Association of Clinical Relapses With Disease Outcomes in Multiple Sclerosis Patients Older Than 50 Years.

BACKGROUND AND OBJECTIVES: Relapse and MRI activity usually decline with aging but are replaced by progression independent of relapse activity (PIRA) in patients with multiple sclerosis (PwMS). However, several older PwMS continue to experience clinical relapses, and the impact on their disease remains undetermined. We aimed to determine the impact of an index relapse on disease outcomes in patients older than 50 years and to identify risk factors of disadvantageous outcomes. METHODS: We performed a secondary analysis from 3 prospective cohorts in Germany. We evaluated all PwMS 50 years and older with a relapse ≤60 days before a baseline visit and at least 18 months of follow-up compared with a control cohort of PwMS without a relapse. Patients were stratified according to age ("50-54" vs "55-59" vs "60+") or disease outcomes ("stable" vs "active" vs "progressive," according to the Lublin criteria). We analyzed relapses, MRI activity, relapse-associated worsening, and PIRA. Regression analysis was performed to evaluate the association of specific baseline risk factors and treatment regimen changes with disease outcomes at month 18. RESULTS: A total of 681 patients were included in the "relapse cohort" (50+: 361; 55+: 220; 60+: 100). The "control cohort" comprised 232 patients (50+: 117; 55+: 71; 60+: 44). Baseline epidemiologic parameters were balanced among cohorts and subgroups. We observed increased abundance of inflammatory activity and relapse-independent disability progression in the "relapse" vs "control" cohort. In the "relapse" cohort, we identified 273 patients as "stable" (59.7%), 114 patients as "active" (24.9%), and 70 patients as "progressive" (15.3%) during follow-up. Cardiovascular risk factors (CVRFs) and older age at baseline were identified as risk factors of progressive, whereas disease-modifying treatment (DMT) administration at baseline favored stable disease. DMT during follow-up was associated with stable over active, but not over progressive disease. DISCUSSION: A relapse-suggesting underlying active disease-in PwMS older than 50 years was associated with continued disease activity and increased risk of PIRA. Presence of CVRF and absence of DMT at baseline appeared as risk factors of disadvantageous disease courses. An escalation of DMT switch was associated with stable over active but not progressive disease.

Post-operative Pain Assessment Following Tooth Extraction Using Liposomal Encapsulated Bupivacaine as a Local Anesthetic in Dogs.

The objective of this study was to evaluate owner assessment of appetite, demeanor, and mouth soreness following dental extractions in dogs receiving either bupivacaine hydrochloride (BH) or liposomal encapsulated bupivacaine (LEB) for dental blocks. Thirty healthy, adult dogs requiring dental extractions were enrolled in the study. All procedures were completed with dogs under general anesthesia. A non-steroidal anti-inflammatory drug was administered subcutaneously in the preoperative period. Dogs were randomly assigned to receive BH or LEB. An owner assessment to evaluate appetite, demeanor, and soreness of mouth was completed at the end of both the first and second day after discharge from the hospital. The total of the owner assessments for day 1 and both days combined was significantly lower for dogs receiving LEB (P = .007). There were no differences in the number of extractions (P = .21), time from block to evaluations (P = .07), in-hospital pain assessments (P = .99), or number of dogs requiring rescue analgesia (P = .99). This study concluded, dogs that received LEB for dental blocks had improved appetite and demeanor, and reduced soreness of mouth, as evaluated by the owner two days postoperatively, when compared to dogs who received BH.

Risk factors for delayed gastric emptying after esophagectomy.

PURPOSE: Delayed gastric emptying (DGE) is a common functional disorder after esophagectomy with gastric tube reconstruction. Little is known about risk factors that can predict this debilitating complication. METHODS: Patients who underwent elective esophagectomy from 2008 to 2016 in a single center were retrospectively reviewed. Diagnosis of DGE was based on clinical, radiological, and endoscopic findings. Uni- and multivariate analyses were performed to identify patient-, tumor-, and procedure-related factors that increase the risk of DGE. RESULTS: One hundred eighty-two patients were included. Incidence of DGE was 39.0%. Overall, 27 (14.8%) needed an endoscopic intervention. Patients in the DGE group had a longer hospital stay (p < 0.01). No differences were found for the 30-day (p = 1.0) and hospital mortality (p = 1.0). On univariate analyses, a significant influence on DGE was demonstrated for pre-existing pulmonary comorbidity (p = 0.04), an anastomotic leak (p < 0.01), and postoperative pulmonary complications (pneumonia: p = 0.02, pleural empyema: p < 0.01, and adult respiratory distress syndrome: p = 0.03). Furthermore, there was a non-significant trend toward an increased risk for DGE for the following variable: female gender (p = 0.09) and longer operative time (p = 0.09). On multivariate analysis, only female gender (p = 0.03) and anastomotic leak (p = 0.01) were significantly associated with an increased risk for DGE. CONCLUSIONS: DGE is a frequent complication following esophagectomy that can successfully be managed with conservative or endoscopic measures. DGE did not increase mortality but was associated with increased morbidity and prolonged hospitalization. We identified risk factors that increase the incidence of DGE. However, this has to be confirmed in future studies with standardized definition of DGE.

Staple Line Leak After Primary Sleeve Gastrectomy-Risk Factors and Mid-term Results: Do Patients Still Benefit from the Weight Loss Procedure?

BACKGROUND: Staple line leak after laparoscopic sleeve gastrectomy (LSG) still represents the most feared complication. The purpose of this study was to investigate whether there are factors that increase the risk for a leakage. Furthermore, we aimed to analyze the impact of a leak on weight change and resolution of comorbidities. METHODS: Since 2005, data from obese patients that undergo bariatric procedures in Germany are prospectively registered. For the current analysis, all adult subjects that had undergone primary LSG from 2005 to 2014 were considered. RESULTS: Overall, 241/15,756 (1.53%) patients experienced a leak. The occurrence of a leakage resulted in a significant increase of the mortality rate (3.7 vs. 0.2%; p < 0.01). Percent excess weight loss did not differ between leak and non-leak patients, both, at 12 (64.2 vs. 60.9%; p = 1.0) and 24 months (68.5 vs. 64.0%, p = 0.86). Similarly, no significant difference was observed for resolution rate of all comorbid conditions. Matched pair analysis confirmed these findings. Multivariable analysis identified operation time, conversion, intraoperative complications, and hypertension and degenerative joint disease as risk factors for a leak. Oversewing the staple line was associated with the lowest risk. CONCLUSION: The postoperative staple line leak after primary LSG significantly increases postoperative morbidity and mortality. We found that there are patient-related factors and operative variables that predispose to leakage after LSG. However, the occurrence of a leakage does not adversely impact the weight loss and resolution of comorbidities in the mid-term.

Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report.

BACKGROUND: Prevalence of cobalamin deficiency is high especially in older patients and an immediate therapy start is necessary to prevent irreversible neurological damages. Unfortunately, the diagnosis of cobalamin deficiency is difficult and at present, there is no consensus for diagnosis of this deficiency. Therefore, we aim to elucidate a meaningful diagnostic pathway by a case report with an initially misleading medical history. CASE PRESENTATION: A 57 year-old Caucasian man suffering from dramatic myelosis of the cervical posterior columns. Apart from associated neurological symptoms (tactile hypaesthesia, reduced vibration sensation, loss of stereognosis and of two-point-discrimination) there were no further complaints; especially no gastrointestinal, haematological or psychiatric disorders were provable. Cobalamin (vitamin B12) serum level was normal. The diagnosis of subacute combined degeneration of spinal cord was confirmed by an elevated methylmalonic acid, and hyperhomocysteinemia. Cobalamin deficiency was caused by asymptomatic chronic atrophic inflammation of the stomach with a lack of intrinsic factor producing gland cells. This was revealed by increased gastrin and parietal cell antibodies and finally confirmed by gastroscopy. Parenteral substitution of cobalamin rapidly initiated regeneration. CONCLUSIONS: This case demonstrates that normal cobalamin serum levels do not rule out a cobalamin deficiency. In contrast, path-breaking results can be achieved by determining homocysteine, holotranscobalamin, and methylmalonic acid.

A European multi-language initiative to make the general population aware of independent clinical research: the European Communication on Research Awareness Need project.

BACKGROUND: The ECRAN (European Communication on Research Awareness Needs) project was initiated in 2012, with support from the European Commission, to improve public knowledge about the importance of independent, multinational, clinical trials in Europe. METHODS: Participants in the ECRAN consortium included clinicians and methodologists directly involved in clinical trials; researchers working in partnership with the public and patients; representatives of patients; and experts in science communication. We searched for, and evaluated, relevant existing materials and developed additional materials and tools, making them freely available under a Creative Commons licence. RESULTS: The principal communication materials developed were: 1. A website ( http://ecranproject.eu ) in six languages, including a Media centre section to help journalists to disseminate information about the ECRAN project 2. An animated film about clinical trials, dubbed in the 23 official languages of the European Community, and an interactive tutorial 3. An inventory of resources, available in 23 languages, searchable by topic, author, and media type 4. Two educational games for young people, developed in six languages 5. Testing Treatments interactive in a dozen languages, including five official European Community languages 6. An interactive tutorial slide presentation testing viewers' knowledge about clinical trials CONCLUSIONS: Over a 2-year project, our multidisciplinary and multinational consortium was able to produce, and make freely available in many languages, new materials to promote public knowledge about the importance of independent and international clinical trials. Sustained funding for the ECRAN information platform could help to promote successful recruitment to independent clinical trials supported through the European Clinical Research Infrastructure Network.

Estrogenic environmental contaminants alter the mRNA abundance profiles of genes involved in gonadal differentiation of the American bullfrog.

Wildlife and human populations are exposed to anthropogenic mixtures of chemicals in the environment that may adversely influence normal reproductive function and development. We determined the effects of exposure to estrogenic chemicals and wastewater effluent (WWE) on developing gonads of the American bullfrog, Rana (Lithobates) catesbeiana, a species whose widespread distribution make it an ideal model for environmental monitoring of endocrine effects of chemical contaminants. Premetamorphic bullfrog tadpoles were exposed to treatment vehicle, 17ß-estradiol (E2; 10(-9)M) or 4-tert-octylphenol (OP; 10(-9)M, 10(-8)M, and 10(-7)M). Additionally, gonadal differentiation was evaluated in bullfrog tadpoles from a WWE-containing site versus those from a reference location receiving no WWE. In both studies, phenotypic sex, steroidogenic factor-1 (nr5a1), and aromatase (cyp19a1) mRNA levels using quantitative real-time PCR were determined. Exposure to E2 or OP did not alter sex ratios. In controls, both nr5a1 and cyp19a1 transcript levels exhibited sexual dimorphism, with males demonstrating higher levels of nr5a1 and females greater abundance of cyp19a1. However, E2 exposure increased cyp19a1 mRNA abundance in testes and decreased levels in ovaries, eliminating the sexual dimorphism observed in controls. E2-exposed males exhibited increased nr5a1 transcript levels in the testes compared to controls, while females demonstrated no E2 effect. OP treatment had no effect on female cyp19a1 mRNA abundance, but exposure to 10(-7)M OP increased testicular transcript levels. Treatment with 10(-9) and 10(-8)M OP, but not 10(-7)M, resulted in decreased abundance of nr5a1 transcript in both ovaries and testes. Animals from the field had sexually dimorphic gonadal levels of cyp19a1, but both sexes from the WWE site exhibited elevated cyp19a1 transcript abundance compared to the reference location. Individual chemical compounds and anthropogenic wastewater effluent dispersed within the environment influence the levels of gonadal mRNA encoding key proteins involved in gonadal differentiation.

[The relevance of head-to-head trials to patient-centred clinical research]. / Die bedeutung von head-to-head-studien für die versorgungsnahe klinische forschung.

Head-to-head trials can contribute considerably to improving patient-centred care. To ensure that patients are optimally supplied with drugs and medical devices following market release, it is necessary to choose the best therapy from several options. The gold standard of efficacy comparisons is randomised head-to-head studies comparing alternative methods. These trials establish the evidence base for choosing and excluding a treatment, which in turn improves the quality of health care services, even from an economic point of view. These trials are performed under high international quality standards of planning, conducting and reporting. Since comparative effectiveness research (CER) largely includes science-initiated investigations, all stakeholders should participate in the funding of these studies.

Weight loss and changes in salivary ghrelin and adiponectin: comparison between sleeve gastrectomy and Roux-en-Y gastric bypass and gastric banding.

BACKGROUND: Weight loss is associated with increased levels of adiponectin with a greater increase observed following Roux-en-Y gastric bypass (RYGB) compared to restrictive procedures. However, currently there are no data on changes in adiponectin following laparoscopic sleeve gastrectomy (LSG). Ghrelin was reported to be also produced by the salivary glands. There are also no data available regarding its changes following bariatric surgery. METHODS: The present study examined weight loss, and salivary ghrelin and HMW adiponectin levels in 43 morbidly obese subjects undergoing three different types of bariatric surgery. RESULTS: We found that weight loss following LSG is superior to laparoscopic adjustable gastric banding (LAGB) and comparable to RYGB at 12 months after surgery. Although blood glucose decreased similarly following all three procedures, fasting insulin continuously declined only in LSG and RYGB patients. Changes in both fasting and postprandial salivary ghrelin greatly varied between all three procedures with no similarities to changes in serum ghrelin reported in the literature. HMW adiponectin significantly increased following LSG, and this increase was more marked than in LAGB patients and almost identical compared to RYGB. CONCLUSIONS: Weight loss following LSG is comparable to RYGB in the short term. Changes in HMW adiponectin are comparable following LSG and RYGB which may further contribute to the successful results after LSG. Furthermore, the results of the present study support the hypothesis that there is an autonomous production of ghrelin in salivary glands irrespective of nutritional status and weight loss.

Comparison of serum and salivary ghrelin in healthy adults, morbidly obese, and patients with metastatic carcinoma.

BACKGROUND: Ghrelin, a known orexigenic hormone, has been demonstrated to be produced and released by salivary glands. Obtaining saliva for metabolism studies would be preferable for patients since the procedure is non-invasive. METHODS: The present study examined serum and salivary ghrelin levels in 41 morbidly obese subjects, 45 healthy controls, and 17 patients with metastatic carcinoma by using a commercial radioimmunoassay. RESULTS: When comparing serum and salivary levels under fasting conditions, ghrelin levels were significantly higher in saliva for morbidly obese and healthy subjects. A significant correlation between salivary and serum ghrelin could only be demonstrated for healthy subjects. Fasting serum ghrelin concentrations in morbidly obese patients were significantly lower compared with healthy controls and cancer patients, however the levels in whole saliva did not differ significantly between all groups. There was only a highly significant inverse correlation between BMI and serum ghrelin. Serum ghrelin correlated positively with age in morbidly obese. There was no significant difference in serum and saliva ghrelin concentrations between men and women. Following the standardized meal, no significant suppression of serum ghrelin levels in morbidly obese was observed, however salivary ghrelin concentrations were significantly decreased. CONCLUSIONS: The results of the present study support the hypothesis that there is an autonomous production of ghrelin in the salivary glands. Further research should focus on factors involved in the regulation of salivary ghrelin. Until the mechanism of regulation is fully understood, the testing of ghrelin levels in saliva is too limited to recommend a switch from serum testing.

[The Coordinating Centers for Clinical Trials (KKS) and the KKS Network: competence for clinical research]. / Die Rolle der Koordinierungszentren für Klinische Studien (KKS) und des KKS-Netzwerks: Kompetenz für klinische Forschung.

The Network of the Coordination Centers for Clinical Trials (CTCs; Koordinierungszentren für Klinische Studien(KKS)) comprises 17 institutions working as scientific service provider for universities, study groups, the pharmaceutical and medical devices industry as well as additional clients associated with clinical research. The CTCs have established planning and conduct of clinical trials according to Good Clinical Practice (GCP) guidelines,with a wide range of study support in academia. One focus according to indications is cancer. Expertise in hematological/oncological research can be requested nationwide and cross-institutional. The KKS network currently cooperates with medical societies and other, even European networks in 20 countries and has been established as a strong platform for oncological trials.

Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model.

INTRODUCTION: The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain. METHODS: Seventy SD-rats (280-310 g) were divided into 1 control and 6 sepsis groups. Sepsis groups received 1 or 5 mg/kg lipopolysaccharide (LPS) intravenously to induce a moderate or severe sepsis syndrome. Thirty minutes later rats were further randomized into subgroups receiving moderate volume therapy alone or additionally continuous norepinephrine (NE) or 1400W infusion. Separately, effects of 1400W on neurofunctional parameters were investigated in 3 rats without sepsis induction. Performing electric forepaw-stimulation evoked potentials (N2-P1 amplitude, P1-latency) and local hemodynamic responses were recorded with surface electrodes and laser Doppler over the somatosensory cortex at baseline and repeatedly after LPS administration. Cytokine levels (tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL6), interferon-gamma (IFNgamma)) and cell destruction markers (neuron-specific enolase (NSE), S-100 calcium binding protein B (S100B)) were obtained at the end of experiments. RESULTS: During sepsis progression resting cerebral blood flow increased and functionally activated hemodynamic responses decreased in a dose-dependent manner. Whereas 1400W and NE improved blood pressure, only 1400W stabilized resting flow levels. However, both regimens were ineffective on the functionally coupled flow responses and destruction markers were similar between groups. CONCLUSIONS: NE and 1400W appeared to be ineffective in mitigating the effects of sepsis on the neurovascular coupling. Other regimens are needed to protect the cerebral microcirculation under septic conditions.

Endotoxin-induced gene expression differences in the brain and effects of iNOS inhibition and norepinephrine.

PURPOSE: We studied gene expression differences in brain homogenate, hippocampus, somatosensory cortex and cerebellum of rats suffering from sepsis-associated delirium and analyzed the effects of norepinephrine and 1,400 W (specific inhibitor of the inducible nitric-oxide synthase). METHODS: We applied microarray screenings to rat brain homogenate 1, 3 and 4.5 h after lipopolysaccharide (LPS, 5 mg/kg) or 0.9% NaCl treatment. Therapy groups were analyzed after 4.5 h. Validations and compartment specific investigations were carried out by real-time PCR. RESULTS: Most striking gene expression differences were seen 4.5 h after LPS administration, especially within the hippocampus (chemokines and endothelial cell-specific molecule 1). Norepinephrine resulted in a discrete chemokine up-regulation, while 1,400 W had hardly any effect. CONCLUSION: Strongest gene regulations were found within the hippocampus. Norepinephrine showed a tendency of having a proinflammatory influence, while 1,400 W had no clear-cut effect onto the gene expression level.

Expression profiling of laser-microdissected intrapulmonary arteries in hypoxia-induced pulmonary hypertension.

BACKGROUND: Chronic hypoxia influences gene expression in the lung resulting in pulmonary hypertension and vascular remodelling. For specific investigation of the vascular compartment, laser-microdissection of intrapulmonary arteries was combined with array profiling. METHODS AND RESULTS: Analysis was performed on mice subjected to 1, 7 and 21 days of hypoxia (FiO2 = 0.1) using nylon filters (1176 spots). Changes in the expression of 29, 38, and 42 genes were observed at day 1, 7, and 21, respectively. Genes were grouped into 5 different classes based on their time course of response. Gene regulation obtained by array analysis was confirmed by real-time PCR. Additionally, the expression of the growth mediators PDGF-B, TGF-beta, TSP-1, SRF, FGF-2, TIE-2 receptor, and VEGF-R1 were determined by real-time PCR. At day 1, transcription modulators and ion-related proteins were predominantly regulated. However, at day 7 and 21 differential expression of matrix producing and degrading genes was observed, indicating ongoing structural alterations. Among the 21 genes upregulated at day 1, 15 genes were identified carrying potential hypoxia response elements (HREs) for hypoxia-induced transcription factors. Three differentially expressed genes (S100A4, CD36 and FKBP1a) were examined by immunohistochemistry confirming the regulation on protein level. While FKBP1a was restricted to the vessel adventitia, S100A4 and CD36 were localised in the vascular tunica media. CONCLUSION: Laser-microdissection and array profiling has revealed several new genes involved in lung vascular remodelling in response to hypoxia. Immunohistochemistry confirmed regulation of three proteins and specified their localisation in vascular smooth muscle cells and fibroblasts indicating involvement of different cells types in the remodelling process. The approach allows deeper insight into hypoxic regulatory pathways specifically in the vascular compartment of this complex organ.