Trimethylamine-N-oxide is elevated in the acute phase after ischaemic stroke and decreases within the first days.

BACKGROUND AND PURPOSE: Trimethylamine-N-oxide (TMAO) is a biomarker of the gut microbiome and correlates with the risk of cardiovascular diseases. However, conflicting data exist on the specific role of TMAO in ischaemic stroke patients. We aimed to analyze the time course of TMAO levels in stroke patients compared with controls. METHODS: In this prospective, case-control study, patients suffering from ischaemic stroke (onset <24 h) and control patients with less than two cardiovascular risk factors were enrolled. Plasma TMAO levels were analyzed on admission, after 48 h and after 3 months. The primary endpoint was the difference in TMAO levels on admission between stroke patients and controls. RESULTS: A total of 196 patients with ischaemic stroke and 100 controls were included between February 2018 and April 2019. Plasma TMAO levels on admission were significantly higher in stroke patients than in controls [median value 4.09 (2.87-6.49) vs. 3.16 (2.08-5.16) µmol/L, P = 0.001]. There was a significant decrease in TMAO levels in stroke patients after 48 h [median at 48 h, 3.49 (2.30-5.39) µmol/L, P = 0.027]. TMAO levels increased again 3 months after stroke [median 4.23 (2.92-8.13) µmol/L, P = 0.047]. In controls, TMAO levels did not change between admission and after 48 h [median at 48 h, 3.14 (1.63-4.61) µmol/L, P = 0.11]. An inverse correlation between TMAO values and kidney function was found (Spearman rho -0.334, P < 0.001). CONCLUSIONS: Our study emphasizes the importance of the time course of TMAO levels after ischaemic stroke. Future studies should define the time point of TMAO analysis, preferably in the acute phase (<24 h).

Long-term ovarian function in women treated with CHOP or CHOP plus etoposide for aggressive lymphoma.

BACKGROUND: Chemotherapy-associated ovarian damage comprises not only infertility, but also premature menopause. The latter has been reported as a consequence of alkylating chemotherapy for breast cancer or Hodgkin's lymphoma. In this study, we assessed the long-term impact of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimens on ovarian function in patients with aggressive non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Long-term survivors after CHOP or CHOP plus etoposide (CHOEP) treatment within the Mabthera International Trial or the NHL-B1 trial of the German NHL Study Group were requested to respond to a questionnaire and to consent to blood sampling for hormone assessment. RESULTS: A total of 46 of 81 contacted patients with a median age of 32.5 years at the time of enrolment into the aforementioned clinical trials responded to the questionnaire. The median follow-up after completion of treatment was 14 years. Last menstrual bleeding occurred significantly earlier in patients compared with the general population (47 versus 51 years, P < 0.0001). In comparison to the distribution of menopausal symptoms in the general population, the percentage of women with moderate or severe menopausal symptoms was increased. In 23 patients who agreed to participate in laboratory analyses, anti-Muller hormone as a marker of ovarian reserve was decreased when compared with correspondent age groups of the general population. CONCLUSION: Although most female patients regain fertility after CHOP-like chemotherapy, late ovarian impairment occurs frequently. Therefore, awareness of such delayed side-effects at the time of counselling is of importance.

Prevalence of renal dysfunction in ischaemic stroke and transient ischaemic attack patients with or without atrial fibrillation.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is associated with a higher risk of stroke and atrial fibrillation (AF). There are limited data on the comorbidity of renal dysfunction and AF in stroke patients. Our aim was to determine the frequency of kidney dysfunction in ischaemic stroke patients with and without AF. METHODS: In a prospectively collected, single center cohort of acute ischaemic stroke and transient ischaemic attack (TIA) patients, glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease equation on admission. Renal function was graded into five categories (cat.): cat. 1, eGRF ≥90 ml/min/1.73 m(2); cat. 2, 60-89; cat. 3, 30-59; cat. 4, 15-29; cat. 5, <15. The diagnosis of AF was based on medical history, a 12-lead electrocardiogram (ECG) and 24-h Holter or continuous ECG monitoring. RESULTS: In total, 2274 patients (1727 stroke, 547 TIA; median age 71.0) were included. Median eGFR was 78.6 ml/min/1.73 m(2) (interquartile range 61/95); 21.1% were in cat. 3, 2.1% in cat. 4, 0.7% in cat. 5. In all, 535 patients (23.5%) suffered from AF; 28.0% of these were in cat. 3, 2.6% and 0.8% in cat. 4 and cat. 5, respectively. In multivariable analysis, age [odds ratio (OR) 1.1], diabetes (OR 1.8), heart failure (OR 1.7) and AF (OR 1.4) were independently associated with kidney dysfunction (eGFR < 60). CONCLUSIONS: Renal dysfunction is far more common in stroke patients than in the general population and more common in AF-related stroke. These findings may have implications for the choice of anticoagulants.

A novel missense mutation T101N in the melanocortin-4 receptor gene associated with obesity.

Mutations in the melanocortin-4 receptor (MC4R) are associated with severe obesity, independent of their effect on cortisol or thyroid-stimulating hormone levels. We examined a morbidly obese male (BMI = 62 kg/m²) with a binge-eating disorder and eight family members for mutations in the MC4R gene and potential differences in leptin levels. Fifty healthy individuals served as controls. Sequence analysis revealed a novel heterozygous missense mutation (c.302 C>A, p.T101N) located in the second transmembrane domain of the receptor, which was not detected in controls. The Fisher exact test revealed an association between the T101N mutation and history of obesity (P < 0.05) in the family. The Kruskal-Wallis test showed an association between the mutation and the leptin/BMI ratio (P < 0.05), while there was no association between the T101N mutation and diabetes or arterial hypertension in the family. Although the available family was small, we could show a significant association between the heterozygous T101N mutation and obesity.

Multicenter analytical evaluation of a high-sensitivity troponin T assay.

BACKGROUND: High-sensitivity cardiac troponin assays are being introduced clinically for earlier diagnosis of acute myocardial infarction (AMI). We evaluated the analytical performance of a high-sensitivity cardiac troponin T assay (hscTnT, Roche Diagnostics) in a multicenter, international trial. METHODS: Three US and 5 European sites evaluated hscTnT on the Modular® Analytics E170, cobas® 6000, Elecsys 2010, and cobas® e 411. Precision, accuracy, reportable range, an inter-laboratory comparison trial, and the 99th percentile of a reference population were assessed. RESULTS: Total imprecision (CVs) were 4.6-36.8% between 3.4 and 10.3 ng/L hscTnT. Assay linearity was up to 10,000 ng/L and the limit of blank and detection were 3 and 5 ng/L, respectively. The 99th percentile reference limit was 14.2 ng/L (n=533). No significant differences between specimen types, assay incubation time, or reagent lots existed. A substantial positive bias (76%) exists between the 4th generation and hscTnT assays at the low end of the measuring range (<50 ng/L). hscTnT serum pool concentrations were within 2SD limits of the mean of means in the comparison trial, indicating comparable results across multiple platforms and laboratories. CONCLUSION: The Roche hscTnT assay conforms to guideline precision requirements and will likely identify additional patients with myocardial injury suspicious for AMI.

Maturity-Onset Diabetes of the Young (MODY) caused by a novel nonsense mutation E41X in the HNF-1α gene.

The most common cause of Maturity-Onset Diabetes of the Young (MODY) are mutations in the Hepatic Nuclear Factor 1α (HNF-1α) gene, resulting in MODY3. In a family afflicted with diabetes, a novel nonsense mutation in HNF-1α, E41X, causing a termination codon behind the dimerization domain, was found. The penetrance in individuals older than 25 years was 81.8%. The age at manifestation of diabetes ranged from 18 to 63 years, only 2 out of 10 diabetic individuals developed the disease at ages younger than 25 years. Although diabetes duration lasted up to 35 years in this family, only one family member suffered from diabetic complications. Additional polymorphisms in HNF-1α, I27L and S487N, were found in this pedigree. Despite its biological inactivity, S487N polymorphism led in combination with E41X to a significant earlier manifestation of diabetes, whereas I27L polymorphism or increased Body Mass Index (BMI) did not. In spite of the severe gene defect, which truncates the protein behind the dimerization domain, the phenotype of E41X was relatively benign without frequent diabetic complications.

[Malignant bowel obstruction]. / Maligne intestinale Obstruktion.

Malignant bowel obstruction (MBO) is a frequent complication in patients with a progressive malignant disorder and represents a major interdisciplinary challenge in palliative care. Gastroenterology plays a pivotal role in the management of MBO. After appropriate diagnostic work-up, it is important to define treatment goals with the patient and his/her relatives, which should focus on symptom relief. Therapeutically, surgical, endoscopic and medical options are available. These will be introduced based on case reports. In the international literature MBO is being more and more considered as a distinct entity. The aim of the present review is to communicate MBO as such in the German medical literature.

Mechanisms of vascular damage by hemorrhagic snake venom metalloproteinases tissue distribution and in situ hydrolysis

Envenoming by viper snakes constitutes an important public health problem in Brazil and other developing countries. Local hemorrhage is an important symptom of these accidents and is correlated with the action of snake venom metalloproteinases (SVMPs). The degradation of vascular basement membrane has been proposed as a key event for the capillary vessel disruption. However, SVMPs that present similar catalytic activity towards extracellular matrix proteins differ in their hemorrhagic activity, suggesting that other mechanisms might be contributing to the accumulation of SVMPs at the snakebite area allowing capillary disruption. These results show a particular tissue distribution of hemorrhagic toxins accumulating at the basement membrane. This probably occurs through binding to collagens, which are drastically hydrolyzed at the sites of hemorrhagic lesions. Toxin accumulation near blood vessels explains enhanced catalysis of basement membrane components, resulting in the strong hemorrhagic activity of SVMPs. This is a novel mechanism that underlies the difference between hemorrhagic and non-hemorrhagic SVMPs, improving the understanding of snakebite pathology.

High-power 808 nm ridge-waveguide diode lasers with very small divergence, wavelength-stabilized by an external volume Bragg grating.

We present data on ridge-waveguide diode lasers having a vertical far-field divergence of only 11.5 degrees (FWHM) owing to an appropriate waveguide design. The lasers emitted an optical power of more than 1 W into the spatial fundamental mode from a ridge width of 5 microm. The emission wavelength was stabilized to a narrow range around 808 nm by placing a volume Bragg grating in front of the outcoupling facet.

Aryl hydrocarbon receptor interacting protein gene (AIP) mutations are rare in patients with hormone secreting or non-secreting pituitary adenomas.

OBJECTIVE: Recent data suggest that mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) are associated with pituitary adenomas. AIP is considered to be a tumour suppressor gene. METHODS: 110 Caucasian patients living in Germany with pituitary adenoma (55 hormone secreting, 55 non-functioning) were examined for AIP mutations. RESULTS: Three patients (2.7%) harboured an AIP germline mutation. A heterozygous mutation, R16H (c.47G>A), was found in two patients and a heterozygous G>C change in the 3'UTR, 60 bp downstream of the termination codon, in one patient. All three patients suffered from non-functioning adenoma. Additionally, a silent polymorphism, D172D (c.516C>T), was found in 3 patients with non-functioning adenoma, in 2 patients with prolactinoma and in one patient with acromegaly. CONCLUSIONS: AIP mutations are rare in sporadic pituitary adenomas in the German population and occur independently from a hormone secretion of the adenoma.

The DG10S478 variant in the TCF7L2 gene is not associated with microvascular complications in type 2 diabetes.

OBJECTIVE: The DG10S478 variant in the transcription factor 7-like 2 (TCF7L2) gene is a tetranucleotide repeat with six alleles. Alleles 0, 8 and 12 were found to account for 98% of chromosomes in population based controls. The composite allele X (non zero) has been associated with type 2 diabetes while allele 0 (no insertion) was described as protective. However, no data exist about the influence of DG10S478 variants on manifestation of diabetes and development of diabetic complications. METHODS: 250 patients with type 2 diabetes were tested for the DG10S478 allele X and its association with diabetic complications, age at diagnosis of diabetes and BMI. RESULTS: Allele 0 was found in 42.4% of the examined patients, 45.2% of the participants were found to be heterozygous and 12.4% homozygous for the composite allele X. The correlation of allele X with the age at diagnosis of diabetes was not significant. There was also no association of allele X with retinopathy, nephropathy or neuropathy. Only the correlation with BMI was statistically significant. CONCLUSIONS: The DG10S478 variant seems to have no influence on manifestation of diabetes and the development of microvascular complications.

Autoantibodies in diabetes mellitus: current utility and perspectives.

Testing of autoantibodies in individuals at risk of developing or being newly diagnosed with diabetes mellitus is currently of very limited clinical value. However, clinical studies evaluating new therapeutic options for the delay or treatment of type 1 diabetes mellitus require sensitive, specific, and reliable assays for autoimmune antibodies associated with diabetes mellitus. With immune modulatory treatment of pre-diabetes mellitus on the horizon the need of reliable assays is evident. In addition, determination of autoimmune antibodies in diabetes mellitus facilitates studies investigating the pathophysiology underlying this disease. Clinicians and researchers should be aware of the tests available, their limitations, their clinical relevance, and their indications. This review focuses on the current knowledge about antibody assays for diabetes associated autoimmunity, their clinical value, their role in diagnosing and predicting autoimmune associated diabetes mellitus, and research applications.

Improved vascular function upon pioglitazone treatment in type 2 diabetes is not associated with changes in mononuclear NF-kappaB binding activity.

Thiazolidinediones such as pioglitazone have been shown to exert anti-inflammatory effects independent of their insulin sensitizing effects by reducing activation of the proinflammatory transcription factor NF-kappaB in animal models of experimental diabetes. Furthermore, short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries of patients with type 2 diabetes. Since inflammation is supposed to impair flow-mediated vasodilatation, we studied the effects of an 8-week pioglitazone intervention on endothelial function and mononuclear NF-kappaB activation in patients with type 2 diabetes. Twenty patients were included in a randomized, double-blind, placebo-controlled study receiving 30 mg pioglitazone or placebo, respectively. Flow-mediated endothelium dependent vasodilatation (FMD) of the brachial artery, NF-kappaB binding activity in peripheral blood mononuclear cells [pBMC, determined by electrophoretic mobility shift assay (EMSA)] and interleukin-6 (IL-6)-transcription rates (determined by real-time PCR) were measured at study entry and after eight weeks of intervention. Pioglitazone treatment resulted in a significant improvement of FMD (4.3%+/-3.3; p=0.003), while no effect was seen under placebo medication (2.0%+/-2.7; p=0.71). The correction of FMD was neither paralleled by a pioglitazone-dependent reduction in mononuclear NF-kappaB binding activity (DeltaNF-kappaB activity: pioglitazone: 9.2%+/-6.7, p=0.24; placebo: 5.7%+/-19.6; p=0.82) nor in NF-kappaB dependent gene transcription as determined for IL-6 (DeltaIL-6 pioglitazone: +1.8%+/-12.0, p=0.93; placebo: -0.2%+/-9.7; p=0.92). These data demonstrate for the first time that pioglitazone treatment improves endothelial dysfunction in patients with type 2 diabetes without affecting NF-kappaB binding activity and NF-kappaB dependent proinflammatory gene expression in pBMC.

[Comparison of Preferential Hyperacuity Perimeter (PHP) test and Amsler grid test in the diagnosis of different stages of age-related macular degeneration]. / Vergleich des Preferential-Hyperacuity-Perimeter (PHP)-Tests mit dem Amsler-Netz-Test bei der Diagnose verschiedener Stadien der altersbezogenen Makuladegeneration.

BACKGROUND: Age-related macular degeneration (ARMD) is the leading cause of blindness in people over 65 years of age. A rapid loss of vision occurs especially in cases with choroidal neovascularisation. Early detection of ARMD and timely treatment are mandatory. We have prospectively studied the results of two diagnostic self tests for the early detection of metamorphopsia and scotoma, the PHP test and the Amsler grid test, in different stages of ARMD. PATIENTS AND METHODS: Patients with ARMD and best corrected visual acuity of 6/30 or better (Snellen charts) were examined with a standardised protocol, including supervised Amsler grid examination and PHP, a new device for metamorphopsia or scotoma measurement, based on the hyperacuity phenomenon in the central 14 degrees of the visual field. The stages of ARMD were independently graded in a masked fashion by stereoscopic ophthalmoscopy, stereoscopic fundus colour photographs, fluorescein angiography, and OCT. The patients were subdivided into 3 non-neovascular groups [early, late (RPE atrophy > 175 microm) and geographic atrophy], a neovascular group (classic and occult CNV) and an age-matched control group (healthy volunteers). RESULTS: 140 patients, with ages ranging from 50 to 90 years (median 68 years), were included in the study. Best corrected visual acuity ranged from 6/30 to 6/6 with a median of 6/12. 95 patients were diagnosed as non-neovascular ARMD. Thirty eyes had early ARMD (9 were tested positive by the PHP test and 9 by the Amsler grid test), and 50 late ARMD (positive: PHP test 23, Amsler grid test 26). The group with geographic atrophy consisted of 15 eyes (positive: PHP test 13, Amsler grid test 10). Forty-five patients presented with neovascular ARMD (positive: PHP test 38, Amsler grid test 36), 34 volunteers served as control group (positive: PHP test 1, Amsler grid test 5). CONCLUSIONS: The PHP and Amsler grid tests revealed comparable results detecting metamorphopsia and scotoma in early ARMD (30 vs. 30 %) and late ARMD (46 vs. 52 %). However, the PHP test more often revealed disease-related functional changes in the groups of geographic atrophy (87 vs. 67 %) and neovascular ARMD (84 vs. 80 %). This implies that the PHP and Amsler grid self tests are useful tools for detection of ARMD and that the PHP test has a greater sensitivity in the groups of geographic atrophy and neovascular AMD.

Passively mode-locked Yb:KLu(WO4)2 oscillators.

We demonstrate passive mode locking based on the novel monoclinic double tungstate crystal Yb:KLu(WO4)2. We report the shortest pulses ever produced with an Yb-doped tungstate laser using a semiconductor saturable absorber. A pulse duration of 81 fs has been achieved for an average power of 70 mW at 1046 nm. We compare the performance of the polarization oriented parallel to the Nm- and Np-crystallo-optic axes. Results in the femtosecond and picosecond regime are presented applying either Ti:sapphire or diode laser pumping. The great potential of Yb:KLu(WO4)2 as an active medium for ultrashort pulses is demonstrated for the first time, to our knowledge.

Postoperative 12-lead ECG predicts peri-operative myocardial ischaemia associated with myocardial cell damage.

Peri-operative myocardial ischaemia is the single most important risk factor for an adverse cardiac outcome after non-cardiac surgery. The present study examines whether intermittent 12-lead ECG recordings can be used as an early warning tool to identify patients suffering from peri-operative myocardial ischaemia and subsequent myocardial cell damage. Fifty-five vascular surgery patients at risk for or with a history of coronary artery disease were monitored for peri-operative myocardial ischaemia using intermittent 12-lead ECG recordings taken pre-operatively and at 15 min, 20 h, 48 h, 72 h and 84 h postoperatively. The effectiveness of the 12-lead ECG was gauged by examining concordance with continuous 3-channel Holter monitoring and capturing peri-operative myocardial ischaemia by serial analyses of creatine kinase myocardial band isoenzyme and cardiac troponin T and I. The incidence of peri-operative myocardial ischaemia detected by 12-lead ECG was 44% and was identifiable in most patients (88%) 15 min after surgery. The incidence of peri-operative myocardial ischaemia detected by continuous monitoring was 53%, with the most severe episodes occurring intra-operatively and during emergence from anaesthesia. The concordance of the 12-lead method with continuous monitoring was 72%. The concordance of creatine kinase myocardial band isoenzyme activity with the 12-lead method was 71% and with Holter monitoring 57%. The concordance of mass concentration of creatine kinase myocardial band with 12-lead ECG recordings was 75%, and the corresponding value for Holter monitoring was 68%. The concordance of cardiac troponin T and I levels with the 12-lead method was 85% and 87%, respectively, and concordance with Holter monitoring was 72% and 66%, respectively. The postoperative 12-lead ECG identified peri-operative myocardial ischaemia associated with subsequent myocardial cell damage in most patients undergoing vascular surgery.

A labeling study to elucidate the biosynthesis of 4-(4-hydroxyphenyl)-butan-2-one (raspberry ketone) by Nidula niveo-tomentosa.

Submerged cells of the basidiomycete Nidula niveo-tomentosa, a microbial producer of 4-(4-hydroxyphenyl)-butan-2-one, were supplemented with (13)C-labeled L-phenylalanines and with [1-(13)C]glucose. Labeled transformation products were detected by a novel method of analyzing stable isotope-labeled metabolites, gas chromatography (GC) coupled to an atomic emission detector, and by GC-mass spectrometry. A benzoate moiety was side chain elongated according to the poly-beta-keto scheme. The presence of an acetyl coenzyme A-carboxylase inhibitor shifted the spectrum of products to benzyl compounds. Hence, the fungal pathway differs from the one established for plant tissues.

Tracking occupational doses of transient workers.

A number of radioactive material licensees in the United States are unaware that they are required to track the occupational doses their radiation workers receive outside thieir facilities. As a result, these licensees may be cited for not tracking offsite occupational doses and quite possible for allowing some individuals to exceed the annual limits established by regulatory agencies. The accounting of occupational doses to "transient" workers is a difficult task. Unfortunately, written guidance to assist licensees on how to properly address this issue is not available. This paper was developed to raise awareness among radiation safety professionals of the need to establish effective measures to properly track transient worker exposures and maintain compliance with regulatory limits.