IgG antibodies to the histone complex H2A-H2B characterize procainamide-induced lupus

Patients treated with procainamide and other drugs commonly develop antinuclear antibodies and occasionally symptoms of lupus erythematosus. However, the pathological events which lead to clinical symptoms in some patients but only abnormal serology in others have not been established. The present study examines the incidence, amount, immunoglobulin class, and antigen-binding specificity of anti-histone and anti-denatured DNA (anti-dDNA) antibodies in three groups of patients. These comprised a prospective study of patients treated with procainamide, patients with clinical drug-induced lupus symptoms, and a group undergoing therapy for many years without any symptoms. Procainamide elicited IgG and IgM anti-dDNA antibodies concordantly. Anti-histone IgM antibodies also appeared de novo during this period but IgG anti-histone antibodies were detected less frequently. Asymptomatic patients tended to have an antibody profile consisting of highly elevated anti-dDNA, IgM antibodies reactive with all histones and IgG antibodies specific for only one or two histone classes. In contrast symptomatic patients usually had little anti-dDNA or antibodies to individual histones but had pronounced IgG antibodies to the histone complex H2A-H2B. This unique antibody was characteristics of procainamide-induced lupus and was not detected in patients whose disease was induced by hydralazine. Anti-(H2A-H2B) decreased after procainamide was discontinued, concomitant with subsidence of symptoms. The finding that autoantibodies elicited by procainamide in patients with lupus symptoms have a characteristic immunoglobulin class and specificity may be of pathogenic significance and suggests that patients susceptible to procainamide-induced lupus have a unique immune response. In addition, this information could be of diagnostic value in predicting which procainamide-treated patients will develop overt symptoms of lupus.     

COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders

In a community sample of 2,327 Caucasians, we tested the hypotheses that polymorphisms in the COMT and DRD3 genes are associated with personality traits conferring vulnerability to anxiety, depression, or alcohol misuse, or with current symptoms of these; and that the association is stronger in persons who also have been exposed to stressor experiences. To conserve resources and to allow replication, the genetic analysis was undertaken in two stages. For the COMT polymorphism, no statistically significant associations were found in the first sample of 862 persons. The remainder of the sample was therefore not analysed for that gene. For the DRD3 polymorphism, those in the first sample with at least one of the Ser(9) alleles had significantly higher scores in neuroticism (p=0.006) and behavioral inhibition (p=0.003). There was a trend, failing to meet the 1% significance criterion, for those with this genotype also to have higher depression and anxiety. The groups did not differ in alcohol use. In persons with the Ser(9) allele who were also exposed to stressors, there was a higher level of depression at the 5% level; and the depression level was higher in homozygotes. But when the remainder of the sample (1,465) was analysed, none of the associations reached statistical significance. We conclude that neither the COMT nor DRD3 polymorphisms are associated with anxiety, depression, or alcohol abuse. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:102-107, 2000 Copyright 2000 Wiley-Liss, Inc.     

Genome macrorestriction analysis of sequential Pseudomonas aeruginosa isolates from bronchiectasis patients without cystic fibrosis.

The respiratory tracts of bronchiectasis patients may be persistently colonized with Pseudomonas aeruginosa, despite intensive chemotherapy. The organism may undergo phenotypic changes in these patients, providing misleading typing results by conventional methods. We prospectively studied eight bronchiectasis patients without cystic fibrosis over a period of 1 year. A high microbial load of P. aeruginosa was found in 70% of sputum samples collected. Of these, 55 sequential P. aeruginosa isolates were characterized by a genotyping method, pulsed-field gel electrophoresis, to overcome the problem of differentiating the P. aeruginosa strains during chemotherapy. Genome macrorestriction fingerprinting patterns were analyzed after digestion with XbaI restriction endonuclease. Of the eight patients, six harbored a single dominant strain of P. aeruginosa, with an intrapatient macrorestriction similarity pattern range of 96 to 100%. The other two patients were infected with mixed bacterial isolates including P. aeruginosa. However, diversity was observed in the P. aeruginosa isolates from all eight patients, with a relatedness of only 55 to 65%. The study further strengthens the fact that pulsed-field gel electrophoresis can be used efficiently and effectively to differentiate P. aeruginosa strains in bronchiectasis patients without cystic fibrosis.     

Optokinetic nystagmus in the rabbit and its modulation by bilateral microinjection of carbachol in the cerebellar flocculus

Summary 1. In the alert, pigmented rabbit, eye movements were recorded during optokinetic nystagmus (OKN) and during optokinetic afternystagmus (OKAN). These responses were elicited by steps in surround-velocity ranging from 5–110°/s during binocular as well as monocular viewing. 2. In the baseline condition, OKN showed an approximately linear build-up of eye velocity to a steady-state, followed by a linear decay of eye velocity during OKAN after the lights were turned off. Build-up during binocular viewing was characterized by a constant, maximum eye-acceleration (about 1°/s²) for stimulus velocities up to 60°/s. OKAN, instead, was characterized by a fixed duration (about 10 s) for stimulus velocities up to 20°/s. Steady-state eye velocity saturated at about 50°/s. 3. Monocular stimulation in the preferred (nasal) direction elicited a build-up that was on average twice as slow as during binocular stimulation. Steady-state velocity during monocular stimulation saturated at about 20°/s. OKAN was of equal duration as during binocular stimulation. In the non-preferred direction, a very irregular nystagmus was elicited without velocity build-up. The stronger response to binocular stimulation, compared to the responses under monocular viewing condition in either nasal and temporal direction suggests potentiation of the signals of either eye during binocular viewing. 4. OKN and OKAN were re-assessed after intra-floccular microinjection of the nonselective cholinergic agonist carbachol. In the binocular viewing condition, eye-acceleration during build-up was strongly enhanced from 1°/s² before to 2.5°/s² after injection. The saturation level of steady-state eye velocity was also increased, from 50°/s before to more than 60°/s after carbachol. The duration of OKAN, however, was shortened from 10 s before to 6 s after injection. The response to monocular stimulation in the preferred direction revealed similar changes. 5. The flocculus appears to be involved in the control of the dynamics of OKN in the rabbit. Cholinergic mechanisms affect the floccular control of the rate at which slow-phase velocity can be built up and the rate of decay of eye velocity during OKAN. Cholinergic stimulation of the flocculus enhances the dynamics of OKN, while velocity storage is shortened.     

Interleukin-6 regulates the cytotoxic effect of tumour necrosis factor on U937 cells.

In this study, we demonstrate that low but not high concentrations of interleukin-6 (IL-6) potentiate the cytotoxic effect of tumour necrosis factor-alpha (TNF-alpha) on U937 cells, in a dose-dependent manner. Killing of U937 cells by 100 U/ml of TNF-alpha, was maximally potentiated by 50 U/ml of IL-6. No potentiation of cell killing was observed when the concentration of IL-6 was increased to 4000 U/ml. At a concentration of 50 U/ml, IL-6 up-regulated TNF receptor expression but no change in TNF receptor number was observed when the concentration of IL-6 was increased to 4000 U/ml. Low concentrations of IL-6 can also induce sub-cytotoxic doses of TNF-alpha (0.1 and 0.33 U/ml) to kill U937 cells. Up-regulation of TNF receptors by IL-6 is dependent on de novo protein synthesis since receptor induction is abolished in the presence of cycloheximide. Taken together the data suggest that the potentiation of cell killing observed by a combination of these lymphokines is mediated in part by IL-6-induced changes in TNF receptor expression.     

In vitro synergistic effect of minocycline combined with antifungals against Cryptococcus neoformans

BackgroundCryptococcus neoformans infections occur in immunocompromised patients, especially those with HIV infection, chemoradiotherapy after cancer, and organ transplantation. Infection can cause pneumonia and meningoencephalitis in severe cases with a high mortality rate if not treated. Although fluconazole and amphotericin B are the first-line treatments for cryptococcosis, the rate of fluconazole resistance has increased significantly due to long-term use. Minocycline is a derivative of tetracycline that exerts its antibacterial effect through inhibition of bacterial protein synthesis. It is also able to pass the blood-brain barrier to act on the central nervous system. The present study investigates the effects of minocycline in combination with antifungals in treating C. neoformans.ObjectiveTo determine in vitro interactions of minocycline combined with itraconazole, voriconazole, posaconazole, fluconazole and amphotericin B against C. neoformans.MethodsThe minimum inhibitory concentrations (MIC) of the antifungals were determined by the CLSI Clinical and Laboratory Standards Institute M27-A3 microdilution method. The in vitro synergistic effects of minocycline combined with itraconazole, voriconazole, posaconazole, fluconazole, and amphotericin B on C. neoformans were detected by the broth microdilution checkerboard technique and disk diffusion testing.Results and ConclusionThe working concentration ranges were 0.125–4 µg/mL for itraconazole, 0.03–0.125 µg/ml for voriconazole, 0.03–1 µg/ml for posaconazole, 0.25–16 µg/ml for fluconazole, and 0.125–2 µg/ml for amphotericin B. The synergistic rates of minocycline combinations against C. neoformans were 55% with itraconazole, 10% with voriconazole, 85% with posaconazole, 20% with fluconazole, and 70% with amphotericin B. The effective MIC value of minocycline in the synergistic combination decreased to 2–32 µg/ml, while the MIC of itraconazole decreased to 0.03–0.125 µg/ml, voriconazole 0.03–0.125 µg/ml, posaconazole 0.03–0.125 µg/ml, 0.125–4 µg/ml fluconazole, and 0.06–0.50 µg/ml amphotericin B. The disk diffusion assay showed that the plates containing minocycline and antifungal drugs produced inhibition zones with diameters larger than the single drug plates. Minocycline showed no antagonistic effect in the combinations. In conclusion, the combination of minocycline and azoles or amphotericin B has synergistic effects against C. neoformans in vitro.     

Ocular measurements in fetal alcohol spectrum disorders

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non‐FASD individuals. We compared ocular measurement centiles in children with FASD to non‐FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non‐FASD children who had various forms of growth deficiency (microcephaly, short‐stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.     

GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.     

Repertoire of transcribed peripheral blood T-cell receptor beta chain variable-region genes in acute rheumatic fever.

Patients with severe group A streptococcal infections have abnormalities in the Vbeta repertoire of peripheral blood T cells that are consistent with superantigen stimulation by cytoplasmic membrane proteins. The purpose of this study was to determine whether similar changes in Vbeta repertoire could be found for patients with acute rheumatic fever (ARF). The mean Vbeta repertoire of peripheral blood T cells in nine hospitalized ARF patients was similar to that of 34 controls and did not change during 6 months of follow-up in 6 of the ARF subjects. We were unable to detect changes in the Vbeta repertoire of peripheral blood T cells from patients with ARF that could be attributed to the influence of a superantigen.