Clinical outcomes after tricuspid surgery : The role of previous cardiac surgery.

BACKGROUND: The aim of our study was to assess the outcomes of surgical treatment for severe tricuspid regurgitation according to whether cardiac surgery had been performed before the tricuspid valve intervention. METHODS: Between 1996 and 2013, 201 consecutive patients with severe tricuspid regurgitation underwent tricuspid surgery at our center. Patients were classified according to whether or not they had undergone previous cardiac surgery, which 33% of the sample had. Perioperative as well as long-term morbidity and mortality were analyzed. RESULTS: Mean patient age was 62.3 years. 32.8% underwent suture annuloplasty, 41.3% underwent ring annuloplasty, 15.4% received a bioprosthesis, and 10.4% received a mechanical prosthesis. There were no significant differences in perioperative mortality between the group that had not undergone previous cardiac surgery and the group that had (12.7% vs. 17.9%, respectively; p = 0.32). The long-term mortality rate (median follow-up time: 53 months) was 43.3%. Long-term survival curves showed no significant differences between the two groups (p = 0.884), and previous cardiac surgery was not a predictive factor for long-term mortality (hazard ratio = 1.211; p = 0.521). CONCLUSION: In a series of patients who underwent tricuspid valve surgery, no significant differences were observed in perioperative mortality or in long-term survival according to whether or not subjects had undergone previous cardiac surgery.

Safety and dose-dependency of eptacog beta (activated) in a dose escalation study of non-bleeding congenital haemophilia A or B patients, with or without inhibitors.

INTRODUCTION: Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. AIM: To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. METHODS: Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 µg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. RESULTS: Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax ) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0-inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. CONCLUSION: In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 µg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia.

Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder (SSD) and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes - processing speed, whole-brain white matter fractional anisotropy (FA) and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased FA and increased risk of SSD. A single SNP, rs8234, in the 3' untranslated region of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity and increased risk of schizophrenia.

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia.

Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.

New genes associated with schizophrenia in neurite formation: a review of cell culture experiments.

New genes consistently associated with schizophrenia include NRG1, Akt, DISC-1 and dysbindin-1. Since these genes participate in neurotransmission, neuroplasticity and neurodevelopment it has not been easy to elucidate which of these roles are abnormal in patients with schizophrenia. Neurite formation is identified as a crucial stage in development, and it is proposed that a defect in neurite formation originating from abnormally encoded proteins by these new genes could be at least an in vitro marker that reflects the most consistent molecular and neuroanatomical findings in schizophrenia. A systematic review of the literature linking the process of neurite formation to genes with replicated evidence that supported their association with schizophrenia was conducted. In addition, an outline of the process of neurite formation was included. Neurite formation was shown to be induced by neuregulins, the product of the gene NRG1. The activation of Akt, a serine/threonine kinase, promoted neurite formation in six independent studies. Conversely, two studies found that Akt inhibits neurite outgrowth. Stronger evidence supporting an association with the new genes related to schizophrenia and neurite formation comes from DISC-1. Defects in DISC-1 protein were shown to directly alter the process of neurite formation. Dysbindin-1 has not yet been directly implicated in neurite outgrowth. These findings suggest that the proteins encoded by NRG1, Akt and DISC-1 are implicated in the process of neurite formation in cellular models as well as, at least in part, animal models during development. Abnormalities in this process could have potential etiologic implications for schizophrenia. Direct evidence, however, of abnormal neurite formation in patients with schizophrenia is still missing. Limitations to this model are identified.

Melatonin prevents cytoskeletal alterations and oxidative stress induced by okadaic acid in N1E-115 cells.

Progressive loss of neuronal cytoarchitecture is a major event that precedes neuronal death, both in neural aging and in neurodegenerative diseases. Cytoskeleton in neurodegenerative diseases is characterized by hyperphosphorylated tau assembled in neurofibrillary tangles. Tau protein promotes microtubule enlargement and its hyperphosphorylation inhibits tubulin assembly. Okadaic acid (OA) causes oxidative stress, tau hyperphosphorylation, and altered cytoskeletal organization similar to those observed in neurons of patients with dementia. Since melatonin acts by both enlarging microtubules and as a free-radical scavenger, in this work we studied the effects of melatonin on altered cytoskeletal organization induced by OA in N1E-115 neuroblastoma cells. Optic microscopy, morphometric analysis, and tubulin immunofluorescence staining of neuroblastoma cells incubated with 50 nM OA showed an intact microtubule network following the neurite profile similar to that observed in the vehicle-incubated cells when melatonin was added to the incubation media 2 h before OA. The melatonin effects on altered cytoskeletal organization induced by OA were dose-dependent and were not abolished by luzindole, the mt(1) melatonin antagonist receptor. Also, increased lipid peroxidation and augmented apoptosis in N1E-115 cells incubated with 50 nM OA were prevented by melatonin. The results support the hypothesis that melatonin can be useful in the treatment of neurodegenerative diseases.

Improved conformation-dependent immunoassay: suitability for human prion detection with enhanced sensitivity.

The presence of pathogenic prion protein (PrP(Sc)) in lymphoid tissues of variant Creutzfeldt-Jakob disease (vCJD) patients raises questions as to whether prions may be present in bodily fluids as well. Currently, transgenic mice are highly sensitive in vivo tools for the study of prions in tissues or fluids containing high levels of normal prion protein (PrP(C)). We report here an in vitro assay with virtually equivalent sensitivity incorporating a capture antibody into a sandwich conformation-dependent immunoassay (CDI), resulting in 30- to 100-fold increased sensitivity compared with the original, direct CDI. Furthermore, spiking plasma with vCJD prions in different preparations demonstrated that sandwich CDI detects prions with different biophysical properties at high sensitivity, even without proteinase K pretreatment of samples. Thus, sandwich CDI represents a powerful tool to study prions in bodily fluids of CJD/vCJD patients, with a turnaround time of less than 24 h.

Differentiation-dependent redistribution of heparan sulfate in epithelial intestinal Caco-2 cells leads to basolateral entry of cytomegalovirus.

Human cytomegalovirus (HCMV) causes a broad spectrum of clinical manifestations in immunocompromised patients, including infection of the gastrointestinal tract. To investigate the role of epithelial cells in the gastrointestinal HCMV disease, we used the intestinal epithelial cell line Caco-2, which is permissive for HCMV replication. In differentiated Caco-2 cells, we showed previously that HCMV infection proceeds preferentially from the basolateral membrane, suggesting that receptors for HCMV may be contained predominantly in the basolateral membrane (A. Esclatine et al., 2000, J. Virol. 74, 513-517). Therefore, we examined expression and localization in Caco-2 cells of heparan sulfate (HS) proteoglycan and annexin II, previously implicated in initial events of HCMV infection. We observed that annexin II is expressed in Caco-2 cells, but is not essential for entry of HCMV. We showed that, during the differentiation process, HS, initially present on the entire surface of the membrane of undifferentiated cells, ultimately became sequestered at the basolateral cell surface of fully differentiated cells. We established by biochemical assays that membrane-associated HS proteoglycan mediates both viral attachment to, and subsequent infection of, Caco-2 cells, regardless of the cell differentiation state. Thus, the redistribution of HS is implicated in the basolateral entry of HCMV into differentiated Caco-2 cells.

The impact of ropinirole on blood pressure and noradrenaline concentration after active orthostasis in Parkinsonian patients.

Orthostatic hypotension is common in Parkinsonian patients. It is probably caused by reduced noradrenaline (NA) release. This effect is further enhanced by therapeutic use of ergot alkaloid dopamine agonists. In this trial we studied the impact of the non-ergot dopamine agonist ropinirole on blood pressure and noradrenaline release in 12 patients suffering from idiopathic parkinsonism (six female, six male, mean age 57.6+/-4.9years). Only de novo patients were included in this study. These patients were started on ropinirole monotherapy. In all patients blood pressure and serum noradrenaline levels at rest were measured supine (after lying down for 10min) and standing (9th minute after positional change). Patients with a drop in blood pressure >10mmHg were excluded from the study. Measurements were repeated after treatment with ropinirole 6mg/day. Before treatment the NA concentration (determined via HPLC) went up by 390.1pg/ml (SD 54) to the 9th minute after rising, but during management with ropinirole it went up only by 338.4+/-78pg/ml. In controls (n=27; eight women, 19 men, aged 60.6+/-10.8years) NA increased by 425+/-230pg/ml. The NA increase thus differed substantially prior to therapy compared with controls, and the difference did not change significantly during treatment. With ropinirole eight patients showed normal, four patients borderline and none of them pathologic decrease in blood pressure. These results do show a small but nonsignificant influence of the non-ergot dopamine agonist on blood pressure response and noradrenaline release, which is much less prominent than the change observed with ergot dopamine agonists.

[Blood pressure adaptation and hormone regulation in Parkinson patients following orthostasis]. / Blutdruckanpassung und hormonelle Regulation bei Parkinson-Patienten nach Orthostase.

OBJECTIVE: To determine whether abnormal orthostatic regulation commonly occurs in patients with Parkinson's disease (PD) and is caused by an abnormal catecholamine release (especially of noradrenaline). PATIENTS AND METHODS: Blood pressure and catecholamine concentration were measured after 10-min recumbency and 1, 3, 5, 7 and 9 min after standing up in 46 patients with PD (15 women, 31 men: mean age 64.3 +/- 11.7 years). Results were compared with those in a group of 27 healthy controls (eight women, 19 men; mean age 60.7 +/- 10.8 years). RESULTS: Among PD patients there were marked hypotonic circulatory reactions, associated with decreased catecholamine concentration and heart rate adaptation; an abnormal orthostatic regulation occurred in 30 patients. In 22 patients noradrenaline concentration changed by less than 200 pg/ml in the 9th min after standing up, while a decreased hormonal release was noted in only four of the controls, all of whom had normal orthostatic regulation. In PD patients the lowest adrenaline rise was always associated with an extremely high fall in blood pressure. Changes in mean blood pressure correlated positively with the rise in noradrenaline. There was no demonstrable correlation between medication for PD, age of patient and the duration or severity of the disease. CONCLUSION: Abnormal orthostatic regulation occurs more frequently in PD than in healthy persons and is associated with changes in noradrenaline release. This suggests multisystem degeneration as a cause of PD.

[Blood pressure and hormonal regulation in active and passive orthostasis]. / Blutdruckverhalten und hormonelle Regulation bei aktiver und passiver Orthostase.

UNLABELLED: The procedure using a tilt-table is far better standardized and less dependent on the patient's compliance compared to the active manoeuvre of standing up. The object of this study is to detect to what extent results are comparable concerning hormonal regulation and the adaptation of blood pressure. In 20 males (59.1 +/- 10.9 years), without any evidence of central nervous disorder, we measured the systolic, diastolic and the median blood pressure, heart frequency and hormone levels (noradrenaline, aldosterone, renin) at rest and over 10 minutes in the upright position after actively or passively (by tilt-table) assuming an orthostatic posture. The blood pressure showed little change after the patient sat upright himself, whereas the passive manoeuvre caused a significant decline of systolic blood pressure lasting over the entire sampling period. The adaptation of hormone levels and heart frequencies, however, showed no significant differences. Renin and aldosterone rose in both examinations. Noradrenaline showed an increase of 100% after active assumption of orthostatic posture and 80% using the tilt-table. Hence in patients who are passively brought into the upright position there is no increased noradrenaline output to stabilize blood pressure. This points to the fact that orthostatic circulatory mechanisms are not sufficiently brought into play after the non-physiological passive manoeuvre. IN CONCLUSION: (1.) the tilt-table compared to active orthostatic posture provides better standardized conditions; (2.) there are no significant differences in hormone levels; and (3.) maneuvering patients into an upright position provides a greater risk of fainting due to a pathological fall in blood pressure.

[Functional studies of the autonomic nervous system]. / Funktionsuntersuchungen des autonomen Nervensystems.

There are many methods to choose from in the investigation of the autonomic nervous system. The value of the individual tests to the clinician varies according to the method of investigation used. No one test can elucidate all the information needed for all functional disturbances. As a routine, measurement of blood pressure and heart rate reaction to active orthostasis and heart rate variation with deep breathing and the Valsalva manoeuvre can be useful. Spectral analysis of the heart rate is an easily performed test, only minimally disturbing for the patient, and is a valid means of investigation which may find a way into routine clinical use in the future.

Identification of the causative antigen in immune complex allergy. A simple method.

Two cases are presented of an anaphylactoid reaction after intravenous drug injection. The first reaction immediately after the operation, the second during the induction. At the first sight it was not clear which substance was responsible. Therefore a technique was developed in cooperation with the Immunologic laboratory in order to diagnose exactly the causative antigen. This method is described.