Topiramate for treating alcohol dependence: a randomized controlled trial

Context  Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of -aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system. Objective  To determine if topiramate is a safe and efficacious treatment for alcohol dependence. Design, Setting, and Participants  Double-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites. Interventions  Up to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention. Main Outcome Measures  Primary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma -glutamyltransferase). Results  Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%). Conclusion  Topiramate is a promising treatment for alcohol dependence. Trial Registration  clinicaltrials.gov Identifier: NCT00210925      

Microscopic colitis: collagenous colitis and lymphocytic colitis

Microscopic colitis is currently classified as a chronic inflammatory bowel disorder and encompasses two entities: lymphocytic colitis and collagenous colitis. Patients with microscopic colitis present with a well-tolerated chronic watery diarrhea, sometimes with abdominal pain. Colonoscopy is normal. Diagnosis of microscopic colitis is established by histologic examination of colonic biopsies, showing a thickened subsurface collagen band higher than 10 microm in collagenous colitis, and an increased number of surface intra-epithelial lymphocytes higher than 20 lymphocytes per 100 epithelial cells in lymphocytic colitis. Causes of microscopic colitis are still unknown, although a drug-induced etiology is found in some cases. Patients are usually treated with budesonide but recurrences are frequent.     

Activating receptors promote NK cell expansion for maintenance,IL-10 production,and CD8 T cell regulation during viral infection

Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H''s role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h^−/−, perforin 1 (Prf1)^−/−, and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mice, but relative to responses in MCMV-infected wt mice, NK cell yields declined in the absence of Ly49h and increased in the absence of Prf1, with high rates of proliferation and Ly49H expression on nearly all cells. The expansion was abolished in mice deficient for both Ly49h and Prf1 (Ly49h^−/−Prf1^−/−), and negative consequences for survival were revealed. The Ly49H-dependent protection mechanism delivered in the absence of Prf1 was a result of interleukin 10 production, by the sustained NK cells, to regulate the magnitude of CD8 T cell responses. Thus, the studies demonstrate a previously unappreciated critical role for activating receptors in keeping NK cells present during viral infection to regulate adaptive immune responses.Classical (non–T) NK cells are generally found at low frequencies in leukocyte populations (Biron et al., 1999). They have the potential to mediate antiviral and immunoregulatory functions through a variety of mechanisms (Orange et al., 1995; Su et al., 2001; Lee et al., 2007; Robbins et al., 2007; Strowig et al., 2008). By altering cell availability, in vivo conditions changing NK cell numbers may indirectly influence all of their effects. Activating receptors on NK cells are linked to stimulatory pathways overlapping with those used by TCRs to drive cell expansions (Murali-Krishna et al., 1998; Pitcher et al., 2003; French et al., 2006; MacFarlane and Campbell, 2006; Biron and Sen, 2007; Lee et al., 2007) and can induce NK cell proliferation (Dokun et al., 2001; French et al., 2006). Although particular activating receptors have been reported to recognize microbial products (Lanier, 1998; Vidal and Lanier, 2006; Jonjic et al., 2008), dramatic NK cell expansion has not been observed during infections. Except under rare experimental conditions (Caligiuri et al., 1991; Yamada et al., 1996; Fehniger et al., 2001; Huntington et al., 2007a; Sun et al., 2009), NK cell division is generally induced for limited periods of time as a consequence of transient innate cytokine exposure (Biron et al., 1984; Biron et al., 1999; Dokun et al., 2001; Nguyen et al., 2002; Yokoyama et al., 2004). Increasing proportions of NK cell subsets with activating receptors recognizing particular viral ligands can be detected during certain infections (Dokun et al., 2001; Gumá et al., 2006), but this is observed without dramatic increases in overall NK cell numbers, and many viral infections induce striking reductions in NK cell functions, frequencies, and yields (Biron et al., 1999; Tarazona et al., 2002; Lehoux et al., 2004; Reed et al., 2004; Azzoni et al., 2005; Vossen et al., 2005; Morishima et al., 2006). Thus, particular conditions of viral challenges must result in differential regulation of NK cell proportions and numbers, with consequences for the delivery of NK cell functions.An NK cell activating receptor in the mouse is Ly49H (Lanier, 1998; Gosselin et al., 1999; Smith et al., 2000; Vidal and Lanier, 2006). This molecule recognizes a mouse CMV (MCMV) ligand (Arase et al., 2002; Smith et al., 2002), is expressed on NK cell subsets in strains of particular genetic backgrounds, including C57BL/6 (B6) mice, and is reported to be an exclusive marker for the classical NK cell subset (Smith et al., 2000). Through an associated molecule, Ly49H stimulates using signaling pathways overlapping with those used by the TCR (MacFarlane and Campbell, 2006; Biron and Sen, 2007). Additional markers for all NK cells include CD49b, expressed on other activated cell types (Arase et al., 2001); NKp46, selectively expressed on classical NK cells (Gazit et al., 2006; Walzer et al., 2007a; Walzer et al., 2007b); CD122, the IL-2Rβ chain, expressed on all NK cells and activated T cells (Huntington et al., 2007b); and NK1.1, exclusively expressed on C57BL6 (B6) NK and NKT cells (Lian and Kumar, 2002; MacDonald, 2002; Yokoyama et al., 2004; Huntington et al., 2007b). The TCR with associated CD3 molecules is not expressed on their cell surfaces (Biron et al., 1999). The mechanisms for NK cell–enhanced resistance to MCMV infection are incompletely characterized (Lee et al., 2007), but Ly49H contributes to their protective effects (Scalzo et al., 1990; Brown et al., 2001; Daniels et al., 2001; Lee et al., 2001; Lee et al., 2003). Engagement of the Ly49H receptor can lead to killing of target cells (Arase et al., 2002; Smith et al., 2002), and the correlation of increases in viral burdens resulting from the absence of Ly49H (Scalzo et al., 1990) as compared with those resulting from defects in cytotoxicity functions, such as mutation of the membrane pore-forming protein perforin 1 (Prf1; Tay and Welsh, 1997; Loh et al., 2005; van Dommelen et al., 2006), supports a role for Ly49H-dependent killing of virus-infected cells in the delivery of NK cell antiviral effects. The receptor may have other functions associated with its ability to stimulate proliferation, however, as the proportions of NK cells expressing Ly49H are increased during MCMV infection (Dokun et al., 2001).The studies presented in this paper were undertaken to dissect the proliferative from the cytotoxic functions accessed through Ly49H, and to define the contribution of the regulation of NK cell numbers to protection during infection. To carry out the work, responses were evaluated, during MCMV infections, in wild-type (wt) B6 mice and mice deficient in Ly49h (Fodil-Cornu et al., 2008), Prf1 (Kägi et al., 1994), or both. As expected, single Ly49h^−/− and Prf1^−/− mice had profoundly increased viral burdens, but significant differences in NK cell expansion were discovered. The NK cell populations were decreasing in infected Ly49h^−/− mice, whereas infected Prf1^−/− mice had an unexpected dramatic proliferation of NK cells uniformly expressing Ly49H. The expansion was proven to be dependent on Ly49H. During uncontrolled infection in the absence of Prf1, Ly49H beneficially promoted effects for survival, because the sustained NK cells produced IL-10 to control the magnitude of the CD8 T cell response and limit immunopathology. The data suggest that Ly49H-dependent cytotoxicity acts to control viral infection and NK cell expansion, but that in the absence of the killing function, Ly49H promotes a continued NK cell expansion critical for supporting life over death because the NK cells are available to regulate adaptive immune responses.     

Restoration of mGluR6 Localization Following AAV-Mediated Delivery in a Mouse Model of Congenital Stationary Night Blindness

PurposeComplete congenital stationary night blindness (cCSNB) is an incurable inherited retinal disorder characterized by an ON-bipolar cell (ON-BC) defect. GRM6 mutations are the third most prevalent cause of cCSNB. The Grm6^−/− mouse model mimics the human phenotype, showing no b-wave in the electroretinogram (ERG) and a loss of mGluR6 and other proteins of the same cascade at the outer plexiform layer (OPL). Our aim was to restore protein localization and function in Grm6^−/− adult mice targeting specifically ON-BCs or the whole retina.MethodsAdeno-associated virus-encoding Grm6 under two different promoters (GRM6-Grm6 and CAG-Grm6) were injected intravitreally in P15 Grm6^−/− mice. ERG recordings at 2 and 4 months were performed in Grm6^+/+, untreated and treated Grm6^−/− mice. Similarly, immunolocalization studies were performed on retinal slices before or after treatment using antibodies against mGluR6, TRPM1, GPR179, RGS7, RGS11, Gβ5, and dystrophin.ResultsFollowing treatment, mGluR6 was localized to the dendritic tips of ON-BCs when expressed with either promoter. The relocalization efficiency in mGluR6-transduced retinas at the OPL was 2.5% versus 11% when the GRM6-Grm6 and CAG-Grm6 were used, respectively. Albeit no functional rescue was seen in ERGs, relocalization of TRPM1, GPR179, and Gβ5 was also noted using both constructs. The restoration of the localization of RGS7, RGS11, and dystrophin was more obvious in retinas treated with GRM6-Grm6 than in retinas treated with CAG-Grm6.ConclusionsOur findings show the potential of treating cCSNB with GRM6 mutations; however, it appears that the transduction rate must be improved to restore visual function.     

Complement cascade in severe forms of COVID-19: Recent advances in therapy

The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.     

Can serotonin transporter genotype predict serotonergic function,chronicity, and severity of drinking?

Serotonin transporter (5-HTT) activity is greater in carriers of the long (L) vs. short (S) alleles of the 5-HTT-linked polymorphic region (5'-HTTLPR) among healthy control subjects but not alcohol-dependent adults. In 198 alcoholics, we determined the relationship between current or lifetime drinking and platelet 5-HTT function and density among allelic variants of the 5'-HTTLPR. SS subjects were younger than L-carriers (LL and LS) (p<0.0085) and had fewer years of lifetime drinking. For L-carriers, the mean of Bmax for paroxetine binding, but not Vmax for serotonin (5-HT) uptake, was lower than that for SS subjects (p<0.05). More L-carriers than their SS counterparts had Vmax for 5-HT uptake below 200 nmol/10(7) platelets-min (p<0.05) and Bmax for paroxetine binding below 600 nmol/mg protein (p<0.06). Current drinking (drinks per day during the past 14 days) correlated positively with Km and Vmax of platelet 5-HT uptake (p<0.05) and negatively with Bmax, but not Kd, of paroxetine binding (p<0.05) for L-carriers alone. Years of lifetime drinking correlated negatively with Km and Vmax of platelet 5-HT uptake (p<0.05) and B(max), but not Kd, of paroxetine binding (p<0.05) for L-carriers alone. Among L-carriers alone, there were higher levels of platelet 5-HT uptake and lower levels of platelet paroxetine binding with increased drinking, and more lifetime drinking was associated with modestly lower levels of 5-HT uptake and paroxetine binding. Thus, 5-HTT expression varies with current and lifetime drinking in L-carriers alone.