Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells

Following recognition of microbial patterns, innate immune receptors provide a rapid innate response and trigger antigen-presenting cell maturation to instruct adaptive immune responses. Here we discuss a family of innate immune receptors for self – the leucocyte immunoglobulin-like receptors (LILRs). These LILRs exert powerful inhibitory effects on antigen-presenting cell phenotype and subsequent T-cell responses, and may act to constrain the effects of Toll-like receptor signalling. Despite their broad ligand specificity, differing affinities of LILRs for individual complexes of peptide–major histocompatiblity complex can determine the nature of their effect on downstream immune responses. Expression and function of LILRs may be skewed in certain conditions such as cancer or human immunodeficiency virus infection, particularly by ectopic expression of human leucocyte antigen-G, a high-affinity LILR ligand. We discuss the relevance of LILR-mediated immune regulation across a range of scenarios from autoimmunity to transplant medicine, infection and cancer.     

Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease

Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the –219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.     

Menstrual Suppression for Adolescents with Developmental Disabilities

The approach to menstrual suppression for adolescents with developmental disabilities has evolved considerably over the years due to changing philosophies and evolving treatment options. We review the medical management options available for menstrual suppression with a focus on the needs and treatment of adolescents with developmental disabilities.     

For the Sciences They Are A‐Changin’: A Response to Commentaries on Núñez et al.’s (2019) “What Happened to Cognitive Science?”

A recent issue of Topics in Cognitive Science featured 11 thoughtful commentaries responding to our article “What happened to cognitive science?” (Núñez et al., 2019). Here, we identify several themes that arose in those commentaries and respond to each. Crucial to understanding our original article is the fundamental distinction between multidisciplinary and interdisciplinary endeavors: Cognitive science began (and has stayed) as multidisciplinary but has failed to move on to form a cohesive interdisciplinary field. We clarify and elaborate our original argument and reiterate the importance of a data‐driven evaluation of the current status of the field, which exhibits a marked disciplinary imbalance, a lack of a coherent conceptual core, and a striking absence of a consistent curriculum in the institutions that grant degrees in this domain. Half a century after the creation of cognitive science, it may now be a good time to revisit goals and visions for how to best approach the ever‐fascinating scientific study of the mind(s).     

Validation of the Johns Hopkins restless legs severity scale

Determine reliability and validity of the Johns Hopkins restless legs severity scale (JHRLSS), an easily used clinical scale assessing severity of the restless legs syndrome (RLS). There is, prior to this study, no validated scale assessing the wide range of RLS severity. The JHRLSS has been used in prior studies to assess RLS severity, but has not previously been validated in relation to direct measures of the morbidity associated with RLS. A consecutive case series of 31 RLS patients was used in the study. The JHRLSS was validated by its correlation with objective measures by a polysomnogram of the sleep disturbances associated with RLS (periodic leg movements of sleep per hour (PLMS/h), and sleep efficiency). Reliability was determined from the independent ratings of two clinicians. Reliability measures for the JHRLSS based on inter-rater agreement were 0.91 (Spearman Rho) and 0.87 (Cramers V). The subjective JHRLSS correlated significantly with both objective measures of sleep: sleep efficiency (R=0.60, P<0.01) and PLMS/h (R=0.45, P=0.01). The JHRLSS provides a reliable, valid, easily used clinical assessment of RLS severity.     

A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy

Objective

Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO‐029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb‐girdle muscular dystrophy).

Methods

This double‐blind, placebo‐controlled, multinational, randomized study included 116 subjects divided into sequential dose‐escalation cohorts, each receiving MYO‐029 or placebo (Cohort 1 at 1mg/kg; Cohort 2 at 3mg/kg; Cohort 3 at 10mg/kg; Cohort 4 at 30mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO‐029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject‐reported outcomes, magnetic resonance imaging studies, dual‐energy radiographic absorptiometry studies, and muscle biopsy.

Results

MYO‐029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO‐029 was supported by a trend in a limited number of subjects toward increased muscle size using dual‐energy radiographic absorptiometry and muscle histology.

Interpretation

This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered. Ann Neurol 2008     

Frequency of mental and addictive disorders among 320 men and women entering the Iowa prison system: use of the MINI-Plus

The Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) was used to assess the frequency of mental and addictive disorders among 320 randomly selected men and women newly committed to the general population of the Iowa prison system. More than 90 percent of offenders met criteria for a current or lifetime psychiatric disorder. The most frequent were substance use disorders (90%), mood disorders (54%), psychotic disorders (35%), antisocial personality disorder (35%), and attention deficit hyperactivity disorder (22%). Offenders had a mean of 4.2 MINI-Plus disorders, and two-thirds had 3 or more disorders. Contrary to expectation, there were few gender-based differences. Thirty percent of the offenders were rated at risk for suicide. We conclude that mental and addictive disorders are common among incarcerated offenders and that these individuals are at risk for suicidal behavior.