Obestatin signalling counteracts glucocorticoid-induced skeletal muscle atrophy via NEDD4/KLF15 axis.

BACKGROUND: A therapeutic approach for the treatment of glucocorticoid-induced skeletal muscle atrophy should be based on the knowledge of the molecular mechanisms determining the unbalance between anabolic and catabolic processes and how to re-establish this balance. Here, we investigated whether the obestatin/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid-induced muscle atrophy. METHODS: In this study, we used an in vivo model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin/GPR39 systems. The findings were extended to in vitro effects on human atrophy using human KM155C25 myotubes. RESULTS: KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15-triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post-translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin-proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re-establish protein synthesis. CONCLUSIONS: The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle-related pathologies. These results highlight the potential of the obestatin/GPR39 system to fine-tune the effects of glucocorticoids on skeletal muscle wasting.

Development and validation of a multivariable prediction rule for detecting a severe acquired ADAMTS13 activity deficiency in patients with thrombotic microangiopathies.

BACKGROUND: Thrombotic microangiopathies (TMAs) are a group of diseases that have different aetiologies and treatments, but a clinical differential diagnosis remains difficult. Among TMAs, thrombotic thrombocytopenic purpura (TTP) is characterised by a severe ADAMTS13 functional deficiency. However, assays exploring ADAMTS13 activity are limited to some specialised laboratories. Our objective was to develop and validate a diagnostic method for TTP in adult patients with TMA. METHODS: We generated a multivariable model (four predictors) on a cohort of 174 TMA patients in order to predict an ADAMTS13 activity deficiency (AUC of 0.927). The multivariable model was simplified into a binary rule to facilitate the interpretation of the predictions. There were two scenarios for a patient: (1) Predicted ADAMTS13 deficiency; if the patient met four conditions simultaneously (platelets ≤44×109/L, creatinine ≤2 mg/dL (≤176.84 µmol/L) for males or ≤1.9 mg/dL (≤168 µmol/L) for females, age ≤68 years and no history of haematopoietic stem cell transplant [HSCT]); or (2) Predicted "normal" activity; if any of the above conditions are not met. This rule was validated on a second cohort of 86 patients and performed with sensitivity of 87.7% and specificity of 92.7%. RESULTS AND CONCLUSIONS: This could lead to the earlier confirmation or rapid exclusion of TTP when ADAMTS13 testing is not avalilable, facilitating a more suitable therapy based on the aetiology of the TMA.

Evaluation of the Quality of Semen and Sexual Function in Men with Inflammatory Bowel Disease.

BACKGROUND: Data on fertility rates and medication safety in men with inflammatory bowel disease (IBD) are limited. The aim of this study was to evaluate whether there is a seminal alteration in patients with IBD and, if so, to evaluate the mechanisms that may play a role according to what has been described in the literature. Its secondary aim was to evaluate the impact on male sexual function of IBD. METHODS: Multicenter, cross-sectional, case series study comparing men with IBD and control subjects. Semen analysis was performed according to the recommendations of World Health Organization. The impact on male sexual function was evaluated with the International Index of Erectile Function questionnaire. RESULTS: On multivariate analysis, patients with Crohn's disease had lower sperm concentrations compared with those with ulcerative colitis (median [interquartile range], 34.5 [19.2-48] versus 70 [34.5-127.5], P = 0.02) and lower seminal zinc levels (mean ± SD, 1475 ± 235 µmol/L versus 2221 ± 1123 µmol/L, P = 0.04). Patients with Crohn's disease on anti-tumor necrosis factor treatment had better progressive motility (mean ± SD, 56.7 ± 17.7 versus 35.1 ± 22.1, P = 0.01) and sperm morphology (14.4 ± 7.1 versus 7.6 ± 4.9, P = 0.04) than those who were not on anti-tumor necrosis factor. Regarding sexual function, no significant differences were found across patients with IBD and control subjects. CONCLUSIONS: Men with Crohn's disease showed a trend toward poorer semen quality than those with ulcerative colitis. Treatment with anti-tumor necrosis factor drugs does not seem to be associated with poor sperm quality. In patients in clinical remission, male sexual function is not affected by IBD.

Association between history of psychosis and cardiovascular disease in bipolar disorder.

OBJECTIVES: To determine whether clinical features of bipolar disorder, such as history of psychosis, and cardiovascular disease (CVD) risk factors contribute to a higher risk of CVD among patients with bipolar disorder. METHODS: This cross-sectional study included a sample of 988 patients with bipolar I or bipolar II disorder or schizoaffective bipolar type confirmed by the Structured Clinical Interview for DSM-IV-TR disorders (SCID). Medical comorbidity burden was quantified utilizing the Cumulative Illness Severity Rating Scale (CIRS). This 13-item organ-based scale includes cardiac disease severity quantification. Confirmed by medical record review, patients who scored 1 (current mild or past significant problem) or higher in the cardiac item were compared by logistic regression to patients who scored 0 (no impairment), adjusting for CVD risk factors that were selected using a backwards stepwise approach or were obtained from the literature. RESULTS: In a multivariate model, age [odds ratio (OR) = 3.03, 95% confidence interval (CI): 1.66-5.54, p < 0.0001], hypertension (OR = 2.43, 95% CI: 1.69-3.55, p < 0.0001), and history of psychosis (OR = 1.48, 95% CI: 1.03-2.13, p = 0.03) were associated with CVD. When CVD risk factors from the literature were added to the analysis, age (OR = 3.19, 95% CI: 1.67-6.10, p = 0.0005) and hypertension (OR = 2.46, 95% CI: 1.61-3.76, p < 0.01) remained significant, with psychosis being at the trend level (OR = 1.43, 95% CI: 0.96-2.13, p = 0.08). CONCLUSIONS: The phenotype of psychotic bipolar disorder may reflect higher illness severity with associated cardiac comorbidity. Further studies are encouraged to clarify the effect of the disease burden (i.e., depression), lifestyle, and treatment interventions (i.e., atypical antipsychotics) on this risk association.

Baseline screening tools as indicators for symptom outcomes and health services utilization in a collaborative care model for depression in primary care: a practice-based observational study.

OBJECTIVE: Within a practice-based collaborative care program for depression, we examined associations between positive baseline screens for comorbid mental and behavioral health problems, depression remission and utilization after 1 year. METHODS: This observational study of 1507 depressed adults examined baseline screens for hazardous drinking (Alcohol Use Disorders Identification Test score ≥ 8), severe anxiety (Generalized Anxiety Disorder 7-item score ≥ 15) and bipolar disorder [Mood Disorders Questionnaire (MDQ) positive screen]; 6-month depression remission; primary care, psychiatric, emergency department (ED) and inpatient visits 1 year postbaseline; and multiple covariates. Analyses included logistic and zero-inflated negative binomial regression. RESULTS: At unadjusted baseline, 60.7% had no positive screens beyond depression, 31.5% had one (mostly severe anxiety), 6.6% had two and 1.2% had all three. In multivariate models, positive screens reduced odds of remission versus no positive screens [e.g., one screen odds ratio (OR) = 0.608, p = .000; all three OR = 0.152, p = .018]. Screening positive for severe anxiety predicted more postbaseline visits of all types; severe anxiety plus hazardous drinking predicted greater primary care, ED and inpatient; severe anxiety plus MDQ and the combination of all three positive screens both predicted greater psychiatric visits (all p < .05). Regression-adjusted utilization patterns varied across combinations of positive screens. CONCLUSIONS: Positive screens predicted lower remission. Severe anxiety and its combinations with other positive screens were common and generally predicted greater utilization. Practices may benefit from assessing collaborative care patients presenting with these screening patterns to determine resource allocation.

A multinational study to pilot the modified Hypomania Checklist (mHCL) in the assessment of mixed depression.

BACKGROUND: Mixed depression is a common, dimensional phenomenon that is increasingly recognized in unipolar and bipolar disorders. We piloted a modified version of the Hypomania Checklist (mHCL-32) to assess the prevalence and clinical correlates of concurrent manic (hypo) symptoms in depressed patients. METHODS: The mHCL-32, Young Mania Rating Scale (YMRS) and Hamilton Rating Scale for Depression (HAMD-24) were utilized in the assessment of unipolar (UP=61) and bipolar (BP=44) patients with an index major depressive episode confirmed by the Structured Clinical Interview for DSM-IV (SCID). Differential mHLC-32 item endorsement was compared between UP and BP. Correlation analyses assessed the association of symptom dimensions measured by mHCL-32, YMRS and HAMD-24. RESULTS: There was no significant difference between mood groups in the mean mHCL-32 and YMRS scores. Individual mHLC-32 items of increased libido, quarrels, and caffeine intake were endorsed more in BP vs. UP patients. The mHCL-32 active-elevated subscale score was positively correlated with the YMRS in BP patients and negatively correlated with HAMD-24 in UP patients. Conversely, the mHCL-32 irritable-risk taking subscale score was positively correlated with HAMD-24 in BP and with YMRS in UP patients. LIMITATIONS: Small sample size and cross-sectional design. CONCLUSION: Modifying the HCL to screen for (hypo) manic symptoms in major depression may have utility in identifying mixed symptoms in both bipolar vs. unipolar depression. Further research is encouraged to quantify mixed symptoms with standardized assessments.

Early predictors of gestational hypertension in a low-risk cohort. Results of a pilot study.

OBJECTIVE: To determine if the clinical or biochemical markers used in pregnancy can be applied as early predictors of gestational hypertension. DESIGN: Prospective cohort study. POPULATION: 315 pregnant women referred from the Prenatal Diagnosis Unit between weeks 10-13 of pregnancy and followed up to the childbirth. METHODS: Biomarkers were measured in serum specimens in the first and second trimester of pregnancy. Blood pressure (BP) was measured in the first, second and third trimester. RESULTS: The cumulative incidence of gestational hypertension was 6.01%. In the first trimester gestational hypertension predictors were uric acid greater than 3.15 mg/dl (P=0.01), BMI greater than 24 kg/m (P=0.003) SBP at least 120 mmHg (P=0.02) and DBP at least 71 mmHg (P=0.007). After applied multivariate analysis just uric acid and SBP were statistically significant. CONCLUSION: In our cohort of healthy pregnant women uric acid above 3.15 mg/dl and SBP at least 120 mmHg are consistent predictors of gestational hypertension in the first trimester. The most important implication of our study is the possibility to identify in the first trimester women at risk to develop gestational hypertension using available markers.

Trasplante de pulmón con donantes no controlados a corazón parado. Factores pronósticos dependientes del donante y evolución inmediata postrasplante / Lung Transplantation with Uncontrolled Non-Heart-Beating Donors. Transplantation. Donor Prognostic Factor and Immediate Evolution Post Transplant

Introducción: La donación en asistolia no controlada (DANC) constituye una alternativa al trasplantepulmonar con donantes en muerte encefálica. El objetivo principal del estudio es describir la incidenciade eventos al mes tras el trasplante con pulmones de DANC, y la influencia de los factores dependientesdel donante y del proceso de donación.Pacientes y métodos: Estudio de una cohorte histórica de 33 receptores de trasplante pulmonar realizadosen los hospitales Puerta de Hierro y Marqués de Valdecilla con 32 DANC procedentes del Hospital ClínicoSan Carlos durante el periodo 2002-2008. Se estudiaron los siguientes eventos: complicaciones quirúrgicasy médicas, disfunción primaria del injerto, rechazo agudo, neumonía y mortalidad. Se evaluaron lascaracterísticas del donante y los tiempos del proceso de donación (minutos).Resultados: La mediana de edad de los receptores fue 50,5 años (rango intercuartílico, 38,5-58); 28 hombresy 5 mujeres. La incidencia acumulada de los eventos al mes fue: neumonía, 10 (31,3%); disfunciónprimaria del injerto, 15 (46,9%); rechazo, 12 (37,5%); mortalidad, 4 (12,1%); complicaciones médicas,25 (78,1%), y quirúrgicas, 18 (56,3%). La mediana del tiempo de asistolia fue mayor en los sujetos conneumonía (15 vs. 7,5; p = 0,027), la mediana del tiempo de isquemia fría fue superior en los sujetos quepresentaron complicaciones quirúrgicas y mortalidad (436 vs. 343,5; p = 0,04; 505 vs. 410; p = 0,033, respectivamente),y las medianas de los tiempos de isquemia total fueron superiores en los receptores quefallecieron (828 vs. 695; p = 0,036).Conclusiones: Los DANC constituyen una alternativa válida para expandir el pool de donantes pulmonaresante la carencia actual de pulmones válidos para el trasplante. La incidencia de complicaciones escomparable con los datos publicados en la literatura(AU)

Introduction: Uncontrolled donation after cardiac death (DACD) has become an alternative to lung transplantationwith encephalic-death donation. The main objective of this study is to describe the incidenceof clinically relevant events in the period of thirty days after lung transplant with uncontrolled DACD andthe influence of factors depending on the donor and donation process as well.Patients and methods: Historical cohort study of 33 lung transplant receivers at Hospital Puerta de Hierro and Hospital Marqués de Valdecilla with 32 DACD from Hospital Clínico San Carlos from 2002 to 2008.We studied surgical and medical complications, primary graft dysfunction, acute rejection, pneumonia and mortality. We made an evaluation of the donor characteristics and donation procedure times (minutes). Results: Median age of recipients was 50.5 years (interquartile range, 38.5-58). There were 28 malesand 5 females. Cumulative incidence of events in the first month was: pneumonia 10 (31.3%); primarygraft dysfunction 15 (46.9%); rejection 12 (37.5%); mortality 4 (12.1%); medical complications 25 (78.1%);and surgical complications 18(56.3%). Median time of cardiac arrest was higher in those who presentedpneumonia (15 vs. 7.5; p = 0.027). Median time of cold ischemia was higher in those who presentedsurgical complications and mortality (436 vs. 343.5; p = 0.04; 505 vs. 410; p = 0.033, respectively), andmedian of total ischemia times were longer in the recipients who died (828 vs. 695; p = 0.036).Conclusions: Uncontrolled DACD are a valid alternative for expanding the donor pool in order to mitigatethe current shortage of lungs that are valid for transplantation. The incidence of complications iscomparable with published data in the literature(AU)

[Lung transplantation with uncontrolled non-heart-beating donors. Transplantation. Donor prognostic factor and immediate evolution post transplant]. / Trasplante de pulmón con donantes no controlados a corazón parado. Factores pronósticos dependientes del donante y evolución inmediata postrasplante.

INTRODUCTION: Uncontrolled donation after cardiac death (DACD) has become an alternative to lung transplantation with encephalic-death donation. The main objective of this study is to describe the incidence of clinically relevant events in the period of thirty days after lung transplant with uncontrolled DACD and the influence of factors depending on the donor and donation process as well. PATIENTS AND METHODS: Historical cohort study of 33 lung transplant receivers at Hospital Puerta de Hierro and Hospital Marqués de Valdecilla with 32 DACD from Hospital Clínico San Carlos from 2002 to 2008. We studied surgical and medical complications, primary graft dysfunction, acute rejection, pneumonia and mortality. We made an evaluation of the donor characteristics and donation procedure times (minutes). RESULTS: Median age of recipients was 50.5 years (interquartile range, 38.5-58). There were 28 males and 5 females. Cumulative incidence of events in the first month was: pneumonia 10 (31.3%); primary graft dysfunction 15 (46.9%); rejection 12 (37.5%); mortality 4 (12.1%); medical complications 25 (78.1%); and surgical complications 18 (56.3%). Median time of cardiac arrest was higher in those who presented pneumonia (15 vs. 7.5; p = 0.027). Median time of cold ischemia was higher in those who presented surgical complications and mortality (436 vs. 343.5; p = 0.04; 505 vs. 410; p = 0.033, respectively), and median of total ischemia times were longer in the recipients who died (828 vs. 695; p = 0.036). CONCLUSIONS: Uncontrolled DACD are a valid alternative for expanding the donor pool in order to mitigate the current shortage of lungs that are valid for transplantation. The incidence of complications is comparable with published data in the literature.

Psychological factors affecting response to antidepressant drugs in fibromyalgia.

BACKGROUND: The use of antidepressant drugs in fibromyalgia is extensive despite small evidence of the real impact in the clinical practice setting. This study was aimed to evaluate the long-term efficiency of antidepressant treatment in fibromyalgia and the role of psychosocial factors in treatment response. METHODS: A total of 102 consecutive patients with fibromyalgia from primary health care centers were studied with psychopathological and psychological assessment interviews and questionnaires. Sustained release venlafaxine was added to previous treatments in flexible doses from 150 to 300 mg daily for a 6-month period. Efficacy measures included the Clinical Global Impression (CGI) scale (patient and clinician versions) and the Fibromyalgia Impact Questionnaire (FIQ) score reduction. RESULTS: At 6 months, 48% patients were considered responders to treatment (CGI change score 1 or 2) and 23.5% had a mild response. Of note, 57.8% had less fatigue and 31.4% had less pain. The proportion of responders was greater in the group with major depression (65%) than in those without depression (45%), but the difference did not reach statistical significance. However, the reduction of FIQ scores was significantly greater in depressed (21.1; IQR: 1.4-42.0) than in non-depressed patients (41.4; IQR: 23.6-52.6) (P<0.05). FIQ score reduction was significantly smaller in patients taking concomitant opiate treatment (P<0.01) and in patients seeking incapacitation (P<0.01). CONCLUSION: Antidepressant treatment in fibromyalgia was effective in patients with and without major depression, but the functional response was greater in depressed patients. Treatment response to antidepressants might be significantly influenced by attitudinal and psychosocial factors of the disease.

Agreement between information provided by stroke patients and their relatives on psychophysical and vascular risk factors.

BACKGROUND: In studies examining vascular risk factors and the effects of stress in stroke patients, information sometimes has to be provided by a close relative. OBJECTIVES: The present study was designed to assess agreement between the information provided by a stroke patient and his/her next-of-kin or other close relative on prior vascular risk factors and situations of psychophysical stress based on a standardized interview within 72 h after stroke. DESIGN: Case-control observational study. PARTICIPANTS AND SETTINGS: All patients with incident stroke aged 18-65 years admitted to our centre were enrolled as cases, and their coinhabiting relatives as controls. The study was conducted from January to June 2008. METHODS: A structured questionnaire about vascular risk factors and psychophysical stress factors were obtained from the participants within 72 h after stroke. Subjects were required to grade themselves or their relatives using validated Spanish versions of the Life Events Stress Scale of Holmes and Rahe, Goldberg's General Health Questionnaire GHQ-28 and the SF-12 Health Survey, as well as the Spanish Type A Behaviour Scale. The questionnaires were self-administered. Cases and controls completed the same questionnaires and which were administered with a time difference of no longer than 24 h between the two groups of subjects. Risk factors were analyzed by determining kappa statistics and interclass correlation coefficients (ICC). Bland-Altman plots were used to examine the scores obtained in graded scales. RESULTS: 25 patients and 25 relatives were recruited. Agreement between cases and controls was good for reported atrial fibrillation, diabetes, alcohol consumption and smoking (range 0.83-1.0). ICC were low for the questionnaires Holmes-Rahe Life Events (0.26; 95%CI: 0.08-0.57), General Health GHQ-28 (0.39; 95%CI: 0.03-0.67) and SF12 Health Survey (0.52; 95%CI: 0.16-0.76 and 0.35; 95%CI: 0.06-0.66), and good for the Type A Behaviour Scale ERCTA (0.62; 95%CI: 0.32-0.81). CONCLUSIONS: The information obtained from family members on patient risk factors could be considered reliable, while that related to psychophysical aspects was not sufficiently reliable for research purposes. Agreement assessments could be useful to avoid misclassification biases.