Summer temperatures reach the thermal tolerance threshold of photosynthetic decline in temperate conifers.

Climate change-related environmental stress has been recognized as a driving force in accelerating forest mortality over the last decades in Central Europe. Here, we aim to elucidate the thermal sensitivity of three native conifer species, namely Norway spruce (Picea abies), Scots pine (Pinus sylvestris) and silver fir (Abies alba), and three non-native species, namely Austrian pine (Pinus nigra), Douglas fir (Pseudotsuga menziesii) and Atlas cedar (Cedrus atlantica). Thermal sensitivity, defined here as a decline of the maximum quantum yield of photosystem II (Fv /Fm ) with increasing temperature, was measured under varying levels of heat stress and compared with the turgor loss point (πtlp ) as a drought resistance trait. We calculated three different leaf thermotolerance traits: the temperature at the onset (5%) of the Fv /Fm decline (T5), the temperature at which Fv /Fm was half the maximum value (T50) and the temperature at which only 5% Fv /Fm remained (T95). T5 ranged from 38.5 ± 0.8 °C to 43.1 ± 0.6 °C across all species, while T50 values were at least 9 to 11 degrees above the maximum air temperatures on record for all species. Only Austrian pine had a notably higher T5 value than recorded maximum air temperatures. Species with higher T5 values were characterized by a less negative πtlp compared to species with lower T5. The six species could be divided into 'drought-tolerant heat-sensitive' and 'drought-sensitive heat-tolerant' groups. Exposure to short-term high temperatures thus exhibits a considerable threat to conifer species in Central European forest production systems.

Predicting the need of aortic valve surgery in patients with chronic aortic regurgitation: a comparison between cardiovascular magnetic resonance imaging and transthoracic echocardiography.

To compare the ability of cardiac magnetic resonance tomography (CMR) and transthoracic echocardiography (TTE) to predict the need for valve surgery in patients with chronic aortic regurgitation on a mid-term basis. 66 individuals underwent assessment of aortic regurgitation (AR) both in CMR and TTE between August 2012 and April 2017. The follow-up rate was 76% with a median of 5.1 years. Cox proportional hazards method was used to assess the association of the time-to-aortic-valve-surgery, including valve replacement and reconstruction, and imaging parameters. A direct comparison of most predictive CMR and echocardiographic parameters was performed by using nested-factor-models. Sixteen patients (32%) were treated with aortic valve surgery during follow-up. Aortic valve insufficiency parameters, both of echocardiography and CMR, showed good discriminative and predictive power regarding the need of valve surgery. Within all examined parameters AR gradation derived by CMR correlated best with outcome [χ2 = 27.1; HR 12.2 (95% CI: 4.56, 36.8); (p < 0.0001)]. In direct comparison of both modalities, CMR assessment provided additive prognostic power beyond echocardiographic assessment of AR but not vice versa (improvement of χ2 from 21.4 to 28.4; p = 0.008). Nested model analysis demonstrated an overall better correlation with outcome by using both modalities compared with using echo alone with the best improvement in the moderate to severe AR range with an echo grade II out of III and a regurgitation fraction of 32% in CMR. This study corroborates the capability of CMR in direct quantification of AR and its role for guiding further treatment decisions particularly in patients with moderate AR in echocardiography.

Middle Meningeal Artery Embolization Using Combined Particle Embolization and n-BCA with the Dextrose 5% in Water Push Technique for Chronic Subdural Hematomas: A Prospective Safety and Feasibility Study.

BACKGROUND AND PURPOSE: Embolization of the middle meningeal artery for treatment of refractory or recurrent chronic subdural hematomas has gained momentum during the past few years. Little has been reported on the use of the n-BCA liquid embolic system for middle meningeal artery embolization. We present the technical feasibility of using diluted n-BCA for middle meningeal artery embolization. MATERIALS AND METHODS: We sought to examine the safety and technical feasibility of the diluted n-BCA liquid embolic system for middle meningeal artery embolization. Patients with chronic refractory or recurrent subdural hematomas were prospectively enrolled from September 2019 to June 2020. The primary outcome was the safety and technical feasibility of the use of diluted n-BCA for embolization of the middle meningeal artery. The secondary end point was the efficacy in reducing hematoma volume. RESULTS: A total of 16 patients were prospectively enrolled. Concomitant burr-hole craniotomies were performed in 12 of the 16 patients. Two patients required an operation following middle meningeal artery embolization for persistent symptoms. The primary end point was met in 100% of cases in which there were no intra- or postprocedural complications. Distal penetration of the middle meningeal artery branches was achieved in all the enrolled cases. A 7-day post-middle meningeal artery embolization follow-up head CT demonstrated improvement (>50% reduction in subdural hematoma volume) in 9/15 (60%) patients, with 6/15 (40%) showing an unchanged or stable subdural hematoma. At day 21, available CT scans demonstrated substantial further improvement (>75% reduction in subdural hematoma volume). CONCLUSIONS: Embolization of the middle meningeal artery using diluted n-BCA and ethiodized oil (1:6) is safe and feasible from a technical standpoint. The use of a dextrose 5% bolus improves distal penetration of the glue.

Psychometric characteristics of the FertiQoL questionnaire in a German sample of infertile individuals and couples.

BACKGROUND: FertiQoL is a questionnaire internationally developed to measure fertility-specific quality of life. It has been validated with infertile populations in many countries and used in several studies focusing on the psychosocial consequences of infertility in Europe, Asia, and North America. METHODS: Over a period of two years, 596 infertile women and men took part in the study conducted at three German fertility clinics. Psychometric properties of FertiQoL were tested by performing confirmatory factor analyses, calculating average variance extracted values, reliability and correlation coefficients. Hierarchical regression analyses were conducted to determine the relations between FertiQoL subscales and both sociodemographic and medical variables. Individual and cross-partner effects were tested for. RESULTS: The confirmatory factor analyses conducted on our FertiQoL data supported the original four-factor solution for both women and men but, resulted in some unsatisfactory indices. Family and friends' support items loaded weakly on the Social subscale of FertiQoL (.27 and .34 in women, .32 and .19 in men). The Emotional and Mind/Body subscales revealed a strong intercorrelation (r = .77, p < .001 in women, r = .74, p < .001 in men). Women scored lower than men on the Emotional and Mind/Body subscales only, and they reported better fertility-specific relational QoL. In women, the perceived cause of infertility and already mothering a child related significantly to individual FertiQoL scores, while in men, age, educational level, and the duration of their wish for a child had an impact on the FertiQoL subscales (all p < .05). The men's educational level, the women's educational level, and the subjective perceived medical cause of fertility problems exerted cross-partner effects on QoL (all p < .05). CONCLUSIONS: Our study results represent a contribution both to research and clinical practice. The findings suggest the importance of considering the personal experience of infertility in different cultural and gender specific settings and that the strong connections between the emotional, physical, and cognitive aspects of an individual's fertility-specific quality of life should be regarded as a more coherent system. TRIAL REGISTRATION: DRKS: DRKS00014707 . Registered 1 May 2018 (retrospectively registered).

Infertile Partners' Coping Strategies Are Interrelated - Implications for Targeted Psychological Counseling.

Background Infertility patients often have high stress levels which, in some cases, represent a risk of developing depression or anxiety. The SCREENIVF questionnaire is a validated tool to evaluate such risks. Some coping strategies have been shown to be correlated with infertile couples' levels of stress. Determining which strategies are correlated with higher levels of risk for depression or anxiety could be useful to offer targeted psychological counseling to reduce the risk of depression or anxiety. Materials and Methods A total of 296 women and men who attended the Fertility Center at Heidelberg University Hospital completed the SCREENIVF questionnaire and the COMPI coping scales. Data were analyzed first on an individual basis and focused on the couple, using the Actor Partner Interdependence Model. Results On an individual level, active avoidance coping was positively correlated with a higher risk of depression or anxiety in women, while meaning-based coping was negatively correlated with risk in men. When the results of couples were viewed together, women and men using active avoidance coping exhibited higher risk scores as individuals (actor effect), as did their partners (partner effect). Women who used meaning-based coping had positive actor and partner effects. Women using active-confronting coping had a negative partner effect (higher risk score for men). Conclusions These findings indicate that some coping strategies may have a protective effect while others may increase the risk of emotional maladjustment in infertile couples. Further analysis of coping strategies could help to identify new counseling approaches for infertile patients.

Effects of medical causes, role concepts and treatment stages on quality of life in involuntary childless men.

Goal of this study was to investigate differences in quality of life in men contingent upon various fertility treatment stages, infertility causes and adoption of roles. A quantitative study with n = 115 men in three German fertility centres was devised. Participants completed a standardised, fertility-specific questionnaire devised for men (TLMK), sociodemographic and role items. Men having experienced severe medical conditions, for example cancer, reported significant higher quality of life compared to men with other infertility reasons [F(1,56) = 12.77, P = 0.001]. Furthermore, allocating participants into distinctive groups by means of kind and duration of treatment revealed significant group differences [F(2,111) = 4.94, P = 0.009], with quality of life decreasing with the use of more invasive fertility methods. A higher satisfaction with life was also stated by men adopting many tasks in the treatment process. The high quality of life displayed by men having experienced severe medical conditions contains valuable and far-reaching information about possible resilience factors that need to be researched more in detail. The finding of decreasing quality of life in men with the use of more invasive methods in treatment applies for increased psychosocial services in fertility clinics.

Improved self- and external assessment of the clinical abilities of medical students through structured improvement measures in an internal medicine bedside course.

BACKGROUND: Bedside courses are of outstanding importance when training medical students. The fact that less and less teaching is taking place nowadays at the patient's bedside makes it all the more important that the available time be put to effective use. The aim of this study was to check whether structured improvement measures in the course (scripts, lecturer briefing, e-learning cases) would improve the abilities of the students on the basis of a subjective self-assessment as well as an external assessment by the lecturers with respect to clinical abilities. METHODS: Bedside teaching takes place in the fourth study year in the Medical Clinics of the TU Munich. Both students and lecturers had the chance to hand in an anonymous, quantitative self- and external assessment of the clinical abilities of the students (German grading system) after every course date. This assessment took place online in the three categories "Medical history & examination", "Diagnosis" and "Therapy". An overall period of four semesters, each with 6 course dates, was investigated. After two of the total of four semesters in the study, the course was changed by introducing scripts, lecturer briefing as well as interactive e-learning cases. The self- and external assessment was compared both within the semester (date 1-3: A; date 4-6: B), during the course as well as before and after introducing the improvement measures ("before" (T0): SS 2012, SS 2013, "after" (T1): WS 2013/2014, SS 2014). RESULTS: There was a significant improvement in one's own abilities on the basis of the self-assessment within each semester when comparing the first (A) and the last (B) course dates. Moreover, there was a significant improvement in the performances in all three categories when T0 was compared with T1, from both the point of view of the students ("Medical history & examination": T0 =2.5±0.9, T1=2.2±0.7, pp<0.001; "Diagnosis" T0=3.1±1.0, T1=2.8 ±0.9, pp<0.001; "Therapy": T0=3.8±1.3, T1=3.5±1.2, pp<0.018) and in two of the three categories from the point of view of the lecturers ("Diagnosis": T0=3.0±1.0, T1=2.7±0.7, p.=0.028; "Therapy": T0=3.8±1.1, T1=3.1±1.0, p<0.001). SUMMARY: The structured measures to improve the course including the interactive e-learning cases could have contributed to improved practical abilities with respect to the medical history and examination techniques as well as diagnostic and therapeutic thinking. The external evaluation by lecturers confirmed the improvement with respect to the diagnostic and therapeutic abilities. They only saw no dynamic change in the student's taking histories and clinical examinations.

Avoiding OHSS: Controlled Ovarian Low-Dose Stimulation in Women with PCOS.

The polycystic ovary syndrome is a common endocrine disorder which influences outcome and potential risks involved with controlled ovarian stimulation for artificial reproductive techniques (ART). Concrete practical recommendations for the dosage of gonadotropins, the preferred protocol and preventive methods to avoid ovarian hyperstimulation syndrome (OHSS) are lacking. We present retrospective data of 235 individually calculated gonadotropin low-dose stimulations for ART in a single center from 2012 to 2014. Clinical data and outcome parameter of patients diagnosed with PCOS according to Rotterdam criteria (n = 39) were compared with patients without PCOS (n = 196). The starting dose of gonadotropins was individually calculated depending on patients' age, BMI, ovarian reserve, ovarian response in previous cycles, and diagnostic criteria of PCOS. Mean age and duration of infertility did not differ between the groups, whereas mean BMI (p = 0.007) and AMH (p < 0.001) were higher in the PCOS-group. A lower mean FSH-starting and maximum dose was administered to women with PCOS (p < 0.001). The biochemical pregnancy rate of 42.4 % and the clinical pregnancy rate of 32.2 % for PCOS-patients did not differ from those of the control group (42.2 % and 34.4 % respectively). Neither mild, nor moderate or severe manifestation of OHSS occurred significantly more often in patients with PCOS. Our study supports the use of a calculated low-dose FSH-stimulation strategy in ART for patients with PCOS. Further randomized clinical trials should confirm this strategy and lead to define individual risk factors for OHSS, which can be used for recommendation of safer ART-techniques like in vitro maturation.

Current Findings and Mechanisms of Action of Disulfiram in the Treatment of Alcohol Dependence.

As an alcohol-aversive agent, disulfiram occupies an exceptional position in the pharmacological relapse prevention of alcohol dependence. In contrast to anti-craving drugs, disulfiram does not modulate neurobiological mechanisms of addiction, but rather works by producing an aversive reaction when combined with alcohol. Therapeutic and adverse effects are therefore closely related: On the one hand, the aversiveness of the disulfiram ethanol reaction has the potential to support abstinence in a subgroup of alcohol-dependent patients, while on the other hand it becomes a health threat if the patient fails to maintain complete abstinence. The exceptional position of disulfiram is also related to the role that expectations play in the mediation of therapeutic effects. These are not determined by the pharmacological effects or the actual occurrence of a disulfiram-ethanol reaction, but are attributable to patient awareness that the drug was consumed and the corresponding anticipation of an aversive reaction if combined with alcohol. This is in line with the findings of a recent meta-analysis that only showed significant effects for disulfiram in open-label trials. The authors of the meta-analysis conclude that due to expectations induced in both the treatment and placebo groups, blinded studies are incapable of distinguishing a difference between groups. The mediation of therapeutic effects through expectation has a number of consequences for clinical practice and future research on disulfiram.

Infertility Specific Quality of Life and Gender Role Attitudes in German and Hungarian Involuntary Childless Couples.

Introduction: As gender role attitudes and the evaluation of parenthood and childlessness have subtle variations in each society, cross-country studies focusing on infertility are needed to draw a complex picture in the psychosocial context of infertility. This study investigates similarities and differences between German and Hungarian infertile couples regarding infertility specific quality of life and personal gender role attitudes. Methods: A cross-sectional study was conducted with data of 540 participants (270 couples) attending the first fertility consultation in one fertility clinic in Germany and in five fertility clinics in Hungary. Data were collected between February 2012 and March 2013. Two psychological questionnaires were applied: The FertiQoL to measure infertility specific quality of life and the PAQ to measure gender role attitudes like "instrumental" acting (as a traditional "masculine" attitude) and "expressive" communicating (as a traditional "femine" attitude) and their combinations "combined" attitude (as both "instrumental" and "expressive") and "neutral" attitude (neither "instrumental" nor "expressive"). Results: German couples seeking assisted reproduction treatment are older aged and have longer lasting relationships than Hungarian couples. Hungarian couples scored higher on all quality of life scales than did German couples. In the Hungarian group, "combined" attitudes (use of both "expressive" and "instrumental" attitudes) is associated with higher levels of quality of life compared with other gender role attitudes. In the German group, individuals with "combined" attitudes seem to show better quality of life than those in "expressive" and "neutral" clusters. Conclusions: The strategy of using combined "expressive" and "instrumental" attitudes proved to act as a buffer against infertility-related stress for both members of the couple in two European countries and can therefore be recommended as helpful in counselling the infertile couple.

Sexuality, Self-Esteem and Partnership Quality in Infertile Women and Men.

Introduction: Infertile couples often report quality-of-life impairments, especially in terms of sexuality, self-esteem and partnership quality. So far, there have been no systematic studies of the sex lives and behaviour of infertile women and men before and after the emergence of their mutual desire for a child. Materials and Methods: From February 2010 to August 2010 all couples starting treatment either at Heidelberg University's Women's Hospital or at the Fertility Center Berlin were asked to fill out the Self-Esteem and Relationship Questionnaire (SEAR). A total of n = 158 women and n = 153 men participated in the study. Results: Decreasing tendencies were observable for both partners in the domains Sexual Relationship Satisfaction and Confidence and in the subscales Self-Esteem and Overall Relationship Satisfaction. There were especially clear indications of a loss of spontaneous sexuality during the experience of infertility. We were also able to establish that infertility has a negative impact on women's self-esteem. Discussion: The results of this study indicate that SEAR can be used as a feasible instrument for identifying infertile women and men whose infertility has a negative effect on their relationship quality and/or sex lives.

Evaluation of the effectiveness of mass trapping with BG-sentinel traps for dengue vector control: a cluster randomized controlled trial in Manaus, Brazil.

The objective of this study was to assess the effectiveness of BG-Sentinel (BGS) traps for mass trapping at the household level to control the dengue vector, Aedes aegypti (L.), in Manaus (Brazil) by performing a cluster randomized controlled trial. After an initial questionnaire and baseline monitoring, 6 out of 12 clusters were randomly allocated to the intervention arm, where participating premises received one BGS trap for mass trapping. The other six clusters did not receive traps and were considered as the control arm. Biweekly monitoring with BGS in both arms assessed the impact of mass trapping. At the end of the study, a serological survey was conducted and a second questionnaire was conducted in the intervention arm. Entomological monitoring indicated that mass trapping with BGS traps significantly reduced the abundance of adult female Ae. aegypti during the first five rainy months. In the subsequent dry season when the mosquito population was lower, no effect of mass trapping was observed. Fewer Ae. aegypti females were measured in the intervention arm during the next rainy period, but no significant difference between arms was observed. The serological survey revealed that in participating houses of mass trapping areas recent dengue infections were less common than in control areas, although this effect was not statistically significant. The majority of participants responded positively to questions concerning user satisfaction. Our results suggest that BGS traps are a promising tool which might be deployed as part of dengue control programs; however, further investigations and larger scale studies are necessary.

[Drug-induced liver injury with an autoimmune phenotype following anti-TNF Therapy - presentation of cases and review of literature]. / Medikamentöse Schädigung der Leber mit autoimmunem Phänotyp durch TNF-Blockade - Fallvorstellung und Review der Literatur.

Therapeutic agents to inhibit tumour necrosis factor alpha (TNF-α) have dramatically improved the treatment options for patients with autoimmune diseases. Common side effects include an increased susceptibility towards infection. Hepatic side effects are less frequently observed. Elevated liver function tests, hyperbilirubinaemia reactivation of chronic viral hepatitis or even acute liver failure have been described. Some cases have exhibited an autoimmune phenotype with the emergence of autoantibodies and characteristic histological lesions. We report on three patients who received anti-TNF therapy for psoriasis and presented with elevated liver function tests in the further course. Histological and serum analysis revealed an autoimmune phenotype of liver injury. In light of the growing use of anti-TNF therapies, drug-induced liver injury (DILI) with an autoimmune phenotype is an important side effect. Since the pathophysiological mechanisms related to the autoimmune phenotype of liver injury during TNF-inhibition are not well understood, the cases detailed herein should help treating physicians to improve their understanding of the situation.

Intrauterine instillation of diluted seminal plasma at oocyte pick-up does not increase the IVF pregnancy rate: a double-blind, placebo controlled, randomized study.

STUDY QUESTION: Does intrauterine application of diluted seminal plasma (SP) at the time of ovum pick-up improve the pregnancy rate by ≥14% in IVF treatment? SUMMARY ANSWER: Intrauterine instillation of diluted SP at the time of ovum pick-up is unlikely to increase the pregnancy rate by ≥14% in IVF. WHAT IS KNOWN ALREADY: SP modulates endometrial function, and sexual intercourse around the time of embryo transfer has been suggested to increase the likelihood of pregnancy. A previous randomized double-blind pilot study demonstrated a strong trend towards increased pregnancy rates following the intracervical application of undiluted SP. As this study was not conclusive and as the finding could have been confounded by sexual intercourse, the intrauterine application of diluted SP was investigated in the present trial. STUDY DESIGN, SIZE, DURATION: A single-centre, prospective, double-blind, placebo-controlled, randomized, superiority trial on women undergoing IVF was conducted from April 2007 until February 2012 at the University Department of Gynaecological Endocrinology and Reproductive Medicine, Heidelberg, Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was powered to detect an 14% increase in the clinical pregnancy rate and two sequential tests were planned using the Pocock spending function. At the first interim analysis, 279 women had been randomly assigned to intrauterine diluted SP (20% SP in saline from the patients' partner) (n = 138) or placebo (n = 141) at the time of ovum pick-up. MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate per randomized patient was 37/138 (26.8%) in the SP group and 41/141 (29.1%) in the placebo group (difference: -2.3%, 95% confidence interval of the difference: -12.7 to +8.2%; P = 0.69). The live birth rate per randomized patient was 28/138 (20.3%) in the SP group and 33/141 (23.4%) in the placebo group (difference: -3.1%, 95% confidence interval of the difference: -12.7 to +6.6%; P = 0.56). It was decided to terminate the trial due to futility at the first interim analysis, at a conditional power of 62%. LIMITATIONS, REASONS FOR CAUTION: The confidence interval of the difference remains wide, thus clinically relevant differences cannot reliably be excluded based on this single study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study cast doubt on the validity of the concept that SP increases endometrial receptivity and thus implantation in humans. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the department's own research facilities. TRIAL REGISTRATION NUMBER: DRKS00004615.

Successful controlled ovarian stimulation despite elevated hCG levels after first-trimester abortion in the context of fertility preservation.

Fertility preservation prior to gonadotoxic chemotherapy by cryopreservation of the ovarian tissue and controlled ovarian stimulation can be effective immediately after induced abortion in the first trimenon. In a reproductive endocrinology and infertility unit of a tertiary care university-based medical centre (University Hospital of Heidelberg) a 37-year-old women with breast cancer was counseled for fertility preservation. Cryopreservation of ovarian tissue, followed by ovarian stimulation for planned intracytoplasmatic sperm injection (ICSI), transvaginal oocyte aspiration and cryopreservation of fertilized eggs was performed in spite of persistently elevated human chorionic gonadotropin (hCG)-levels after induced abortion. Twenty-four fertilized oocytes with a fertilization rate of 92% were cryopreserved. Ovarian stimulation and oocyte cryopreservation can be successfully performed with good results immediately after miscarriage, despite persistent high hCG-levels.

IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis.

Interleukin-7 receptor alpha (IL7RA) is among the top listed candidate genes influencing the risk to develop multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Soluble IL-7RA (sIL-7RA) protein and mRNA levels vary among the four common IL7RA haplotypes. Here we show and confirm that protective haplotype carriers have three times lower sIL-7RA serum levels than the other three haplotypes. High sIL-7RA concentrations significantly decrease IL-7-mediated STAT5 phosphorylation in CD4(+) T cells. Transcriptome analysis of unstimulated and stimulated CD4(+) T cells of MS patients carrying the different IL7RA haplotypes revealed complex and overlapping patterns in genes participating in cytokine signaling networks, apoptosis, cell cycle progression and cell differentiation. Our findings indicate that genetic variants of IL7RA result in haplotype-associated differential responsiveness to immunological stimuli that influence MS susceptibility not exclusively by varying levels of sIL-7RA.

Calibrated nanoscale capacitance measurements using a scanning microwave microscope.

A scanning microwave microscope (SMM) for spatially resolved capacitance measurements in the attofarad-to-femtofarad regime is presented. The system is based on the combination of an atomic force microscope (AFM) and a performance network analyzer (PNA). For the determination of absolute capacitance values from PNA reflection amplitudes, a calibration sample of conductive gold pads of various sizes on a SiO(2) staircase structure was used. The thickness of the dielectric SiO(2) staircase ranged from 10 to 200 nm. The quantitative capacitance values determined from the PNA reflection amplitude were compared to control measurements using an external capacitance bridge. Depending on the area of the gold top electrode and the SiO(2) step height, the corresponding capacitance values, as measured with the SMM, ranged from 0.1 to 22 fF at a noise level of ~2 aF and a relative accuracy of 20%. The sample capacitance could be modeled to a good degree as idealized parallel plates with the SiO(2) dielectric sandwiched in between. The cantilever/sample stray capacitance was measured by lifting the tip away from the surface. By bringing the AFM tip into direct contact with the SiO(2) staircase structure, the electrical footprint of the tip was determined, resulting in an effective tip radius of ~60 nm and a tip-sample capacitance of ~20 aF at the smallest dielectric thickness.

[Monitoring of the misuse of prescription drugs by clients of outpatient addiction treatment centres (PHAR-MON, formerly: Ebis-med). Monitoring of medication misuse]. / Monitoring des Arzneimittelmissbrauchs bei Klienten ambulanter Suchtberatungsstellen (PHAR-MON, ehemals: ebis-med). Monitoring des Arzneimittelmissbrauchs.

OBJECTIVES: The monitoring system PHAR-MON (formerly: ebis-med) documents the misuse of pharmaceuticals in addiction counseling centres as an early warning system. It is described as a diagnostic instrument according to its aims and tasks, implementation and assessing procedures and is evaluated according to the main quality criteria of diagnostic instruments. In addition, selected results are reported about the misuse of medicaments in the year 2004. METHODS: In analogy to diagnostic instruments, the main quality criteria objectivity, reliability and validity are applied to evaluate PHAR-MON, they are extended, however, by the validity of the sample of reference outpatient centers. Statistical methods for proving results are applied and discussed concerning their appropriateness for cross-sectional and longitudinal analyses of PHAR-MON data. The selected results are based on the survey data for 2004 of 32 counseling centers with 629 medicaments abused by 500 clients. The representativity was checked by comparison with the outpatient addiction statistics. RESULTS: The sample of counseling centers is representative for all addiction counseling centers in Germany. The dominant influence factor on the abuse of medicaments is the main diagnosis of the clients. Therefore, the analysis is separated for the main diagnoses as to alcohol, illegal drugs and medicaments. The statistical methods of confidence intervals and other statistical procedures are useful in proving data for cross-sectional and longitudinal analyses. In 2004 there was an increase of abused buprenorphine by 5.7% compared to the previous year. The rate of misuse of hypnotics, which is the largest group of abused medicaments, only slightly increased by 2.4%. CONCLUSIONS: The monitoring system PHAR-MON is a sensitive and valid monitoring system for the abuse of medicaments in addiction counseling centres. By documenting individual criteria of abuse in the new version of the documentation sheet, the results of medicament abuse can be analyzed in a more valid way. To improve the PHAR-MON system a study about reliability is planned. Because of the health risks associated with the abuse of medicaments, continuous information for physicians about the risks of medicament abuse is helpful to prevent negative consequences.

Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset.

BACKGROUND: Mutations in GBA and LRRK2 genes have been implicated in Parkinson disease (PD), particularly in Ashkenazi Jews. METHODS: An Israeli Ashkenazi cohort of 420 patients with PD, 333 elderly controls, and 3,805 young controls was screened for eight GBA mutations, which are associated with mild (N370S, R496H) and severe (84GG, IVS2 + 1, V394L, D409H, L444P, RecTL) Gaucher disease. Patients with PD and elderly controls were also genotyped for LRRK2 G2019S. RESULTS: GBA carrier frequency was 17.9% in patients with PD compared to 4.2% in elderly and 6.35% in young controls. The proportion of severe mutation carriers among PD patient GBA carriers was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and affected the average age at PD onset (AAO), 55.7 and 57.9 years, compared to 60.7 years in patients without known GBA or LRRK2 mutations. CONCLUSIONS: These data demonstrate genotype-phenotype correlations between different GBA mutations and Parkinson disease (PD) risk and AAO in Ashkenazi Jews. Additionally, an earlier AAO was observed in LRRK2 G2019S carrier PD patients. Finally, these data demonstrate that a surprisingly high frequency, more than one third of our patient population, carried a mutation in GBA or LRRK2.

The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect?

BACKGROUND: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson disease (PD) identified to date, and have been implicated in both familial and sporadic forms of the disease. The G2019S change in LRRK2 exon 41 has been associated with disease at varying frequencies in Asian, European, North American, and North African populations, and is particularly prevalent among Ashkenazi Jews. METHODS: We assessed the occurrence of the LRRK2 G2019S, I2012T, I2020T, and R1441G/C/H mutations in our cohort of Jewish Israeli patients with PD, and determined the LRRK2 haplotypes in 76 G2019S-carriers detected and in 50 noncarrier Ashkenazi patients, using six microsatellite markers that span the entire gene. RESULTS: Only the G2019S mutation was identified among our patients with PD, 14.8% in the Ashkenazi and 2.7% in the non-Ashkenazi patients, and in 26% and 10.6% of the Ashkenazi familial and apparently sporadic cases. The carrier frequencies in the Ashkenazi and non-Ashkenazi control samples were 2.4% and 0.4%. A common shared haplotype was detected in all non-Ashkenazi and half-Ashkenazi carriers and in all full-Ashkenazi carriers tested, except two. Women and patients with a positive family history of PD were significantly over-represented among the G2019S mutation carriers. Age at disease onset was similar in carriers and noncarriers. CONCLUSIONS: Our data suggest that the LRRK2 G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients. Although testing symptomatic patients may help establish the diagnosis of PD, the value of screening asymptomatic individuals remains questionable until the penetrance and age-dependent risk of this mutation are more accurately assessed, and specific disease prevention or modifying interventions become available.