Targeting GD2 after allogeneic SCT: effector cell composition defines the optimal use of ch14.18 and the bispecific antibody construct NG-CU (GD2-CD3).

We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT). Different antibody concentrations and effector-to-target ratios (E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1). Mean specific lysis of LS cells utilizing PBMCs from healthy donors and ch14.18 (1 µg/ml) was 40/66/75% after 12/24/48 h compared to 66/93/100% in the presence of NG-CU (100 ng/ml). NG-CU showed enhanced cytotoxicity compared to ch14.18, even at lower concentrations and E:T ratios, and completely eradicated LS cells after 72 h. To decipher the influence of effector cell subsets on lysis, different ratios of T and NK cells were tested. At a ratio of 1:1, ch14.18 was more effective than NG-CU. Using patient PBMCs taken at different time points posttransplant, significant lysis with both constructs was detectable depending on percentages and total numbers of T and NK cells; in the early posttransplant phase, NK cells were predominant and ch14.18 was superior, whereas later on, T cells represented the majority of immune cells and NG-CU was more effective. Our study highlights the importance of analyzing effector cell subsets in patients before initiating antibody-based therapy. Consequently, we propose an adjusted administration of both antibody constructs, considering the state of posttransplant immune recovery, to optimize anti-tumor activity.

Level of knowledge on radiation exposure and compliance to wearing protective equipment: where do endourologists stand? An ESUT/EULIS survey.

PURPOSE: Fluoroscopy is valuable in modern endourology. We present the results of a survey where compliance to radiation safety measures was tested according to surgical exposure, and level of understanding of the radiation rules and risks associated with it. METHODS: A 52-item, anonymous questionnaire, structured by 6 ESUT/EULIS experts was distributed at 3 different endourological meetings during 2017-2018. Main aim was to evaluate level of knowledge on radiation physics and the protective measures taken against radiation exposure by participants. Fisher's exact test, Kruskal-Wallis test and ROC curve were used for statistical analysis. RESULTS: 211 responses were evaluated. Number of correct answers (median 7.00) differed significantly according to age (p = 0.001), working position (p = 0.005), working field (p < 0.001), number of semirigid (p < 0.001)/flexible URS (p < 0.001) and PNL (p < 0.001) performed per year. Physicians aged 50-60 years, consultants, academics and those who performed more procedures achieved higher scores. In our study 51.7% of responders used shields in the operating room, 89.6% wore lead aprons, 84.4% thyroid shields, while glasses and gloves were used by 14.7% and 8.1%, respectively. Age, working field and number of correct answers did not affect significantly the use of protection in contrast with endourology fellowship training, working position and lessons on radiation. Interestingly, residents, untrained endourologists and those who were provided with lessons on radiation were more compliant. CONCLUSIONS: Our study revealed that majority of modern urologists advocate radiation protection during endourology practice. Senior consultants and academic urologists performing a high volume of procedures seem to understand physics and rules of radiation use.

68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making.

OBJECTIVE: To evaluate the diagnostic performance of [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions. MATERIAL AND METHODS: We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had 68Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making. RESULTS: The median time from RP to BCR was 36 months (IQR 16-72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58-1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. CONCLUSIONS: We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.

[Cutaneous manifestations of sarcoidosis]. / Kutane Manifestationen bei Sarkoidose.

Skin manifestations of sarcoidosis occur in up to 30% of cases. This review summarizes and illustrates in detail the differences between specific and unspecific skin manifestations of sarcoidosis. Important differential diagnoses, such as tuberculosis, cutaneous lymphoma and syphilis have to be excluded. The indications for systemic treatment are primarily determined by the extent of organ involvement and also by the cosmetic impairment.

General anaesthesia-induced anaphylaxis: impact of allergy testing on subsequent anaesthesia.

BACKGROUND: Immunoglobulin E-mediated allergy to drugs and substances used during general anaesthesia as well as non-allergic drug hypersensitivity reactions may account for anaesthesia-induced anaphylaxis. As IgE-mediated anaphylaxis is a potentially life-threatening reaction, identification of the culprit allergen is essential to avoid anaphylaxis recurrence during subsequent general anaesthesia. OBJECTIVE: To study whether preventive recommendations derived from allergy testing after intraoperative anaphylaxis were followed in subsequent general anaesthesia. METHODS: Results of standardized allergy testing after anaesthesia-induced anaphylaxis and outcome of subsequent general anaesthesia were analysed retrospectively. RESULTS: Fifty-three of 107 patients were diagnosed with IgE-mediated allergy to a drug or substance used during general anaesthesia, and 54 patients were test negative. Twenty-eight of 29 allergy patients tolerated subsequent general anaesthesia uneventfully. One patient with cefazolin allergy suffered from anaphylaxis recurrence due to accidental reapplication of cefazolin. Twenty-two of 24 test-negative patients tolerated subsequent general anaesthesia, whereas two patients again developed anaphylaxis despite pre-medication regimens. CONCLUSION AND CLINICAL RELEVANCE: Our results confirm the practical impact of allergy testing in general anaesthesia-induced anaphylaxis. By identification of the allergen, it is possible to avoid allergic anaphylaxis during subsequent anaesthesia. In most cases, recommended pre-medication seems to prevent the recurrence of non-allergic drug hypersensitivity reactions.

Early Endothelial Progenitor Cells (eEPCs) in systemic sclerosis (SSc) - dynamics of cellular regeneration and mesenchymal transdifferentiation.

BACKGROUND: Patients with systemic sclerosis (SSc) are endagered by tissue fibrosis and by microvasculopathy, with the latter caused by endothelial cell expansion/proliferation. SSc-associated fibrosis potentially results from mesenchymal transdifferentiation of endothelial cells. Early Endothelial Progenitor Cells (eEPCs) act proangiogenic under diverse conditions. Aim of the study was to analyze eEPC regeneration and mesenchymal transdifferentiation in patients with limited and diffuse SSs (lSSc and dSSc). METHODS: Patients with both, lSSc and dSSc were included into the study. The following parameters were evaluated: eEPC numbers and regeneration, concentrations of vasomodulatory mediators, mesenchymal properties of blood-derived eEPC. Serum samples of healthy subjects and SS patients were used for stimulation of cultured human eEPC, subsequently followed by analysis of mesenchymal cell characteristics and mobility. RESULTS: Twenty-nine patients were included into the study. Regenerative activity of blood-derived eEPCs did not differ between Controls and patients. Circulating eEPC were significantly lower in all patients with SSc, and in limited and diffuse SSc (lSSc/dSSc). Serum concentrations of promesenchymal TGF-b was elevated in all patients with SSc. Cultured mononuclear cells from SS patients displayed higher abundances of CD31 and of CD31 and aSMA combined. Finally, serum from SSc patients inhibited migration of cultured eEPCs and the cells showed lower sensitivity towards the endothelin antagonist Bosentan. CONCLUSIONS: The eEPC system, which represents an essential element of the endogenous vascular repair machinery is affected in SSc. The increased appearance of mesenchymal properties in eEPC may indicate that alterations of the cells potentially contribute to the accumulation of connective tissue and to vascular malfunction.

Impact of gender on success and complication rates after ureteroscopy.

PURPOSE: To investigate the impact of gender differences on treatment success, intraoperative and postoperative complications in patients undergoing ureteroscopy (URS). MATERIALS AND METHODS: A prospectively maintained database of 927 consecutively performed ureteroscopies on solitary ureteral stones in four different centers was retrospectively analyzed. Stones were detected with preoperative computed tomography scans or intravenous urography imaging. Patients received intravenous antibiotics as perioperative prophylaxis. Patients with symptomatic urinary tract infections (UTI) prior to surgery were excluded. Follow-up was up to 2 weeks after URS or stent removal. RESULTS: Two hundred and eighty-six women and 641 men were included in this study. Mean stone size was 9 mm (range 2-35 mm). A double-J stent was placed in 240 (83 %) women and 527 (82 %) men at the end of surgery (p = 0.075). There was no significant gender difference in terms of stent dislocation (p = 0.239). Two hundred and fifty-one women (87 %) and 564 men (87 %) were stone-free after the first procedure (p = 0.917). Intraoperative complications were observed in 14 (4.8 %) women and 37 (5.9 %) men (p = 0.313). Severe UTI presenting with fever (>38 °C) and requiring prolonged hospitalization with parenteral antibiotics were observed in 11 (3 %) women and 8 (1 %) men postoperatively. This difference was statistically significant (p = 0.025). CONCLUSION: No significant differences between female and male patients harboring ureteral stones with respect to intraoperative complications were detected. Although stone characteristics were comparable between groups, a small number of women had significantly more severe UTI's postoperatively. Our current therapy regimen for URS seems to be efficient and safe both for females and males.

[Correction of Acidosis in Neonatal Intensive-care Medicine: A National Survey]. / Azidose-Ausgleich in der neonatologischen Intensivmedizin: Eine nationale Umfrage.

BACKGROUND: Metabolic acidosis is a common problem of patients on neonatal intensive care units. Only little data exists in literature and there are no clinical guidelines. The aim of this national survey was to assess criteria for correction of metabolic acidosis in neonatal patients and if there were effects to be observed. METHODS: We designed an online survey and sent it to 304 German children's hospitals. 101 questionnaires were included in our study. RESULTS: The question "How often do you buffer on your ward a week?" was answered 63 times with "zero". In perinatal asphyxia newborns with gestation age over 36+0 weeks 4% of the neonatologists would frequently perform a correction of acidosis, 74.3% would do it rarely and 21.8% never. In syndrome of persistent fetal circulation 28.4% would correct acidosis frequently, 42.0% would correct it rarely and 29.5% would never correct it. In case of sepsis 8.7% would correct acidosis frequently, 70.7% would do it rarely and 20.7% would never correct it. 75.2% of the participants distinguish in buffering a premature or a mature infant. 44.4% of neonatologists saw an improvement of the clinical status of the patient after buffering. 38.3% saw different effects, 16.0% saw no changes and 1.2% saw a worsening of the clinical status. 49.4% of those questioned saw side effects after using sodium bicarbonate as a buffer. CONCLUSION: Correction of acidosis with a buffer is rarely performed on German neonatology wards. The indication of buffering depends on the clinical picture and its underlying problem. Benefits from buffering were seen, as well as side effects.

Clinical nodal staging scores for prostate cancer: a proposal for preoperative risk assessment.

BACKGROUND: Pelvic lymph node dissection in patients undergoing radical prostatectomy for clinically localised prostate cancer is not without morbidity and its therapeutical benefit is still a matter of debate. The objective of this study was to develop a model that allows preoperative determination of the minimum number of lymph nodes needed to be removed at radical prostatectomy to ensure true nodal status. METHODS: We analysed data from 4770 patients treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2011 from eight academic centres. For external validation of our model, we used data from a cohort of 3595 patients who underwent an anatomically defined extended pelvic lymph node dissection. We estimated the sensitivity of pathological nodal staging using a beta-binomial model and developed a novel clinical (preoperative) nodal staging score (cNSS), which represents the probability that a patient has lymph node metastasis as a function of the number of examined nodes. RESULTS: In the development and validation cohorts, the probability of missing a positive lymph node decreases with increase in the number of nodes examined. A 90% cNSS can be achieved in the development and validation cohorts by examining 1-6 nodes in cT1 and 6-8 nodes in cT2 tumours. With 11 nodes examined, patients in the development and validation cohorts achieved a cNSS of 90% and 80% with cT3 tumours, respectively. CONCLUSIONS: Pelvic lymph node dissection is the only reliable technique to ensure accurate nodal staging in patients treated with radical prostatectomy for clinically localised prostate cancer. The minimum number of examined lymph nodes needed for accurate nodal staging may be predictable, being strongly dependent on prostate cancer characteristics at diagnosis.

Aminopenicillin-associated exanthem: lymphocyte transformation testing revisited.

BACKGROUND: The lymphocyte transformation test (LTT) has been promoted as in-vitro test for diagnosis of drug hypersensitivity. For determination of statistical LTT sensitivity, series of patients with clinically uniform reactions followed by complete drug hypersensitivity work-up are mandatory. Assessment of LTT specificity requires control patients who tolerated exposure to the drug studied. OBJECTIVE: To prospectively determine the diagnostic value of the LTT in a clinically and diagnostically well-defined series of patients. METHODS: Patients with exanthematous skin eruptions after ampicillin (AMP) intake were included in this study. After exclusion or confirmation of delayed-onset allergic AMP hypersensitivity by skin and provocation testing, two independent LTTs were performed: one standard LTT and a modified LTT with additional anti-CD3/anti-CD28 monoclonal antibody stimulation. RESULTS: By testing, delayed-onset allergic AMP hypersensitivity was diagnosed in 11 patients and definitely ruled out in 26. The standard LTT reached a diagnostic sensitivity of 54.5% while the modified LTT yielded 72.7%. However, the methodical test modification resulted in a decline of specificity from 92.3% (standard LTT) to 76.9%. CONCLUSIONS AND CLINICAL RELEVANCE: In cases of AMP-associated exanthems, the diagnostic value of the LTT compared with routine allergy testing is limited. When evaluating such exanthems, provocation testing remains the gold standard. Delayed reading of intradermal skin tests remains most useful to avoid positive provocation reactions.

A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

Validation of RiskCheck Bladder Cancer ©, version 5.0 for risk-adapted screening of bladder cancer.

INTRODUCTION: The aim of the study was to assess the strength of the online tool RiskCheck Bladder Cancer©, version 5.0 (RCBC) for early detection of bladder cancer (BC). MATERIALS AND METHODS: RCBC was evaluated retrospectively based on the data of 241 patients, of which 141 were suffering from BC. Statistical analysis was performed by descriptive statistics, nonparametric group comparison, classification tree analysis and ROC analysis. RESULTS: ROC analysis of the risk classification showed a sensitivity of 71.6%, a specificity of 56.5%, a positive predictive value of 67.8%, a negative predictive value of 52% and an accuracy of 63.5%. BC risk factors ranked by importance are time of smoking (p < 0.0001), gender (within the nonsmoking group: p < 0.009), occupational toxin exposure (within the group <35 years of smoking: p < 0.048) and amount of consumed cigarettes resulting in a 95% association with BC (within the group >35 years of smoking: p < 0.0001). CONCLUSIONS: The high predictive power of RCBC for the identification of asymptomatic patients living under risk could be demonstrated.

[Serious complications following gluteal injection of silicone]. / Schwere Komplikationen nach glutealer Silikoninjektion.

Silicone has a broad range of medical applications and plays an important role, for example, in plastic reconstruction. The use of silicone, however, may result in unpredictable consequences for the patient. These range from swelling and erythema at the site of injection and regional lymphadenopathy to the development of disseminated granulomas distant from the administration site. We report a woman who developed extensive distally-spreading ulcerations in both buttocks several years after gluteal silicone injection. Potential systemic reactions of silicone include intrapulmonary granulomas, embolism and related pneumonitis. Moreover, an association with the development of autoimmune diseases and neoplasias has been discussed. Therapeutic options include surgically removing the silicone and topical or systemic anti-inflammatory drug therapy. However, due to the diffuse dissemination of silicone, the former is often not completely possible and for the latter empirical data are limited and follow-up studies are missing. Liquid silicone is no longer authorized in Europe or in the U.S.A. When silicone implants are used, the decision should be weighed carefully and the patient adequately counseled. In addition, follow-up care on a regular basis is mandatory for both those with implants and those who obtained injections of liquid silicone in the past.

Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML.

Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations.

Impairment of muscular endothelial cell regeneration in dermatomyositis.

Background and aim: Inflammatory myopathies are heterogeneous in terms of etiology, (immuno)pathology, and clinical findings. Endothelial cell injury, as it occurs in DM, is a common feature of numerous inflammatory and non-inflammatory vascular diseases. Vascular regeneration is mediated by both local and blood-derived mechanisms, such as the mobilization and activation of so-called proangiogenic cells (PACs) or early endothelial progenitor cells (eEPCs). The current study aimed to evaluate parameters of eEPC integrity in dermatomyositis (DM), compared to necrotizing myopathy (NM) and to non-myopathic controls. Methods: Blood samples from DM and NM patients were compared to non-myositis controls and analyzed for the following parameters: circulating CD133+/VEGFR-2+ cells, number of colony-forming unit endothelial cells (CFU-ECs), concentrations of angiopoietin 1, vascular endothelial growth factor (VEGF), and CXCL-16. Muscle biopsies from DM and NM subjects underwent immunofluorescence analysis for CXCR6, nestin, and CD31 (PECAM-1). Finally, myotubes, derived from healthy donors, were stimulated with serum samples from DM and NM patients, subsequently followed by RT-PCR for the following candidates: IL-1ß, IL-6, nestin, and CD31. Results: Seventeen (17) DM patients, 7 NM patients, and 40 non-myositis controls were included. CD133+/VEGFR-2+ cells did not differ between the groups. Both DM and NM patients showed lower CFU-ECs than controls. In DM, intramuscular CD31 abundances were significantly reduced, which indicated vascular rarefaction. Muscular CXCR6 was elevated in both diseases. Circulating CXCL-16 was higher in DM and NM in contrast, compared to controls. Serum from patients with DM but not NM induced a profound upregulation of mRNS expression of CD31 and IL-6 in cultured myotubes. Conclusion: Our study demonstrates the loss of intramuscular microvessels in DM, accompanied by endothelial activation in DM and NM. Vascular regeneration was impaired in DM and NM. The findings suggest a role for inflammation-associated vascular damage in the pathogenesis of DM.

Treatment outcomes of bladder stones in children with intact bladders in developing countries: A systematic review of >1000 cases on behalf of the European Association of Urology Bladder Stones Guideline panel.

INTRODUCTION: Bladder stones (BS) are still endemic in children in developing nations and account for a high volume of paediatric urology workload in these areas. The aim of this systematic review is to comparatively assess the benefits and risks of minimally invasive and open surgical interventions for the treatment of bladder stones in children. METHODS: This systematic review was conducted in accordance with Cochrane Guidance. Database searches (January 1970- March 2021) were screened, abstracted, and assessed for risk of bias for comparative randomised controlled trials (RCTs) and non-randomised studies (NRSs) with >10 patients per group. Open cystolithotomy (CL), transurethral cystolithotripsy (TUCL), percutaneous cystolithotripsy (PCCL), extracorporeal shock wave lithotripsy (ESWL) and laparoscopic cystolithotomy (LapCL) were evaluated. RESULTS: In total, 3040 abstracts were screened, and 8 studies were included. There were 7 retrospective non-randomised studies (NRS's) and 1 quasi-RCT with 1034 eligible patients (CL: n=637, TUCL: n=196, PCCL: n=138, ESWL: n=63, LapCL n=0). Stone free rate (SFR) was given in 7 studies and measured 100%, 86.6%-100%, and 100% for CL, TUCL and PCCL respectively. CL was associated with a longer duration of inpatient stay than PCCL and TUCL (p<0.05). One NRS showed that SFR was significantly lower after 1 session with outpatient ESWL (47.6%) compared to TUCL (93.5%) and CL (100%) (p<0.01 and p<0.01 respectively). One RCT compared TUCL with laser versus TUCL with pneumatic lithotripsy and found that procedure duration was shorter with laser for stones <1.5cm (n=25, p=0.04). CONCLUSION: In conclusion, CL, TUCL and PCCL have comparable SFRs but ESWL is less effective for treating stones in paediatric patients. CL has the longest duration of inpatient stay. Information gathered from this systematic review will enable paediatric urologists to comparatively assess the risks and benefits of all urological modalities when considering surgical intervention for bladder stones.

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

[Uncommon cutaneous ulcerative and systemic sarcoidosis. Successful treatment with hydroxychloroquine and compression therapy]. / Seltene ulzerierende kutane und systemische Sarkoidose. Erfolgreiche Therapie mit Hydroxychloroquin und medizinischer Kompressionstherapie.

Sarcoidosis is a granulomatous multisystemic disease of unclear etiology, which can affect any organ. The cutaneous manifestations are variable, but ulcerative cutaneous sarcoidosis is very rare. One must rule out other granulomatous skin diseases, especially necrobiosis lipoidica. There is no standarized therapy; usually an interdisciplinary approach over years taking multiple side effects into consideration is needed. A 58-year-old woman with a long history of cutaneous, nodal and pulmonary sarcoidosis suddenly developed ulcerations within the disseminated skin lesions on her legs. The combination of systemic hydroxychloroquine and modern wound management lead to complete healing of the ulcers and a significant improvement in the remaining skin lesions.

Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.

BACKGROUND: Dienogest is a selective progestin that has been investigated in a clinical trial programme for the treatment of endometriosis. The current non-inferiority trial compared the efficacy and safety of dienogest against leuprolide acetate (LA) for treating the pain associated with endometriosis. METHODS: Patients with confirmed endometriosis were randomized to treatment with dienogest (2 mg/day, orally) or LA (3.75 mg, depot i.m. injection, every 4 weeks) for 24 weeks. The primary efficacy variable was absolute change in pelvic pain from baseline to end of treatment, assessed by visual analogue scale (VAS). Safety variables included adverse event profile, laboratory parameters, bone mineral density (BMD), bone markers and bleeding patterns. RESULTS: A total of 252 women were randomized to treatment with dienogest (n = 124) or LA (n = 128); 87.9 and 93.8% of the respective groups completed the trial. Absolute reductions in VAS score from baseline to Week 24 were 47.5 mm with dienogest and 46.0 mm with LA, demonstrating the equivalence of dienogest relative to LA. Hypoestrogenic effects (e.g. hot flushes) were reported less frequently in the dienogest group. As expected, bleeding episodes were suppressed less with dienogest than with LA. Changes in mean lumbar BMD between screening and final visit were +0.25% with dienogest and -4.04% with LA subgroups (P = 0.0003). Markers of bone resorption increased with LA but not dienogest. CONCLUSIONS: Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.