[The upper airway in obstructive sleep apnea patients is pathological even when awake]. / Der obere Atemweg bei OSA-Patienten ist auch im Wachzustand pathologisch.

Obstructive sleep apnea (OSA) is characterized by partial or complete obstruction of the pharyngeal airway. Anatomical factors can be distinguished from non-anatomical factors. Age and obesity are the main risk factors for OSA; however, approximately 50% of patients are not obese. In older patients (>60 years), the importance of obesity decreases. There is an increased prevalence of OSA among patients with normal weight. The effects of chronic intermittent hypoxemia, low-grade inflammation, increased sympathetic tone and mechanical stress contribute to a transformation of muscle fibers in the upper airway, resulting in reduced muscle mass and strength. Less frequently encountered non-anatomical factors include decreased muscle tone, increased arousal threshold, and altered sensitivity of CO2 chemoreceptors.

[The search for the "node of life": breathing regulation]. / Die Suche nach dem "Knoten des Lebens" ­ die Atemregulation.

The article provides a historical overview of developments in the understanding of respiratory rhythm and its control mechanisms over the last two centuries. In the 19th century, a structure in the medulla oblongata was first described as the "node of life". In 1743, Taube discovered the carotid body, and in 1927 the Spaniard de Castro described its morphology and innervation. It was only with the work of father and son Heymans that the physiological and pharmacological significance of the carotid and aortic body was recognized. Today we understand that the generation and control of respiration are mediated by a complex neuronal network in the brainstem. Chemo-, mechano- and proprioreceptos convey information from blood, airways and muscles to the control centre. The respiratory centre integrates the afferent input from the receptors, the autonomic nervous system, the cardiovascular system, and voluntary input from the cerebral cortex to modulate the degree of respiratory activation of motoneurons and respiratory muscles.

Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice.

Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1ß in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1ß decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B).

[Langhans' or Langerhans' cells? - The problem of the eponym]. / Langhans'sche oder Langerhans'sche Zellen? ­ Das Problem des Eponyms.

There is frequent confusion between Theodor Langhans (1839-1915) and Paul Langerhans (1847-1888) in the literature. Theodor Langhans was a German pathologist who discovered and described the "giant cells" with nuclei close to the outer membrane of the tubercles. Today, these cells are called "Langhans' giant cells". The eponym "Langerhans' cells" refers to dendritic cells in the stratum spinosum of the epidermis. Paul Langerhans described these cells for a competition organised by the Berlin Medical Faculty when he was still a student. Most doctors know Paul Langerhans through the first description of the "Langerhans' islet cells" of the pancreas. Langerhans died of tuberculosis at the age of 40 after a long exile on the island of Madeira.

[The bronchial arteries: a small but vital contribution to lung perfusion after lung transplantation]. / Die Bronchialarterien ­ ein kleiner, aber lebenswichtiger Beitrag zur Lungenperfusion nach Lungentransplantation.

Blood supply to the lungs is carried out by the pulmonary and bronchial-arterial system. The bronchial-arterial vessels are involved in supplying the small airways all the way up to the terminal bronchioles. The bronchial-arterial system is also necessary for the regulation of airway temperature, humidity and mucociliary clearance. Chronic ischaemia of the small airways due to damage or injury to bronchial arterial supply increases the risk of fibrosis of the small airways (bronchiolitis obliteration), especially in lung transplantation (LTx). Although survival after LTx has improved over time, it is, with a 5-year survival rate of only 50 to 60%, still significantly worse than that of other organ transplants. It is likely that bronchial arterial revascularisation at the time of LTx plays an important transplant-preserving function.

Inflammation and Wasting of Skeletal Muscles in Kras-p53-Mutant Mice with Intraepithelial Neoplasia and Pancreatic Cancer-When Does Cachexia Start?

Skeletal muscle wasting critically impairs the survival and quality of life in patients with pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting, we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism and capillarization, as well as the integrity of neuromuscular junctions (NMJ, pre-/postsynaptic co-staining) and mitochondria (electron microscopy) in the hindlimb muscle of LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre mice with intraepithelial-neoplasia (PanIN) 1-3 and PDAC, compared to wild-type mice (WT). Significant decreases in fiber CSA occurred with PDAC but not with PanIN 1-3, compared to WT: These were found in the gastrocnemius (type 2x: −20.0%) and soleus (type 2a: −21.0%, type 1: −14.2%) muscle with accentuation in the male soleus (type 2a: −24.8%, type 1: −17.4%) and female gastrocnemius muscle (−29.6%). Significantly higher densities of endomysial CD68+ and cyclooxygenase-2+ (COX2+) cells were detected in mice with PDAC, compared to WT mice. Surprisingly, CD68+ and COX2+ cell densities were also higher in mice with PanIN 1-3 in both muscles. Significant positive correlations existed between muscular and hepatic CD68+ or COX2+ cell densities. Moreover, in the gastrocnemius muscle, suppressor-of-cytokine-3 (SOCS3) expressions was upregulated >2.7-fold with PanIN 1A-3 and PDAC. The intracellular pools of proteinogenic amino acids and glutathione significantly increased with PanIN 1A-3 compared to WT. Capillarization, NMJ, and mitochondrial ultrastructure remained unchanged with PanIN or PDAC. In conclusion, the onset of fiber atrophy coincides with the manifestation of PDAC and high-grade local (and hepatic) inflammatory infiltration without compromised microcirculation, innervation or mitochondria. Surprisingly, muscular and hepatic inflammation, SOCS3 upregulation and (proteolytic) increases in free amino acids and glutathione were already detectable in mice with precancerous PanINs. Studies of initial local triggers and defense mechanisms regarding cachexia are warranted for targeted anti-inflammatory prevention.

[The Road to Discovery of the Pulmonary Gas Exchange - From the "Phlogiston-" to the "Oxygen Theory"]. / Der Weg zur Entdeckung des pulmonalen Gasaustausches.

The discovery of oxygen and pulmonary gas exchange was a major advancement in our understanding of breathing. For centuries it was believed that the lungs were primarily necessary to cool the heart or to "refine" the blood. Richard Lower (1631-1691) observed that the blood had a different colour before and after passage through the lung. His assumption was that breathing must have been added a special substance to the blood. Georg Ernst Stahl (1660-1734) formulated a fire substance "phlogiston" (phlox = flame) with his phlogiston theory. He postulated that phlogiston is contained in all combustible substances and escapes when burned. John Mayow (1641-1679) recognised that about one fifth of the breathing gas is important for the breathing process. He called the gas "spiritus nitro aerius". Oxygen was first discovered in the early 1770 s by the Swedish-German pharmacist Carl Wilhelm Scheele (1742-1786) and the English chemist Joseph Priestley (1733-1804) - independently of each other. Antoine-Laurent Lavoisier (1743-1794) recognised oxygen as element and for the first time described the oxidation process accurately.

Predisposing factors of daytime sleepiness in obese OSA patients.

Excessive daytime sleepiness is a common symptom in obese patients with obstructive sleep apnea. We investigated predisposing factors of excessive daytime sleepiness by comparing obese non-sleepy with sleepy patients with obstructive sleep apnea. Excessive daytime sleepiness was determined by the Epworth Sleepiness Scale in 43 patients (34 men and 9 women) with obstructive sleep apnea (apnea-hypopnea index ≥ 15 events per hr) and obesity (body mass index ≥ 30 kg m-2 ). Two subgroups were formed with (Epworth Sleepiness Scale ≥ 11) and without (Epworth Sleepiness Scale < 11) excessive daytime sleepiness. The concept of excessive daytime sleepiness was compared with other established daytime performance tests (Stanford Sleepiness Scale, Multiple Sleep Latency Test, Pupillographic Sleepiness Test, Marburger Vigilance test). Associations were calculated between excessive daytime sleepiness and demographic, metabolic and polysomnographic data. We included 19 sleepy patients (mean Epworth Sleepiness Scale score 15.2) and 24 non-sleepy patients (mean Epworth Sleepiness Scale score 5.8). Epworth Sleepiness Scale was negatively correlated with age and morning cortisol. Epworth Sleepiness Scale was positively correlated with body mass index, Stanford Sleepiness Scale, Beck's Depression Inventory and Marburger Vigilance test. Sleepy obese patients were significantly younger (mean 49.1 years), showed lower morning cortisol level (mean 9.41 µg L-1 ) and a trend to higher body mass index (mean 37.5 kg m- ²) compared with non-sleepy obese patients (mean: 59.3 years, 5.7 µg L-1 , 34.6 kg m- ², respectively). Many different excessive daytime sleepiness phenotypes are probably enclosed in obese patients with obstructive sleep apnea. Epworth Sleepiness Scale scores were best reflected by the objective Marburger Vigilance test results. The objective test can be particularly useful in cohorts where subjective reports are unreliable and operational readiness is paramount. Sleepy and non-sleepy obese patients with obstructive sleep apnea were similar in all polysomnographic parameters. Sleepy patients were younger, heavier and showed lower morning cortisol levels than non-sleepy patients.

Determining factors for compensatory movements of the left arm and shoulder in violin playing.

Introduction: Despite a large number of available ergonomic aids and recommendations regarding instrument positioning, violin players at any proficiency level still display a worrying incidence of task-specific complaints of incompletely understood etiology. Compensatory movement patterns of the left upper extremity form an integral part of violin playing. They are highly variable between players but remain understudied despite their relevance for task-specific health problems. Methods: This study investigated individual position effects of the instrument and pre-existing biomechanical factors likely determining the degree of typical compensatory movements in the left upper extremity: (1) left elbow/upper arm adduction ("Reference Angle α", deviation from the vertical axis), (2) shoulder elevation ("Coord x", in mm), and (3) shoulder protraction ("Coord y", in mm). In a group of healthy music students (N = 30, 15 m, 15 f, mean age = 22.5, SD = 2.6), "Reference Angle α" was measured by 3D motion capture analysis. "Coord x" and "Coord y" were assessed and ranked by a synchronized 2D HD video monitoring while performing a pre-defined 16-s tune under laboratory conditions. These three primary outcome variables were compared between four typical, standardized violin positions varying by their sideward orientation ("LatAx-CSP") and/or inclination ("LoAx-HP") by 30°, as well as the players' usual playing position. Selected biomechanical hand parameter data were analyzed as co-factors according to Wagner's Biomechanical Hand Measurement (BHM). Results: Mean "Reference Angle α" decreased significantly from 24.84 ± 2.67 to 18.61 ± 3.12° (p < 0.001), "Coord x" from 22.54 ± 7.417 to 4.75 ± 3.488 mm (p < 0.001), and "Coord y" from 5.66 ± 3.287 to 1.94 ± 1.901) mm (p < 0.001) when increasing LatAx-CSP and LoAx-HP by 30°. Concerning the biomechanical co-factors, "Reference Angle α", "Coord y", but not "Coord x", were found to be significantly increased overall, with decreasing passive supination range (r = -0.307, p = <0.001 for "Passive Supination 250 g/16Ncm", and r = -0.194, p = <0.001 for "Coord y"). Compensatory movements were larger during tune sections requiring high positioning of the left hand and when using the small finger. Discussion: Results may enable to adapt individually suitable instrument positions to minimize strenuous and potentially unhealthy compensation movements of the left upper extremity.

[Salerno, the first medical school in Europe - Birthplace of university medicine]. / Salerno, die erste Medizinschule Europas ­ Die Geburtsstätte der Hochschulmedizin.

Salerno in southern Italy is regarded as the birthplace of modern European university medicine. A practical and scientifically oriented medical discipline developed from monastic and monastery medicine. The Salernitan school, which considered itself as "Civitas Hippocratica", was based initially on the traditions of Hippocrates, the Alexandrian doctors and Galen. In the 11th century a new era began with Constantinus Africanus, who translated the scripts of Greco-Arabic medicine into Latin. By the 12th century, nearly the entire literature by Aristotle, Hippocrates, Galen, Avicenna and Rhazes was available in Latin. Salerno became an important medical training centre - for women and men - with a fixed course curriculum and provided a public health system. Medical training was firmly established under Emperor Friedrich II who placed it under state supervision.

Muscle Activation and Subjectively Perceived Effort in Typical Violin Positions.

Violinists display a high incidence of task-specific musculoskeletal problems. Sources pertaining to violin playing and teaching traditions as well as musicians' medicine research offer only imprecise and contradictory recommendations regarding suitable instrument positions. The aim of this study was to add to a growing scientific base for teaching and medical counseling regarding violin positioning. The study evaluated muscle activation (EMG) and subjectively perceived effort (Borg scale) in four standardized typical violin positions, as well as the violinists' normally used one. The hypothesis, the smaller the angle between the instrument's longitudinal axis (LoAx) and the player's central sagittal plane (CSP) and the angle between its lateral axis (LatAx) and the player's horizontal plane (HP), the more muscle activation and perceived effort in the violinist's left arm, was confirmed: Decreasing the LoAx-CSP angle from 50° to 20° and the LatAx-HP angle from 50° to 20° resulted in a highly significant and independent increase of EMG and Borg scale self-ratings mean values. Results may allow for a first step in decision-making on violin positioning for ergonomic adaptations in teaching as well as prevention and therapy of playing-related health problems at all levels of proficiency.

The Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Therapy on Skeletal Muscle Lipid Content in Obese and Nonobese Men.

Obstructive sleep apnea (OSA), independently of obesity (OBS), predisposes to insulin resistance (IR) for largely unknown reasons. Because OSA-related intermittent hypoxia triggers lipolysis, overnight increases in circulating free fatty acids (FFAs) including palmitic acid (PA) may lead to ectopic intramuscular lipid accumulation potentially contributing to IR. Using 3-T-1H-magnetic resonance spectroscopy, we therefore compared intramyocellular and extramyocellular lipid (IMCL and EMCL) in the vastus lateralis muscle at approximately 7 am between 26 male patients with moderate-to-severe OSA (17 obese, 9 nonobese) and 23 healthy male controls (12 obese, 11 nonobese). Fiber type composition was evaluated by muscle biopsies. Moreover, we measured fasted FFAs including PA, glycated hemoglobin A1c, thigh subcutaneous fat volume (ScFAT, 1.5-T magnetic resonance tomography), and maximal oxygen uptake (VO2max). Fourteen patients were reassessed after continuous positive airway pressure (CPAP) therapy. Total FFAs and PA were significantly (by 178% and 166%) higher in OSA patients vs controls and correlated with the apnea-hypopnea index (AHI) (r ≥ 0.45, P < .01). Moreover, IMCL and EMCL were 55% (P < .05) and 40% (P < .05) higher in OSA patients, that is, 114% and 103% in nonobese, 24.4% and 8.4% in obese participants (with higher control levels). Overall, PA, FFAs (minus PA), and ScFAT significantly contributed to IMCL (multiple r = 0.568, P = .002). CPAP significantly decreased EMCL (-26%) and, by trend only, IMCL, total FFAs, and PA. Muscle fiber composition was unaffected by OSA or CPAP. Increases in IMCL and EMCL are detectable at approximately 7 am in OSA patients and are partly attributable to overnight FFA excesses and high ScFAT or body mass index. CPAP decreases FFAs and IMCL by trend but significantly reduces EMCL.

[From the anatomical teaching dissection to tuition at the bedside-A historical appraisal]. / Von der anatomischen Lehrsektion zum Unterricht am Krankenbett ­ eine geschichtliche Würdigung.

At all times anatomists endeavored to procure scientific foundations for medicine. The anatomist dissected corpses in order to serve the living. The knowledge of anatomy is a prerequisite for the understanding of physiological and pathophysiological processes. In the "Hippocratic corpus" there is no clear reference to the performance of human autopsies. Anatomy was taught on a human corpse for the first time in Alexandria around 300 B.C. For more than 1300 years anatomy and medicine then stood under the influence of Galen of Pergamon (131-201 A.D.). The Italian Mondino dei Luzzi (1275-1326) was the first to introduce systematic anatomy lessons with a regular inclusion of teaching dissections in the teaching curriculum in Bologna. Andreas Vesalius (1514-1564) from Belgium founded the scientifically based human anatomy during the modern era and corrected many errors in the traditional views on anatomy of Galen. In the seventeenth and eighteenth centuries the Dutch universities, particularly the University of Leiden, were the leaders with respect to the clinical and practical student training.

High Plasma Cystine Levels Are Associated with Blood Pressure and Reversed by CPAP in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) independent of obesity (OBS) imposes severe cardiovascular risk. To what extent plasma cystine concentration (CySS), a novel pro-oxidative vascular risk factor, is increased in OSA with or without OBS is presently unknown. We therefore studied CySS together with the redox state and precursor amino acids of glutathione (GSH) in peripheral blood mononuclear cells (PBMC) in untreated male patients with OSA (apnea-hypopnea-index (AHI) > 15 h-1, n = 28) compared to healthy male controls (n = 25) stratifying for BMI ≥ or < 30 kg m-2. Fifteen OSA patients were reassessed after 3-5-months CPAP. CySS correlated with cumulative time at an O2-saturation <90% (Tu90%) (r = 0.34, p < 0.05) beside BMI (r = 0.58, p < 0.001) and was higher in subjects with "hypoxic stress" (59.4 ± 2.0 vs. 50.1 ± 2.7 µM, p < 0.01) defined as Tu90% ≥ 15.2 min (corresponding to AHI ≥ 15 h-1). Moreover, CySS significantly correlated with systolic (r = 0.32, p < 0.05) and diastolic (r = 0.31, p < 0.05) blood pressure. CPAP significantly lowered CySS along with blood pressure at unchanged BMI. Unexpectedly, GSH antioxidant capacity in PBMC was increased with OSA and reversed with CPAP. Plasma CySS levels are increased with OSA-related hypoxic stress and associated with higher blood pressure. CPAP decreases both CySS and blood pressure. The role of CySS in OSA-related vascular endpoints and their prevention by CPAP warrants further studies.

[Historical (cultural) view of the heart and cardiovascular system]. / Herz und Herz-Kreislauf-System in der (kultur-)historischen Betrachtung.

Who discovered the cardiovascular and capillary systems? When students in advanced semesters are asked about historical matters that have decisively influenced the path to present day medicine, as a rule no answer or a false answer is forthcoming. Whoever wants to understand scientific thinking and action, cannot do better than to grapple with the historical and cultural developments in medicine; however, more than any other science the natural sciences and medicine provide evidence that new ways and knowledge must be consistently sought for the benefit of patients. The aim of this article is to make a contribution to remembering how the cardiovascular system was discovered and the cultural and historical importance of the heart. Last but not least, however, the article aims to convey the impression of the huge personal sacrifice, including one's own life, and the stony path which led to the acquisition of this knowledge.

No renal dysfunction or salt and water retention in acute mountain sickness at 4,559 m among young resting males after passive ascent.

This study examined the role and function of the kidney at high altitude in relation to fluid balance and the development of acute mountain sickness (AMS), avoiding confounders that have contributed to conflicting results in previous studies. We examined 18 healthy male resting volunteers (18-40 yr) not acclimatized to high altitude while on a controlled diet for 24 h at Lausanne (altitude: 560 m) followed by a period of 44 h after reaching the Regina Margherita hut (4,559 m) by helicopter. AMS scores peaked after 20 h at 4,559 m. AMS was defined as functional Lake Louise score ≥ 2. There were no significant differences between 10 subjects with and 8 subjects without AMS for urinary flow, fluid balance, and weight change. Sodium excretion rate was lower in those with AMS after 24 h at altitude. Microalbuminuria increased at altitude but was not different between the groups. Creatinine clearance was not affected by altitude or AMS, whereas clearances of sinistrin and p-aminohippuric acid decreased slightly, somewhat more in those without AMS. Plasma concentrations of epinephrine, norepinephrine, atrial natriuretic factor, and vasopressin increased whereas renin activity, angiotensin, and aldosterone decreased at altitude. Circulating hormone concentrations did not differ between those with and without AMS. Summarizing, in healthy resting young men flown by helicopter to 4,559 m, renal function was not affected by hypoxia except for minor microalbuminuria, high altitude diuresis did not occur, and AMS was not associated with salt and water retention or renal dysfunction.NEW & NOTEWORTHY Kidney function remained essentially unaffected and acute mountain sickness (AMS) was not associated with salt and water retention in healthy young men flown to and resting at the Margherita hut (4,559 m) under strictly controlled conditions maintaining water, salt, and food intake at pre-exposure levels. Thus, renal dysfunction and fluid retention are not essential factors contributing to the pathophysiology of AMS.

Age-related differences in skeletal muscle microvascular response to exercise as detected by contrast-enhanced ultrasound (CEUS).

BACKGROUND: Aging involves reductions in exercise total limb blood flow and exercise capacity. We hypothesized that this may involve early age-related impairments of skeletal muscle microvascular responsiveness as previously reported for insulin but not for exercise stimuli in humans. METHODS: Using an isometric exercise model, we studied the effect of age on contrast-enhanced ultrasound (CEUS) parameters, i.e. microvascular blood volume (MBV), flow velocity (MFV) and blood flow (MBF) calculated from replenishment of Sonovue contrast-agent microbubbles after their destruction. CEUS was applied to the vastus lateralis (VLat) and intermedius (VInt) muscle in 15 middle-aged (MA, 43.6±1.5 years) and 11 young (YG, 24.1±0.6 years) healthy males before, during, and after 2 min of isometric knee extension at 15% of peak torque (PT). In addition, total leg blood flow as recorded by femoral artery Doppler-flow. Moreover, fiber-type-specific and overall capillarisation as well as fiber composition were additionally assessed in Vlat biopsies obtained from CEUS site. MA and YG had similar quadriceps muscle MRT-volume or PT and maximal oxygen uptake as well as a normal cardiovascular risk factors and intima-media-thickness. RESULTS: During isometric exercise MA compared to YG reached significantly lower levels in MFV (0.123±0.016 vs. 0.208±0.036 a.u.) and MBF (0.007±0.001 vs. 0.012±0.002 a.u.). In the VInt the (post-occlusive hyperemia) post-exercise peaks in MBV and MBF were significantly lower in MA vs. YG. Capillary density, capillary fiber contacts and femoral artery Doppler were similar between MA and YG. CONCLUSIONS: In the absence of significant age-related reductions in capillarisation, total leg blood flow or muscle mass, healthy middle-aged males reveal impaired skeletal muscle microcirculatory responses to isometric exercise. Whether this limits isometric muscle performance remains to be assessed.

Enriching a protein drink with leucine augments muscle protein synthesis after resistance exercise in young and older men.

Maximizing anabolic responses to feeding and exercise is crucial for muscle maintenance and adaptation to exercise training. We hypothesized that enriching a protein drink with leucine would improve anabolic responses to resistance exercise (RE: 6 × 8 knee-extension repetitions at 75% of 1-RM) in both young and older adults. Groups (n = 9) of young (24 ± 6 y, BMI 23 ± 2 kg m-2) and older men (70 ± 5 y, BMI 25 ± 2 kg m-2) were randomized to either: (i) RE followed by Slim-Fast Optima (SFO 10 g PRO; 24 g CHO) with 4.2 g of leucine (LEU) or, (ii) RE + SFO with 4.2 g of alanine (ALA; isonitrogenous control). Muscle biopsies were taken before, immediately after, and 1, 2 and 4 h after RE and feeding. Muscle protein synthesis (MPS) was measured by incorporation of [1, 2-13C2] leucine into myofibrillar proteins and the phosphorylation of p70S6K1 by immunoblotting. In young men, both area under the curve (AUC; FSR 0-4 h P < 0.05) and peak FSR (0.11 vs. 0.08%.h.-1; P < 0.05) were greater in the SFO + LEU than in the SFO + ALA group, after RE. Similarly, in older men, AUC analysis revealed that post-exercise anabolic responses were greater in the SFO + LEU than SFO + ALA group, after RE (AUC; FSR 0-4 h P < 0.05). Irrespective of age, increases in p70S6K1 phosphorylation were evident in response to both SFO + LEU and SFO + ALA, although greater with leucine supplementation than alanine (fold-change 2.2 vs. 3.2; P < 0.05), specifically in the older men. We conclude that addition of Leucine to a sub-maximal PRO bolus improves anabolic responses to RE in young and older men.

Lower hypoxic ventilatory response in smokers compared to non-smokers during abstinence from cigarettes.

BACKGROUND: Carotid body O2-chemosensitivity determines the hypoxic ventilatory response (HVR) as part of crucial regulatory reflex within oxygen homeostasis. Nicotine has been suggested to attenuate HVR in neonates of smoking mothers. However, whether smoking affects HVR in adulthood has remained unclear and probably blurred by acute ventilatory stimulation through cigarette smoke. We hypothesized that HVR is substantially reduced in smokers when studied after an overnight abstinence from cigarettes i.e. after nicotine elimination. METHODS: We therefore determined the isocapnic HVR of 23 healthy male smokers (age 33.9 ± 2.0 years, BMI 24.2 ± 0.5 kg m-2, mean ± SEM) with a smoking history of >8 years after 12 h of abstinence and compared it to that of 23 healthy male non-smokers matched for age and BMI. RESULTS: Smokers and non-smokers were comparable with regard to factors known to affect isocapnic HVR such as plasma levels of glucose and thiols as well as intracellular levels of glutathione in blood mononuclear cells. As a new finding, abstinent smokers had a significantly lower isocapnic HVR (0.024 ± 0.002 vs. 0.037 ± 0.003 l min-1 %-1BMI-1, P = 0.002) compared to non-smokers. However, upon re-exposure to cigarettes the smokers' HVR increased immediately to the non-smokers' level. CONCLUSIONS: This is the first report of a substantial HVR reduction in abstinent adult smokers which appears to be masked by daily smoking routine and may therefore have been previously overlooked. A low HVR may be suggested as a novel link between smoking and aggravated hypoxemia during sleep especially in relevant clinical conditions such as COPD.

Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status.

BACKGROUND: Elevated total plasma homocysteine (tHcy) is considered to be an independent cardiovascular disease risk factor, although tHcy lowering by B-vitamins improves only certain clinical endpoints. N-acetylcysteine (NAC), a thiol-containing antioxidant, acutely lowers tHcy and possibly also blood pressure. However, to our knowledge, at present no conclusive long-term evaluation exists that controls for factors such as hyperlipidemia, smoking, medication, and disease stage, all of which affect the thiol redox state, including tHcy. OBJECTIVE: We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers. DESIGN: We evaluated the effect of 4 wk of oral NAC (1.8 g/d) on tHcy (primary endpoint), plasma thiol (cysteine), and intracellular glutathione concentrations as well as on blood pressure. The HYL group had total cholesterol >220 mg/dL or triglycerides >150 mg/dL. RESULTS: NAC treatment significantly (P = 0.001, multivariate analysis of variance for repeated measures) lowered postabsorptive plasma concentrations of tHcy by -11.7% ± 3.0% (placebo: 4.1% ± 3.6%) while increasing those of cysteine by 28.1% ± 5.7% (placebo: 4.0% ± 3.4%) with no significant impact of hyperlipidemia or smoking. Moreover, NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008) but not in the NOL group. An explorative stepwise multiple regression analysis identified 1) post-treatment cysteine as well as 2) pretreatment tHcy and 3) albumin plasma concentrations as being significant contributors to tHcy reduction. CONCLUSIONS: Four weeks of oral NAC treatment significantly decreased plasma tHcy concentrations, irrespective of lipid or smoking status, and lowered systolic blood pressure in both normolipidemic and hyperlipidemic men, with significant diastolic blood pressure reductions in the HYL group only. Increased oral intake of cysteine may therefore be considered for primary or secondary prevention of vascular events with regard to the 2 independent risk factors of hyperhomocysteinemia and arterial hypertension.