Targeting p38 MAPK pathway for the treatment of Alzheimer's disease

Accumulating evidence indicates that p38 mitogen-activated protein kinase (MAPK) could play more than one role in Alzheimer's disease (AD) pathophysiology and that patients suffering from AD dementia could benefit from p38 MAPK inhibitors. The p38 MAPK signalling has been widely accepted as a cascade contributing to neuroinflammation. However, deepening insight into the underlying biology of Alzheimer's disease reveals that p38 MAPK operates in other events related to AD, such as excitotoxicity, synaptic plasticity and tau phosphorylation. Although quantification of behavioural improvements upon p38 MAPK inhibition and in vivo evaluation of p38 MAPK significance to various aspects of AD pathology is still missing, the p38 MAPK is emerging as a new Alzheimer's disease treatment strategy. Thus, we present here an update on the role of p38 MAPK in neurodegeneration, with a focus on Alzheimer's disease, by summarizing recent literature and several key papers from earlier years.     

Relationship between IS901 in the Mycobacterium avium Complex Strains Isolated from Birds, Animals, Humans, and the Environment and Virulence for Poultry

A total of 738 strains of Mycobacterium avium complex (MAC) were examined in biological experiments on poultry by use of PCR methods with primers for detection of the insertion sequence IS901. Serotype strains of MAC from all known 28 serotypes were examined. Further strains were isolated from human immunodeficiency virus (HIV)-negative and HIV-positive patients, 6 animal species, 17 bird species, and the environment. Of 165 strains virulent for poultry, characterized by generalized tuberculosis, 164 strains contained IS901, a result which is statistically highly significant (P, 0.01). The remaining 573 strains were nonvirulent; however, IS901 was present in 24 strains. From among 20 strains of serotypes 1, 2, and 3, IS901 was found in 15 strains, only 5 of which were virulent for poultry. The remaining 111 strains, of serotypes 4 to 28, were nonvirulent and did not incorporate IS901. None of the 152 strains isolated from humans was virulent for poultry, including 12 strains which were IS901 positive.     

Data Improvement Through Simplification: Implications for Low-Resource Settings

Background

The focus of many data collection efforts centers on creation of more granular data. The assumption is that more complex data are better able to predict outcomes. We hypothesized that data are often needlessly complex. We sought to demonstrate this concept by examination of the American Society of Anesthesiologists (ASA) scoring system.

Methods

First, we created every possible consecutive two, three and four category combinations of the current five category ASA score. This resulted in 14 combinations of simplified ASA. We compared the predictive ability of these simplified scores for postoperative outcomes for 2.3 million patients in the NSQIP database. Individual model performance was assessed by comparing receiver operator characteristic (ROC) curves for each model with the standard ASA.

Results

Two of our 4-category models and one of our 3-category models had ability to predict all outcomes equivalent to standard ASA. These results held for all outcomes and on all subgroups tested. The performance of the three best performing simplified ASA scores were also equivalent to the standard ASA score in the univariate analysis and when included in a multivariate model.

Conclusions

It is assumed that the most granular data and use of the largest number of variables for risk-adjusted predictions will increase accuracy. This complexity is often at the expense of utility. Using the single best predictor in surgical outcomes research, we have shown this is not the case. In this example, we demonstrate that one can simplify ASA into a 3-category variable without losing any ability to predict outcomes.

     

Complications of intravascular catheters in ICU: definitions,incidence and severity. A randomized controlled trial comparing usual transparent dressings versus new-generation dressings (the ADVANCED study)

Purpose

To describe all post-insertion complications involving most used intravascular access, and to determine whether the use of a new-generation transparent dressing (3M? IV Advanced) might reduce their number and impact on ICU patient outcomes.

Methods

Patients older than 18, with an expected length of stay ≥48 h and requiring at least one central venous catheter (CVC), arterial catheter (AC), haemodialysis catheter (HDC), pulmonary arterial catheters (PAC) or peripheral venous catheter (PVC) were randomized into two groups: a new-generation transparent dressing, or the hospital’s classical transparent dressing, and were followed daily for any infectious and non-infectious complications. Complications were graduated for severity by an independent international multicentre multidisciplinary panel of practitioners using a Delphi process.

Results

We included 628 patients, 2214 catheters (873 PVCs, 630 CVCs, 512 ACs and 199 HDCs and PACs) and 4836 dressings. Overall incidence rate was of 60.9/1000 catheter-days. The most common complication was dysfunction (34.6/1000 catheter-days), mainly for PVCs (16/1000 catheter-days) and ACs (12.9/1000 catheter-days). Infectious complications incidence rate in CVCs and ACs was of 14.5/1000, mostly due to colonization (14.2/1000 catheter-days). Thrombosis incidence was of 3.8/1000 catheter-days with severe and very severe complications in 16 cases (1.8/1000 catheter-days) and one thrombosis-related death. 3M? IV Advanced dressing did not decrease the rate of catheters with at least a minor complication [57.37/1000 vs. 57.52/1000 catheter-days, HR 1.03, CI (0.84–1.27), p = 0.81]. Incidence rates for each single complication remained equivalent: infectious [HR 0.93 (0.62–1.40), p = 0.72], deep thrombosis [HR 0.90 (0.39–2.06), p = 0.80], extravasation and phlebitis [HR 1.40 (0.69–2.82), p = 0.35], accidental removal [1.07 (0.56–2.04), p = 0.84] and dysfunction [HR 1.04 (0.80–1.35), p = 0.79].

Conclusion

The ADVANCED study showed the overall risk of complications to intravascular catheters in ICU patients being dysfunction, infection and thrombosis. The 3M? IV Advanced dressing did not decrease complication rates as compared to standard dressings.

     

Wnt5a Regulates Ventral Midbrain Morphogenesis and the Development of A9–A10 Dopaminergic Cells In Vivo

Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9–10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5–E13.5. Analysis of Wnt5a−/− mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a−/− mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors.     

Parenting styles and typology of drinking among children and adolescents

Background: Recent studies show that the parenting styles may play a significant role in the patterns of alcohol use among children and adolescents. Aim: The aim of our study is to examine the influence of specific parenting factors on the incidence of drunkenness and frequency of alcohol use and, on the basis of these findings, propose a typology of drinking among children and adolescents. Methods: A cross-sectional survey was conducted using the EFE Survey Questionnaire – Adolescents Questionnaire. The research sample, selected using a two-stage random sampling design, consisted of 1255 students aged 10–18 years (mean age?=?14.7 years, 54% boys and 46% girls). Results: The results indicate a significant relationship between the frequency of alcohol use among the children, adolescents and perceived family rules, family communication, and parental control and warmth/affection. The incidence of drunkenness in the last 30 days correlated significantly with perceived the family rules, parental control, emotional warmth, and discussion of problems. Conclusion: Parental behaviour and parenting styles may significantly affect the pattern of adolescent drinking. Primary prevention therefore needs to focus both on research and the practical application and implementation of the programmes, in which parents and their children are involved.     

Salvage treatment with upfront melphalan 100 mg/m2 and consolidation with novel drugs for fulminant progression of multiple myeloma

Patients (pts) with fulminant progression (FPG) of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) have poor prognosis. Pancytopenia, extramedullary disease, and/or renal impairment are often present, and treatment options are limited. We have retrospectively evaluated 31 pts with FPG of MM after ASCT who were treated upfront salvage therapy with melphalan 100 mg/m² (MEL 100) followed by PBSC support and consolidation therapy using regimens containing thalidomide (n?=?16) or bortezomib (n?=?15). The overall response rate (ORR) was 58% (18/31). After MEL 100, one patient achieved complete remission (3%), 26% of pts very good partial remission, 29% of pts partial remission, and 42% of pts stable disease. Progression within 3 months after MEL 100 occurred in 35% of pts. The median follow-up from MEL 100 was 8 months. The median TTP was 5 months (range, 2–15 months), and the median OS was 8 months (range, 3–23 months). There were no treatment-related deaths. In fulminant progression of MM, upfront MEL 100 is a safe salvage regimen with good response rate (ORR, 58%). Treatment with upfront MEL 100 followed by a thalidomide- or bortezomib-based regimen can prolong overall survival to more than 12 months in 33% of pts with fulminant progression of MM.     

Thick Melanoma: Prognostic Value of Positive Sentinel Nodes

Background  

Sentinel lymph node biopsy (SNB) is a widely accepted procedure used to accurately stage patients with melanoma. Its value in patients with thick melanoma (Breslow thickness >4 mm) is reason for discussion because of the generally poor prognosis of these patients. The purpose of this study was to report on the incidence of SNB positivity in patients with thick melanoma and to analyze the prognostic value of SNB in these patients.     

Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis

Neurofilaments are cytoskeletal proteins localized within axons, which may interact with the immune system during and following tissue destruction in multiple sclerosis (MS). Antibodies against the medium neurofilament subunit synthesized intrathecally may reflect axonal damage in MS patients. Both immunoglobulin G (IgG) and M (IgM) responses against the purified native medium subunit of neurofilaments (NFM) using enzyme-linked immunosorbent assay (ELISA) were determined in paired serum and cerebrospinal fluid samples obtained from 49 MS patients, 16 normal controls (CN), 21 control patients with miscellaneous diseases (CD) and 14 patients with neurodegenerative disorders (CDEG). Intrathecal production of IgM and IgG antibodies to NFM were elevated in MS patients compared with the CN or CD groups (p < 0.04 for IgM, p < 0.01 for IgG). The increase was present in all the MS courses (relapsing-remitting, primary and secondary progressive). Similar local anti-NFM IgG and IgM synthesis occurred in the MS and CDEG groups. MS patients with short and long disease duration did not differ in terms of their anti-NFM IgM and IgG responses. Repeated examinations showed stable intrathecal anti-NFM production. Intrathecal IgG and IgM antibodies against NFM were increased in MS patients and may serve as a potential marker for axonal pathology. The extent of anti-NFM levels did not correspond to any individualized clinical profiles of MS patients.