Cantharidin increases the force of contraction and protein phosphorylation in isolated human atria.

Cantharidin, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), is known to increase the force of contraction and shorten the time to relaxation in human ventricular preparations. We hypothesized that cantharidin has similar positive inotropic effects in human right atrial appendage (RAA) preparations. RAA were obtained during bypass surgery performed on human patients. These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. For comparison, we studied isolated electrically stimulated left atrial (LA) preparations and isolated spontaneously beating right atrial (RA) preparations from wild-type mice. Cumulatively applied (starting at 10 to 30 µM), cantharidin exerted a positive concentration-dependent inotropic effect that plateaued at 300 µM in the RAA, LA, and RA preparations. This positive inotropic effect was accompanied by a shortening of the time to relaxation in human atrial preparations (HAPs). Notably, cantharidin did not alter the beating rate in the RA preparations. Furthermore, cantharidin (100 µM) increased the phosphorylation state of phospholamban and the inhibitory subunit of troponin I in RAA preparations, which may account for the faster relaxation observed. The generated data indicate that PP1 and/or PP2A play a functional role in human atrial contractility.

Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways.

The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.

Frequency-selective non-linear blending for the computed tomography diagnosis of acute gangrenous cholecystitis: Pilot retrospective evaluation.

PURPOSE: To compare the diagnostic performance of frequency-selective non-linear blending and conventional linear blending contrast-enhanced CT for the diagnosis of acute (AC) and gangrenous (GC) cholecystitis. MATERIALS AND METHODS: Following local ethics committee approval for retrospective data analysis, a database search derived 39 patients (26 men, mean age 67.8 ±â€¯14.6 years) with clinical signs of acute cholecystitis, contrast enhanced CT (CECT) evaluation, cholecystectomy, and pathological examination of the resected specimen. The interval between CECT and surgery was 4.7 ±â€¯4.1 days. Pathological gross examination was used to categorize the cases into AC and GC. Subsequently, two radiologists categorized the CECT studies in a blinded and independent fashion into AC and GC, during two different reading sessions using linear blending and frequency-selective non-linear blending CECT. RESULTS: Histologic analysis diagnosed 31/39 (79.4%) cases of GC and 8/39 (20.6%) cases of AC. Image interpretation of linear blending CECT resulted in classification of 7/39 (17.9%) patients as GC and 32/39 (82.1%) as AC, whereas image interpretation of frequency-selective non-linear blending CECT resulted in classification of 29/39 (74.3%) patients as GC and 10/39 (25.7%) as AC. Sensitivity/specificity/PPV/NPV for detection of GC were 22.6%/100%/100%/25% with linear blending CECT and 80.6%/50%/86.2%/40% with frequency-selective non-linear blending CECT, respectively. Based on the histopathologic diagnosis frequency-selective non-linear blending had a significant improvement (p > 0.0001) in the diagnostic accuracy of gangrenous cholecystitis compared with linear blending. CONCLUSION: Frequency-selective non-linear blending post-processing increases the diagnostic accuracy of gangrenous cholecystitis owing to improved visualization of absence of focal enhancement and mural ulcerations.

A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis.

The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.

The impact of immediate breast reconstruction after mastectomy on time to first adjuvant treatment in women with breast cancer in a community setting.

BACKGROUND: The impact of immediate breast reconstruction on the time to first adjuvant therapy is controversial. METHODS: Retrospective study design comparing time to first treatment in women undergoing mastectomy with and without immediate reconstruction in a community cancer center. RESULTS: Seventy-six cases fit inclusion criteria of which 44 (58%) underwent mastectomy with immediate reconstruction. Women undergoing immediate reconstruction were younger, had more bilateral mastectomies and had fewer prior breast procedures. The median time to first adjuvant therapy was longer in the immediate reconstruction group [80.5days (36-343) versus 53.5 days (18-96), p = 0.003]. Fifteen of 44 patients had the start of adjuvant treatment over 90 days after resection, 14 of whom (93%) had immediate reconstruction versus 1 (7%) who did not (p = 0.01). CONCLUSION: In this study immediate breast reconstruction was associated with a longer time to first adjuvant treatment, with adjuvant therapies being more likely delayed over 90 days.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Evaluation of six PCR assays in combination with patient related data for the diagnosis of Clostridium difficile-associated infections.

BACKGROUND: The aim of this multicenter study was to establish a diagnostic algorithm using molecular methods for the diagnosis of C. difficile-associated infection (CDI). In addition patient specific data were taken into consideration for the interpretation of the results. METHODS: We compared the performance of six different commercially available PCR-tests, two toxin immunoassays, and a glutamat-dehydrogenase test by analysing liquid stool specimens from patients with suspected CDI. Toxigenic culture on CLO-agar was used as reference method. RESULTS: In total 250 stool specimens were collected at two study sites. 77 (30.8%) stool samples were culture-positive for toxigenic C. difficile. 173 (69.2%) specimens showed no growth of C. difficile. As a result, each of the PCR assays tested for C. difficile had a significantly higher sensitivity (94.8% - 100%) and NPV (97.6% - 100%) than the TOX-EIA with a sensitivity of 57.1% and NPV of 83.8%. Specificity of the PCR tests was 94.1% to 96.0% and PPV between 86.5% and 91.6%. The analysis of the patient data revealed a significant difference (p-value 0.0202) between toxin-positive and toxin-negative patients regarding prior antibiotic treatment, especially for cephalosporins. CONCLUSIONS: Our findings support the recommendation to restrict the use of antibiotics as a cornerstone in the prevention of CDI. We conclude that all of the PCR assays evaluated in this study can be applied in a diagnostic algorithm.

Healthcare worker-related MRSA cluster in a German neonatology level III ICU: a true European story.

Here we investigated a cluster of eight newly Methicillin-resistant Staphylococcus aureus (MRSA)-colonized neonates at an ICU, and present data on molecular strain characterization as well as the source identification process in which we analyze the impact of MRSA-colonized HCWs. Molecular strain characterization revealed a unique pattern which was identified as spa-type t 127--an extremely rare strain type in Germany. Environmental sampling and screening of parents of colonized neonates proved negative. However, staff screening identified one healthcare worker (HCW; 1/134) belonging to a group of recently employed Romanian HCWs who was colonized with the spa 127 strain. Subsequent screening also detected MRSA in 9/51 Romanian HCWs (18%) and 7/9 (14% of all) isolates showed the same molecular pattern as the index case (spa/PFGE type). All carriers were successfully decolonized, after which no new patient cases occurred. As a result, we have now implemented a universal screening programme of all new employees as part of our infection control management strategy. MRSA-colonized HCWs can act as a source for in hospital transmission. Since HCWs from high endemic countries are particular prone to being colonized, they may pose a risk to patients.

Osteosarcoma of the mobile spine.

BACKGROUND: The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. PATIENTS AND METHODS: Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. RESULTS: The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age <40 years, nonmetastatic disease at diagnosis and complete remission predicted for better overall survival (OS, P < 0.05). CONCLUSIONS: Osteosarcomas of the mobile spine are rare. With complete resection (and potentially radiotherapy) and chemotherapy, prognosis may be comparable with that of appendicular osteosarcomas.

Controversies in childhood osteosarcoma.

Osteosarcoma, the most frequent bone cancer of children and adolescents, will almost always result in death due to pulmonary metastatic disease unless treated by surgery and effective multidrug chemotherapy. Imaging of the primary tumor is by X-ray and magnetic resonance imaging. Imaging of the chest is by computed tomography, but many questions regarding the interpretation of small, nonspecific findings and how to deal with them remain. The diagnosis must be confirmed by a well-placed biopsy. Chemotherapy is usually initiated prior to definitive surgery. Treatment generally includes high-dose methotrexate, doxorubicin, and cisplatin, with some regimens also incorporating ifosfamide. While limb-saving resections have become standard after completion of skeletal growth, reconstruction in the growing child poses much greater challenges. The use of modern, expandable endoprostheses, but also rotation-plasties and even amputation may all be valid options in selected cases. Histologic response of the primary to preoperative chemotherapy has been identified as an important prognostic factor. Various imaging methods can help to predict tumor response to preoperative chemotherapy, yet all have their limitations. Results of a randomized trial assessing if modifying postoperative treatment based on the extent of response will improve results, EURAMOS-1, are pending. The debate about whether biologic agents or targeted therapies added to chemotherapy might improve outcomes is ongoing. Follow-up to detect late-effects of treatment and recurrences of osteosarcoma must be continued for several decades.

Pancreatic neuroendocrine tumors: signal pathways and targeted therapies.

Pancreatic neuroendocrine tumors (PNETs) are rare but are well understood to cover a broad spectrum of clinical presentation, tumor biology and prognosis. More than 60% of PNETs are diagnosed at advanced disease stage and are ineligible for surgical resection. Prior to 2011, streptozocin was the only approved agent for unresectable advanced PNETs. In recent years, breakthroughs in signal pathway research have led to the identification of new therapeutic targets and agents directed at the molecular level. In 2011, two new targeted therapeutic agents, sunitinib and everolimus, were approved by the Food and Drug Administration (FDA). Sunitinib is an inhibitor of multiple tyrosine kinases, and everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway. This review discusses the major signaling pathways that are frequently mutated or deregulated in PNETs, and the implications of molecular alterations for PNET therapy. Biologic therapy through targeting relevant pathways represents a promising approach in the therapy of advanced and unresectable PNETs.

Molecular characterization and phylogenetic analysis of Eimeria from turkeys and gamebirds: implications for evolutionary relationships in Galliform birds.

In order to determine the evolutionary relationships among Eimeria species that parasitize birds of the Galliformes, the 18s rDNA gene and a portion of the cytochrome oxidase subunit 1 (cox-1) were amplified from Eimeria species isolated from turkeys, chukars, and pheasants. The phylogenetic analysis of these sequences suggests that species infecting chickens are polyphyletic and, therefore, do not all share a direct common ancestor. Both the 18s rDNA and the cox-1 sequences indicate that Eimeria tenella and Eimeria necatrix are more closely related to Eimeria of turkeys and pheasants than to other species that infect the chicken. It is, therefore, likely that the chicken Eimeria spp. represent 2 separate ancestral colonizations of the gut, one of which comprises E. tenella and E. necatrix that infect the ceca, while the other includes Eimeria acervulina, Eimeria brunetti, Eimeria maxima, and Eimeria mitis, which infect the upper regions of the intestine.

[Medical and psychosocial care needs of cancer patients: a systematic review comparing urban and rural provisions]. / Versorgung und psychosozialer Betreuungsbedarf von Krebspatienten im Stadt-Land-Vergleich - eine Literaturübersicht.

BACKGROUND AND OBJECTIVE: The psychological and oncological care needs of patients with cancer and an adequate structure for their medical care have so far been only marginally considered with regard to disparities in patients' residence (rural or urban). Even though there are thought to be such differences, for example with regard to existing care services and obvious specific care needs for patients in rural areas. This study addresses these issues in a systematic survey of the pertinent literature. METHODS: Publications in the last ten years dealing with identified problems were reviewed. A total of 27 studies met the criteria for analysis. RESULTS: Significant differences between medical care, psychosocial stress and the desired support were reported. Rural patients were more likely to be at a disadvantage compared with their urban counterparts with regard to medical care, being more often burdened cumulatively, and they strongly expressed the wish for psychological and oncological care. But the comparability of these results and transferring these findings to conditions in Germany proved difficult. CONCLUSION: When investigating the demand for psycho-oncological care, one needs to be aware of potential differences between rural and urban areas. Hence, in order to reliably distinguish between rural and urban living areas, a set of concrete criteria which define rural and urban surroundings needs to be established.

Depression and anxiety in patients undergoing herniated disc surgery: relevant but underresearched - a systematic review.

BACKGROUND: An association between depression and anxiety and musculoskeletal disorders has been consistently reported in the past years. This article provides a systematic overview of the literature on the prevalence rates of depression and anxiety in patients undergoing surgery for a herniated disc. METHODS: A systematic literature search was conducted in the following electronic databases: PubMed, PsycINFO, Web of Science, Cochrane Library and PSYNDEXplus. The identified articles were evaluated for prevalence rates of depression and anxiety, methodological issues, change of depression and anxiety over time, and major findings on the impact of depression and anxiety on patients undergoing disc surgery. RESULTS: Fourteen studies were identified. Prevalence rates for depression and anxiety in patients undergoing disc surgery varied between 21.5% and 49.3% before and between 4.1% and 79.6% after disc surgery. The study designs, the use of assessment instruments and cut-off values varied greatly. Depression and anxiety decreased within the population of disc surgery patients over time. Depression and anxiety were found to have a great impact on the postoperative outcome of surgery, return to work, analgesia abuse, pain experience, and abnormal illness behaviour. CONCLUSIONS: Little research has been done to investigate depression and anxiety in patients undergoing surgery for a herniated disc. Evidently disc surgery patients are at higher risk of suffering from depression and anxiety than the general population. The review outlines the importance for clinicians to be more sensitive to psychological concerns in patients undergoing disc surgery. Psychological assessment and assistance from mental health professionals should be considered during the hospital stay and rehabilitation period, depending on local feasibility. Further investigations are necessary to examine whether the implementation of a multidisciplinary in-patient treatment program will improve postoperative outcome in patients undergoing intervertebral disc surgery.

A review of the biomechanics of intrinsic replacement in ulnar palsy.

The actions of the interossei and lumbricals are many and their loss causes significant impairment of hand function. Many procedures have been described to restore intrinsic function following ulnar nerve palsy. There are many biomechanical issues involved in tendon transfers, including choice of muscle-tendon unit, route, insertion site, tension and drag. The surgeon, therefore, should have a good understanding of biomechanical principles to ensure optimal results. In this article the principles of biomechanics are reviewed with specific reference to tendon transfers for intrinsic reconstruction in ulnar palsy, along with their practical implications.

Anxiety and depression in cancer patients compared with the general population.

The objective of this study was to compare the prevalence of anxiety and depression in cancer patients with the prevalence found in the general population, using the Hospital Anxiety and Depression Scale (HADS). Participants were 1529 cancer patients treated between 2002 and 2004 in Germany and 2037 persons from the German general population. In the cancer patients, the risk of psychiatric distress was nearly twice that of the general population. While for older age groups (61 years and above) there were only small differences between cancer patients and the general population, the differences in both scales were high for young persons. There were differences between the HADS mean scores of the patients with different tumour localisations, with high values for brain cancer and low scores for prostate cancer. The influence of the tumour stage on anxiety and depression was weak. However, depression scores of patients with a survival time less than 1 year were elevated. The results show that large sample sizes are necessary to evaluate the psychological situation of cancer patients, and that age and gender differences must be taken into account when several samples are compared.

[Psychosocial support care wanted and actually received by patients with cancer. Gender-specific differences]. / Psychosoziale Unterstützungswünsche und tatsächlich erhaltene Versorgung onkologischer Patienten. Geschlechtsspezifische Unterschiede.

BACKGROUND AND OBJECTIVES: Professional psychosocial support of patients with cancer is an essential component of the entire process of medical care of these patients. But so far gender specific differences have only rarely been investigated. Yet some studies have suggested that there are differences between male and female patients regarding their psychological burden and their use of psychosocial support facilities. This article discusses the latter issue, based on empirical data. METHODS: At the beginning of their treatment (t1) the patients were asked to answer a questionnaire exploring their needs and wishes regarding medical and psychological care, as well as regarding self-support. There were 252 patients (60% males; mean age of males = 60.1 ; mean age of females = 55.5) with different kinds of cancer (39.7% of males had prostate cancer; 26.7% of females had breast cancer). The follow-up (t2) took place half a year after t1. As part of the follow-up questionnaire data regarding the meeting of the individual patient's needs was collected. Standardized scales were used (t1, t2), as well as a clinical interview (SKID) (t1), which recorded psychological co-morbidity. RESULTS: The need for support was found not to differ significantly between the genders but depended on the grade of co-morbidity and on the particular group of supporting professionals, respectively. Most frequently, within the overall condition "medical support" the patients' need for support (t1) and the actually received support (t2) were found to be coincident (85.7 - 94.2 %) for women as for men. Particularly with regard to psychological and social care, multivariate analysis revealed the need for care (t1) being a predictor of actually received support (t2). Especially within the group of women the factor "living alone" was found to explain the congruence between the need for care and the received support. CONCLUSION: Few gender-specific differences regarding need for care and actually received support have been found within this cohort of male and female patients with cancer. It is a unclear to what degree such differences could be due to the design of the study. It is important to assess the patient's wishes and needs for multiprofessional care at the beginning of cancer treatment. In addition the family and social situation must be taken into account.

[The role of next of kin in medical decision-making--empirical findings from haemato-oncological diseases]. / Die Rolle der Angehörigen bei medizinischen Entscheidungen--Empirische Befunde zu hämatoonkologischen Erkrankungen.

AIM OF THE STUDY: Models of shared decision making in the patient-doctor relationship are attracting increasing attention. A recent study focuses on the so far inadequate attention paid to the role of next of kin. It was examined in which decision areas next of kin of haematological cancer patients were included, further what support next of kin could provided and finally which factors encouraged the participation of next of kin in that process. METHODS: From 2006-2008 empirical data were collected from hemato-oncological patients undergoing treatment as well as from their families. The participating family members of patients were mailed questionnaires based on the patient sample (designation of a family member by the patient: 118/177 or 66.7%) on average half of a year following the patient's (in- or outpatient) treatment. The response rate of the participants was 67.8% (80/118). Of the respondents, 65% were spouses or partners of the patients, the average age was 53.9 years, and 66.3% were female. RESULTS: Family members think it makes sense for them to take an active part in medical decisions affecting their loved ones and a majority of them reported having participated in decision-making processes concerning a variety of issues. Being involved in their loved one's discussions with their doctors has a significant influence on this. Family members' level of education was the only clear predictor for participation in discussions with doctors that could be isolated. CONCLUSION: It is clear that family members, especially spouses and partners, consider it meaningful to participate in medical decisions affecting their loved ones, and that they want to be able to do this in the clinical context. One limitation that must be mentioned is that due to the small size of the sample and an approach that focused on initial exploration, the results should be interpreted as a point of orientation. Further studies should look in more detail at how inner family structures play a role in patient-doctor shared decision-making, as well as the concrete conditions and implications that play a role in family members' participation in this process, i.e., adherence to "doctor's orders" and possible decision-making conflicts on the part of the patient.

A rare case of Clostridium sordellii bacteremia in an immunocompromised patient.

Clostridium sordellii is a gram-positive, anaerobic sporeforming rod with peritrichous flagella that is rarely associated with disease in humans. In most cases, infections occur after trauma, childbirth and routine gynecological procedures or intravenous drug abuse. C. sordellii produce several exotoxins that lead to progressive edema and shock, and C. sordellii infections have high mortality rates of up to 70%. Since its first report in 1922, only a few cases of bacteremia have been reported. This report describes a case of C. sordellii bacteremia in a patient with rectum carcinoma and liver metastases.