[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.

Acoustic Monitoring of Night-Time Respiratory Symptoms in 14 Patients with Exacerbated COPD Over a 3- Week Period.

Introduction: In clinical practice, wheezing and coughing represent a worsening of the respiratory situation of COPD patients and should be monitored long-term during and after an Acute Exacerbation of COPD (AECOPD) to observe the therapy. We investigated if overnight monitoring of wheezing and coughing is feasible during AECOPD and whether automatic long - term monitoring enables an objective assessment during and after an AECOPD. Methods: In 14 patients (age: 56-80 years) with pre-existing COPD (stages B-D) nighttime wheezing and coughing events were monitored for a period of three weeks. The portable LEOSound® monitor recorded three nights into AECOPD (nights 1, 3 and 6) during the hospital stay, and the 20th night post- AECOPD ambulatory. Before each recording the subjective symptom severity was assessed by a COPD Assessment Test (CAT) and a Modified British Medical Research Council (MMRC) dyspnoea index questionnaire. Results: In all 14 patients, lung sounds were recorded in good quality during each of the 4 recording nights. Wheezing ranged between 5% and 90% (79 -539.5 minutes) of the recording time on the first night. All patients showed some coughs, in four patients coughing was particularly pronounced and largely receding over the total investigation period. As group, the percentages of wheezing and the number of coughs did not show significant differences between the four recording times. The CAT scores (p<0.001) declined over the course of investigation period, suggesting a subjective improvement of symptoms. Conclusion: The observational study showed that standardized long-term recording can be performed in high-quality during acute COPD exacerbation as it does not require the patient's cooperation. The good-quality data of coughs and wheezing were analyzed qualitatively and quantitatively. The long-term presentation of respiratory symptoms during an AECOPD offers the opportunity to evaluate factors that influence exacerbations and therapeutic approaches.

[Franciscus Sylvius: A Life for Clinic, Research, Teaching And a Little Gin]. / Franciscus Sylvius: Ein Leben für Klinik, Forschung, Lehre und ein bisschen Gin.

Franciscus Sylvius, latinized from Franz de le Boë (*15 March 1614 in Hanau; † 14 November 1672 in Leiden), was a Hessian-Dutch physician, anatomist, and natural scientist of Flemish descent. He was an important clinician and iatrochemist, and is considered the founder of scientifically oriented medicine and clinical chemistry. Sylvius introduced the concept of affinity and dealt with digestive processes and body fluids. He was one of the leading exponents of the concept of blood circulation developed by William Harvey. As the person responsible for practical medicine in Leiden, Sylvius established bedside teaching as part of the medical curriculum, and he introduced his students to clinical medicine in an experimental way, both contrary to the rules of the time. He was also interested in pharmacology, herbalism and botany. For heartburn and digestive disorders, Sylvius mixed juniper berries, herbs and alcohol to create a medicine. According to legend, Sylvius marketed this medicine as Genever, for which the name Gin was later adopted in the British Isles, but not only used for medical purposes. Accordingly, the city of birth of Sylvius today calls itself a "birthplace of gin".

Disease control in patients with asthma and respiratory symptoms (wheezing, cough) during sleep.

INTRODUCTION: The Global Initiative for Asthma (GINA)-defined criteria for asthma control include questions about daytime symptoms, limitation of activity, nocturnal symptoms, need for reliever treatment and patients' satisfaction. Patients with nocturnal symptoms like wheezing and cough often suffer from lower sleep quality and impaired daytime performance. The lack of an appropriate method for standardized and objective monitoring of respiratory symptoms leads to difficulties in asthma management. The aim of this study is to present a new method for automated wheeze and cough detection during sleep and to assess the actual level of asthma control by the Asthma Control Test (ACT). METHODS: Respiratory symptoms like wheezing and cough were recorded with the LEOSound-Monitor for one night in 55 asthmatic patients in their individual domestic setting. Patients were asked to assess their level of asthma subjectively with the ACT. The study consisted of 37 women and 18 men, with a mean age of 41 years, and a mean BMI of 27 kg/m2. Most of the patients had been taking an ICS/LABA combination and would resort to a SABA as their rescue medication. RESULTS: 60% of the participants were classed as having controlled, and 40% were classed as having partially- or uncontrolled asthma. During sleep wheezing was found in 8 of the 55 asthma patients (14.5%) and coughing was found in 30 patients (54.5%). The median ACT score in wheezing-patients was 14, while in non-wheezing patients it was 21. Uncontrolled asthma was found in 6 of the 8 wheezing-patients. Coughing versus non-coughing patients did not show a significant difference in the ACT-score (20, 22 respectively). CONCLUSION: Wheezing is a sign of uncontrolled asthma. The ACT-score in wheezing patients is worse compared to patients without wheezing. LEOSound proofed to be a useful tool in providing an objective evaluation of respiratory symptoms, like coughing and wheezing. In clinical practice, this may allow an improvement in asthma therapy.

[Maurice Raynaud (1834-1881) and the Mystery of "Raynaud's Phanomenon"]. / Maurice Raynaud (1834­1881) und das Mysterium "Raynaud-Phänomen".

Maurice Raynaud first described color changes and symptoms of the fingers due to cold-induced vasospasm and restricted blood flow in his medical school thesis in 1862. Raynaud's phenomenon is common and exists as an uncomplicated primary Raynaud phenomenon and a Raynaud phenomenon secondary to underlying diseases and medication. Mechanisms contributing to altered vasoconstrictor activity are endothelial and not-endothelial. Cold-induced vasospasm is probably a thermoregulatory problem and effects are mediated by sympathetic activity and selective stimulation of alpha2c-adrenoreceptors.

Alpha-synuclein levels in blood plasma decline with healthy aging.

There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001), possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.

Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer's Disease: Results of the DIAN Study.

OBJECTIVE: We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer's disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). METHODS: The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. RESULTS: At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. CONCLUSIONS: The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.

Altered serum IgG levels to α-synuclein in dementia with Lewy bodies and Alzheimer's disease.

Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against α-synuclein is not well known. We explored serum IgG levels to monomeric α-synuclein in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-α-synuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against α-synuclein in DLB and AD, which may relate to a disturbed α-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target α-synuclein in neurodegenerative disease.

No differences of butyrylcholinesterase protein activity and allele frequency in Lewy body diseases.

Butyrylcholinesterase (BChE) genotypes and protein (BuChE) activity, especially in combination with Apolipoprotein E4 (ApoE4), have been investigated as risk factors for developing Alzheimer disease (AD) and may be associated with the rate of progression of cognitive decline. Despite similar pathologic (e.g. amyloid deposition) and neurochemical (e.g. cholinergic deficits) aspects between AD and Lewy body diseases (LBD), scarce data is obtainable about BChE genotypes and BuChE activity in LBD. We measured BuChE activity levels in serum and cerebrospinal fluid (CSF) of 114 LBD subjects (59 of them were demented) and 31 elderly controls. We found higher CSF BuChE activity in males compared to females, and a negative correlation of serum BuChE activity with age and cognitive function. Demented LBD patients, non-demented LBD patients and controls did not differ significantly with regard to serum and CSF BuChE activity. Furthermore, BChE K variant and ApoE4 allele frequencies were determined. The BChE K variant was significantly associated with lower serum activity; the same trend was observable in CSF. The subgroups did not differ significantly with regard to BChE K/ApoE4 occurrence. These data confirm and extend previous results on the relationship between BChE gene and BuChE activity, and argue rather against a major impact of BuChE on LBD-associated pathologies.

Up-regulation of platelet-derived growth factor by peripheral-blood leukocytes during experimental allergic encephalomyelitis.

In multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), clinical disease is associated with infiltration of the central nervous system (CNS) by immune cells. Subsequent remission with remyelination has been linked to an increased occurrence of oligodendrocyte progenitor (O2A) cells. Platelet-derived growth factor (PDGF) and fibroblast growth factor-2 (FGF-2) are key growth factors for O2A cells, yet little is known about their relevance in EAE and MS. We analyzed the expression of PDGF, FGF-2, and their receptors by peripheral-blood leukocytes (PBLs) and lymphocyte subsets during MBP-induced EAE. Strong up-regulation of PDGF, but not FGF-2, was observed in PBLs, with the highest expression after the disease maximum. T, NK, and NKT cells expressed PDGF, which is a novel observation because thus far only monocytes/macrophages have been reported to express PDGF. These results extend the idea that growth factors may contribute to improved CNS tissue repair, including PDGF, which is secreted by lesion-homing immune cells. The production of PDGF by lymphocytes may have potential therapeutic value when activating or modulating T-cell responses in demyelinating diseases.

BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls.

Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) are common forms of dementia in the elderly. Recent findings have suggested an involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of AD. BDNF is an endogenous protein involved in the maintenance of neuronal function, synaptic plasticity and structural integrity in the adult brain. BDNF serum and cerebrospinal fluid (CSF) concentrations were assessed by a sensitive ELISA in 27 AD patients in comparison to 9 NPH patients and 28 age-matched healthy controls (10 CSF samples). We found a significant decrease of BDNF serum concentration in AD (18.6ng/ml) and NPH patients (18.1ng/ml) as compared to healthy controls (21.3ng/ml; p=0.041/p=0.017). BDNF serum concentrations did not correlate with CSF levels, age or MMSE scores both in AD and NPH patients. In unconcentrated CSF samples, BDNF could be detected in AD patients in 8/27 cases (29.6%; mean of 4.6pg/ml), in NPH patients in 1/9 cases (11.1%; mean of 6.4pg/ml) and in the control subjects in 5/10 cases (50%; mean of 1.6pg/ml) with no significant differences as regards mean concentration and frequency of detectable BDNF in CSF. The decrease of BDNF serum levels in AD and NPH may reflect a lack of trophic support and thus contribute to progressive degeneration in both diseases. In contrast to serum, CSF seems to be no useful source to determine BDNF in AD or NPH because of too low concentrations. Further examinations have to follow to elucidate the potential sources and the meaning of reduced BDNF levels in the blood in AD and NPH.

Structure-based discovery of nonpeptidic small organic compounds to block the T cell response to myelin basic protein.

We have utilized a computational structure-based approach to identify nonpeptidic small organic compounds that bind to a human leukocyte antigen (HLA) DR1301 molecule (HLA-DR1301 or DR1301) and block the presentation of myelin basic protein peptide 152-165 (MBP 152-165) to T cells. A three-dimensional (3D) structure of DR1301 was derived by homology modeling followed by extensive molecular dynamics simulation for structural refinement. Computational structure-based database searching was performed to identify nonpeptidic small-molecule candidates from the National Cancer Institute (NCI) database containing over 150 000 compounds that can effectively interact with the peptide-binding groove of the HLA molecule. By in vitro testing of 106 candidate small molecules, two lead compounds were confirmed to specifically block IL-2 secretion by DR1301-restricted T cells in a dose-dependent and reversible manner. The specificity of blocking DR1301-restricted MBP presentation was further validated in a binding assay using an analogue of the most potent lead compound. Computational docking was performed to predict the three-dimensional binding model of these confirmed small molecule blockers to the DR1301 molecule and to gain structural insight into their interactions. Our results suggest that computational structure-based searching is an effective approach to discover nonpeptidic small organic compounds to block the interaction between DR1301 and T cells. The nonpeptidic small organic compounds identified in this study are useful pharmacological tools to study the interactions between HLA molecules and T cells and a starting point for the development of a novel therapeutic strategy for the treatment of multiple sclerosis (MS) or other immune-related disorders.

The human T cell response to myelin oligodendrocyte glycoprotein: a multiple sclerosis family-based study.

Myelin oligodendrocyte glycoprotein (MOG) is an encephalitogenic myelin protein and a likely autoantigen in human multiple sclerosis (MS). In this work, we describe the fine specificity and cytokine profile of T cell clones (TCC) directed against MOG in three nuclear families, comprised of four individuals affected with MS and their HLA-identical siblings. TCC were generated from PBMC by limiting dilution against a mixture of eleven 20-mer overlapping peptides corresponding to the encephalitogenic extracellular domain of human MOG (aa 1-120). The frequency of MOG peptide-reactive T cells was surprisingly high (range, 1:400 to 1:3,000) and, unexpectedly, cloning efficiencies were highest at low seeding densities of 10(2) or 10(3) PBMC per well. A total of 235 MOG peptide-reactive TCC were produced, all of which were CD4(+)CD8(-)TCRalphabeta(+)TCRgammadelta(-). All 11 MOG peptides were recognized by the TCC, and different epitopes of MOG appeared to be immunodominant in the HLA-identical siblings. The patterns of cytokine secretion by TCC from single individuals were generally similar. The healthy individuals exhibited Th2-, Th0-, and T regulatory cell 1-like cytokine profiles, whereas TCC from one sibling with MS had a striking Th1-like phenotype, producing high levels of IFN-gamma and TNF-alpha, and low IL-4 levels. Thus, MOG-reactive T cells appear to constitute an important part of the natural T cell repertoire, a finding that could contribute to the development of autoimmunity to this protein.