A review of psychosocial factors and stroke: A new public health problem.

The role of psychosocial factors (PSF) in increased risk of stroke is a novel public health challenge, but unclear definitions for PSF and the multiple stroke subtypes have led to inconsistent reports. A review of this issue is therefore warranted. METHODS: Several databases were used for this narrative systematic review (Medline, Embase and Cochrane Library). Two independent reviewers evaluated articles from between 2001 and 2018 on the themes of PSF and stroke/transient ischemic attack (TIA). PSF criteria were job strain, psychological interpersonal and behavioral stress, and social deprivation. Ischemic and hemorrhagic stroke and TIA subtypes were also identified. RESULTS: Forty-five cohorts, five case-control studies and two meta-analyses were included. Despite mixed results, PSF were associated with an increased risk of ischemic and hemorrhagic stroke in populations of all ages, and more predominantly in women. CONCLUSION: This broad review shows that the presence of PSF is associated with an increased risk stroke and TIA. As such, PSF must figure in both public health policy and stroke prevention programs, similar to other established metabolic and environmental factors.

Air pollution and stroke. A new modifiable risk factor is in the air.

Evidence from epidemiological studies has demonstrated that outdoor air pollution is now a well-known major problem of public health, mainly in low and middle income countries. Contrasting with myocardial infarction, there are few data on the association of air pollution and stroke. METHODS: We propose a narrative literature review of the effects and the underlying biological mechanisms of short- and long-term exposure to air pollutants on stroke risk and mortality, using the following key-words: stroke, cerebrovascular events, ischemic and haemorrhage stroke, transient ischaemic attack, mortality, air pollution and air pollutants. RESULTS: Twenty-one papers were selected. Air pollution, of which whose small particulate matter are the most toxic, contributes to about one-third of the global burden of stroke. We can identify vulnerable patients with classical neuro-vascular risk factors or a prior history of stroke or transient ischemic attack or persons living in low-income countries. Biological mechanisms of this new morbid association are discussed. CONCLUSION: Air pollution should be recognized as a silent killer inducing stroke whose mortality rates remain elevated by its role as a new modifiable neurovascular risk factor, needing public health policies.

Clinical features of pain in amyotrophic lateral sclerosis: A clinical challenge.

Pain in amyotrophic lateral sclerosis (ALS) is paradoxical in this disease of the upper and lower motor neurons. As such, it remains an underestimated and neglected clinical problem because it is poorly identified by physicians, its mechanisms are numerous and its treatments are generally not effective. Pain may be primary in the form of cramps, spasticity and neuropathy, or secondary as nociceptive pain, and may arise before the first motor symptoms. It may also lead to depression and, in all cases, affect patients' daily activities and quality of life. Given the high frequency of pain in ALS, the use of analgesic or sedative drugs is necessary and should reduce the course of the disease. Nevertheless, it is important to understand the pathophysiological mechanisms of pain in ALS, and to train physicians how to detect ALS pain early on and provide dedicated treatments. In France, the implementation of ALS centers is a positive response to the public-health problem resulting from this disorder.

Relationship of negative emotionality, NIAAA recovery, and 3- and 6-month drinking outcomes among adults in treatment for alcohol use disorder.

BACKGROUND: The National Institute of Alcohol Abuse and Alcoholism (NIAAA) recently released a new definition of recovery from alcohol use disorder (AUD). A patient is considered recovered if they are remitted from DSM-5 AUD and report cessation of heavy drinking. The NIAAA has also recently proposed the Addictions Neuroclinical Assessment (ANA) to guide treatment research. Negative emotionality is one of three domains of the ANA and theory proposes that AUD is maintained by negative reinforcement via the relief of negative affect. The purpose of the current study was to examine: (1) the relationship of end-of-treatment negative emotionality and NIAAA recovery, and (2) the ability of NIAAA recovery at the end of treatment to predict three- and six-month drinking outcomes. METHOD: At baseline and end-of-treatment, women and men (n = 181) in treatment for AUD completed measures of negative emotionality, drinking, and were assessed for DSM-5 AUD diagnostic criteria. At three- and six-months post-treatment, drinking was re-assessed. RESULTS: 22.5% (n = 24) of participants met full criteria for NIAAA recovery at end-of-treatment. Lower levels of end of treatment negative emotionality were associated with increased odds of achieving NIAAA recovery. Meeting NIAAA recovery predicted greater percent days abstinent (PDA) and lower percent heavy drinking days (PHDD) at 3-months, but not at 6-months post-treatment. CONCLUSIONS: This study is among the first to report a relationship between the negative emotionality domain of the ANA and NIAAA recovery. Results underscore the importance of addressing negative emotionality in treatment. Findings also suggest that NIAAA recovery predicts positive short term drinking outcomes.

[Management of ischemic stroke in the acute phase]. / Prise en charge de l'infarctus cérébral à la phase initiale.

Ischemic stroke accounts for 80% of overall stroke, and is one of the leading causes of death, disability and dementia in worldwide. Management of patients with acute ischemic stroke dramatically improved over time with the implementation of intensive care stroke units, the development of acute recanalization strategies, the optimization of the management of post-stroke complications, and the prevention of early stroke recurrence. The objective of this article is to provide a general overview of the current management of patients with acute ischemic stroke aiming at improving post-stroke outcome.

[Acute management of ischemic stroke in 2017]. / Prise en charge aiguë des infarctus cérébraux en 2017.

Acute management of ischemic stroke is a burning topic in 2017 since stroke represents the leading cause of acquired handicap in adults. Over the last past years, major improvement took place, especially with the demonstration of the efficacy of mechanical thrombectomy, thus needing to better organize care pathways, and optimize access to neurologists and interventional neuroradiology platforms. Intensive care stroke units remain the pivotal place of patients' management. A multidisciplinary coordination is required, with continuous teaching of all the actors involved in stroke management, so as to increase the number of patients who could benefit from available active treatments.

[Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid]. / Corrélation entre présence d'anticorps anti-antigène de type 2 de la pemphigoïde et démence chez les sujets âgés sans manifestation clinique de pemphigoïde.

BACKGROUND: Pemphigoid is a form of auto-immune bullous dermatosis characterised by the production of antibodies directed against components of hemidesmosomes in the basal membrane. The physiopathological process responsible for unmasking of these antigens is unknown. Pemphigoid is more common in elderly subjects and is most often seen in debilitated subjects. The prevalence of pemphigoid anti-pemphigoid antibodies (anti-PB) is not known in the elderly population presenting no dermatological signs evocative of the disease. We studied the prevalence of anti-PBAg2 antibodies in elderly subjects with no signs of pemphigoid as well as in the correlation between the presence of these antibodies and diagnosis of dementia. PATIENTS AND METHODS: Elderly subjects (aged over 69 years) with no signs of pemphigoid were recruited consecutively in dermatology and geriatrics departments (138 subjects). Details of concomitant medication were recorded for all subjects and clinical examination was performed with calculation of MMS (Mini Mental Score). The subjects were then divided into two groups based on MMS score. The first group comprised subjects without dementia (MMS > 24) while the second comprised subjects with dementia. Serum anti-PBAg2 antibodies were determined by ELISA and indirect immunofluorescence with confirmation by Western blot. Antinuclear antibodies, used as a control for non-specific immune response, were assayed in all serum samples. The prevalence of these antibodies was compared between the two groups. RESULTS: The two groups were comparable in terms of age, sex and presence of dermatological diseases (ulcers, bedsores, erysipelas). Each group comprised 69 subjects. The overall presence of anti-PBAg2 antibodies in subjects with no signs are suggestive of pemphigoid was 3.6%. Presence of anti-PBAg2 antibodies was associated with diagnosis of dementia (p=0.04; 0% and 7% in groups 1 and 2, respectively). No correlation was seen between the presence of anti-PBAg2 antibodies and concomitant medication or dermatological disease. The overall prevalence of antinuclear antibodies was 14.5% and the figure was similar between the two groups. DISCUSSION: The presence of anti-PBAg2 could be associated with the diagnosis of dementia in elderly subjects.

Effect of acute oral administration of alcohol on superoxide anion production from mouse alveolar macrophages.

The production of superoxide anions (superoxide) from alveolar macrophages stimulated or not with opsonized zymosan was investigated in the mouse after acute oral administration of alcohol (6.5 g/kg). Superoxide production was assayed using a nitroblue tetrazolium (NBT) reduction and chemiluminescence assay. In the absence of opsonized zymosan, superoxide concentration was not affected 1 h after ethanol treatment but was significantly increased 15 and 24 h after treatment. In the presence of opsonized zymosan, a biphasic response was observed. Superoxide production was significantly reduced 1 and 3 h after administration but was increased 15 and 24 h after treatment. One hour after treatment, the percentage of cells that phagocytized opsonized zymosan and reduced NBT was significantly decreased, whereas 24 h after alcohol treatment, phagocytosis was normal and the percentage of cells reducing NBT was significantly increased. The activity of cytosolic superoxide dismutase from alveolar macrophages was not altered 1 h after administration but was significantly reduced 24 h later. Considering the functions of alveolar macrophages in the defense of the lung, these alterations in the production of reactive oxygen species after ingestion of alcohol could explain why alcoholics are more sensitive to pulmonary infections.

Tolerance of once-daily dosing of netilmicin and teicoplanin, alone or in combination, in healthy volunteers.

The purposes of this study were to test the pharmacokinetics and renal and otologic tolerances of a once-daily regimen of netilmicin and teicoplanin administered intramuscularly, alone or in combination (4.5 and 6 mg/kg, respectively), for 7 days in 30 healthy male volunteers. Teicoplanin induced only a mild increase in enzymuria. Nephrotoxicity was moderate and reversible with netilmicin; there was increased enzymuria and alteration in diluting ability, without significant changes in urinary beta 2-microglobulin levels, concentrating ability, and glomerular filtration rate. Ototoxicity was not detected in any of the subjects. Our results suggest that (1) teicoplanin and netilmicin given once daily induced only slight, reversible tubular damage, without any sign of ototoxicity; (2) their combination was not more toxic; and (3) clinical studies can be envisaged to evaluate the efficacy and tolerance of once-daily regimens in long-term treatment.

Cloning of branched chain amino acid biosynthesis genes and assays of alpha-acetolactate synthase activities in Leuconostoc mesenteroides subsp. cremoris.

A genomic library from Leuconostoc mesenteroides subsp. cremoris (Lmc) in Escherichia coli was screened for alpha-acetolactate synthase (ALS) activity using a phenotypic test detecting the production of acetolactate or related C4 derivatives (diacetyl, acetoin or 2,3-butanediol) in the culture. Four recombinant E. coli clones, with plasmids containing overlapping DNA fragments and displaying anabolic ALS activity, were selected. This activity is encoded by an ilvB gene belonging to a putative operon which contains genes highly similar to the genes of the branched chain amino acid (BCAA) operon of Lactococcus lactis subsp. lactis. This putative BCAA operon is not functional as the ilvA gene is interrupted by a single mutation and the strain is auxotrophic for the three BCAAs. Only a very low anabolic ALS activity was present in cell-free extracts of Lmc and no transcript from the ilvB gene could be detected. Instability of ilvB expression in E. coli was the consequence of a frequent IS5 insertion sequence in this gene. Despite the detection of a high catabolic ALS activity in Lmc, no catabolic ALS activity gene could be found in the BCAA gene locus, indicating the presence of a catabolic als gene in the Lmc chromosome that could be absent or not expressed in the screened library.

Antiviral action of trehalose dimycolate against EMC virus: role of macrophages and interferon alpha/beta.

Preventive treatment of mice with trehalose 6,6' dimycolate (TDM), an immunomodulator of bacterial origin, enhances their resistance to encephalomyocarditis (EMC) virus infection. The protective effect of TDM is totally abolished by the injection of silica particles in mice, demonstrating the role of macrophages in the antiviral action of TDM. In vitro, peritoneal macrophages from mice treated with TDM (TDM-PM) exhibit an intrinsic antiviral activity against EMC virus, while resident peritoneal macrophages (RES-PM) are permissive to this virus. Greater amounts of interferon are detected in supernatants of cultures of TDM-PM than of RES-PM. Neutralization of interferon (IFN) by addition in vitro of anti-IFN alpha/beta serum markedly reduces the antiviral activity of TDM-PM. These results indicate that interferon alpha/beta is involved in the intrinsic anti-EMC virus activity of peritoneal macrophages from mice treated with TDM.

Role of trehalose dimycolate-induced interferon-alpha/beta in the restriction of encephalomyocarditis virus growth in vivo and in peritoneal macrophage cultures.

Preventive intraperitoneal trehalose dimycolate (TDM) treatment of mice, inoculated with encephalomyocarditis (EMC) virus by the same route, caused restriction of virus growth in the peritoneum, which was correlated to IFN production in peritoneal fluids prior to infection. Peritoneal macrophages from TDM-treated mice (TDM-PM) spontaneously secreted IFN-alpha/beta in large amounts. By their supernatants, TDM-PM could transfer an antiviral state against EMC virus to permissive resident peritoneal macrophages from control mice. IFN-alpha/beta produced by TDM-PM was found to be involved in this transfer activity. TDM-PM also exerted a strong antiviral effect on EMC virus-infected L-929 cells, which increased with time and the macrophage-target cell ratio. This activity also occurred by an IFN-alpha/beta-dependent mechanism. These data point to the role of IFN-alpha/beta production prior to EMC virus infection in the antiviral activities of TDM-PM and, more generally, in the outcome of viral infection.

Insertional mutagenesis of an industrial strain of Streptococcus thermophilus.

Random mutagenesis of an industrial strain of Streptococcus thermophilus was achieved through an adapted version of a two-plasmid system. The mutagenesis strategy is based on random integration of derivatives of the non-replicative (Rep(-)) plasmid pORI19 by means of homologous recombination following a temperature shift that eliminates replication of the temperature-sensitive (Rep(ts)) helper plasmid pVE6007. In this way mutants were generated which were affected in bacteriophage sensitivity or sucrose metabolism. Homologues were identified of a protein related to folate metabolism from a bacteriophage-resistant mutant and of two subunits of an oligopeptide transport system from a mutant deficient in sucrose utilisation.

Influence of intestinal bacterial flora on cytokine (IL-1, IL-6 and TNF-alpha) production by mouse peritoneal macrophages.

The effect of bacterial flora on cytokine production from resident peritoneal macrophages was investigated in the mouse. The production of IL-1, IL-6 and TNF-alpha was determined in germ-free, and "conventionalized" mice, as well as in monoxenic mice implanted with either the Gram-negative bacterium E. coli, or the Gram-positive organism Bifidobacterium bifidum. Macrophages from the "conventionalized" mice produced significantly more IL-1 and IL-6 in vitro than those of the germ-free mice. IL-1 and IL-6 production from germ-free mice implanted with E. coli was comparable to that from "conventionalized" mice. However, implantation with Bifidobacterium bifidum did not increase production of these two cytokines above levels observed for macrophages from the germ-free mice. A little TNF-alpha was produced by only the macrophages from the "conventionalized" and monoxenic mice implanted with E. coli. Soon after implantation, the bacterial flora stimulated cytokine production by mouse peritoneal macrophages and our results suggest that Gram negative bacteria are the most efficient stimulus for this production.

The intestinal microflora regulates cytokine production positively in spleen-derived macrophages but negatively in bone marrow-derived macrophages.

Besides its role as a barrier against potential pathogens, intestinal flora is presumed to protect the host by priming the immunological defense mechanisms. In this respect, the influence of intestinal flora on macrophage precursors was examined, and its modulating effect was compared on LPS-induced cytokine production by macrophages derived from bone marrow and spleen precursors (BMDM and SDM respectively). The regulation of IL-1, IL-6, TNF-alpha and IL-12 production in macrophages from germ-free and from three groups of flora-associated mice, conventional, conventionalized and E. coli-mono-associated mice, was investigated. The whole flora inhibited IL-1, TNF-alpha and IL-12 secretion by BMDM, whereas it had a stimulatory effect on IL-12 secretion by SDM. Implantation of E. coli alone enhanced cytokine secretion by BMDM but had a more limited effect than whole flora on SDM, enhancing only TNF-alpha and IL-12 secretion. Study of expression of mRNA showed a correlation with protein secretion for IL-6 but not for TNF-alpha and IL-1. IL-12 enhancement in BMDM seemed to be dependent on regulation of p35 mRNA expression while it was correlated to increased p40 mRNA expression in SDM. The results demonstrated that intestinal flora modulated bone marrow and spleen macrophage cytokine production in a differential manner and suggested a role for bacteria other than E. coli among the whole flora. The contrasting effects exerted by the intestinal flora on bone marrow and spleen precursors are an interesting observation in view of the different functions of these organs in immunity. The finding that intestinal flora enhanced IL-12 production in spleen is also potentially important since this cytokine is implicated in the determination of the relative levels of Th1 and Th2 responses and plays a pivotal role in host defense against intracellular microorganisms.

Neurological manifestations of systemic lupus erythematosus: role of antiphospholipid antibodies.

Antiphospholipid antibodies (APL) are associated with venous and arterial thrombosis in SLE patients. Various thrombotic and non-thrombotic neurological manifestations have been reported in SLE but whether or not they are related to the presence of APL antibodies remains uncertain. To assess the possible association between neurological involvement in SLE and APL antibodies, IgG anticardiolipin antibodies (IgG ACL) were looked for using an ELISA technique in 92 consecutive SLE patients seen over a one-year period. Other APL determinations included VDRL and lupus anticoagulant (LAC) testing using APTT and the diluted thromboplastin time. Twenty-four SLE patients presented with neurological manifestations (40 episodes): 15/24 (62.5%) were found positive for APL antibodies (11 VDRL, 8 LAC, 7 ACL antibodies) versus 22/68 patients (32%) without neurological symptoms (p < 0.01). APL antibodies antedated neurological symptoms in 13/16 cases. Neurological manifestations were subsequently divided into 3 groups: thrombotic (n = 14), psychosis and convulsions (n = 15), miscellaneous (n = 10). No correlation was found between APL antibodies and any of the 3 subgroups. Among patients with neurological SLE, APL antibodies were present in two with valvular heart disease, as well as in seven with a history of either deep vein thrombosis, livedo reticularis or miscarriage. Among 7 patients with thrombocytopenia and neurological symptoms, 6 had APL antibodies. These data suggest that APL syndrome is associated with neuro-ophthalmological manifestations of SLE regardless of whether or not the mechanism of neurological involvement is thrombotic. SLE patients with APL antibodies may be at risk for future neurological manifestations. However, it is still questionable that APL positivity has definite therapeutic consequences.

Simultaneous production of IFN-gamma, IFN-alpha/beta and nitric oxide in peritoneal macrophages from TDM-treated mice.

Peritoneal macrophages (PM) were isolated from mice treated with Dimycolate of Trehalose (TDM), a glycolipid extracted from the cell wall of Mycobacterium tuberculosis. PM from TDM-treated mice (TDM-PM) were shown to secrete consistent amount of IFN-gamma, which was not detectable in control Resident-PM (Res-PM), as revealed by ELISA. In addition, biologically active IFN was detected in the supernatants of TDM-PM, whereas no IFN production was found in those of control Res-PM. The addition of specific antisera to PM cultures revealed the simultaneous production of both type I and II IFNs in TDM-PM cultures. No reciprocal regulation in the production of IFN-gamma and IFN-alpha/beta was found in these cultures. In parallel, nitric oxide (NO) production was measured in TDM-PM cultures by detecting nitrites (NO2-). TDM-PM cultures accumulated high amounts of NO2- which decreased to the level of Res-PM in the presence of NMMA, an inhibitor of NO-synthases. In vitro, neither type I nor type II IFNs were involved in the stimulation of NO production. The capacity of macrophages to simultaneously secrete IFN-gamma, IFN-alpha/beta and NO upon in vivo TDM-treatment could be of particular relevance for the defense process of innate immunity in which macrophages play a crucial role.

Specific binding characteristics of high affinity monoclonal antidigitoxin antibodies.

The specificity of various monoclonal antidigitoxin antibodies was characterized using 6 cardiac glycoside analogs. Spleen cells from BALB/c mice, immunized with BSA- or KLH-digitoxin conjugates, were fused with NS1 myeloma cells, and antibody-producing hybrids were identified by radioimmunoassay. Twenty-one monoclonal antidigitoxin-specific antibodies were obtained, 10 of which were cloned and characterized for affinity and specificity. All the antibodies had a high affinity constant, ranging from 8.10(8) to 2.5.10(10) 1/M. On the basis of their binding specificities, the antibodies could be classified into 3 groups: the first contained 7 antibodies exhibiting high cross reactivity (42-100%) with digitoxigenin, whereas the second and third groups did not recognize this analog (cross-reactivity of 1%). In the former group, the absence of the sugar moiety only slightly affected the binding reaction, although for the two other groups, this structure did appear to be involved in antibody recognition. Changes in the functional groups of the hapten molecule led to considerable changes in the antibody-antigen reaction. For all the antibodies except one, saturation of the lactone ring considerably affected binding. These results demonstrated that monoclonal antibodies of different specificities with respect to both the steroid backbone and the sugar moiety of digitoxin can be induced using a digitoxin-protein conjugate.

[Anti-beta 2 glycoprotein 1 antibodies in idiopathic livedo reticularis]. / Les anticorps anti-Bêta 2 glycoprotéine 1 dans le livedo reticularis idiopathique.

INTRODUCTION: Idiopathic livedo reticularis can be a sign of systemic disease since certain complications are frequently associated: cerebral thrombotic events in Sneddon's syndrome, necrotic ulcerations of the lower limbs. Antiphospholipid antibodies have been found in 0 to 85 p. 100 of patients with Sneddon's syndrome and anti-beta 2-glycoprotein 1 antibodies in 65 p. 100 of a series of 20 cases with Sneddon's syndrome. The aim of our study was to determine the prevalence of anti-beta 2-glycoprotein 1 antibodies in idiopathic livedo reticularis. PATIENTS AND METHODS: Twelve patients in a series of 17 with idiopathic livedo reticularis seen between 1981 and 1992 were studied progressively. All underwent a clinical examination and simple laboratory tests with search for anticardiolipin antibodies, lupus type circulating anticoagulant and anti-beta 2-glycoprotein 1 antibodies. RESULTS: Eight of our 12 patients (60 p. 100) were positive for anti-beta 2-glycoprotein 1 antibodies, 3 of whom also had episodes of thrombosis similar to those described in antiphospholipid syndrome. Only one of the 8 patients also had anticardiolipin antibodies and no chronic manifestation of thrombosis. DISCUSSION: beta 2-glycoprotein 1 is a cofactor which increases anticardiolipin antibody adhesion to cardiolipin in ELISA. Anti-beta 2-glycoprotein 1 antibodies are associated with thrombosis and antiphospholipid antibodies with lupus. Our results would suggest that the prevalence of anti-beta 2-glycoprotein 1 antibodies is high in idiopathic livedo, but, due to the small number of patients, do not allow confirmation that anti-beta 2-glycoprotein 1 antibodies are associated with thrombosis. Anti-beta 2-glycoprotein 1 antibody assay would be justified in routine evaluation of patients with livedo and at follow-up examinations.