[Mortality after high-risk surgery in Jehovah's Witness patients]. / Letalität nach operativen Risikoeingriffen bei Zeugen Jehovas.

BACKGROUND: Jehovah's Witness (JW) patients strictly refuse allogeneic blood transfusion for religious reasons. Nevertheless, JW also wish to benefit from modern therapeutic concepts including major surgical procedures without facing an excessive risk of death. The Northwest Hospital in Frankfurt am Main Germany is a confidential clinic of JW and performs approximately 100 surgical interventions per year on this patient group. MATERIAL AND METHODS: A retrospective analysis of closed medical cases performed in the years 2008-2018 at the Northwest Hospital aimed to clarify (1) the frequency of surgical procedures in JW patients associated with a statistical allogeneic transfusion risk (presence of preoperative anemia and/or in-house transfusion probability >10%) during this time period, (2) the degree of acceptance of strategies avoiding blood transfusion by JW and (3) the anemia-related postoperative mortality rate in JW patients. RESULTS: In the 11- year observation period 123 surgical procedures with a relevant allogeneic transfusion risk were performed in 105 JW patients. Anemia according to World Health Organization (WHO) criteria was present in 44% of cases on the day of surgery. Synthetic and recombinant drugs (tranexamic acid, desmopressin, erythropoetin, rFVIIa) were generally accepted, acute normovolemic hemodilution (ANH) in 92% and cell salvage in 96%. Coagulation factor concentrates extracted from human plasma and therefore generally refused by JW so far, were accepted by 83% of patients following detailed elucidation. Out of 105 JW patients 7 (6.6%) died during the postoperative hospital stay. In 4 of the 7 fatal cases the cause of death could be traced back to severe postoperative anemia. CONCLUSION: Given optimal management JW patients can undergo major surgery without an excessive risk of death. The 6.6% in-hospital mortality observed in this institution was in the range of the 4% generally observed after surgery in Europe. The majority of JW patients accepted a variety of blood conservation strategies following appropriate elucidation. This also included coagulation factor concentrates extracted from human plasma enabling an effective treatment of even severe bleeding complications. In this analysis postoperative hemoglobin concentrations below 6 g/dl in older JW patients were associated with a high mortality risk due to anemia.

Directed threat imagery in generalized anxiety disorder.

BACKGROUND: Worrying has been suggested to prevent emotional and elaborative processing of fears. In cognitive-behavioral therapy (CBT), generalized anxiety disorder (GAD) patients are exposed to their fears during the method of directed threat imagery by inducing emotional reactivity. However, studies investigating neural correlates of directed threat imagery and emotional reactivity in GAD patients are lacking. The present functional magnetic resonance imaging (fMRI) study aimed at delineating neural correlates of directed threat imagery in GAD patients. METHOD: Nineteen GAD patients and 19 healthy controls (HC) were exposed to narrative scripts of either disorder-related or neutral content and were encouraged to imagine it as vividly as possible. RESULTS: Rating results showed that GAD patients experienced disorder-related scripts as more anxiety inducing and arousing than HC. These results were also reflected in fMRI data: Disorder-related v. neutral scripts elicited elevated activity in the amygdala, dorsomedial prefrontal cortex, ventrolateral prefrontal cortex and the thalamus as well as reduced activity in the ventromedial prefrontal cortex/subgenual anterior cingulate cortex in GAD patients relative to HC. CONCLUSION: The present study presents the first behavioral and neural evidence for emotional reactivity during directed threat imagery in GAD. The brain activity pattern suggests an involvement of a fear processing network as a neural correlate of initial exposure during directed imagery in CBT in GAD.

[Integration of primary and secondary data in the Study of Health in Pomerania and description of clinical outcomes using stroke as an example]. / Die Integration von Primär- und Sekundärdaten in der Study of Health in Pomerania und die Beschreibung von klinischen Endpunkten am Beispiel Schlaganfall.

OBJECTIVE: This study describes (i) the procedure of obtaining patients' consent for secondary data usage, (ii) the complexity of integrating data from multiple sources, and (iii) the correspondence among patients' self-reports, physician reports, routine data, hospital discharge diagnosis, and cause-of-death coding regarding stroke. METHODS: Data from the first follow-up (N=3 186) of the population-based Study of Health in Pomerania (SHIP) were used. These data were combined with secondary data from the Greifswald University Hospital, the association of statutory health insurance physicians Mecklenburg-Western Pomerania, physician reports, and death certificates. RESULTS: Consent for using health-related information from all data sources in question was obtained from more than 90% of the SHIP participants. Follow-up data from at least one source were available for 2 747 (86%) participants. For 92 participants information about the occurrence of stroke was found in at least one data source. In 59 cases the event appeared in only one data source, in 24 cases the event was found in 2 sources, and for 9 participants 3 data sources reported on the event. CONCLUSION: Participants of a population-based cohort are highly willing to give consent for using their health-related information from secondary data sources. Yet, data integration is challenging due to considerable differences in data type, structure and coverage.

Encefalopatía por Kernicterus. serie clínica / Kernicterus (bilirubin encephalopathy): case reports

Introducción: La ictericia es común en los recién nacidos (RN). Niveles de bilirrubina a partir de 20 mg/dL (en RN de término) pueden causar parálisis cerebral coreoatetósica, hipoacusia sensorioneural, trastornos de la mirada y displasia del esmalte dental, cuadro clínico conocido como kernicterus. Objetivo: Describir 5 casos de kernicterus controlados en una Unidad de Neurología, entre los años 2002-2012. Casos clínicos: Se presentan 5 niños con edades gestacionales entre 35 y 39 semanas, con peso de nacimiento rango 2.580 y 4.250 g y niveles de bilirrubina entre 24 y 47 mg/dL. Dos RN estaban en su domicilio cuando iniciaron la encefalopatía aguda. Todos se trataron con fototerapia y en 3 casos se realizó además exanguineotransfusión. La edad del diagnóstico de kernicterus fluctuó entre los 12 días y 10 años (3 pacientes se diagnosticaron en etapa neonatal) con una resonancia magnética que demostró impregnación de ganglios basales. Todos evolucionaron con trastornos del movimiento de severidad variable. En 3 pacientes se diagnosticó hipoacusia sensorioneural y en dos hubo trastornos de la mirada. Los test psicométricos evaluaron retraso cognitivo en 3 pacientes y desarrollo normal en los restantes. Conclusión: El kernicterus en una enfermedad devastadora que aún está presente en la realidad nacional. Es una causa de parálisis cerebral prevenible, por lo cual es necesario educar a los padres, población y equipo de salud para la detección precoz y tratamiento oportuno de la hiperbilirrubinemia neonatal.

Introduction: Jaundice is common in newborn babies (NB). Bilirubin levels of 20 mg/dL or higher may cause choreoathetoid cerebral palsy, sensorineural hearing loss, eye disorders and enamel dysplasia in term infants; clinical picture compatible with kernicterus. Objective: To describe five cases of kernicterus treated at a Neurology Unit between 2002 and 2012. Case reports: Five cases of babies with gestational ages between 35 and 39 weeks, birth-weight ranging from 2580 to 4250 grams and bilirubin levels between 24 and 47 mg/dL are presented. Two infants were at home when acute encephalopathy developed, all were treated with phototherapy and 3 of them underwent exchange transfusion. The age of diagnosis of kernicterus was between 12 days to 10 years; three patients were diagnosed in neonatal period through MRI that revealed basal ganglia impregnation. All patients evolved presenting movement disorders of varying severity. Three of them were diagnosed with sensorineural hearing impairments and two presented eye disorders. Psychometric tests showed cognitive delay in three patients and normal development in the remaining children. Conclusion: Kernicterus in a devastating disease present in the national reality. It is a preventable cause of cerebral palsy; therefore, it is necessary to educate parents, population and health care professionals about neonatal hyperbilirubinemia early detection and treatment.

Dimethylaminoparthenolide and gemcitabine: a survival study using a genetically engineered mouse model of pancreatic cancer.

BACKGROUND: Pancreatic cancer remains one of the deadliest cancers due to lack of early detection and absence of effective treatments. Gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has limited clinical benefit. Treatment of pancreatic cancer cells with gemcitabine has been shown to induce the activity of the transcription factor nuclear factor-kappaB (NF-κB) which regulates the expression of genes involved in the inflammatory response and tumorigenesis. It has therefore been proposed that gemcitabine-induced NF-κB activation may result in chemoresistance. We hypothesize that NF-κB suppression by the novel inhibitor dimethylaminoparthenolide (DMAPT) may enhance the effect of gemcitabine in pancreatic cancer. METHODS: The efficacy of DMAPT and gemcitabine was evaluated in a chemoprevention trial using the mutant Kras and p53-expressing LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mouse model of pancreatic cancer. Mice were randomized to treatment groups (placebo, DMAPT [40 mg/kg/day], gemcitabine [50 mg/kg twice weekly], and the combination DMAPT/gemcitabine). Treatment was continued until mice showed signs of ill health at which time they were sacrificed. Plasma cytokine levels were determined using a Bio-Plex immunoassay. Statistical tests used included log-rank test, ANOVA with Dunnett's post-test, Student's t-test, and Fisher exact test. RESULTS: Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas. The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver. No significant differences in the percentages of normal pancreatic ducts or premalignant pancreatic lesions were observed between the treatment groups. Pancreata in which no tumors formed were analyzed to determine the extent of pre-neoplasia; mostly normal ducts or low grade pancreatic lesions were observed, suggesting prevention of higher grade lesions in these animals. While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1α (IL-1α), IL-1ß, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1ß), eotaxin, and tumor necrosis factor-alpha (TNF-α), all of which are NF-κB target genes. CONCLUSION: In summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

Identification of rosmarinic acid as the major active constituent in Cordia americana.

ETHNOPHARMACOLOGICAL RELEVANCE: Preparation from leaves of Cordia americana have been widely used in traditional medicine in South Brazil to treat wounds and various inflammations. AIM OF THE STUDY: The objective of this work was to identify the effective compounds in the ethanolic extract prepared from the leaves of Cordia americana, which is used in traditional South Brazilian medicine as anti-inflammatory and wound healing remedy. MATERIALS AND METHODS: Isolation and structure elucidation techniques were performed in order to identify the compounds of Cordia americana and HPLC analysis was used for the quantification. The major constituent and the ethanolic extract were investigated for inhibition of 5-lipoxygenase, p38alpha MAPK, TNFalpha release and NF-kappaB as well as in the fibroblast scratch assay. RESULTS: Rosmarinic acid (1) was identified as the major compound with an amount of 8.44% in the ethanolic extract of the leaves of Cordia americana. The ethanolic extract as well as (1) exhibited the highest inhibitory effects on 5-lipoxygenase (IC(50)=0.69 and 0.97microg/mL, resp., IC50 of BWA4C as reference: 0.3microM) and p38alpha (IC50=3.25 and 1.16microg/mL, resp., IC50 of SB203580 as reference: 0.046microM) and moderate inhibitory effects on TNFalpha release. Slight effects were observed in the fibroblast scratch assay. CONCLUSIONS: This study increases our knowledge on the effective compound in Cordia americana and supports its use in traditional medicine. We demonstrated for the first time pharmacological effects of Cordia americana and we provide evidences for a crucial role of rosmarinic acid as the major key player.

Biological studies on Brazilian plants used in wound healing.

AIM OF THE STUDY: n-Hexanic and ethanolic extracts from twelve plants (Brugmansia suaveolens Brecht. et Presl., Eupatorium laevigatum Lam., Galinsoga parviflora Cav., Iresine herbstii Hook., Kalanchöe tubiflora Hamet-Ahti, Petiveria alliacea L., Pluchea sagittalis (Lam.) Cabrera, Piper regnellii DC., Schinus molle L., Sedum dendroideum Moç et Sessé ex DC., Waltheria douradinha St. Hill., Xanthium cavanillesii Schouw.) used in traditional South Brazilian medicine as wound healing agents were investigated in various biological assays, targeting different aspects in this complex process. MATERIALS AND METHODS: The extracts were investigated on NF-kappaB DNA binding, p38alpha MAPK, TNF-alpha release, direct elastase inhibition and its release as well as on caspase-3. Fibroblasts migration to and proliferation into the wounded monolayers were evaluated in the scratch assay, the agar diffusion test for antibacterial and the MTT assay for cytotoxic effects. RESULTS: The hydrophilic extracts from Galinsoga parviflora, Petiveria alliacea, Schinus molle, Waltheria douradinha and Xanthium cavanillesii as well as the lipophilic extract of Waltheria douradinha turned out to be the most active ones. CONCLUSIONS: These results increase our knowledge on the wound healing effects of the investigated medicinal plants. Further studies are necessary to find out the effective secondary metabolites responsible for the observed effects.

[Shaping the future of vocational rehabilitation of adults: eight fields of action as starting points for a cross-actor innovation process]. / Die Zukunft der beruflichen Rehabilitation Erwachsener gestalten: Acht Handlungsfelder als Ausgangspunkt für einen akteursübergreifenden Innovationsprozess.

Established by the Federal Ministry of Labour and Social Affairs (BMAS) in October 2007, the Scientific Expert Group RehaFutur had been commissioned to elaborate cornerstones for the medium- and long-term development of vocational rehabilitation of adults with disabilities (re-integration). Initial questions inter alia were as follows: Which function should vocational rehabilitation have in a service- and knowledge-oriented working world that will increasingly be affected by demographic change? How can disabled persons' right to occupational participation by way of vocational rehabilitation, a right stipulated both under the German constitution and in German law, be realized as needed also in the future? Various fields of action have been derived on the basis, for one, of an investigation of the factors, social law, social and education policy as well as European, influencing vocational rehabilitation and, for the other, of an evaluation of current labour market and demographic developments. Dealt with in the fields of action outlined are the aspects: equitable opportunities of access, developmental and needs orientation, closeness to the real occupational and working world, as well as the role of self-determination and self-responsibility. The fields of action are to be understood as framework concept for shaping a cross-actor innovation process. Sustainable vocational rehabilitation is characterized in particular by the fact that it is specifically targeted at promoting disabled persons' self-determination and self-responsibility actively using these in the process and that it strengthens an independent lifestyle, ensures social participation by inclusive structures; also, it facilitates continued participation in working life by ongoing education involving holistic development of professional and personal competencies oriented towards the individual's resources and potentials, safeguarding it by systematic networking with companies. The concept presented for vocational rehabilitation of adults with disabilities encompasses a change of paradigms which service carriers and providers will have to face jointly and including the service users, the rehabilitants.

[Risk scores and outcomes after cholecystectomy: a comparison between a university hospital and a short-stay clinic--a prospective observational study]. / Risikoprofil und Ergebnisqualität nach Cholezystektomie--Ein Vergleich zwischen einer Universitäts- und Praxisklinik.

BACKGROUND: This study was designed to compare the risks of morbidity and mortality of patients in a surgical department of an academic medical centre and a short-stay clinic. Furthermore, economic and patient-related parameters were assessed. METHODS: A number of 50 respectively 33 consecutive patients scheduled for a cholecystectomy were included in this prospective study. Data were collected well-assorted against the POSSUM score, the duration of the operation, complications and the length of stay as well as quality of life and patient satisfaction. RESULTS: No differences among patients of the two hospitals became apparent as they were referenced against the POSSUM score, nor were any discrepancies in expected respectively ex-post complications upon cholecystectomy observed. The continuance of the operative procedure was found to be significantly lengthened in the university hospital as compared with the non-academic clinic (120.1 +/- 34.3 min vs. 65.6 +/- 16.3 min; p < 0.001). The difference in durability splits up in 1.2 days pre-operatively versus 2.4 days post-operatively. In return, the post-operative pain therapy was esteemed much better in the university hospital. CONCLUSION: The POSSUM score is a reliable tool to assess morbidity and mortality in surgical patients. The scores were found to be equal for patients in a university hospital and those in a short-stay clinic. Complications likewisely were equally low in both hospitals. The longer duration of the operation and the higher length of stay revealed structural benefits of the smaller unit. Advantages of the academic centre were found in the standards for pain therapy. The present study is taken both as a reference and as a basis for a fundamental process-redesign to the benefit of involved parties e. g. patients, relatives, staff in the university hospital.

Influence of intestinal stoma on spiritual quality of life of U.S. veterans.

PURPOSE: To examine spiritual quality of life (QOL) of veterans with intestinal ostomies. DESIGN: Mixed-method cross-sectional. METHODS: Male veterans with total scores in the upper (n = 59) and lower (n = 61) quartiles of the City of Hope Quality-of-Life-Ostomy survey provided spiritual QOL data. Analyses included chi-square and analysis of variance with significance set at p < .05. Content analysis was used to explicate narratives and focus groups. RESULTS: The high spiritual QOL group was more likely to be married, older, and report more years since surgery (each p < .0001). Upper quartile participants had more favorable scores for several spiritual QOL domains (all p < .0001). Qualitative comments reflected high or low total QOL scores. CONCLUSIONS: Spiritual QOL is influenced by an intestinal stoma. Qualitative comments lend insight into the meaning of spirituality items. Findings can assist in the provision of holistic care in this population.

Peri-operative anaesthetic management of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is a long and complex procedure with significant blood and fluid loss during debulking and important pathophysiological alterations during the HIPEC phase. We performed a retrospective analysis of 78 consecutive patients undergoing cytoreductive surgery with HIPEC at a university hospital. Our data demonstrate large intra-operative fluid turnover, with 51% of patients requiring a blood transfusion. During HIPEC, airway pressure and central venous pressure increased with a lower oxygenation ratio as a result of increased intra-abdominal pressure with the closed abdomen technique. As a consequence of the raised body temperature, heart rate, end tidal carbon dioxide and arterial lactate levels increased with a slight metabolic acidosis. Peri-operative analysis of routine clotting parameters revealed disturbances of the coagulation status. For pain management, 72% of patients received supplementary thoracic epidural analgesia with consequential peri-operative opioid sparing and a reduced duration of postoperative ventilation.

Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies.

INTRODUCTION: Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-kappaB), PI3K/AKT, and mitogen-activated protein kinase (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. MATERIALS AND METHODS: PANC-1, PaCa-2, and BxPC-3 cells were treated with curcumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electrophoretic mobility shift assay. RESULTS: Each agent dose-dependently decreased proliferation. All cells decreased NF-kappaB activity with curcumin(24 h) except PaCa-2, MEK activity with PD325901(24 h), and PI3Kinase with LY294002(3 h). However, PI3K rebounded to(PaCa-2) or above (Panc-1,BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferative inhibition. For PANC-1, curcumin + gemcitabine was nearly synergistic, correlating with gemcitabine-induced NF-kappaB activity. LY294002 + gemcitabine was nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 was only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. CONCLUSIONS: These results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

[Elastic stable intramedullary nailing as alternative therapy for pediatric Monteggia fractures]. / Die elastisch-stabile Marknagelung als Therapiealternative in der Versorgung kindlicher Monteggia-Frakturen.

Forearm fractures are some of the most common injuries in childhood. Monteggia fractures and Monteggia equivalents are rare injuries of the proximal forearm, but they are important because of their special biomechanics. Many authors have reported good results with excellent function if the Monteggia injuries are diagnosed primarily and treated by an axial reposition of the ulna and by an exactly repositioned proximal radioulnar joint. In our investigation, some clinical cases of pediatric Monteggia fractures were operated upon using the technique of elastic stable intramedullary nailing (ESIN). In correct indications, ESIN could be used as a minimally invasive therapeutic alternative to plate osteosynthesis for treating pediatric Monteggia injuries.

Effect of celecoxib and novel agent LC-1 in a hamster model of lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer deaths in the United States. Inflammatory molecules, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) have been implicated in lung carcinogenesis. The therapeutic potential of celecoxib, a COX-2 selective inhibitor, and LC-1, a pro-apoptotic drug with accompanying inhibition of NF-kappaB, were investigated. MATERIALS AND METHODS: Syrian golden hamsters (n = 140) underwent N-nitroso-bis(2-oxopropyl)amine (BOP) injection weekly for 6 wk. Hamsters were randomized into seven groups: placebo and low/high doses of LC-1, celecoxib, and LC-1/celecoxib. Treatments were given via orogastric lavage for 32 wk. Immunohistochemistry was used to determine COX-2 expression and NF-kappaB activity. Ki-67 labeling was used as an index of proliferation. COX activity was measured by prostaglandin E(2) enzyme-linked immunosorbent assay. RESULTS: BOP successfully induced lung adenocarcinoma in 63% of placebo animals. Lung tumors strongly expressed COX-2 and NF-kappaB. Prostaglandin E(2) levels were decreased in celecoxib compared with placebo groups (P < 0.05) reflecting suppression of COX activity, but no decrease in NF-kappaB was seen as measured by immunohistochemistry in the tumors. There was no significant difference in tumor size, tumor incidence, or tumor proliferation index between placebo and treatment groups. CONCLUSIONS: Carcinogen exposure results in increased COX-2 and NF-kappaB expression and suggests a role in carcinogenesis. Celecoxib and LC-1 did not have any effect in preventing lung cancer development when co-administered with and continued after the carcinogen BOP. Higher doses that can result in suppression of NF-kappaB activity will need to be explored to determine the viability of this approach to prevent lung cancer development.

Demographic, clinical, and quality of life variables related to embarrassment in veterans living with an intestinal stoma.

OBJECTIVE: The study aims were to identify demographic, clinical, and quality of life variables related to embarrassment for people living with ostomies and to determine the experiences and/or feelings of veterans who were embarrassed by their ostomy. DESIGN: This was a cross-sectional, correlational study. SETTING AND SUBJECTS: A convenience sample of veterans (n = 239) living with ostomies from 3 VA medical centers was studied. The veterans were primarily Caucasian (84%), male (92%), and older (M = 69). INSTRUMENTS: The modified City of Hope Quality of Life-Ostomy questionnaire was used. Additionally, an open-ended question related to living with an ostomy was asked. METHODS: The questionnaire packets were mailed to participants and self-administered. RESULTS: Approximately half of the participants (48%) rated their embarrassment as low, but 26% reported high embarrassment. Participants with high embarrassment were compared to those with low embarrassment on demographic, clinical, and quality of life variables. High embarrassment was associated with poorer total quality of life (P < .001) and poorer quality of life on the physical (P < .001), psychological (P < .001), social (P < .001), and spiritual (P < .001) subscales. Younger (P < .001) and unpartnered veterans (P < .001) were more likely to be highly embarrassed. Veterans with high embarrassment had higher anxiety (P < .001) and depression (P < .001), more difficulty with intimacy (P < .001), and felt more isolated (P < .001). Spiritual domain variables like hopefulness were associated with low embarrassment (P < .001). Sources of embarrassment included leakage, odor, and noise. CONCLUSIONS: Embarrassment may negatively impact a person's quality of life; therefore, the variables associated with high embarrassment should be recognized and addressed.

Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo.

The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-kappaB (NF-kappaB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-kappaB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/COX-2 levels or activity in any of the treatment groups. NF-kappaB DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents.

A novel, non-substrate-based series of glycine type 1 transporter inhibitors derived from high-throughput screening.

The synthesis and structure-activity relationships (SAR) of a series of indane and tetralin inhibitors of the type 1 glycine transporter, derived from a high-throughput screening (HTS) hit, are described. Key modifications that reduced the 5HT1B receptor affinity of the HTS hit and the P450 2D6 inhibition of subsequent analogues are delineated. While these modifications led to potent and selective GlyT1 inhibitors, HERG affinity and human microsomal clearance remain an issue for this series of compounds.

Isolation and synthesis of acmellonate, a new unsaturated long chain 2-ketol ester from Spilanthes acmella.

Paracress (Spilanthes acmella) is commonly used as a spice, e.g., in Madagascar. To get more information about the taste active compounds, Jambu oleoresin produced from Spilanthes acmella and extracts prepared directly from the plant were fractionated and the fractions were analysed and evaluated by tasting. In addition to the long known tingling compounds (2E,6Z,8E)-deca-2,6,8-trienoic acid N-isobutyl amide (spilanthol) and (2E,6Z,8E)-deca-2,6,8-trienoic acid N-(2-methylbutyl) amide, as a minor constituent also the new 2-ketol ester (7Z,9E)-2-oxo-undeca-7,9-dienyl 3-methylbut-2-enoate (acmellonate) was isolated. The structure of the latter compound was verified by total synthesis of the ketol ester via the reaction of tris(trimethylsilyloxy)ethene and (6Z,8E)-deca-6,8-dienoic acid chloride and subsequent classical esterification. Acmellonate shows a weak tingling and numbing effect on the tongue and contributes only to a small extend to the overall flavour of Jambu.

Functionality or aesthetics? A pilot study of music therapy in the treatment of multiple sclerosis patients.

INTRODUCTION: Neuro-degenerative diseases are, and will remain, an enormous public health problem. Interventions that could delay disease onset even modestly will have a major public health impact. The aim of this study is to see which components of the illness are responsive to change when treated with music therapy in contrast to a group of patients receiving standard medical treatment alone. MATERIAL AND METHODS: Twenty multiple sclerosis patients (14 female, 6 male) were involved in the study, their ages ranging from 29 to 47 years. Ten participants formed the therapy group, and 10 the matched control group matched by age, gender and the standard neurological classification scheme Expanded Disability Status Scale (EDSS). Exclusion criteria were pregnancy and mental disorders requiring medication. Patients in the therapy group received three blocks of music therapy in single sessions over the course of the one-year project (8-10 sessions, respectively). Measurements were taken before therapy began (U1), and subsequently every three months (U2-U4) and within a 6-month follow-up without music therapy (U5) after the last consultation. Test battery included indicators of clinical depression and anxiety (Beck Depression Inventory and Hospital Anxiety and Depression Scale), a self-acceptance scale (SESA) and a life quality assessment (Hamburg Quality of Life Questionnaire in Multiple Sclerosis). In addition, data were collected on cognitive (MSFC) and functional (EDSS) parameters. RESULTS: There was no significant difference between the music-therapy treatment group and the control group. However, the effect size statistics comparing both groups show a medium effect size on the scales measuring self-esteem (d, 0.5423), depression HAD-D (d, 0.63) and anxiety HAD-A (d, 0.63). Significant improvements were found for the therapy group over time (U1-U4) in the scale values of self-esteem, depression and anxiety. In the follow-up, scale values for fatigue, anxiety and self-esteem worsen within the group treated with music therapy. DISCUSSION: A therapeutic concept for multiple sclerosis, which includes music therapy, brings an improvement in mood, fatigue and self-acceptance. When music therapy is removed, then scale scores worsen and this appears to intimate that music therapy has an influence.