Frequency stabilization of a terahertz quantum-cascade laser to the Lamb dip of a molecular absorption line.

We demonstrate the frequency stabilization of a terahertz quantum-cascade laser (QCL) to the Lamb dip of the absorption line of a D2O rotational transition at 3.3809309 THz. To assess the quality of the frequency stabilization, a Schottky diode harmonic mixer is used to generate a downconverted QCL signal by mixing the laser emission with a multiplied microwave reference signal. This downconverted signal is directly measured by a spectrum analyzer showing a full width at half maximum of 350 kHz, which is eventually limited by high-frequency noise beyond the bandwidth of the stabilization loop.

Clustering and variable selection in the presence of mixed variable types and missing data.

We consider the problem of model-based clustering in the presence of many correlated, mixed continuous, and discrete variables, some of which may have missing values. Discrete variables are treated with a latent continuous variable approach, and the Dirichlet process is used to construct a mixture model with an unknown number of components. Variable selection is also performed to identify the variables that are most influential for determining cluster membership. The work is motivated by the need to cluster patients thought to potentially have autism spectrum disorder on the basis of many cognitive and/or behavioral test scores. There are a modest number of patients (486) in the data set along with many (55) test score variables (many of which are discrete valued and/or missing). The goal of the work is to (1) cluster these patients into similar groups to help identify those with similar clinical presentation and (2) identify a sparse subset of tests that inform the clusters in order to eliminate unnecessary testing. The proposed approach compares very favorably with other methods via simulation of problems of this type. The results of the autism spectrum disorder analysis suggested 3 clusters to be most likely, while only 4 test scores had high (>0.5) posterior probability of being informative. This will result in much more efficient and informative testing. The need to cluster observations on the basis of many correlated, continuous/discrete variables with missing values is a common problem in the health sciences as well as in many other disciplines.

Long-term outcomes of children with symptomatic congenital cytomegalovirus disease.

OBJECTIVE: To assess long-term outcomes of children with symptomatic congenital cytomegalovirus (CMV) disease detected at birth. STUDY DESIGN: We used Cox regression to assess risk factors for intellectual disability (intelligence quotient <70), sensorineural hearing loss (SNHL; hearing level ⩾25 dB in any audiometric frequency) and vision impairment (best corrected visual acuity >20 or based on ophthalmologist report). RESULTS: Among 76 case-patients followed through median age of 13 (range: 0-27) years, 56 (74%) had SNHL, 31 (43%, n=72) had intellectual disability and 18 (27%, n=66) had vision impairment; 28 (43%, n=65) had intellectual disability and SNHL with/without vision impairment. Microcephaly was significantly associated with each of the three outcomes. Tissue destruction and dysplastic growth on head computed tomography scan at birth was significantly associated with intellectual disability and SNHL. CONCLUSION: Infants with symptomatic congenital CMV disease may develop moderate to severe impairments that were associated with presence of microcephaly and brain abnormalities.

Circadian Rhythm and the Gut Microbiome.

Circadian rhythms are 24-h patterns regulating behavior, organs, and cells in living organisms. These rhythms align biological functions with regular and predictable environmental patterns to optimize function and health. Disruption of these rhythms can be detrimental resulting in metabolic syndrome, cancer, or cardiovascular disease, just to name a few. It is now becoming clear that the intestinal microbiome is also regulated by circadian rhythms via intrinsic circadian clocks as well as via the host organism. Microbiota rhythms are regulated by diet and time of feeding which can alter both microbial community structure and metabolic activity which can significantly impact host immune and metabolic function. In this review, we will cover how host circadian rhythms are generated and maintained, how host circadian rhythms can be disrupted, as well as the consequences of circadian rhythm disruption. We will further highlight the newly emerging literature indicating the importance of circadian rhythms of the intestinal microbiota.

A randomized controlled trial of mindfulness-based stress reduction to prevent flare-up in patients with inactive ulcerative colitis.

BACKGROUND/AIMS: The primary therapeutic goals in ulcerative colitis (UC) are to maintain excellent quality of life (QOL) by treating flare-ups when they occur, and preventing flare-ups. Since stress can trigger UC flare-ups, we investigated the efficacy of mindfulness-based stress reduction (MBSR) to reduce flare-ups and improve QOL. METHODS: Patients with moderately severe UC, in remission, were randomized to MBSR or time/attention control. Primary outcome was disease status. Secondary outcomes were changes in markers of inflammation and disease activity, markers of stress and psychological assessments. RESULTS: 55 subjects were randomized. Absence of flares, time to flare and severity of flare over 1 year were similar between the two groups. However, post hoc analysis showed that MBSR decreased the proportion of participants with at least one flare-up among those with top tertile urinary cortisol and baseline perceived stress (30 vs. 70%; p < 0.001). MBSR patients who flared demonstrated significantly lower stress at the last visit compared to flared patients in the control group (p = 0.04). Furthermore, MBSR prevented a drop in the Inflammatory Bowel Disease Quality of Life Questionnaire during flare (p < 0.01). CONCLUSION: MBSR did not affect the rate or severity of flare-ups in UC patients in remission. However, MBSR might be effective for those with high stress reactivity (high perceived stress and urinary cortisol) during remission. MBSR appears to improve QOL in UC patients by minimizing the negative impact of flare-ups on QOL. Further studies are needed to identify a subset of patients for whom MBSR could alter disease course.

mGluR5 is necessary for maintenance of methamphetamine-induced associative learning.

Conditioned place preference (CPP) reflects the significance of contextual cues that are associated with rewarding effects of abused drugs such as methamphetamine (Meth). Glutamate neurotransmission is augmented following exposure to stimulants and associated cues. Activation of group I metabotropic glutamate receptors (mGluR) is critical for the acquisition and expression of stimulant-induced CPP. We hypothesized that the maintenance of Meth-induced CPP would also require activated mGluR, and that the role of mGluR1 vs. mGluR5 group I subtypes may differ. To test this hypothesis, negative allosteric modulators (NAMs) of these receptors were administered following the development of Meth-induced CPP. NAMs exert their functional effects by displacing agonist from agonist-occupied receptors, thus NAMs selectively target brain regions with glutamate release. Conditioning with Meth every other day for six days resulted in significant preference for the Meth-paired compartment. Two once-daily injections of the mGluR1 NAM, JNJ16259685 (0.3mg/kg, i.p.) or its vehicle on days 13 and 14 after Meth-conditioning did not influence the maintenance of Meth-induced CPP; however, administration of the mGluR5 NAMs MTEP (3mg/kg, i.p.) and MPEP (30 mg/kg, i.p.) inhibited maintenance processes necessary for CPP to be expressed. These findings suggest a subtype-specific role of mGluR5 receptors in the maintenance of place preference memory and potential of mGluR5 NAMs as a useful target for Meth addiction therapy.

Evaluation of the ability of neurobiological, neurodevelopmental and socio-economic variables to predict cognitive outcome in premature infants.

BACKGROUND: When developed in the 1990s, the Neurobiologic Risk Score (NBRS) and Neurodevelopmental Risk Exam (NRE) correlated well with developmental outcomes in premature infants. Given recent advances in neonatology, we assessed their present ability to predict cognitive outcome, alone and combined with socio-economic factors. METHODS: One hundred and twenty-nine neonates <32 weeks gestational age were assessed at 6, 12 and/or 24 months corrected age with the Cognitive Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS). Indices of socio-economic status included maternal education and marital status. RESULTS: At 24 months corrected age (n= 67), the NBRS (r=-0.5), maternal education (r= 0.46) and marital status (r= 0.37) correlated with the CAT/CLAMS. These correlations increased when NBRS and maternal education were combined (r= 0.63) and when specific NBRS components (intraventricular haemorrhage, periventricular leukomalacia, seizures) and maternal education were combined (r= 0.66). CONCLUSIONS: In the contemporary neonatal intensive care unit, measures used to predict cognitive outcome should incorporate both neurobiological risk factors and socio-economic variables.

[Hepatocellular carcinoma and cholangiocarcinoma]. / Hepatozelluläres Karzinom und Cholangiokarzinom.

Hepatocellular carcinoma and cholangiocarcinoma are relatively rare tumors of the gastrointestinal tract in western Europe but their incidence has been increased in recent years. Newly diagnosed intrahepatic lesions or intrahepatic cholestasis require extensive laboratory tests and imaging studies in order to confirm the diagnosis of hepatocellular carcinoma, intrahepatic or extrahepatic cholangiocarcinoma. The treatment options range from liver resection or liver transplantation to conservative measures (in cases of non-resectable lesions). This review article aims to provide an overview on the diagnostic options and the subsequent treatment.

Liver transplantation utilizing old donor organs: a German single-center experience.

INTRODUCTION: Due to the current profound lack of suitable donor organs, transplant centers are increasingly forced to accept so-called marginal organs. One criterion for marginal donors is the donor age >65 years. We have presented herein the impact of higher donor age on graft and patient survival. PATIENTS AND METHODS: Since 2004, 230 liver transplantations have been performed at our center, including 54 donor organs (23.5%) from individuals >65 years of age. We performed a retrospective analysis of recipient and graft survivals. RESULTS: The overall 1-year mortality was 22.2% (12/54) among recipients of organs from older donors versus 19.5% among recipients whose donors were <65 years. When donor organs were grouped according to age, the 1-year mortality in patients receiving organs from donors aged 65-69 years was 30% (6/20); 70-74 years, 29.4% (5/17); and donors >75 years, 5.9% (1/17). There was no significant correlation between mortality rate and the number of additional criteria of a marginal donor organ. DISCUSSION: The current lack of donor organs forces transplant centers to accept organs from older individuals; increasingly older patients are being recruited for the donor pool. Our results showed that older organs may be transplanted with acceptable outcomes. This observation was consistent with data from the current literature. It should be emphasized, however, that caution is advised when considering the acceptance of older organs for patients with hepatitis C-related cirrhosis.

[Damage control concept in liver trauma. Package strategies and secondary measures]. / Damage-control-Konzept bei Leberverletzungen. Package-Strategien und sekundäre Massnahmen.

Liver injuries may occur alone as well as within the broader context of polytrauma. Immediate surgical intervention is indicated in hemodynamically instable patients with detection of free intra-abdominal fluid as demonstrated by imaging studies. For these patients, a damage control concept has been devised in order to decrease early mortality after trauma. With this strategy complex reconstructive interventions are avoided during the initial phase. Stabilization of the patient by treatment of the lethal triad consisting of hypothermia, coagulopathy and metabolic acidosis is at the core of this therapeutic concept. Should there be a need for reconstructions or other major surgical interventions these will be performed with delay after stabilization of the patient. Packing for the temporary treatment of liver injuries is part of the damage control concept.

Exanthema in Legionnaires' disease mimicking a severe cutaneous drug reaction.

Legionnaires' disease is an acute bacterial infection, generally caused by Legionella pneumophila, which primarily involves the lower respiratory tract, although it is often associated with multisystemic extrapulmonary features. Cutaneous features are very uncommon and may include erythematous or petechial, macular or maculopapular lesions. We report a male patient who expressed all features of a severe lobular pneumonia. Over the course of the disease the patient developed a livid erythematous, maculopapular exanthem rapidly extending over the entire body. Given the rapid development and target-like appearance of the skin lesions with extensive skin involvement and blister formation, the initial diagnosis was that of a severe cutaneous drug reaction. However, histological examination of biopsy did not confirm this diagnosis, but instead was suspicious for a viral exanthem or a more aggressive inflammatory response due to sensitization to bacterial antigens. L. pneumophila infection was verified during the course of the disease.

[Indications and results of palliative gastric resection in advanced gastric carcinoma]. / Indikationen und Ergebnisse der palliativen Magenresektion beim fortgeschrittenen Magenkarzinom.

BACKGROUND: Gastric carcinoma is often diagnosed at UICC stage 3 b or 4. R0 resection can be achieved only in very few such cases. Even for these patients the 5-year survival rate is less than 5 %. Surgical palliation is traditionally reserved for the treatment of severe tumour complications not responding to other forms of treatment. PATIENTS AND METHODS: We report on 21 patients who underwent palliative resection for gastric carcinoma at our institution between 2004 and 2007. Ten of these were assigned to palliative surgical treatment pre-operatively while this choice was made for 11 patients on the grounds of the intra-operative findings. We performed 17 gastrectomies, 3 proximal gastric resections and one distal gastric resection. RESULTS: It has been shown that the patients have an improved overall survival time as compared to patients who received non-surgical treatment. The perioperative risk was reasonable when patients were carefully selected. Median survival for resected patients was 16 months. 80 % of patients were alive after 6 months and approximately 60 % of patients were alive after 12 months. The perioperative mortality was 0 % with a mean hospital stay of 12 days. All patients were discharged home with proper bowel passage and analgesia as individually required. CONCLUSIONS: We are convinced that palliative gastric resection provides a pronounced survival benefit over any other palliative treatment options. Patients also have an improved quality of life.

DNA methylation is not responsible for p21WAF1/CIP1 down-regulation in osteoarthritic chondrocytes.

OBJECTIVE: In this study, we were interested in the overall methylation level in aged and degenerated cartilage. Also, we looked at one gene which might be involved in the re-initiation of replicative activity in osteoarthritis (OA) chondrocytes, p21(WAF1/CIP1). p21(WAF1/CIP1) was previously suggested to be down-regulated in OA chondrocytes and is known to be regulated by epigenetic modulation. METHODS: Total methylation levels were analyzed by high pressure liquid chromatography (HPLC), mRNA expression of p21(WAF1/CIP1) and DNMT enzymes by real-time polymerase chain reaction. The methylation status of the p21(WAF1/CIP1)- promotor using bisulfite genomic sequencing was evaluated. RESULTS: General methylation analysis of genomic DNA showed no difference in between normal and aged/OA chondrocytes. Also no difference in methylation of the promotor of the p21(WAF1/CIP1) gene was detectable, which was significantly down-regulated in OA chondrocytes. DNMT1 and DNMT3a were expressed with no significant changes of expression levels found in OA chondrocytes. CONCLUSION: Cell cycle progression inhibitor p21(WAF1/CIP1) is expressed in normal and significantly down-regulated in OA articular chondrocytes, which may mediate the re-initiation of cell proliferation in OA cartilage. However, the suppression of p21(WAF1/CIP1) mRNA expression is not due to hypermethylation of its promotor. No overall changes in genome methylation levels were found in aged or OA cartilage. Interestingly, significant expression of DNA methyltransferases was found in articular chondrocytes, which supports that DNA methylation could still be a relevant mechanism of gene regulation in (osteoarthritic) chondrocytes, though not on an overall genomic level nor specifically for the regulation of the p21(WAF1/CIP1) gene.

Efficient non-viral transfection of primary human adult chondrocytes in a high-throughput format.

OBJECTIVE: The development of a reliable high-throughput transfection protocol for primary human articular chondrocytes. METHODS: Primary human chondrocytes were isolated from adult knee cartilage by an optimized enzymatic digestion protocol and cultivated in high-density monolayer culture for 3-5 days. Isolated chondrocytes were transfected with a green fluorescent protein (GFP)-expressing reporter construct using amaxa's Nucleofector 96-well Shuttle System. Transfection efficiencies were measured by fluorescence activated cell sorting and cell viability was determined by an adenosine-5'-triphosphate (ATP) assay. siRNA oligonucleotides (against glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) were transfected into the cells using the optimized nucleofection protocol and mRNA knockdown values were determined by a branched-DNA assay. RESULTS: Transfection efficiencies of more than 70% of surviving cells were achieved routinely with the nucleofection protocol presented in this article. Cell viability 24h post transfection was around 80%. The cell number used per transfection was reduced to 2x10(5) per sample. In addition, the protocol proved to be well suited for the transfer of siRNA molecules into primary human chondrocytes with suppression rates on the mRNA level of more than 95% (for GAPDH). CONCLUSIONS: We present the successful use of nucleofection on primary human chondrocytes using a microtiter plate compatible format that for the first time allows the efficient transfection of up to 96 samples in parallel. The optimized nucleofection protocol is offering maximum substrate flexibility by allowing transfer of DNA and siRNA oligonucleotides with the same set of parameters. Moreover, the transfection procedure requires substantially lower cell numbers than single cuvette protocols and is therefore perfectly suited for applications requiring multiple experimental replicates.

Epidemiology of diabetes mellitus in German general practitioners' consultation--results of the SESAM 2-study.

The treatment of chronic diseases is of eminent importance in primary care, and type 2-diabetes mellitus is one of the most common dysfunctions. Its world-wide prevalence has been increasing from year to year. Thus, to estimate the prevalence and incidence of diabetes mellitus, we performed the SESAM (Sächsiche epidemiologische Studie in der Allgemeinmedizin) 2-study in cooperation with general practitioners (GPs) from the German state of Saxony; 270 of the 2510 (10.8%) solicited physicians participated. Cross-sectional data were collected from 1 October 1999 until 30 September 2000, from randomly selected patients previously known to the practitioner. From a total of 8877 consultations with 270 GPs, diabetes was prevalent in 14% (n = 1241) of the patients and the incidence was 0.3% (27 of 8877 cases). The consultation prevalence was estimated at 14.3% (n = 1268; CI 13.6-15%). Of the diabetic patients, 3.5% (n = 44) suffered from type 1-diabetes, while type 2-diabetes was found in 66.9% (n = 848) of the cases. "Other diabetes" was determined in 19.2% (n = 244), and "not further specified diabetes", in 10.4% (n = 132) of the cases. Related to the German population in general, the prevalence ranged from 7.9 to 9.2%. The estimated consultation prevalence is about four times higher than that in other European countries. These data are of importance in illustrating the epidemiology of diabetes in the population and the direct repercussions for GPs. They also point out the significance of diabetes as a major challenge to the German health care system.

[Respiratory symptoms in the general practice. An analysis of the Leipzig SESAM Study]. / Atemwegsbeschwerden in der allgemeinärztlichen Sprechstunde. Eine Auswertung der Leipziger SESAM-Studie.

The Saxon Study of General Medicine (SESAM) investigated the reasons why patients consulted the general practitioner, which diagnoses were established and how the patients were subsequently treated. In the majority of cases, the respiratory symptoms were simple infections of the upper and lower respiratory tract. Pneumonia must always be considered, while severe pulmonary diseases are of no significance in the differential diagnosis of respiratory complaints in the general practice.

Weak VLPP and MUCP correlation and their relationship with objective and subjective measures of severity of urinary incontinence.

The aims of the present study were to find the correlation between Valsalva leak-point pressure (VLPP) and cough leak-point pressure (CLPP) and to determine whether the water perfusion maximum urethral closure pressure (MUCP) correlates with VLPP. Seventy-nine women with previously untreated stress urinary incontinence were recruited to participate in a clinical study. Their mean age was 56.4 years, mean BMI was 27.8, and mean parity was 1.9. The mean values of VLPP and CLPP were 50.4 and 52.9 cm H(2)O, respectively. We did not find statistically significant differences in the mean values of VLPP and CLPP. The mean value of MUCP at rest was 44.2 cm H(2)O and the mean value of MUCP during maximal Valsalva maneuver was 37.2 cm H(2)O; with 500 ml of sterile saline in the bladder the difference between them is statistically significant. In the study group (n=79), 56 patients (77%) had low VLPP (< or =60 cm H(2)O), 21 patients (30%) had low MUCP (< or =30 cm H(2)O), and 8 patients had MUCP< or =20 cm H(2)O (all at rest). Of the 56 patients with low VLPP, 16 also had a low MUCP (< or =30 cm H(2)O). This study mainly compares two parameters-the MUCP and the VLPP. Based on our results we can conclude that there is no correlation between these parameters. MUCP measures urethral resistance at rest and VLPP measures urethral resistance during increased intra-abdominal pressure (Valsalva maneuver).