The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells

Deletion of the gene encoding the Fc immunoglobulin G receptor IIB (FcgammaRIIB) results in a fulminant, lupus-like disease in C57BL/6 but not BALB/c mice. Here we have investigated this strain-specific, epistatic loss of tolerance using gene-targeted immunoglobulin variable heavy-chain (V(H)) alleles 3H9 or 56R, which encode DNA-specific heavy chains, expressed on the C57BL/6 or BALB/c background. The combination of C57BL/6 and V(H) 56R (B6.56R) resulted in a loss of tolerance; hybridoma and single-cell analysis indicated an FcgammaRIIB-independent difference in immunoglobulin light-chain usage, consistent with an alteration in receptor editing. FcgammaRIIB deficiency resulted in an increase in immunoglobulin G (IgG) antibodies to DNA in the serum, an increased frequency of anti-DNA-reactive IgG(+) B cells with a plasma cell phenotype and immune complex deposition in the glomeruli and renal disease in B6.56R mice. Thus, FcgammaRIIB provides a distal peripheral checkpoint to limit the accumulation of autoreactive plasma cells, thereby maintaining tolerance.     

The Validity of the Neale and Kendler Model-Fitting Approach in Examining the Etiology of Comorbidity

Given that knowledge regarding the etiology of comorbidity between disorders can have a significant impact on research regarding the classification, treatment, and etiology of the disorders, the ability to reject incorrect hypotheses regarding the causes of comorbidity is very important. A simulation study was conducted to assess the validity of the Neale and Kendler (1995) model-fitting approach in examining the etiology of comorbidity between two disorders. First, data were simulated under the assumptions of the 13 alternative comorbidity models described by Neale and Kendler. Second, model-fitting analyses testing the comorbidity models were conducted on the simulated datasets. Thirteen sets of data with varying model parameters were simulated to test Neale and Kendler's assertion that their model-fitting approach is appropriate across a range of potential prevalences and degrees of familiality. The validity of the model-fitting approach in examining unselected twin data and a combination of selected family data and unselected family data was explored. The model-fitting approach successfully discriminated several classes of comorbidity models, although discrimination between models within classes of related models was less accurate. Results suggest that the model-fitting approach can be a useful tool in examining the etiology of the comorbidity between disorders if the caveats of the present study's results are considered carefully. As predicted by Neale and Kendler, variations in the disorder prevalences and familial correlations did not affect the validity of their model-fitting approach, but affected the power to discriminate the correct model. As suggested by Neale and Kendler, the model-fitting approach can be applied to both unselected and selected data and to both twin and family data.     

Which treatment for whom for ADHD? Moderators of treatment response in the MTA

Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators.     

The effect of hydrolytic enzymes on the acetylcholine sensitivity of the skeletal muscle cell membrane

Isometric tension developed by rat soleus and extensor digitorum longus (EDL) muscles in response to acetylcholine (Ach) applied in vitro was recorded. Tension of contractures elicited in response to Ach increased after muscles had been incubated with phospholipase C, pepsin, or soluble fractions prepared from muscle homogenate.Using intracellular microelectrodes, resting membrane potential (RMP) and depolarisation in response to Ach added to the bathing medium were recorded in endplate-free regions of the muscle fibres. No significant change in RMP was observed in muscles incubated with soluble muscle fraction or phospholipase C, but depolarisation in response to Ach or carbachol was significantly increased. The time course for the increase in depolarisation and the contracture response to Ach was similar.When all available receptors were blocked with -bungarotoxin prior to incubation so that no response to Ach could be elicited, with subsequent incubation in muscle soluble fraction or phospholipase C, both contractures and depolarisation in response to Ach returned. These results support the hypothesis that receptors, not previously available to interact with Ach or -bungarotoxin were revealed following incubation.     

Differential diagnosis of dementia and depression in the elderly using neuropsychological methods

This study examined the utility of the Halstead-Reitan Neuropsychological Battery in the differential diagnosis of dementia, major depression, and general neurological impairment. Orthogonal contrasts between groups showed superior performance for depressives on most Halstead-Reitan subtests. Contrasts between organically impaired groups showed that these groups did not differ significantly (p >.05) on any of the Halstead-Reitan subtests. A step-wise discriminant analysis indicated that on the basis of neuropsychological variables alone, demented patients were differentiated from elderly depressed with clinical levels of accuracy. However, when neurologically impaired and demented patients were considered together in a single group reflecting organic impairment, hits increased dramatically. The results were discussed in terms of their implications for differentially diagnosing dementia and depression in the elderly.     

Molecular genetic methods in the diagnosis of hematologic neoplasms

Leukemias and lymphomas are monoclonal neoplasms that arise as a result of molecular abnormalities. These abnormalites are diverse but can be grouped into two general categories, chromosomal translocations that usually result in oncogene activation and inactivation of tumor suppressor genes. Recent advances in our understanding of chromosomal translocations have led to improved classification of leukemias and lymphomas. For example, the t(9;22)(q34;q11) is now considered a defining feature of chronic myeloid leukemia, and the t(2;5)(p23;q35) defines a clinically and biologically unique subset of anaplastic large cell lymphomas. In this review, we focus on chromosomal translocations in hematologic neoplasms and the techniques used for their detection. We also briefly discuss tumor suppressor genes and assessment of clonality in lymphoid neoplasms.     

Psychiatric disorders associated with risk for the development of eating disorders during adolescence and early adulthood

Longitudinal data were used to investigate whether anxiety, depressive, disruptive, personality, or substance use disorders are associated with risk for the development of eating disorders during adolescence or early adulthood. Psychiatric disorders were assessed among 726 youths from a random community sample during adolescence and early adulthood. Depressive disorders during early adolescence were associated with elevated risk for the onset of eating disorders, dietary restriction, purging behavior, and recurrent weight fluctuations after preexisting eating problems and other psychiatric disorders were controlled statistically. Disruptive and personality disorders were independently associated with elevated risk for specific eating or weight problems. The present findings suggest that depressive disorders during early adolescence may contribute to the development of eating disorders during middle adolescence or early adulthood.     

Correlation between Presence of Viable Bacteria and Presence of Endotoxin in Middle-Ear Effusions

The presence of endotoxin (detected by the Limulus amebocyte lysate assay) was compared to the presence of viable Haemophilus influenzae and Moraxella catarrhalis (detected by PCR) in 106 middle-ear effusions from pediatric patients with chronic otitis media. Endotoxin was found in 81 of the 106 specimens. Of these 81 specimens, 66 (81.5%) also tested positive for one or both of the gram-negative bacteria H. influenzae and M. catarrhalis. The data suggest that viable gram-negative bacteria, detectable by PCR but often undetectable by culture, may be the source of endotoxin in middle-ear effusions.     

High-resolution analysis of locomotor activity rhythms indisconnected,a visual-system mutant ofDrosophila melanogaster

Free-running locomotor activity and eclosion rhythms ofDrosophila melanogaster, mutant at thedisconnected (disco) locus, are substantially different from the wild-type phenotype. Initial periodogram analysis revealed little or no rhythmicity (Dushayet al., 1989). We have reanalyzed the locomotor activity data using high-resolution signal analysis (maximum-entropy spectral analysis, or MESA). These analyses, corroborated by autocorrelograms, uncovered significant residual circadian rhythmicity and strong ultradian rhythms in most of the animals tested. In this regard thedisco mutants are much like flies expressing mutant alleles of theperiod gene, as well as wild-type flies reared throughout life in constant darkness. We hypothesize that light normally triggers the coupling of multiple ultradian oscillators into a functional circadian clock and that this process is disrupted indisco flies as a result of the neural lesion.This work was supported in part by NIH Grant FM-33205.