Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department.

Background: Vaso-occlusive pain crisis (VOC) is the most frequent cause for Emergency Department (ED) visits and hospital admissions for patients with sickle cell disease (SCD). Nitric oxide plays a critical role in the pathogenesis of vaso-occlusion. The amino acid, citrulline, is the main endothelial nitric oxide booster that offers the potential to ameliorate vaso-occlusion and decrease the risk of hospitalization. Objective: In this two-part study, the goal of the first part is to determine the pharmacokinetic profile of intravenous (IV) l-citrulline and optimal dose for the second part of the study, which is to determine the efficacy and tolerability of the intervention in patients with SCD. Design: A phase I/IIA open-label dose-finding study with subsequent double-blind, placebo-controlled, randomized Study of l-citrulline in children and adolescents with SCD presenting to the ED in VOC. Methods: Part 1: Subjects experiencing VOC are enrolled in an open-label, ascending dose of IV l-citrulline to identify the optimum dose with endpoints of pharmacokinetic parameters, pain scores, reduction of opioid use, quality of life, proportion admitted to the hospital for treatment of pain, readmission rates, and assessment of adverse events. Part 2 of the trial is a double-blind, placebo-controlled adaptive "pick-the-winner" design to evaluate the efficacy and tolerability of IV l-citrulline in patients with SCD while receiving standard of care therapy for VOC. Summary: This ED based sickle cell adaptive trial will determine the optimal dose for IV citrulline and whether the intervention improves outcome as a potential novel therapy for VOC in SCD.

Artificial urethral sphincter in male dogs with urethral sphincter mechanism incompetence: 19 cases (2010-2017).

OBJECTIVE: To assess the outcome and safety of surgically placed artificial urethral sphincters in male dogs with urethral sphincter mechanism incompetence. MATERIALS AND METHODS: We included dogs with urethral sphincter mechanism incompetence treated by placing an artificial urethral sphincter from January 1, 2010 to December 31, 2017. The continence score (scale 1 to 5, with 5 indicating complete continence) was evaluated before and after implantation. Follow-up information was obtained from the institution's medical records (short-term up to 12 months) and questionnaires were completed by telephone (long-term ≥12 months) for evaluation. RESULTS: Medical therapy was unsuccessful in 18 dogs and unknown in one dog before the artificial urethral sphincter placement. Short-term continence improved in 16 of the 19 (84%) dogs. Four patients were lost to follow-up. Nine of 15 (60%) dogs showed long-term continence improvement, eight of 15 (53%) remained completely continent. The median follow-up was 1785 (range 2 to 3234) days. The complication rate was 56% (9/16). Minor complications, including haematoma, stranguria/temporary dyssynergia and mild inflammation at the port, were reported in four of 16 (25%) dogs. Five of 16 (31%) experienced major complications, including stranguria/mechanical urethral obstruction, persistent dyssynergia, fistula at the port and port rotation. CLINICAL SIGNIFICANCE: Artificial urethral sphincter placement is a valid option for treating incontinent male dogs that show an insufficient response or become refractory to medical or other prior surgical management. A high-complication rate is associated with this procedure.

Retrospective analysis after endoscopic urethral injections of glutaraldehyde-cross-linked-collagen or dextranomer/hyaluronic acid copolymer in bitches with urinary incontinence.

OBJECTIVES: To evaluate the outcome of endoscopic injection of two different bulking agents, glutaraldehyde cross-linked collagen and dextranomer/hyaluronic acid copolymer into the urethral submucosa in female dogs with urinary incontinence caused by urethral sphincter mechanism incompetence. MATERIALS AND METHODS: Retrospective review of records and follow-up communication with owners of dogs that received an endoscopically guided urethral bulking procedure. In each dog, either cross-linked collagen (2007 to 2011) or dextranomer/hyaluronic acid copolymer (2012 to 2015) was used. At least three injections were made in a circular arrangement in the midurethral region until the urethral lumen was closed. RESULTS: Complete questionnaires were available from 50 of 100 pet owners. The mean interval between the treatment and interview was 67 (range: 57 to 114) months in the cross-linked collagen group and 19 (range: 2 to 48) months in the dextranomer/hyaluronic acid copolymer group. The mean duration of continence was 45∙8 months (range: 12 to 84 months) in the cross-linked collagen group and 20∙5 months (range: 12 to 48 months) in the dextranomer/hyaluronic acid copolymer group. The success rate at 6 months or more after the procedure was 71% after the injection of cross-linked collagen and 58% after injection of dextranomer/hyaluronic acid copolymer. One minor complication (transient haematuria) occurred in one dog. There were no major complications. CLINICAL SIGNIFICANCE: Urethral injection of dextranomer/hyaluronic acid copolymer in bitches with urethral sphincter mechanism incompetence is a useful alternative to cross-linked collagen injection, which is no longer available in the European market. Dextranomer/hyaluronic acid copolymer injection is a minimally invasive alternative to surgical procedures and has a low complication rate.

Reticulocytosis in non-anaemic cats and dogs.

OBJECTIVE: To evaluate the proportion of blood samples diagnosed with reticulocytosis without anaemia in cats and dogs and report the aetiology and mortality rate of affected animals. MATERIALS AND METHODS: Retrospective multicentre study including haematological examination of 3956 cats and 11,087 dogs admitted to seven German veterinary clinics (2012 to 2014). The proportion of blood samples with reticulocytosis without anaemia was calculated, and after exclusion of multiple measurements of the same animal, clinical data were evaluated. Animals with reticulocytosis without anaemia were classified as healthy or diseased, and diseased patients were assigned to 12 disease groups. Pretreatment (i.e. non-steroidal anti-inflammatory drugs, glucocorticoids, dipyrone) was recorded. RESULTS: The proportion of blood samples with reticulocytosis without anaemia was 3·1% (124/3956) in cats and 4·4% (492/11,087) in dogs. Overall, 1·8% (2/111) of cats and 1·5% (7/458) of dogs with reticulocytosis without anaemia were healthy. Blood loss/anaemia, cardiac/respiratory disorders, gastrointestinal disorders and inflammatory disorders as well as cancer were the most frequent underlying diseases. Pretreatment was noted in 39·5% (43/111) of cats and 42·4% (194/458) of dogs. The mortality rate was 37·8% (42/111) in cats and 29·7% (136/458) in dogs with reticulocytosis without anaemia; the median survival time in non-survivors was 1 day (range: 0 to 376 days in cats, 0 to 444 days in dogs). CLINICAL SIGNIFICANCE: In both species, reticulocytosis without anaemia was observed in a low proportion of blood samples (dogs>cat). Though a bias towards sick animals is possible in our sample, reticulocytosis without anaemia was mainly seen in diseased animals and associated with a mortality rate of approximately one-third of patients.

Canine splenic haemangiosarcoma: influence of metastases, chemotherapy and growth pattern on post-splenectomy survival and expression of angiogenic factors.

Splenic haemangiosarcomas (HSAs) from 122 dogs were characterized and classified according to their patterns of growth, survival time post splenectomy, metastases and chemotherapy. The most common pattern of growth was a mixture of cavernous, capillary and solid tumour tissue. Survival time post splenectomy was independent of the growth pattern; however, it was influenced by chemotherapy and metastases. Immunohistochemical assessment of the expression of angiogenic factors (fetal liver kinase-1, angiopoietin-2, angiopoietin receptor-2 and vascular endothelial growth factor A) and conventional endothelial markers (CD31, factor VIII-related antigen) revealed variable expression, particularly in undifferentiated HSAs. Therefore, a combination of endothelial markers should be used to confirm the endothelial origin of splenic tumours.

Association of the CLCA1 p.S357N variant with meconium ileus in European patients with cystic fibrosis.

In Cftr-/- mice that mostly die because of intestinal obstruction, intestinal expression of Clca3 is decreased, whereas upregulation of Clca3 results in amelioration of intestinal disease. The aim of the study was to investigate whether the p.S357N variant in CLCA1, the human orthologue of Clca3, acts as a modifier gene in a cohort of 682 European patients with cystic fibrosis (CF)-99 patients with meconium ileus. The 357SS genotype was significantly overrepresented in both patients with meconium ileus and also with a severe CFTR genotype (P = 0.009) and in p.F508del homozygotes (P = 0.002). This suggests that CLCA1 has similar important functions in CF-related intestinal obstruction in humans as in Cftr-/- mice.

[Somatoform disorders with pain as the predominant symptom: results to distinguish a common group of diseases]. / Somatoforme Störungen mit Leitsymptom Schmerz: Ergebnisse zur Differenzierung einer häufigen Krankheitsgruppe.

According to a population-based prevalence study, medically unexplained pain syndromes are highly prevalent in the German general population. With a 1-year prevalence of 8% for somatoform pain disorders and a lifetime prevalence of 12.7%, they rank among the most prevalent conditions in the community. Until now, few studies have been conducted to characterize and differentiate patients with somatoform pain disorders in more detail. The present study is the first to examine a large patient cohort from a university hospital outpatient unit with somatoform disorders presenting with pain as the predominant complaint (n=282). Patients with a nociceptive or neuropathic pain mechanism were excluded after interdisciplinary diagnostic procedures, and all patients were differentiated in terms of comorbid psychic disorders and their symptom presentation. Psychic disorders were assessed using a standardized structured interview (SCID-I and SCID-II) and a structured biographical case history (MSBI) to assess chronification factors. The extent and distribution of bodily symptoms were collected using the screening for somatoform disorders (SOMS). A total of 69% of the patients examined suffered from anxiety and depressive disorders or other mental disorders, and only 14% had a comorbid personality disorder. More than 90% had further bodily symptoms apart from pain. The presence of mental disorders and the duration of the illness were associated with a higher number of bodily symptoms (e.g., fatigue, dizziness), for which they may also consult a doctor. In addition, the frequency of fibromyalgia syndrome increases with the extent of somatization. Our results ultimately support the idea of classifying this group of patients as an independent diagnostic group. They further suggest a future differentiation regarding the degree of impairment within this group similar to the systems of stages used in depressive disorders.

Maternal smoking increases risk of allergic sensitization and wheezing only in children with allergic predisposition: longitudinal analysis from birth to 10 years.

BACKGROUND: The role of passive smoking for allergies and asthma in children above the age of 3 years remains unclear and possible interactive effects with parental allergies have not been formally evaluated in long-term studies. To examine the interaction of passive smoking and an allergic predisposition regarding allergic sensitization, allergic airway symptoms and respiratory infections during the first 10 years of life. METHODS: In a prospective multicenter birth cohort study with 1314 recruited children in Germany, we assessed serum immunoglobulin E against common allergens at seven time points, and parental smoking and respiratory symptoms annually by using questionnaires. Longitudinal analyses were performed using generalized estimating equation models (stratified by parental allergy status). RESULTS: During the first 10 years, 18% of the children were exposed to regular maternal smoking since pregnancy, 43% to irregular maternal or only paternal smoking. Among children with two allergic parents, a mother who smoked regularly significantly increased the odds for allergic sensitization (adjusted OR 4.8, 95% CI 1.3-18.2) and wheezing (adjusted OR 5.7, 95% CI 1.7-19.0) in her child compared with children who were never exposed. For those with only one allergic parent, the odds were doubled and also statistically significant, whereas in children without allergic parents maternal smoking had no effects. There was no association of maternal smoking with allergic rhinitis or respiratory infections. CONCLUSIONS: Our results suggest that regular maternal smoking is a strong risk factor for allergic sensitization and asthma symptoms during the first 10 years of life, but only in children with allergic parents.

Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence.

Childhood asthma is frequently perceived as a disease with uniform clinical pathways. This perception might be an oversimplification. The aim of the present study was to investigate the incidence and natural course of wheeze over the first 13 yrs of life and analyse the risk factors predicting wheeze at 11-13 yrs of age. The Multicentre Allergy Study, a German birth cohort, recruited 1,314 children in 1990. Physical examinations, interviews on atopic diseases, immunoglobulin (Ig)E and lung function tests were performed up to 13 yrs of age. Complete data on the course of wheeze were available for 441 children. It was found that incidence of wheezing declined with age. The first wheezing episode was reported by 29, 9 and 9% of participants at < or = 3 (early wheezers), 3-6 (late wheezers), and > 6 yrs (very late wheezers) of age, respectively. Wheezing at the age of 13 yrs was associated with parental atopy, and with IgE sensitisation to common allergens, elevated total IgE and exposure to high levels of indoor allergens in early life. All these associations were remarkably stronger among early wheezers than among early nonwheezers. In conclusion, the relevance of an early expression of atopy as a predictor of wheezing at age 13 yrs declines with increasing age of wheezing onset.

[Chronic low back pain as a somatoform pain disorder]. / Chronischer Rückenschmerz als somatoforme Schmerzstörung.

Chronic low back pain as a leading symptom of a somatoform pain disorder is a remnant diagnostic category for many physicians, general practitioners and orthopaedic surgeons. Patients with somatoform pain disorder (ICD-10: F45.4) are often not diagnosed until after several years and multiple diagnostic procedures, in some cases after iatrogenic impairment. A more precise knowledge of the disorder can prevent chronification. This article outlines the clinical features, diagnostic procedure and differential diagnosis in somatoform pain patients and presents current psychotherapeutic approaches.

Primary prevention of allergy: avoiding risk or providing protection?

Primary prevention strategies of allergy so far have been aimed to fight allergy causes, by avoiding risk factors and inhibiting their mechanisms of action. The results of trials testing food or airborne allergen avoidance as a prevention strategy were, however, rather disappointing. A reverse approach for primary prevention of allergies aims to facilitate exposure to protecting factors which promote the induction of immunologic tolerance against innocuous antigens. These factors are associated with farming environment and a 'traditional lifestyle', but identification of these factors is quite difficult. Major candidates include food-borne microbes, helminths or their components, which are able to stimulate mucosal immunity, particularly in the gut. Similarly, new preventive and therapeutic strategies are being tested to induce specific food-allergen oral tolerance through the ingestion of progressively increasing doses of the offending food. This shifting of allergy prevention research from avoidance to tolerance induction will hopefully allow us to reverse the epidemic trend of allergy diseases.

Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn's disease but also ulcerative colitis.

BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

A novel hearing-loss-related mutation occurring in the GJB2 basal promoter.

Mutations in the GJB2 gene are a major cause of non-syndromic recessive hearing loss in many countries. In a significant fraction of patients, only monoallelic GJB2 mutations known to be either recessive or of unclear pathogenicity are identified. This paper reports a novel GJB2 mutation, -3438C-->T, found in the basal promoter of the gene, in trans with V84M, in a patient with profound hearing impairment. This novel mutation can abolish the basal promoter activity of GJB2. These results highlight the importance of extending the mutational screening to regions outside the coding region of GJB2.

Cerebral activation in patients with somatoform pain disorder exposed to pain and stress: an fMRI study.

Patients with somatoform pain disorders are supposed to suffer from an early acquired defect in stress regulation. In order to look for common alterations of the pain- and stress-responsive cortical areas, we prospectively recorded cerebral activations induced by pin-prick pain, by cognitive stress and emotional stress using functional magnetic resonance imaging (fMRI) in a group of 17 patients and an age-matched control group. In addition, the hippocampal volumes of both groups were measured. Patients showed increased activations of the known pain-processing areas (thalamus, basal ganglia, operculo-insular cortex), but also of some prefrontal, temporal and parietal regions during first pain exposure and of temporal and parietal areas during cognitive stress, but reduced activations during emotional stress. In contrast to these functional differences, hippocampal volume was not significantly reduced in patients. Although the superior temporal gyrus was the only common area of an "overactivation" in patients in the pain and stress condition, findings of our study support the current concept of mechanisms involved in somatoform pain disorders: central processing of pain and of cognitive stress is increased in patients possibly due to exaggerated memory and/or anticipation of pain exposure and to a disturbance of stress-regulating systems which has to be worked out on a cortical level in more detail. Our finding of a reduced responsiveness to emotional stress is surprising, but not contradictive to these results because some sort of neglect or coping mechanisms may have developed over time as a response to early adversities.

Polymorphisms in eosinophil pathway genes, asthma and atopy.

BACKGROUND: Eosinophilic inflammation is considered to play an important role in the development as well as in the perpetuation of asthma. As eosinophil production and survival is under genetic control we investigated whether polymorphisms in eosinophil regulation pathway genes (IL-3, IL-5, GM-CSF and their respective enhancers and receptors) may influence the development of atopic diseases. METHODS: In two large study populations of children, the German part of the International Study of Asthma and Allergy in Childhood (ISAAC II) and the German Multicentre Atopy Study (MAS), 3099 and 824 children, seven polymorphisms previously associated with the development of atopic diseases were genotyped: two in and around the GM-CSF gene (Ile117Thr and T3085G), one in IL-3 (Pro27Ser), in IL-5 (C-746T), and in the IL-5 high affinity receptor chain IL-5R (G-80A) and two in the common receptor chain CSFR2b for IL-3, IL-5, and GM-CSF (Asp312Asn and Glu249Gln). Statistical analyses were performed using chi-squared tests and variance analyses. Gene by gene interactions were evaluated in logistic regression models. RESULTS: The T allele at position -746 in the IL-5 gene was significantly protective for atopy in the ISAAC II population (P = 0.006). Furthermore, the risk for atopic asthma was decreased in carriers of the T allele (P = 0.036) and evidence for interaction with the enhancer polymorphism 3085 bp 3' of GM-CSF was detected. CONCLUSIONS: IL-5 C-746T influenced atopic outcomes and showed evidence for gene by gene interaction. No significant associations were found with all other tested polymorphisms in the eosinophil regulation pathway after correction for multiple testing.

Confirmation of association of IL-15 with pediatric asthma and comparison of different controls.

BACKGROUND: Interleukin (IL)-15 is an important mediator in chronic inflammatory diseases. Recently, we have described the association of IL-15 haplotypes with bronchial asthma. Asthma genetics is highly complex - about every second candidate gene is not confirmed in consecutive studies. We were interested in whether association of asthma with IL-15 holds in a second population. Furthermore, we sought to investigate the effect of different controls. METHODS: Five IL-15 polymorphisms were genotyped on the German Multicenter Allergy Study (MAS) cohort consisting of 886 children who were followed up from birth to 10 years of age. At 10 years of age, 96 were found to be asthmatic. MAS children who never had any wheezing symptoms (n = 576), who were never diagnosed with asthma (n = 790) and 129 super controls who had never had any atopic disorder were used as controls. Finally, 270 randomly chosen adults served as controls. RESULTS: Association was confirmed with single polymorphism and haplotypes. The super controls showed the highest difference to the asthmatics regarding haplotype frequencies. However, the effect escaped statistical significance, most likely because of the small sample size. CONCLUSION: Association of IL-15 with asthma was confirmed. Although super controls might be the most suitable, more numbers are needed. This might hamper the value of these controls especially when investigating common diseases.

Psychological defense styles, childhood adversities and psychopathology in adulthood.

OBJECTIVE: The present study explores the link between reported sexual and/or physical abuse and psychological defense styles, as well as the association of both with psychological distress in adulthood. In two patient samples that differ in psychological distress and somatization, we examine whether the adversities reported and immature defense styles are associated with psychopathological symptoms. METHOD: We examined 266 consecutive inpatients in the psychosomatic department and 109 consecutive inpatients who had been treated for low-back pain in the orthopedic department of a German university hospital. Psychological defense styles were assessed by a two-factor solution of the German modified adaptation of the Defense Mechanism Inventory (DMI), childhood adversities by a structured interview, psychological distress by the SCL-90-R, and somatization by the Screening for Somatoform Disorders (SOMS). RESULTS: Both samples demonstrated a significant link between immature defense styles and the extent of overall psychological distress as well as somatization. Reported sexual and/or physical abuse of patients in both patient samples was directly associated with somatization. CONCLUSION: Recollections of sexual and/or physical abuse in childhood and immature defense styles have an association with psychopathology in adulthood. This finding suggests that immature defense styles may act, in part, as mediators between the adversities investigated and adult psychopathology.

Polymorphisms of UDP-glucuronosyltransferase 1A7 are not involved in pancreatic diseases.

BACKGROUND: Xenobiotic mediated cellular injury is thought to play a major role in the pathogenesis of pancreatic diseases. Genetic variations that reduce the expression or activity of detoxifying phase II biotransformation enzymes such as the UDP-glucuronosyltransferases might be important in this respect. Recently, a UGT1A7 low detoxification activity allele, UGT1A7*3, has been linked to pancreatic cancer and alcoholic chronic pancreatitis. OBJECTIVE: To investigate whether UGT1A7 polymorphisms contribute to the risk of pancreatitis and pancreatic cancer. METHODS: Genetic polymorphisms in the UGT1A7 gene were assessed in a large cohort of patients with different types of pancreatitis and pancreatic cancer originating from the Czech Republic (n = 93), Germany (n = 638), Netherlands (n = 136), and Switzerland (n = 106), and in healthy (n = 1409) and alcoholic (n = 123) controls from the same populations. Polymorphisms were determined by melting curve analysis using fluorescence resonance energy transfer probes. In addition, 229 Dutch subjects were analysed by restriction fragment length polymorphism. RESULTS: The frequencies of UGT1A7 genotypes did not differ between patients with acute or chronic pancreatitis or pancreatic adenocarcinoma and alcoholic and healthy controls. CONCLUSIONS: The data suggest that, in contrast to earlier studies, UGT1A7 polymorphisms do not predispose patients to the development of pancreatic cancer and pancreatitis.

Variability of total serum immunoglobulin E levels from birth to the age of 10 years. A prospective evaluation in a large birth cohort (German Multicenter Allergy Study).

BACKGROUND: Many environmental factors influence the concentration of total serum IgE (tIgE); however, tIgE synthesis is believed to be under strong genetic influence. Multiple genetic studies on tIgE regulation have been performed. For these population-based studies tIgE was commonly determined at one time-point, assuming that tIgE phenotypes (adjusted for age and gender) are stable over time. OBJECTIVE: We assessed correlations of tIgE levels from birth to the age of 10 years in the birth cohort MAS (Multicenter Allergy Study; n=1314). MATERIALS AND METHODS: We determined cord-blood IgE levels, total and specific IgE at the age of 1, 2, 3, 5, 6, 7, and 10 years. Spearman correlation coefficients were calculated for tIgE at different time-points. All analyses were performed in the entire cohort, adjusted for gender, as well as in non-atopic children only. RESULTS: tIgE percentiles increased steadily from birth to the age of 10 years with higher values for boys than for girls at each time-point. tIgE values from birth to 3 years of age correlated poorly with tIgE levels at 10 years (r<0.5). However, good correlations (r>0.8) were observed for tIgE concentrations at 6, 7 and 10 years. The same results were observed when the analyses were limited to non-atopic children. CONCLUSION: In childhood, tIgE levels underlie remarkable variation over time even in the absence of atopy. For cross-sectional population-based genetic and epidemiologic studies, tIgE values of children <5 years should be interpreted with caution since these values correlate poorly with tIgE levels later in life.