Changes of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) after autologous hematopoietic stem cell transplantation in multiple sclerosis

Elevated levels of matrix metalloproteinase-9 (MMP-9) associates with predictors of multiple sclerosis (MS) activity. We analysed serum levels and mRNA expression of MMP-9 and its inhibitor TIMP-1 in peripheral mononuclear cells of 14 MS patients after autologous hematopoietic stem cell transplantation (AHSCT). All but 2 patients stabilized after AHSCT. A significant decrease of MMP-9 levels was seen up to 36 months after AHSCT. TIMP-1 levels did not change. MMP-9 mRNA levels correlated with the CD4+ T cell count (p<0.0001). The significant and persistent change in MMP-9 activity after AHSCT may be caused in part by the effect of AHSCT in the CD4+ T cell count.     

Incidence of post-thrombotic syndrome and its association with various risk factors in a cohort of Spanish patients after one year of follow-up following acute deep venous thrombosis

Post-thrombotic syndrome (PTS) is a frequent complication of deep venous thrombosis (DVT). However, neither the incidence nor the moment of PTS appearance are known. The main reason are the criteria used to define PTS, the characteristics of the patients, the study design and the time of follow-up. Our aims were to estimate the early incidence of PTS and its associated factors in a cohort of carefully defined DVT patients. 135 patients with a previous episode of acute idiopathic, phlebographically confirmed DVT, in the lower limbs, were followed up over 12 months. Phlebography was then repeated to determine the appearance of PTS. In addition, we used a validated clinical scale in order to assess the correlation between the clinical and phlebographical diagnosis of the PTS. This scale was applied at 6 and 12 months. The incidence of phlebographically confirmed PTS within the first year was 56.3% for the isolated PTS and 5.9% for PTS plus recurrent DVT, regardless of age, sex, platelet count, INR, or anticoagulation. None of these patients could be diagnosed as having PTS using the clinical validated scale. However, those patients with phlebographically diagnosed PTS had a higher clinical score than those without (P=0.012). The only factor related to a higher risk of developing a PTS was the localization of the DVT, subjects with both proximal and distal DVT having the highest incidence (P=0.001). In conclusion, although patients had appropriate anticoagulation, early incidence of PTS was very high, thus making it necessary to develop better diagnostic methods in order to evaluate the PTS impact.     

Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations

Rapid eye movement sleep behavior disorder (RBD) in the setting of parkinsonism or dementia often reflects an underlying synucleinopathy. Lewy bodies, intraneuronal aggregates containing abnormal alpha-synuclein, are absent in most cases of parkinsonism with parkin mutations (Park2). We performed clinical history and video-polysomnography in 10 Park2 patients (seven men; age, 51.2 +/- 11.6 years; parkinsonism duration, 18.3 +/- 11.2 years) and found RBD in 6. In all instances, RBD followed the onset of motor symptoms by several years. Our study shows that RBD is frequent in Park2, suggesting that mechanisms other than synuclein deposition can cause RBD in neurodegenerative disorders.     

The therapeutic role of 5-HT1A and 5-HT2A receptors in depression

The selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs, because they are well tolerated and have no severe side effects. They rapidly block serotonin (5-HT) reuptake, yet the onset of their therapeutic action requires weeks of treatment. This delay is the result of presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition. The prevention of a negative feedback mechanism operating at the 5-HT autoreceptor level enhances the neurochemical and clinical effects of SSRIs. The blockade of 5-HT2A receptors also seems to improve the clinical effects of SSRIs. These receptors are located postsynaptically to 5-HT axons, mainly in the neocortex. Pyramidal neurons in the prefrontal cortex are particularly enriched in 5-HT2A receptors. Their blockade may affect the function of prefrontal-subcortical circuits, an effect that probably underlies the beneficial effects of the addition of atypical antipsychotic drugs, which are 5-HT2A receptor antagonists, to SSRIs in treatment-resistant patients.     

Improving the outcome of bipolar disorder through non-pharmacological strategies: the role of psychoeducation

The present paper addresses the efficacy of psychoeducation and related strategies in bipolar disorders. Recently, several randomised clinical trials have shown the efficacy of psychological interventions--namely identification of prodromal signs, cognitive-behavioral therapy, psychoeducation and family-focused interventions--as a prophylactic add-on to medication. All these studies are presented hereby, together with the pioneer studies in the field. There are several topics that every psychoeducational program should include to ensure its usefulness, and they will be summarized in twelve points. Roughly, psychoeducation should contain general information about bipolar illness, compliance enhancement elements, teaching on early recognition of relapses and lifestyle regularity issues. Nowadays, several treatment guidelines include psychoeducation as a crucial prophylactic tool. Clinicians should be aware of this and start performing psychoeducation in their everyday clinical practice.     

Relationship between hospital structural level and length of stay outliers. Implications for hospital payment systems

BACKGROUND: Hospital structural level has been suggested as a factor that could explain part of the resource use variation left unexplained by diagnosis related groups (DRGs). However, the relationship between hospital structural level and the presence of cases of extreme resource use (outliers) is not known. Some prospective payment systems pay these cases separately. OBJECTIVES: To analyze the relationship between different hospital structural levels, defined according to hospital size, teaching activity and location, and the presence of length of stay (LOS) outliers. RESEARCH DESIGN: A logit model was used to analyze the patient discharge records of the acute care public hospitals' Minimum Data Set in Catalonia (Spain) in 1998. The final population contained 631,096 discharges grouped in 329 adjacent DRGs. MEASURES: LOS outliers were defined as cases with a LOS exceeding the geometric mean plus two standard deviations of all the stays in the same DRG. The 64 public hospitals of the Catalan health system were classified into large urban teaching hospitals, medium-sized teaching and community hospitals, and small community hospitals according to their structural complexity. The model also controlled for patient and health care process characteristics. RESULTS: Outliers accounted for 4.5% of total discharges distributed as follows: large urban teaching hospitals (5.6%), medium-sized teaching and community hospitals (4.6%), small community hospitals (3.6%). The probability of a patient being an outlier was higher in hospitals with greater structural complexity: large urban teaching hospitals (OR = 1.59), medium teaching and community hospitals (OR = 1.30) and small community hospitals (OR = 1). Adjustment through the control variables reduced differences among hospitals: large urban teaching hospitals (OR = 1.32), medium-sized teaching and community hospitals (OR = 1.22), and small community hospitals (OR = 1), but the differences remained significant (P < 0.01). CONCLUSIONS: Hospital structural level influences the presence of outliers even when controlling for patient and process characteristics. Thus, some outliers are due to hospital structural level and are not justified by patient characteristics.     

Characterization of HER2/neu and topoisomerase IIα status by FISH in locally advanced breast cancer

Background

HER2/neu encodes a receptor related to breast cancer pathogenesis and topoisomerase IIα is an enzyme involved in response to anthracycline chemotherapy. The aim of this study is to analyse HER2/neu and topoisomerase IIα in a homogenous series of 49 patients with locally-advanced breast cancer (LABC) to determine their status and predictive value with respect to response to treatment.

Material and methods

Paraffin-embedded tissues samples from patients with LABC (prior to their neoadjuvant chemotherapy programme) were analysed using the FISH technique.

Results

HER2 amplification was noted in 29% of cases of which 77% presented amplification in the topoisomerase IIα gene, 15% had deletion and 8% did not show any aberration in topoisomerase IIα status.

Conclusions

These preliminary analyses show a correlation between HER2 amplification and topoisomerase IIα status (92%), and suggest that patients with non-amplified HER2/neu or topoisomerase IIα have better response and have and increase (albeit not statistically significant) in disease-free survival (DFS). However, the limited numbers of patients in the study preclude definitive conclusion regards the value of these genes in predicting patient response to anthracycline-based chemotherapy.     

A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and betaA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.     

Prion susceptibility and protective alleles exhibit marked geographic differences

A total of 616 chromosomes from control individuals of all major continental groups, and six individuals affected by either Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI), were typed with a new single-reaction protocol method and were also sequenced, with total reproducibility to screen variation at important positions (385A>G: M129V and 655G>A: E219K) in the human prion protein gene (PRNP). We have found, for the first time, that 129V allele is highly represented in some populations from the Americas, and that 129M and 129V are in similar frequencies in Africa. The 129M susceptibility allele was found at high frequencies in Old World populations, very high in the Pacific ( approximately 81%) and up to 93% in Central and East Asia, but at a low frequency (approximately 30%) in Native Americans. The protective 219L allele was restricted to Asian and Pacific populations. Susceptibility alleles exhibit marked geographic differences in frequency, and thus, differences in probability to develop prion diseases.