Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms.

Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.

Crossbred steer temperament as yearlings and whole genome association of steer temperament as yearlings and calf temperament post-weaning.

cattle often have the reputation for a poor or dangerous temperament. Identification of genomic regions that associate with temperament of such cattle may be useful for genetic improvement strategies. The objectives of this study were to evaluate subjective temperament scores (1 to 9; higher scores indicated more unfavorable temperament) for aggressiveness, nervousness, flightiness, gregariousness, and overall temperament of one-half steers in feedlot conditions at 1 yr of age and compare those scores of those steers when evaluated approximately 1 mo postweaning, and conduct whole genome association analyses using SNP markers and the temperament traits of those steers at 1 yr of age and for temperament traits of all calves at weaning. Contemporary groups ( < 0.001) were steers born in the same year and season, and fed in the same feedlot pen. Aggressiveness of steers at 1 yr of age was not associated with aggressiveness at weaning (linear regression coefficient did not differ from 0; = 0.96), but regressions of all other yearling scores of steers on the scores at weaning were positive (coefficients ranged from 0.26 ± 0.04 to 0.32 ± 0.04; < 0.001). Estimates of Pearson correlation coefficients (using unadjusted values and residual values) of the different traits measured at 1 yr of age were large ( > 0.63; < 0.008) except for aggressiveness with nervousness, flightiness, or gregariousness, which did not differ from 0 ( > 0.1). Five SNP on BTA 1, 24, and 29 had suggestive associations (0.17 < [adjusted for FDR] < 0.24) with aggressiveness, nervousness, or flightiness at evaluation postweaning and 13 SNP on 11 chromosomes had suggestive associations (0.07 < [adjusted for FDR] < 0.24) with aggressiveness, nervousness, flightiness, or overall temperament score of steers at 1 yr of age. Genes close to these loci with roles in neural systems of various organisms included synaptotagmin 4 (BTA 24), FAT atypical cadhedrin 3 (BTA 29), tubulin tyrosine ligase-like 1 (BTA 5), spermatogenesis associated 17 (BTA 16), stanniocalcin 2 (BTA 20), and GABA receptor γ 3 (BTA 21).

Prevalence, location, grade of pressure ulcers and association with specific patient characteristics in adult spinal cord injury patients during the hospital stay: a prospective cohort study.

STUDY DESIGN: This was a prospective cohort study. OBJECTIVES: The objective was to describe the incidence, prevalence, characteristics of pressure ulcers (PUs) and the association with specific patient characteristics in a consecutive sample of in-patients with a spinal cord injury (SCI). SETTING: An acute care and rehabilitation clinic specialized in SCIs in Switzerland. METHODS: The presence and characteristics of PUs for all adult patients with a SCI admitted to the clinic from 1 September 2009 to 28 February 2010 were recorded on a daily basis during their complete hospitalization. Risk factors were analyzed in univariate and multivariate logistic regression models. RESULTS: A total of 185 patients were included in the study and observed for the entirety of their hospitalization. The prevalence of at least one PU was 49.2% in all patients, compared with 25.4% in the group of patients admitted without PUs. The incidence was 2.2 per person and year. In 91 patients, a total of 219 PUs were observed. PUs were most frequently located on the foot (36.1%), and the coccyx/sacrum (15.1%). The risk for occurrence of a PU increased with age (odds ratio (OR)=1.04) and post SCI (OR=1.03). In the multivariate analyses, the risk for PUs was lower for patients with the American Spinal Injury Association (ASIA) Impairment Scale (AIS) of C or D (ORC=0.25, ORD=0.28) compared with patients with an AIS of A. CONCLUSION: Using a daily documentation system, PUs were detected as a frequent complication of SCIs. Completeness of injury, age and time since injury were significant risk factors for PUs. The foot was a region at high risk for PUs.

Latent Class Factor Analysis of the Functional Independence Measure confirmed four distinct dimensions in patients undergoing neurological rehabilitation.

AIM: The FIM instrument is broadly applied in varying rehabilitation services for outcome assessment. Thus, it is important to examine its applicability for services which may differ from the situations and patients for which it was originally developed. The aims of the present study were to examine 1) whether the four FIM dimensions "activities of daily living", "sphincter management", "mobility", and "executive function" can be retrieved by Latent Class Factor Analysis (LCFA); and 2) whether the four dimensions show floor effects in patients with acquired brain injuries undergoing intensive post-acute rehabilitation. METHODS: We analyzed the FIM data of 269 patients with acquired brain injuries undergoing intensive post-acute rehabilitation. To examine the dimensional structure of the FIM instrument we carried out LCFA. Cronbach's alpha was used to measure the internal consistency. We examined the distribution of the dimension scores to identify floor effects. RESULTS: LCFA confirmed the postulated four dimensions. The explained variance of items assigned to the four dimensions ranged from 46% to 89%. Cronbach's alpha coefficients of the four subscales ranged from 0.94 to 0.96. The percentage of patients scoring the minimum possible score in each of the retrieved dimensions ranged from 22.3% to 47.9%. CONCLUSION: When applying the FIM instrument to patients undergoing intensive neurological rehabilitation its dimensionality should be kept in mind. For some patients this outcome measure might not be discriminative enough due to floor effects.

Identification of problems in individuals with spinal cord injury from the health professional perspective using the ICF: a worldwide expert survey.

STUDY DESIGN: Worldwide Internet survey. OBJECTIVES: The specific aims of the study were (1) to identify problems of individuals with SCI in the early post-acute and the long-term context, respectively, addressed by health professionals and (2) to summarize these problems using the ICF. SETTING: International. METHODS: Physicians, nurses, physical therapists, occupational therapists, social workers and psychologists were asked for problems in the functioning and contextual factors of individuals with SCI using open-ended questions. All answers were translated ('linked') to the ICF based on established rules. Absolute and relative frequencies of the linked ICF categories were reported stratified by the context. RESULTS: Out of 243 selected experts, 144 (59.3%) named 7.650 different themes, of which 78.8% could be linked to ICF categories. In the early post-acute context, 30.7% of the 88 categories belonged to the component Body Functions, 14.8% to Body Structures, 30.7% to Activities and Participation and 23.9% to Environmental Factors. In all, 16 ICF categories were unique for the early post-acute context. In the long-term context, 27.2% of the 92 categories belonged to the component Body Functions, 13.0% to Body Structures, 35.9% to Activities and Participation and 23.9% to Environmental Factors. A total of 20 ICF categories were unique for the long-term context. CONCLUSION: Health professionals identified a large variety of functional problems reflecting the complexity of SCI. Unique aspects of functioning exist for the early post-acute and the long-term context, respectively. The ICF provided a comprehensive framework to integrate answers from different professional backgrounds and different world regions.

Steroid-induced ptosis: case studies and histopathologic analysis.

PURPOSE: The purpose of this study was to review patients who developed ptosis after subtenon's steroid injection and to study the mechanism of steroid-induced ptosis in an animal model. METHODS: Part 1. Twenty-two patients with uveitis who had received posterior subtenon's triamcinolone acetonide injections were retrospectively reviewed. Demographics, type of uveitis, type and number of surgeries, pre and postoperative marginal reflex distance (MRD1), and clinical outcomes were evaluated. Part 2. Study of rabbit levator muscle and aponeurosis histopathology after subtenon's triamcinolone injection was performed. RESULTS: Part 1. The average age was 44.6 years (range: 14-85 years) with a mean follow-up of 14 months. The most common causes of uveitis included uveitis after cataract extraction (five), pars planitis (three), multifocal choroiditis (three), and juvenile rheumatoid arthritis (three). The average time to documented onset of ptosis was 13.9 months (range: 0-49 months). In patients who received only one steroid injection, the average time to ptosis recorded was 2.7 months (range: 0-6 months). Seventeen patients underwent ptosis repair. Part 2. No ptosis was noted in the experimental and control groups. Histopathologic analysis of levator tissues revealed no significant difference in atrophy or degree of inflammation between experimental and control groups. CONCLUSIONS: Ptosis following subtenon's steroid injection ranged from mild to moderate and occurred a few months after steroid injection. Prior studies of muscles and periocular tissues exposed to corticosteroids demonstrated degenerative muscle changes; our studies revealed no histopathologic changes in the levator muscle or aponeurosis.

[Primary malignant melanoma of the uterine cervix. Report of two cases and review of the literature]. / Primäres malignes Melanom der Cervix uteri. Zwei Fallberichte und Literaturübersicht.

The manifestation of a malignant melanoma in the uterus is very rare, more often it is the result of metastasis rather than a primary tumor. A malignant melanoma at this site can originate either from melanocytic elements within the cervical epithelium or from the cervical stroma. We report on two cases of primary malignant melanoma of the uterine cervix and compare them with other cases from the literature.

Chronic orthotopic aortic valve implantation model.

BACKGROUND AND AIM OF THE STUDY: The ideal animal model to assess implanted prosthetic aortic valves has yet to be universally accepted. The majority of mechanical valves are used for aortic valve replacement (AVR), yet historically animal models have provided data mainly after mitral valve implantation, due to the poor survival of animals undergoing AVR. Proposed regulations will require data from site-specific models. Thus, we modified previously reported chronic ovine models used for orthotopic implantation of aortic valves, to conduct preclinical aortic valve evaluation and to establish a predictive animal model needed for safety, hemodynamics, pathology and handling. METHODS: Fourteen sheep underwent AVR with 19 mm mechanical valves. Each animal was placed on cardiopulmonary bypass and the prosthetic valve implanted using a complete transverse ascending aortic transection. Hemodynamic data and aortography were obtained intraoperatively and again after 20 weeks, at which time hemodynamic studies, aortography, and pathological examination were performed. RESULTS: There were two operative deaths, but no significant complications in the other 12 sheep, 11 of which survived for 20 weeks. One animal died two weeks before sacrifice due to valve thrombosis. Chronic hemodynamic and aortographic data were within normal limits for all 11 sheep, and gross pathology of the implanted valve revealed no abnormalities. CONCLUSION: This study demonstrated the feasibility of the ovine model for orthotopic AVR, thus allowing greater confidence in the predictive value of in vivo hemodynamic and angiographic data gathered before clinical trials. Compared with other species, this ovine model provided improved rates of morbidity and mortality, reproducibility, ease of postoperative care, availability and acceptable anatomical similarities to humans. Future aortic valve studies at Medtronic will build on this knowledge base, making ovines - with this surgical technique - our animal model of choice.

[Primary osteosarcoma of the liver. Case report and literature review]. / Primäres Osteosarkom der Leber. Fallbericht und Literaturübersicht.

Primary sarcomas of the liver are rare. Most of them are angiosarcomas often related to exposure to thorotrast or polyvinyl chloride. We report a case of primary osteosarcoma of the liver in a 72-year-old man and compare it with the seven cases from the literature

[Differential giant cell epulis diagnosis--malignant melanoma of the mouth mucosa]. / Differentialdiagnose der Riesenzellepulis--das maligne Melanom der Mundschleimhaut.

Malignant melanoma of the oral mucosa is a rare tumor. The clinical image can vary, so that diagnostic errors are possible. The case of a primary malignant melanoma camouflaging a giant cell granuloma is presented. The importance of biopsy and histological diagnosis is underlined.

Azathioprine-induced multisystem organ failure and cardiogenic shock.

Azathioprine is administered to treat increasing numbers of disorders over a wide range of organ systems. The potential for the drug to cause widespread organ dysfunction is not fully appreciated. In fact, azathioprine can cause multisystem organ dysfunction involving the kidneys, liver, and cardiovascular system. The discovery of global cardiac dysfunction as one component of this complication may indicate a mechanism of hypotension. Clinicians must be aware of the potential for azathioprine to cause such toxicities to facilitate appropriate patient management.

[Demonstration of IgG- and IgA-antibodies against Epstein-Barr virus-associated antigens with a microtiter enzyme immunoassay system. The determination of serum antibodies against the viral capsid antigen and the early antigen complex in the sera of tumor and infectious mononucleosis patients]. / Nachweis von IgG- und IgA-Antikörpern gegen Epstein-Barr-Virus-assoziierte Antigene mit einem Enzymimmunoassay im Mikrotitersystem. Bestimmung der Serumantikörper gegen das Viruskapsidantigen und den Frühantigenkomplex in Seren von Tumorpatienten und Patienten mit infektiöser Mononukleose.

An enzyme-linked immunosorbent assay (ELISA) using micro-titre plates has been established for determination of IgG and IgA antibodies to the Epstein-Barr virus (EBV)-associated early antigen complex (EA) and the viral capsid antigen (VCA). The results obtained correlated well with the antibody titre determinations by the standard immunofluorescence technique. The ELISA was found to be about 15 to 30 times more sensitive than the immunofluorescence assay. Because of its high sensitivity, specificity and rapid performance the enzyme-immunoassay is a useful tool for large scale epidemiological studies of EBV-associated diseases as well as for the early diagnosis and monitoring of patients with EBV-associated tumours: Burkitt's lymphoma and nasopharyngeal carcinoma. IgG and IgA antibody titres to EA and VCA were determined in sera obtained from healthy controls, patients with EBV-associated tumours, infectious mononucleosis and various diseases known to be associated with EBV-reactivation, i.e. lymphomas and leukaemias. Except in sera of patients with nasopharyngeal carcinoma, IgA antibodies to VCA and EA could only be detected at a rather high frequency (36% IgA anti-VCA+, 21% IgA anti-EA+) and in substantial titres in sera obtained from patients with chronic lymphatic leukaemia.

Enzyme-linked immunosorbent assay for IgG antibodies to Epstein-Barr virus-associated early antigens and viral capsid antigen.

An enzyme-linked immunosorbent assay has been developed for the detection of IgG antibodies to Epstein-Barr virus-associated early antigens and late antigens including the viral capsid antigen. The antibody titers of human sera determined in this way correlate well with those by indirect immunofluorescence. ELISA was more sensitive than the IF method. The assays described may be used for rapid and sensitive diagnosis of EBV-related diseases. In addition, the ELISA will be useful for the determination of antibody titers to isolated EBV-associated antigens, e.g., purified components of the EA complex.

Detection of IgA antibodies to Epstein-Barr virus-associated antigens by ELISA.

The detection of IgA antibodies to the Epstein-Barr virus (EBV)-associated viral capsid antigen (VCA) and early antigens (EA) is of diagnostic and prognostic importance for patients with nasopharyngeal carcinoma (NPC). An ELISA for the determination of serum IgG antibodies to these antigens has been developed which uses the double antibody method. 136 sera obtained from healthy donors and patients with non-EBV related tumors and lymphomas were tested by ELISA; only 3 sera, from patients with chronic lymphatic leukemia, hairy cell leukemia and Burkitt-like lymphoma, contained antibodies of IgA class to VCA and EA. Ninety-five sera from patients suspected of having NPC were tested. IgA anti-VCA was found in 28 sera (29.5%), 12 of which also contained IgA anti-EA. The assays described are suitable for diagnosis and follow-up of patients with EBV-associated nasopharyngeal carcinoma. Furthermore, isolated EA components may be tested for their reactivity with IgA antibodies, as was shown for the 60 kDa polypeptide associated with the EA complex.

Enzyme-linked immunosorbent assay for antibodies to Epstein-Barr virus-associated early antigens and the viral capsid antigen.

The determination of serum antibody titers to Epstein-Barr virus (EBV)-associated antigens is of diagnostic and prognostic importance in the case of patients with EBV-associated tumors, ie, Burkitt's lymphoma and nasopharyngeal carcinoma, and in infectious mononucleosis. Enzyme-linked immunosorbent assays (ELISA) were developed for the detection of antibodies to EBV-associated early antigens (EA) and the viral-capsid antigen. The antibody titers obtained by the ELISA method correlate well with the antibody titers determined by the standard indirect immunofluorescence technique. An ELISA developed for the quantitation of early antigens in cell extracts was used to purify a protein of the EA complex. Interestingly, some of the high anti-EA titered sera, as determined by immunofluorescence, did not contain significant amounts of antibodies to this component detectable by the ELISA with immobilized partially purified protein. Anti-EA negative sera did not react with the isolated EA component.