Role of Vitamin K in Bone and Muscle Metabolism.

Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key role in bone and muscle homeostasis. In vivo and in vitro models for osteoporosis and sarcopenia suggest the vitamin K could exert a positive effect in both conditions. In bone, it increases osteoblastogenesis, whilst decreases osteoclast formation and function. In muscle, it is associated with increased satellite cell proliferation and migration and might play a role in energy metabolism. Observational trials suggest that high levels of vitamin K are associated with increased bone mineral density and reduced fracture risk. However, interventional studies for vitamin K supplementation yielded conflicting results. Clinical trials in sarcopenia suggest that vitamin K supplementation could improve muscle mass and function. One of the main limitations on the vitamin K studies are the technical challenges to measure its levels in serum. Thus, they are obtained from indirect sources like food questionnaires, or levels of undercarboxylated proteins, which can be affected by other environmental or biological processes. Although current research appoints to a beneficial effect of vitamin K in bone and muscle, further studies overcoming the current limitations are required in order to incorporate this supplementation in the clinical management of patients with osteosarcopenia.

Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy.

The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.

Unconventional apoptosis of polymorphonuclear neutrophils (PMN): staurosporine delays exposure of phosphatidylserine and prevents phagocytosis by MΦ-2 macrophages of PMN.

Apoptosis of polymorphonuclear neutrophils (PMN) and subsequent 'silent' removal represents an important check-point for the resolution of inflammation. Failure in PMN clearance resulting in secondary necrosis-driven tissue damage has been implicated in conditions of chronic inflammation and autoimmunity. Apoptotic PMN undergo profound biophysical changes that warrant their efficient recognition and uptake by phagocytes before fading to secondary necrosis. In this study, we demonstrate that staurosporine (STS), a non-selective but potent inhibitor of cyclin-dependent kinase and protein kinase C, exerts a drastic impact on PMN apoptosis. PMN treated with STS underwent an unconventional form of cell death characterized by a delayed exposure of aminophospholipids, including phosphatidylserine (PS) and phosphatidylethanolamine and an increased exposure of neo-glycans. STS caused an impaired cellular fragmentation and accelerated DNA fragmentation. Phagocytosis of STS-treated PMN lacking PS on their surfaces was decreased significantly, which highlights the importance of PS for the clearance of apoptotic PMN. Specific opsonization with immune complexes completely restored phagocytosis of STS-treated PMN, demonstrating the efficiency of back-up clearance pathways in the absence of PS exposure.

[Treatment of non-specific, functional and somatoform bodily complaints]. / Umgang mit Patienten mit nicht-spezifischen, funktionellen und somatoformen Körperbeschwerden.

In primary and secondary medicine "non-specific, functional, and somatoform bodily complaints" are common and often take a chronic course, with the patients' quality of life usually markedly impaired, and give rise to high direct and indirect costs. They are challenging as they can deteriorate in case of inappropriate behavior on the physician's part. Coordinated by both German professional associations of Psychosomatic Medicine a new evidence based guideline was developed, aiming to transfer relevant diagnostic and therapeutic knowledge to all physicians who are in charge of these patients. After establishing a stable therapeutic alliance a symptom- and coping-oriented attitude could be demonstrated to be helpful. A biopsychosocial diagnostic evaluation combines a thorough assessment of bodily complaints and early introduces a sensitive discussion of signs of psychosocial stress, which can be extended carefully in case problems of this type are present. In less severe courses, physical/social activation is recommended and the patient's explanatory disease model should be extended towards a psychological dimension. More severe and complicated courses require a more structured approach consisting of regular appointments (as opposed to ad-hoc appointments whenever the patient feels worse) and an active cooperation of the patient. A coordinated, multimodal management includes additional measures as graded activation, psychotherapy, relaxation training or--if indicated--temporary medication.

[Current data and trends on the development of antibiotic resistance of Clostridium difficile]. / Aktuelle Daten und Trends zur Antibiotikaresistenzentwicklung von Clostridium difficile.

Clostridium difficile is the most common pathogen causing antibiotic-associated diarrhea. Antibiotic therapy also favors the development and the epidemic spreading of multiresistant strains. In this present retrospective study clinical isolates from the University of Saarland Medical Center and of other German isolate referring hospitals were characterized by genotyping and antibiotic resistance testing. The most prevalent strains were ribotypes 001 (18%), 014 (16%) and 027 (15%). Sensitivity to metronidazole and vancomycin was demonstrated for 99.7 % of the clinical isolates independent of the genotype. Of the isolates 96 % were rifampicin susceptible; however, significantly more cases of rifampicin resistance were found among 027 strains (12 %). Of the isolates 58% were clarithromycin sensitive and 57% moxifloxacin sensitive. In contrast to the various sporadic genotypes the majority of epidemic strains were macrolide or fluoroquinolone resistant (001, 027 and 078); however, discrimination between epidemic strains by antibiotic resistance profiles could not be discerned. A combination of consistent adherence to hygiene management guidelines and to a prudent and rational use of antimicrobials (antibiotic stewardship) may help to reduce the total number of C. difficile infections (CDI) and also the selection of multiresistant strains. On the other hand in the collection of isolates the sensitivity towards the standard oral antibiotic agents used for C. difficile treatment appears to be unimpaired by the global changes of C. difficile resistant profiles.

Does increased sunlight exposure work as a strategy to improve vitamin D status in the elderly: a cluster randomised controlled trial.

SUMMARY: Sunlight exposure by improving vitamin D status could be a simple public health strategy in reducing falls among frail elder people. In a randomised controlled trial, adherence to sunlight exposure was low (median adherence, 26%) and no effect of increased UV exposure on falls risk was observed (incidence rate ratio (IRR) 1.06, P = 0.73). INTRODUCTION: This study aimed to determine whether increased sunlight exposure was effective to improve vitamin D status and reduce falls in the elderly. METHODS: In a cluster randomised controlled trial (NCT00322166 at ClinicalTrials.gov), 602 residents aged 70 or more (mean age, 86.4 years; 71% female) were recruited from 51 aged care facilities in Northern Sydney, Australia. Participants were randomised by facility to receive either increased sunlight exposure (additional 30-40 min/day in the early morning) with (UV+) or without (UV) calcium supplementation (600 mg/day) or neither (control) for a year. The co-primary endpoints were change in serum 25 hydroxy vitamin D (25OHD) and falls incidence after 12 months. RESULTS: Adherence to sunlight exposure was low (median adherence, 26%; IQR, 7%-45%). Serum 25OHD levels were low at baseline (median, 32.9 nmol/L) and increased only slightly depending on the number of sunlight sessions attended over 12 months (P = 0.04). During the study, 327 falls occurred in 111 (54%) subjects in the control group, 326 falls in 111 (58%) subjects in the UV only group and 335 falls in 108 (52%) subjects in the UV+ group. By intention-to-treat analysis, there was no significant effect of increased UV exposure on falls risk (IRR, 1.06; 95% CI, 0.76-1.48; P = 0.73). However, in 66 participants who attended ≥130 sessions per year (adherence, ≥50% of 260 sessions-five per week), falls were significantly reduced (IRR, 0.52; 95% CI, 0.31-0.88; P = 0.01) compared with the control group. CONCLUSIONS: Increased sunlight exposure did not reduce vitamin D deficiency or falls risk in frail older people. This public health strategy was not effective most likely due to poor adherence to the intervention.

Torsional bridge setup for the characterization of integrated circuits and microsensors under mechanical shear stress.

We present a torsional bridge setup for the electro-mechanical characterization of devices integrated in the surface of silicon beams under mechanical in-plane shear stress. It is based on the application of a torsional moment to the longitudinal axis of the silicon beams, which results in a homogeneous in-plane shear stress in the beam surface. The safely applicable shear stresses span the range of ±50 MPa. Thanks to a specially designed clamping mechanism, the unintended normal stress typically stays below 2.5% of the applied shear stress. An analytical model is presented to compute the induced shear stress. Numerical computations verify the analytical results and show that the homogeneity of the shear stress is very high on the beam surface in the region of interest. Measurements with piezoresistive microsensors fabricated using a complementary metal-oxide-semiconductor process show an excellent agreement with both the computational results and comparative measurements performed on a four-point bending bridge. The electrical connection to the silicon beam is performed with standard bond wires. This ensures that minimal forces are applied to the beam by the electrical interconnection to the external instrumentation and that devices with arbitrary bond pad layout can be inserted into the setup.

Hyperhomocysteinemia is associated with impaired fracture healing in mice.

Hyperhomocysteinemia (HHCY) has been shown to disturb bone metabolism and to increase the incidence of osteoporosis and osteoporotic fractures. However, there is a complete lack of information on whether these metabolic alterations affect bone repair. The aim of this study was to analyze the impact of HHCY on fracture healing. One group of mice was fed a homocystine-supplemented diet (n = 12), whereas another group received the accordant standard diet for control (n = 13). Four weeks after the stable fixation of a closed femoral fracture, animals were killed to prepare bones for histomorphometric and biomechanical analyses. In addition, blood samples were obtained to evaluate serum concentration of homocysteine (HCY). Quantitative analysis of blood samples revealed severe HHCY as indicated by significantly increased serum concentrations of HCY in animals fed the homocystine-supplemented diet (102.2 +/- 64.5 micromol/l) compared to controls (2.8 +/- 1.5 micromol/l). Biomechanical evaluation of bone repair revealed significantly decreased bending stiffness of the femora of homocystine-fed animals (45.5 +/- 18.2 N/mm) compared with controls (64.6 +/- 15.8 N/mm). Histomorphometric analysis demonstrated a slightly smaller callus diameter in HHCY animals but no significant differences in the tissue composition of the callus. In conclusion, the homocystine-supplemented diet leads to severe HHCY, which is associated with an impaired biomechanical quality of the healing bone.

Cortical correlates of auditory sensory gating: a simultaneous near-infrared spectroscopy event-related potential study.

Sensory gating refers to the ability of cerebral networks to inhibit responding to irrelevant environmental stimuli, a mechanism that protects the brain from information overflow. The reduction of the P50 amplitude (an early component of the event-related potential/ERP in electrophysiological recordings) after repeated occurrence of a particular acoustic stimulus is one means to quantitatively assess gating mechanisms. Even though P50 suppression has been extensively investigated, neuroimaging studies on the cortical correlates of auditory sensory gating are so far very sparse. Near-infrared spectroscopy (NIRS) is an optical imaging technique perfectly suitable for the investigation of auditory paradigms, since it involves virtually no noise. We conducted a simultaneous NIRS-ERP measurement to assess cortical correlates of auditory sensory gating in humans. The multi-channel NIRS recording indicated a specific activation of prefrontal and temporo-parietal cortices during conditions of increased sensory gating (dual-click trials). Combining the hemodynamic data with an electrophysiological index of the "gating quality" (gating quotient Q) revealed a positive correlation between the amount of sensory gating and the strength of the hemodynamic response during dual-clicks in the left prefrontal and temporal cortices. The results are in line with previous findings and confirm a possible inhibitory influence of the prefrontal cortex on primary auditory cortices.

Experimental hyperhomocysteinaemia: differences in tissue metabolites between homocystine and methionine feeding in a rat model.

AIM: Hyperhomocysteinaemia, diagnosed by serum levels, is regarded as an independent risk indicator for cardiovascular events and is associated with various diseases. The pathomechanisms seem to be partly due to concentrations of homocysteine metabolites and their effect on the cellular transmethylation processes. METHODS: We compared two common models for experimental hyperhomocysteinaemia - high methionine diet and homocystine-enriched diet - regarding their effects on tissue concentrations of homocysteine metabolites. RESULTS: Both diets induced hyperhomocysteinaemia without affecting renal function or vitamine status. However, the tissue contents of homocysteine and its precursors S-adenosyl-homocysteine (SAH) and S-adenosyl-methionine exhibited major differences between both models. Transmethylation potential was elevated 1.7-fold in liver of rats fed the methionine diet, whereas it was unaltered after homocystine-enriched diet. Kidneys of rats fed the methionine diet did not show any alterations in tissue content of homocysteine and its precursors, whereas in the homocystine group homocysteine and the transmethylation inhibitor SAH were elevated from 23.1 +/- 10.4 to 78.0 +/- 26.0 nmol g(-1) and from 106 +/- 4 to 170 +/- 22 nmol g(-1) respectively. Homocysteine tissue content was elevated in the homocystine, but not in the methionine group. CONCLUSIONS: Alterations to homocysteine metabolism are distinct in both models. These findings may explain divergent results, which have been published for these models of hyperhomocysteinaemia and which have resulted in controversial discussions in the past.

Far field potentials from the brain stem after transcutaneous vagus nerve stimulation.

Recently, the vagus nerve has gained particular interest in neuropsychiatry, as neurodegenerative diseases like Alzheimer's and Parkinson's disease are supposed to affect the brainstem nuclei of the vagus nerve early in their course. In addition, electric stimulation of the vagus nerve has therapeutic effects in otherwise therapy-refractory epilepsies and depressions. So far, no method is available to assess vagus nerve function in this context. On this background and based on the established techniques of early acoustic evoked potentials we investigated if a transcutaneous electric stimulation of the sensory auricular branch of the vagus nerve innervating parts of the outer ear is feasible in healthy subjects using this hypothesis-generated approach. We were able to record a clear, reproducible Vagus Sensory Evoked Potential (VSEP) measured as far field potential probably originating in vagus nuclei in the brainstem. Further studies are needed to test the interindividual stability and test-retest reliability of this new method before potential diagnostic and therapeutic applications might be evaluated.

Repeated exposure of flight phobics to flights in virtual reality.

The present study examined the effects of repeated exposure of flight phobics to flights in virtual reality (VR). Flight phobics were randomly assigned either to complete one VR test flight followed by four VR exposure flights (VR group; N=15) in one lengthy session or to complete one VR test flight followed by a lengthy relaxation training session (relaxation group; N=15). All participants completed a second VR test flight at the end of the session. Fear reports and physiological fear reactions (heart rate, skin conductance level) during VR exposures were registered, and fear of flying was assessed psychometrically from 3 weeks before to 3 months after exposure. Exposure to VR flights elicited subjective and physiological fear responses in flight phobics, and these responses attenuated within and across VR flights. Fear reduction associated with repeated VR exposure was greater than fear reduction caused by relaxation training. Fear of flying improved in both treatment groups, but several outcome measures indicated greater effects in the VR treated group than in the relaxation group. These findings indicate that exposure in virtual reality may offer a new and promising approach for the treatment of fear of flying.

Childhood experiences and adult behavior in a group of women with pain accounted for by psychological factors and a group recovered from major depression.

OBJECTIVE: In this study twenty-four women with pain accounted for by psychological factors (DSM-IV, 307.80) and twenty-four with major depression diagnosed according to DSM-III-R were compared to study the relationship between pain and depression. METHOD: They were examined by a semi-structured, tape-recorded interview to study their childhood experiences and adult behavior. The interviews were rated by two independent and blind raters. Interrater correlation (Cohen-Kappa) varied between good and close agreement. RESULTS: Of childhood experiences, "brutality between parents," "brutality toward child," and "sexual abuse" were often found in both groups and were more strongly represented in these than in comparison groups of former studies. As adults, the pain group had experienced more serious illness (p = 0.037) and surgery (p = 0.014). The depression group more often had a history of depression (15/24 vs. 4/24; p = 0.001). The pain group spoke negatively of its physicians (p = 0.001), was more hostile during the interview (p = 0.041), was less convinced of the benefit of the hospital stay (p = 0.029), felt less self-responsible, and was more pessimistic (p = 0.013). The pain patients also provoked negative emotions in the raters, whereas the latter's reaction to the depression group was compassion and interest (p = 0.0005) (Pearson's chi2 and Fisher's exact tests). CONCLUSIONS: The results show that negative childhood experiences are prominent and similar in patients with pain accounted for by psychological factors and in patients after major depression. Adult behavior, however, is very different.

Melithiazols, new beta-methoxyacrylate inhibitors of the respiratory chain isolated from myxobacteria. Production, isolation, physico-chemical and biological properties.

New antibiotic compounds, melithiazols, were isolated from the culture broth of strains of the myxobacteria Melittangium lichenicola, Archangium gephyra, and Myxococcus stipitatus. The compounds belong to the group of beta-methoxyacrylate (MOA) inhibitors and are related to the myxothiazols. The melithiazols show high antifungal activity, but are less toxic than myxothiazol A and its methyl ester in a growth inhibition assay with mouse cell cultures. The melithiazols inhibit NADH oxidation by submitochondrial particles from beef heart. Melithiazol A blocks the electron transport within the bc1-segment (complex III) and causes a red shift in the reduced spectrum of cytochrome b.

Is there a syndrome of tuberothalamic artery infarction? A case report and critical review.

Short-term post-acute neuropsychological, neurological, and neuroradiological test results and a 16-month follow-up of a 65-year-old patient with a right hemisphere ischemic lesion in the tuberothalamic area of vascular supply are reported. During a 6-week period of examinations the originally left- but trained right-handed patient exhibited fluctuating neuropsychological disorders including aphasia, visuo-perceptive and visuoconstructive disorders, and memory and attention deficits. In the follow-up examination the patient exhibited no aphasia and significant improvements in most neuropsychological tasks. Based on three-dimensional reconstruction of MRI, lesion topography and involvement of thalamic nuclei were established. We discuss the neuropsychological and neurological symptoms of the present case against the background of the 'syndrome of unilateral tuberothalamic artery territory infarction' proposed by Bogousslavsky and coworkers (1986) and the neuropsychological literature on unilateral ischemic anterior/anterolateral thalamic infarction.

Microbiological examinations and in-vitro testing of different antibiotics in therapeutic endoscopy of the biliary system.

BACKGROUND AND STUDY AIMS: Prior to endoscopic therapeutic procedures, no antibiotic prophylaxis is administered routinely. Because of the reported incidence of infectious complications, which may reach up to 10%, a prospective study was undertaken to investigate the effects of a prophylactic dose of cefuroxime on the incidence of bacteremia and clinical signs of infection, but no significant effects could be demonstrated. In addition to this published work, blood and bile cultures obtained in this trial were also investigated, and the in-vitro susceptibility to several antibiotics was tested in order to recommend the appropriate substances. PATIENTS AND METHODS: Ninety-nine consecutive patients (51 men, 48 women; mean age 61.4 +/- 17 years) with biliary obstruction who underwent an endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography with drainage (PTCD) were included. Sequential blood cultures were taken before and up to 60 minutes after the endoscopic intervention. Bile cultures were obtained in 56 patients with biliary drainage. Aerobic and anaerobic cultures were prepared from all obtained specimens and the isolated organisms were identified. In the case of positive cultures, an in-vitro resistance test for 15 different antibiotics was performed. RESULTS: The incidence of bacteremia was 11.1% (n = 11), and 16 bacteria were isolated. Twelve different microorganisms were detected, with Escherichia coli found in four cases. From 41 positive out of 56 prepared bile cultures (73.2%), 91 isolates were found with 25 different species. A single agent was detected in eight cases (19.5%), while a mixed growth, with pathogens ranging from two to six species, was found in 33 cases (80.5%). The seven most frequently isolated germs were E. coli and Enterococcus (each n = 19), Klebsiella (n = 10), Streptococcus viridans (n = 9), Staphylococcus epidermidis (n = 5), Morganella morganii (n = 4), and Bacteroides fragilis (n = 3), representing 76% of all agents. Examination for fungal infection revealed positive cultures of Candida albicans in 16.1% of bile cultures (nine of 56). Interestingly, the use of proton-pump inhibitors (PPIs), with a consequent rise in the gastric pH value, led to an increase in the rate of bacteremia to 26.2% (five of 19) compared to the other patients not on PPIs (n = 80), who developed bacteremia in only six cases (7.5%; p = 0.02). In-vitro testing of different antibiotics was carried out in 73 isolates. Imipenem showed the best antimicrobial activity (98.4%), followed by trimethoprim and sulfamethoxazole (90%), amoxicillin plus clavulanic acid (87.3%), vancomycin (82.4%), and ofloxacin (76.9%). CONCLUSIONS: Escherichia coli was found to be the pathogen most frequently detected in blood and bile following endoscopic interventions in the biliary tract. Enterococci, Klebsiella and Streptococcus viridans were found in bile cultures with an incidence exceeding 10%. In view of the in-vitro test results, possible side effects, and contraindications, amoxicillin plus beta-lactamase inhibitors or quinolones are considered to be suitable antibiotics for the prophylaxis of biliary infections.

[Optimization of local anesthesia in ambulatory surgery]. / L'adaptation de l'anesthésie locale pour la chirurgie ambulatoire.

The optimization of local anesthesia will be one essential condition to enlarge and improve the ambulatory surgery and its acceptation by the patients. Indication to local anesthesia can be increased by prolongation of its duration through adjunction of adrenaline to lidocaine at a 1:200,000 concentration and by diminishing injection-related pain through buffering the anesthetic solution with a 8.4% sodium bicarbonate solution at a concentration of 1 ml to 10 ml of lidocaine. However, this preparation is unstable and must be utilized within a few days.

[Antibiotic prophylaxis using cefuroxime in bile duct endoscopy]. / Antibiotische Prophylaxe mit Cefuroxim bei endoskopischen Eingriffen an den Gallenwegen.

OBJECTIVE: To assess prospectively the effectiveness of a single prophylactic dose of cefuroxim before therapeutic endoscopy, in view of the general practice not to give antibiotics routinely. PATIENTS AND METHODS: In a prospective study endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography with drainage (PTCD) together with simultaneous stone extraction, dilatation or stent implantation were performed in 99 patients (51 men, 48 women; mean age 60.6 +/- 19.2 years). Group A (n = 49) received 1500 mg cefuroxim i.e. 30 min before the procedure, while none was given to group A patients (n = 50). Several blood cultures were taken up to 60 min after the endoscopy. The number of septicaemias (bacteraemia with fever, rigor, circulatory reactions, leukocytosis or leukopenia) were noted. Bile cultures were obtained in 56 patients with indwelling biliary drainage. RESULTS: Incidence of bacteraemia was 6.1% (3 of 49) in group A, 16% (8 of 50) in group B, but this difference is not statistically significant. The septicaemia rate was 6.1% in group A and 10% in group B (not significant). There were eleven positive blood cultures with 12 different microorganisms, Escherichia coli in four (A: n = 3). In vitro cefuroxim sensitivity was 53.3%. 25 different bacterial species were isolated from 73.2% of bile cultures, of which 53.4% were sensitive to cefuroxim and 8.2% moderately so. CONCLUSION: Although the obtained differences between the two groups were not statistically different, the reduction in bacteraemia/septicaemia rate may be of clinical use. Further studies are needed with higher dosages or antibiotic combinations to improve these results.