were analysed for progesterone metabolites by gas chromatography−mass spectrometry and normalised for creatinine excretion. Results: In boys with autism, the majority of progesterone metabolites were reduced, such as progesterone, 6a-OH-3a5b-TH-progesterone, or 20a-DH-progesterone (p < 0.01 for all). In girls with autism, a similar pattern of reduction in progesterone metabolites was detected; however, potentially due to the relatively small sample, this pattern was only detectable on the level of a trend. Discussion: As stated, androgen levels are higher in boys and girls with autism, but evidence for progesterone metabolites is much sparser. The pattern of a decrease in progesterone metabolites suggests the existence of an altered routing of steroid metabolites, probably in combination with a dysregulation of the HPAG axis. As, recently, increased CYP17A1 activity has been suggested, the stronger routing towards androgens is further implied in line with our findings of lower progesterone concentrations in boys and girls with autism than healthy controls.

Lymphocytes are less sensitive to autophagy than monocytes during fasting and exercise conditions.

The concomitant investigation of apoptosis (a regulated cell death) and autophagy (a conserved cell survival mechanism) in immune cells is rare. More detailed knowledge of these two types of self-consumption in circulating lymphocytes and monocytes would be important, since conditions such as fasting and acute exercise could promote health by a coordinated/linked modulation of autophagy and apoptosis in these mononuclear cells. In this study we performed flow cytometry to quantify numbers of apoptotic and autophagic mononuclear cells, lymphocytes and monocytes in fasting, standardized fed, and exercise conditions, using Annexin V, LC3B, and p62, respectively. We show that within total mononuclear cells lymphocytes are less apoptotic and autophagic than monocytes during fasting (p < 0.001, p < 0.05, respectively) and after acute exercise (p < 0.01, p < 0.05, respectively). Fasting increased circulating autophagic monocyte concentrations, but not lymphocytes compared to the fed control condition. Acute exercise elevated circulating autophagic lymphocyte concentrations, but not monocytes. Interestingly, Western blotting analysis of the fasting samples showed that higher LC3BII/I ratios were correlated with lower numbers of autophagic mononuclear cells (r = - 0.74, p = 0.02, n = 8), which could be attributed to the monocyte subgroup, but not lymphocytes. These results extend the current knowledge of the two types of self-consumption in circulating immune cells and underline their possible importance in pro-inflammatory monocytes during fasting and exercise as health promoting interventions.

Variability in the Aerobic Fitness-Related Dependence on Respiratory Processes During Muscle Work Is Associated With the ACE-I/D Genotype.

Background: The efficiency of aerobic energy provision to working skeletal muscle is affected by aerobic fitness and a prominent insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE-I/D) gene for the major modulator of tissue perfusion. We assessed whether variability in the fitness state is dependent on the contribution of multiple aspects of oxygen transport to the development of muscle power, and the respective control coefficients, are associated with the ACE-I/D genotype. Methods: Twenty-five women and 19 men completed a ramp test of cycling exercise to exhaustion during which serial steps of oxygen transport [oxygen uptake (L O2 min-1) (VO2), minute ventilation in (L min-1) (VE), cardiac output in equivalents of L min-1 (Q), arterial oxygen saturation (SpO2), muscle oxygen saturation (SmO2), and total hemoglobin concentration (g dL-1) (THb) in Musculus vastus lateralis and Musculus gastrocnemius, respiration exchange ratio (RER)], blood lactate and glucose concentration, were continuously monitored. The contribution/reliance of power output (PO) on the parameters of oxygen transport was estimated based on the slopes in Pearson's moment correlations (|r| > 0.65, p < 0.05) vs. power values over the work phase of the ramp test, and for respective fractional changes per time (defining control coefficients) over the rest, work, and recovery phase of the ramp test. Associations of variability in slopes and control coefficients with the genotype and aerobic fitness were evaluated with ANOVA. Results: All parameters characterizing aspects of the pathway of oxygen, except THb, presented strong linear relationships [(|r| > 0.70) to PO]. Metabolic efficiency was 30% higher in the aerobically fit subjects [peak oxygen uptake (mL O2 min-1) (VO2peak) ≥ 50 ml min-1 kg-1], and energy expenditure at rest was associated with the fitness state × ACE-I/D genotype, being highest in the fit non-carriers of the ACE D-allele. For VO2, VE, and RER the power-related slopes of linear relationships during work demonstrated an association with aerobic fitness, being 30-40% steeper in the aerobically fit than unfit subjects. For VE the power-related slope also demonstrated an association with the ACE-I/D genotype. For increasing deficit in muscle oxygen saturation (DSmO2) in Musculus vastus lateralis (DSmO2 Vas), the power-related slope was associated with the interaction between aerobic fitness × ACE-I/D genotype. Conclusion: Local and systemic aspects of aerobic energy provision stand under influence of the fitness state and ACE-I/D genotype. This especially concerns the association with the index of the muscle's mitochondrial respiration (SmO2) which compares to the genetic influences of endurance training.

How Is CYP17A1 Activity Altered in Autism? A Pilot Study to Identify Potential Pharmacological Targets.

Background: Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha hydroxylase) and C17/20 lyase activity. However, to what extent steps are altered in affected children with autism versus healthy controls remains to be elucidated. Methods: Urine samples from 48 boys with autism (BMI 19.1 ± 0.6 kg/m2, age 14.2 ± 0.5 years) and a matched cohort of 48 healthy boys (BMI 18.6 ± 0.3 kg/m2, 14.3 ± 0.5 years) as well as 16 girls with autism (BMI 17.5 ± 0.7 kg/m2, age 13.8 ± 1.0 years) and a matched cohort of 16 healthy girls (BMI 17.2 ± 0.8 kg/m2, age 13.2 ± 0.8 years) were analyzed for steroid hormone metabolites by gas chromatography-mass spectrometry. Results: The activity of 17-alpha Hydroxylase increased by almost 50%, whereas activity of 17/20 Lyase activity increased by around 150% in affected children with autism. Furthermore, the concentration of Cortisol was higher as compared to the average increase of the three metabolites TH-Corticosterone, 5α-TH-Corticosterone and TH-11ß-DH-Corticosterone, indicating, in addition, a stimulation by the CRH-ACTH system despite a higher enzymatic activity. Discussion: As it was shown that oxidative stress increases the 17/20-lyase activity via p38α, a link between higher steroid hormone levels and oxidative stress can be established. However, as glucocorticoid as well as androgen metabolites showed higher values in subjects affected with autism as compared to healthy controls, the data indicate, despite higher CYP17A1 activity, the presence of increased substrate availability in line with the Cholesterol theory of autism.

Stranded because of exhaustion while high-altitude mountaineering in the Swiss Alps: a retrospective nationwide study.

Fortunately, fatal accidents while high-altitude mountaineering have decreased in recent years, but the number of emergencies has increased. These nonfatal emergencies might represent situations where alpinists are stranded (emergencies in which alpinists are no longer able to continue their tour on their own because of, for example, exhaustion, equipment problems, or weather). We analyzed 4596 cases of high-altitude-mountaineering emergencies in the period 2009 to 2020 from the SAC (Swiss Alpine Club) emergency registry. In total, 1951 cases (41.6%) were due to being stranded, 1348 cases were due to falls (28.7%), and 352 cases were due to illness (7.5%); these were the three most common classes. In cases of being stranded, 90% of alpinists were uninjured or not seriously injured. In addition, we found only eight fatal cases. More than 50% of cases occurred while ascending a summit above 4000 m. The main causes of becoming stranded were exhaustion and weather changes. These findings suggest that alpinists contact rescue organizations before experiencing serious troubles; these situations thus present risks and dangers both to those stranded and to emergency services. Since exhaustion and weather changes are the two main causes, adequate preparation and tour planning may help prevent such emergencies.

4000ers of the Alps-So beautiful, so dangerous: An analysis of falls in the Swiss Alps between 2009-2020.

BACKGROUND: This study aimed to analyze falls regarding their demographic characteristics, severity, frequency over time, and the localization of injuries while high-altitude mountaineering in the Swiss Alps. METHODS: Data on fall-related emergencies during mountaineering between 2009 to 2020 from the Swiss Alpine Club central registry were analyzed retrospectively. The variables age, sex, time of occurrence, severity of an event quantified by NACA-Score (National Advisory Committee for Aeronautics Score), and injury localization were examined descriptively. Changes in injury severity, number of total emergencies, and fatal emergencies over time were analyzed using linear regression models. RESULTS: Out of 1347 (28.7%) victims of fall-related emergencies, 1027 were men (76.2%) and 320 (23.8%) women. Around 70% of the cases happened during summer in July and August. The mean age was 49.9 ± 14.9 years for men and 51.3 ± 14.4 years for women with no between-sex difference. Higher NACA-Scores were found in men than women (3.6 ± 2.2 vs. 3.1 ± 1.6; p < 0.01). Approximately 80% of all victims originated from the countries close to the Alps (Switzerland, Germany, Italy, France, and Austria). There was a slight decrease of total cases (R2 = 0.104) and fatal cases over time (R2 = 0.183). NACA-Scores decreased over time (R2 = 0.168). Likewise, risk aversion decreased over time as the severity of emergencies decreased. Injuries occurred predominantly at the extremities (90%). Out of all cases, 228 fatal emergencies (16.9%) could be identified of which 82 occurred while climbing one of the classic 4000ers. CONCLUSIONS: The decrease of the number and severity implies that security standards of the average alpinist have in tendency increased. Nevertheless, the high number of emergencies on classic 4000ers implies that despite the potentially improved security standards, many tours on famous mountains still have high requirements in terms of alpine skills.

Cases of Lightning Strikes during Mountain-Sports Activities: An Analysis of Emergencies from the Swiss Alps.

BACKGROUND: Lightning strikes are a risk during mountain-sport activities. Yet little is known about the prevalence of injuries related to lightning strikes during mountain hiking, backcountry skiing, or high-altitude mountaineering. This study therefore examined the occurrence and characteristics of lightning-strike-related emergencies during mountain-sport activities in the Swiss Alps. METHODS: We analyzed 11,221 alpine emergencies during mountain hiking, 4687 during high-altitude mountaineering, and 3044 during backcountry skiing in the observational period from 2009 to 2020. Identified cases were analyzed in detail regarding age, sex, the time of occurrence, altitude, location, the severity of the injury as quantified by its NACA Score (National Advisory Committee for Aeronautics Score), and injury pattern. RESULTS: We found no cases related to backcountry skiing. Eight cases of lightning strikes during mountain hiking (four female and four male) were identified. The mean age was 32.5 ± 17.5 years, the mean NACA Score was 2.5 ± 1.9, and the mean altitude was 1883.8 ± 425.7 m. None of these cases were fatal, and only one victim was seriously injured. Fifteen cases were identified during high-altitude mountaineering (four female and 11 male). The mean age was 38.7 ± 5.2 years, the mean NACA Score was 3.1 ± 2.5, and the mean altitude was 3486.4 ± 614.3 m. Two lightning strikes were fatal. In these two cases, rope partners were injured by a lightning strike (NACA Score = 4). Most cases were on relatively exposed terrain, such as the Matterhorn Hörnligrat or the Eiger Mittellegigrat. DISCUSSION: The typical victims were 30-40-year-old men. It is possible that the lightning strikes are a consequence of a lower risk aversion among these alpinists, which is be supported by the fact that most of the events occurred on famous mountains such as the Matterhorn or Eiger. Furthermore, since most of the locations were on relatively exposed terrain where one could not quickly find shelter, we recommend careful tour planning with serious consultation of the weather forecast and the likelihood of thunderstorms before climbing exposed sections to prevent emergencies related to lightning strikes.

Accelerated Muscle Deoxygenation in Aerobically Fit Subjects During Exhaustive Exercise Is Associated With the ACE Insertion Allele.

Introduction: The insertion/deletion (I/D) polymorphism in the gene for the major regulator of vascular tone, angiotensin-converting enzyme-insertion/deletion (ACE-I/D) affects muscle capillarization and mitochondrial biogenesis with endurance training. We tested whether changes of leg muscle oxygen saturation (SmO2) during exhaustive exercise and recovery would depend on the aerobic fitness status and the ACE I/D polymorphism. Methods: In total, 34 healthy subjects (age: 31.8 ± 10.2 years, 17 male, 17 female) performed an incremental exercise test to exhaustion. SmO2 in musculus vastus lateralis (VAS) and musculus gastrocnemius (GAS) was recorded with near-IR spectroscopy. Effects of the aerobic fitness status (based on a VO2peak cutoff value of 50 ml O2 min-1 kg-1) and the ACE-I/D genotype (detected by PCR) on kinetic parameters of muscle deoxygenation and reoxygenation were assessed with univariate ANOVA. Results: Deoxygenation with exercise was comparable in VAS and GAS (p = 0.321). In both leg muscles, deoxygenation and reoxygenation were 1.5-fold higher in the fit than the unfit volunteers. Differences in muscle deoxygenation, but not VO2peak, were associated with gender-independent (p > 0.58) interaction effects between aerobic fitness × ACE-I/D genotype; being reflected in a 2-fold accelerated deoxygenation of VAS for aerobically fit than unfit ACE-II genotypes and a 2-fold higher deoxygenation of GAS for fit ACE-II genotypes than fit D-allele carriers. Discussion: Aerobically fit subjects demonstrated increased rates of leg muscle deoxygenation and reoxygenation. Together with the higher muscle deoxygenation in aerobically fit ACE-II genotypes, this suggests that an ACE-I/D genotype-based personalization of training protocols might serve to best improve aerobic performance.

Microvascular endothelial dysfunction in heart failure patients: An indication for exercise treatment?

BACKGROUND: Endothelial dysfunction represents a diagnostic marker to differentiate disease severity in chronic heart failure (CHF) patients. Retinal vessel phenotyping was applied in CHF patients as it has been acknowledged as a sensitive diagnostic tool to quantify microvascular health and overall cardiovascular risk. METHODS: The central retinal arteriolar (CRAE) and venular diameter equivalents (CRVE) as well as the retinal microvascular function, quantified by arteriolar (aFID) and venular flicker-light induced dilatation (vFID), were analyzed in 26 CHF patients. These data were compared with 26 age- and sex-matched healthy peers. The effects of an exercise intervention on retinal microvascular health in one CHF patient were investigated to demonstrate potentially beneficial effects of exercise treatment in a case report format as proof of concept. RESULTS: CHF patients showed narrower CRAE (170 ± 16 µm vs. 176 ± 16 µm, p = 0.237) and wider CRVE (217 ± 20 µm vs. 210 ± 17 µm, p = 0.152), resulting in a significantly lower arteriolar-to-venular diameter ratio (AVR, 0.79 ± 0.07 vs. 0.84 ± 0.06, p = 0.004) compared to controls. More strikingly, CHF patients showed significantly lower mean aFID (1.24 ± 1.14% vs. 3.78 ± 1.85%, p < 0.001) and vFID (2.89 ± 1.33% vs. 3.88 ± 1.83%, p = 0.033). Twelve weeks of exercise therapy induced wider CRAE (143 ± 1.0 µm vs. 153 ± 0.9 µm), narrower CRVE (183 ± 3.1 µm vs. 180 ± 2.4 µm) and improved aFID (0.67% vs. 1.25%) in a male 78 years old CHF patient. CONCLUSIONS: aFID is a sensitive diagnostic tool to quantify microvascular impairments in CHF patients. Exercise treatment in CHF patients has high potential to improve retinal microvascular health as a marker for vascular regeneration and overall risk reduction, which warrants further examination by randomized controlled trials.

Has Being Lost While High-Altitude Mountaineering Become Less Frequent? A Retrospective Analysis from the Swiss Alps.

BACKGROUND: High-altitude mountaineering is becoming more popular. Despite technical developments such as global positioning systems, mountaineers still lose their way. This study aimed to analyze characteristics of alpinists that lost their way while high-altitude mountaineering in Switzerland. MATERIAL AND METHODS: Data from the central registry of the Swiss Alpine Club between 2009 and 2020 were retrospectively analyzed. Changes in the number of cases and severity of injuries over time were examined using simple linear regression models. Descriptive analyses were performed for age, time of emergency occurrence, and factors associated with being lost. The Mann-Whitney U test assessed between-sex comparisons. RESULTS: Of the 4596 emergency cases during the observation period, 275 cases (5.9%) were due to being lost (76.4% male). A mean of 22.9 ± 9.6 cases per year was detected. The number of cases did not change significantly over time. Similarly, this was the case for the NACA-Score (National Advisory Committee for Aeronautics Score) with the majority of mountaineers remaining uninjured (77.8%). The median age was 42 (35-54) years for the full sample and 45 (35-56) years and 40 (33-48) years for males and females, respectively. Fog or weather changes, exhaustion, and inadequate tour planning (time and darkness) were frequently documented by rescuers as perceived reasons for being lost. Regarding the time of emergency occurrence, three peaks were detected, around 10 am, 5 pm, and 8 pm. CONCLUSIONS: Our findings show that the number of emergencies due to being lost was stable during the 12-year period. Furthermore, we presented factors that might be associated with losing one's way during mountaineering. These results may form an important basis for future studies determining risk factors for being lost and the prevention of such emergencies.