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.

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.

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.

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.

[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.

Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjögren's syndrome.

OBJECTIVE: To investigate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin antibodies (AKA) in patients with primary Sjögren's syndrome. METHODS: 149 patients with a diagnosis of primary Sjögren's syndrome according to the European/American consensus criteria were recruited from three French medical centres. The presence of anti-CCP was determined by enzyme linked immunosorbent assay and of AKA antibodies by indirect immunofluorescence. Radiographs of hands and feet were evaluated at the time of anti-CCP analysis. RESULTS: Six patients with radiological erosions and nine patients with non-erosive arthritis fulfilling ACR criteria for rheumatoid arthritis were thought to have rheumatoid arthritis and secondary Sjögren's syndrome, while 134 were considered to have primary Sjögren's syndrome (mean (SD) disease duration, 11.1 (6.6) years). Of these, 80 tested positive for IgM rheumatoid factor (RF) (59%), 10 (7.5%) for anti-CCP, 7 (5.2%) for AKA, and 5 (3.7%) for both anti-CCP and AKA. There was no difference in clinical and biological features, including prevalence of RF, between anti-CCP positive and negative patients. The nine Sjögren patients with non-erosive arthritis, fulfilling ACR criteria for rheumatoid arthritis, were all CCP positive. Their response to disease modifying antirheumatic drugs could be different from classical rheumatoid patients. CONCLUSIONS: Most patients with primary Sjögren's syndrome are negative for AKA and anti-CCP, but positive test results should not rule out this diagnosis. Anti-CCP positive patients, who may be prone to developing rheumatoid arthritis, require cautious clinical and radiographic follow up.

Second generation anti-cyclic citrullinated peptide (anti-CCP2) antibodies can replace other anti-filaggrin antibodies and improve rheumatoid arthritis diagnosis.

We compared the diagnostic performance of anti-cyclic citrullinated peptide antibodies detected with second-generation enzyme immunoassay (anti-CCP2) with that of IgM-rheumatoid factor (RF), anti-perinuclear factor (APF), and anti-keratin antibodies (AKA). The sensitivity of anti-CCP2 was better than that of APF and AKA: they were detected in 25% rheumatoid arthritis (RA) patients without detectable APF or AKA. Their specificity, evaluated in other inflammatory rheumatic disease, was similar to that of APF and AKA. Despite the lower specificity, IgM-RF in combination with anti-CCP2 is interesting, as they do not completely overlap. Anti-CCP2 antibody detection seems to be a good alternative to other anti-filaggrin antibodies in the diagnosis of RA.

Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage.

OBJECTIVE: To study the value of antibodies to citrullinated proteins/peptides for predicting joint outcomes in patients with recent onset rheumatoid arthritis (RA). METHODS: 191 patients with RA onset within the past year were followed up prospectively for five years. Serum samples obtained from 145 patients at baseline before disease modifying antirheumatic drug treatment were examined using three anticitrullinated protein/peptide antibody assays: antiperinuclear factor (APF) by indirect immunofluorescence (IIF), antikeratin antibodies (AKA) by IIF, and anti-cyclic citrullinated peptide (CCP) antibodies by enzyme linked immunosorbent assay (ELISA). Radiographs of the hands and feet taken at baseline and after three and five years were evaluated using Sharp scores modified by van der Heijde. RESULTS: Anti-CCP ELISA was positive in 58.9% of patients. APF/anti-CCP agreement was 77%. The likelihood of a total Sharp score increase after five years was significantly greater among patients with anti-CCP antibodies (67%; odds ratio (OR) 2.5; 95% confidence interval (95% CI) 1.2 to 5.0) or APF (57%; OR 2.4; 95% CI 1.2 to 4.9) but not rheumatoid factor (RF; OR 0.7; 95% CI 0.3 to 1.5). Mean values for radiographic damage, erosion, and joint narrowing scores at the three times were significantly higher in patients with anti-CCP or APF than in those without. AKA did not significantly predict radiographic damage. In separate analyses of patients with and without RF, anti-CCP or APF was better than RF for predicting total joint damage and joint damage progression after five years. CONCLUSION: Antibodies to citrullinated proteins/peptides determined early in the course of RA by APF IIF or anti-CCP ELISA are good predictors of radiographic joint damage. Further studies of clinical, laboratory, and genetic parameters are needed to improve RA outcome prediction in clinical practice.

A peptide derived from bovine beta-casein modulates functional properties of bone marrow-derived macrophages from germfree and human flora-associated mice.

The purpose of this study was to evaluate the immunomodulatory activity of a peptide derived from bovine beta-casein (beta-CN), the beta-CN (193-209) peptide, on mouse macrophages that were obtained either from germfree (GF) or from human flora-associated (HF) mice. Macrophages were derived from bone marrow (BMDM) in the presence of recombinant macrophage colony-stimulating factor and exposed to the peptide or lipopolysaccharide (LPS). Membrane marker expression [F4/80, Mac-1, major histocompatibility complex (MHC) class II antigens] and phagocytic activity were assessed by flow cytometry. Production of tumor necrosis factor-alpha and interleukin (IL)-6 was measured by bioassays and production of IL-1alpha, IL-1beta and IL-12 by ELISA. The expression of cytokine mRNA was determined using semi-quantitative reverse transcription-polymerase chain reaction. The beta-CN (193-209) peptide up-regulated MHC class II antigen expression and phagocytic activity of BMDM from GF and HF mice. Its enhancing effect on phagocytosis was greater than that after LPS stimulation (P < 0.01). The peptide induced notable levels of cytokine mRNA in BMDM from GF and HF mice, but it was a significantly weaker inducer of cytokine secretion than LPS. Nevertheless, although flora implantation had no stimulatory influence on basal MHC class II and basal cytokine levels, cells from HF mice were more susceptible than those from GF mice to the peptide effects on these variables. These results indicate that the beta-CN (193-209) peptide could enhance antimicrobial activity of macrophages without proinflammatory effects.

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.

Immunohistochemical model to predict risk for coronary artery disease and failure in heart transplant patients.

Transplant coronary artery disease is the leading cause of long-term morbidity and mortality in cardiac transplantation. We developed a model for early identification of patients who subsequently develop coronary artery disease and graft failure. Serial biopsies obtained from 141 cardiac allografts (5.5 +/- 0.1 biopsies/patient) during the first 3 months post-transplant were evaluated immunohistochemically for deposition of myocardial fibrin, depletion of arteriolar tissue plasminogen activator, presence of arterial/arteriolar endothelial activation markers, and changes in vascular antithrombin. An immunohistochemical risk score was developed with a minimum value of 0 (normal) and a maximum value of 4 (most abnormal). Scores of 0 (low risk), 0.5-3.0 (moderate risk), and 3.5-4.0 (high risk) were analyzed for association with graft failure and development, severity, and progression of coronary artery disease detected using serial coronary angiograms (3.9 +/- 0.2/patient). Allografts with high immunohistochemical risk scores in the first 3months post-transplant developed more coronary artery disease (p<0.001), developed coronary artery disease earlier (p<0.001), developed more severe disease (p<0.001), and showed more disease progression (p<0.001) than allografts with moderate or low scores. Allografts with high immunohistochemical risk scores in the first 3 months post-transplant failed more (p<0.001) and failed earlier (p<0.001) than allografts with moderate or low scores. The present study demonstrates that early changes in the microvasculature are associated with impending coronary artery disease and graft failure in cardiac allograft recipients and suggests that treatment needs to be instituted early after transplantation in order to improve outcome.

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.

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.

Systemic lupus erythematosus-associated catastrophic antiphospholipid syndrome occurring after typhoid fever: a possible role of Salmonella lipopolysaccharide in the occurrence of diffuse vasculopathy-coagulopathy.

We report a case of well-documented typhoid fever in a 30-year-old woman with inactive systemic lupus erythematosus with asymptomatic lupus anticoagulant and high-titer anticardiolipin antibody (aCL). Despite prompt eradication of the Salmonella typhi obtained with appropriate antibiotic therapy, multiple organ system dysfunction occurred. The central nervous system was involved, with ischemic infarcts in the occipital lobes. High-dose corticosteroid therapy failed to improve the neurologic manifestations, which responded to repeated plasmapheresis. A sharp fall in aCL and anti-beta2-glycoprotein I antibody titers was recorded before the start of plasmapheresis. At the same time, IgM and IgG antibodies to Salmonella group O:9 lipopolysaccharide became detectable; the IgM antibodies disappeared within 4 months, whereas the IgG antibodies remained detectable during the next 13 months. Despite treatment with high-dose corticosteroids and cyclophosphamide, rapidly progressive glomerulonephritis developed, leading to chronic renal failure. There is convincing evidence of a link between the S. typhi infection and the ensuing catastrophic syndrome in this patient, probably precipitated by bacterial antigens.

Using specific polyclonal antibodies to study the malolactic enzyme from Leuconostoc oenos and other lactic acid bacteria.

Specific polyclonal antibodies directed against the malolactic enzyme of Leuconostoc oenos were obtained. Despite the homologies between the malolactic enzymes from Leuc. oenos and Lactococcus lactis, no immunological relationship was detected with the L. lactis malolactic enzyme, suggesting differences in their structural organization. The use of the antiserum also demonstrated that the problem of heterologous expression occurring in the recombinant Escherichia coli strain (Labarre et al. 1996a) resulted in a low synthesis of the malolactic enzyme from Leuc. oenos. Moreover, a small amount of the protein was found to be peripherally associated to the membrane of Leuc. oenos.

Influence of intestinal microflora on murine bone marrow and spleen macrophage precursors.

To investigate the adjuvant effect of intestinal flora on macrophage-colony-stimulating factor-responsive macrophage progenitors from spleen and bone marrow, we compared progenitor numbers and phenotypic characteristics of in vitro matured macrophages in germ-free and flora-associated mice (conventional, Escherichia coli-monoassociated and conventionalized mice). The data obtained show that the flora affected differentially bone marrow and spleen progenitors. It increased the numbers of progenitors in the spleen but not in the bone marrow. It did not modify the expression of F4/80, Mac-1 and major histocompatibility complex (MHC) class II on bone-marrow-derived macrophages (BMDM), while it clearly up-regulated MHC class II expression on spleen-derived macrophages (SDM). This effect was more pronounced in flora-associated ex germ-free mice than in conventional mice and it was greatly enhanced in the absence of M-CSF. In vitro stimulation by lipopolysaccharide had no effect on marker expression of BMDM, while it decreased F4/80 and enhanced MHC class II molecules on SDM from germ-free and flora-associated mice. However, the expression of MHC class II remained lower in germ-free mice. Enhancement of MHC class II molecule expression on SDM may contribute to the protective role of flora, because successful immune responses are dependent on the expression of these molecules.

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.