Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.     

Suppressor cell function and anti-DNA antibody idiotypes in the serum of SLE patients and their first-degree relatives

Sixteen-six (16/6) is a major cross-reactive idiotype of monoclonal anti-DNA antibodies, which was derived from the fusion of lymphocytes of a patient with systemic lupus erythematosus (SLE). Antibodies with the 16/6 idiotype (16/6 Id) are increased in the sera of patients with SLE and deposited in their gomeruli and skin. Since stimulated lymphocytes from healthy persons have the capacity to produce 16/6 Id, the mechanisms controlling its expression in health and their possible failure in SLE are of considerable interest. A defect in suppressor cell function was found in a high proportion of patients with SLE and in some of their first-degree relatives. Suppressor cell function in 15 SLE patients and in 53 relatives was compared with the level of 16/6 Id as well as with immunoglobulin levels and anti-DNA antibodies. Ten of 15 SLE patients and 26 of 53 first-degree relatives had increased serum 16/6 levels, which was found in only 1 of 35 healthy controls and household members. Of the 10 SLE patients with increased 16/6, six had a suppressor cell defect (P less than 0.1). Among the 26 first-degree relatives with elevated 16/6 Id levels, 12 had associated suppressor defect and in only two cases was a suppressor cell defect unaccompanied by increased 16/6 (P less than 0.005). For the group of 18 patients and relatives showing concomitant suppressor cell defect and increased 16/6, a correlation was found between the severity of the suppressor cell defect and the level of 16/6 Id in the serum. The increased 16/6 in the relatives was not associated with hypergammaglobulinemia or with measurable anti-DNA activity in the serum. We conclude that the suppressor cell defect in relatives of SLE patients is often associated with increased expression of antibodies with the 16/6 idiotype. However, additional mechanisms are involved in the regulation of 16/6 Id and the development of clinical SLE, since increased 16/6 was commonly found in the presence of a normal suppressor T-cell function.     

Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives.

Some neuropsychological abilities, particularly those affecting memory, attention and executive function, are impaired amongst both schizophrenic patients and their unaffected relatives, implying that these deficits are at least partly genetic in origin. However neuropsychological performance can be altered by medication, and has rarely been examined in first onset, drug naive patients. The objective of this study was to determine whether selected neurocognitive abilities are impaired in first-onset schizophrenic patients and their relatives compared to controls. We examined attention and speed of information processing, memory and learning, verbal function, visuoconstructive abilities and executive function in 207 first-episode schizophrenic patients (163 of whom were drug na?ve), 322 of their first-degree relatives and 133 unrelated normal controls. The data were subjected to multilevel modeling to compare neurocognitive performance between schizophrenic probands, relatives and controls while taking into account potential correlations among members of the same family; age, gender, and years of education were included as covariates. Of the three groups, schizophrenic patients performed poorest at all neuropsychological tests, suggestive of a broad range of neurocognitive deficits. Their first-degree relatives showed a narrower pattern of poor performance at Digit Symbol, Digit Span, Trail Making, Verbal Fluency test, Tower of Hanoi, and WCST-M tests. Our findings show that selected neurocognitive deficits especially attention and executive function are impaired in the families of schizophrenic patients. These patterns of neurocognitive deficits may represent "endophenotypes" denoting varying degrees of vulnerability to schizophrenia and may be of value in future molecular genetic studies.     

Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives

Several studies have reported that patients with schizophrenia and their relatives perform poorly on antisaccade tasks and have suggested that this deficit represents saccadic disinhibition. If this proposition is correct, then varying task parameters that specifically increase the difficulty with which unwanted saccades can be inhibited should exacerbate deficits. Forty-two schizophrenia patients, 42 of their first-degree biological relatives, 21 psychotic affective disorder patients, and 38 nonpsychiatric comparison subjects were given fixation and antisaccade tasks. The introduction of distracters and the presence of visible fixation stimuli were parameters used to vary the difficulty in suppressing unwanted saccades (inhibitory load). It is known that the presence of a fixation stimulus at the time when a saccade must be inhibited results in fewer reflexive errors on antisaccade tasks. Performance on fixation tasks without (low load) vs with distracters (high load) and antisaccade tasks that had fixation stimuli still visible (low load) vs already extinguished (high load) at the time when the reflexive saccade must be inhibited was compared. The schizophrenia patients and their first-degree biological relatives showed evidence of increased saccadic disinhibition that was most pronounced during high inhibitory load conditions. These data indicate that dysfunctional inhibitory processes, at least in the oculomotor domain, are associated with the liability to schizophrenia. Results also suggest that this genetic liability may be related to dysfunctional prefrontal cortical areas that provide top-down inhibitory control over reflexive saccade generation.     

酒依赖患者及其一级亲属听觉ERP研究

目的：对酒依赖患者及其一级亲属（父母、同胞或子女）组与正常对照组的听觉事件相关电位（ERP）进行对照研究,以了解酒依赖患者认知功能状况及酒依赖的遗传易感性。方法：收集40例男性酒依赖患者以及40例一级亲属和40例健康对照者进行听觉ERP检测。结果：酒依赖组和亲属组ERP的P3波（P300成分）波幅均明显低于对照组（均为P〈0．05）;而P3波幅在患者组和亲属组之间比较差异无显著意义（P〉0．05）;酒依赖组N2、P3潜伏期延长（P〈0．01）,而N2、P3潜伏期在亲属组和对照组之间的比较差异则无显著意义（P〉0．05）。结论：ERP反映酒依赖认知功能损害,可以作为酒依赖认知功能损害评估的重要检测手段之一;P3波幅可能是酒依赖的遗传易感性标志,可以作为预测酗酒的指标;对酒依赖一级亲属进行听觉ERP检测可早期发现高危人群,及时提供干预措施。     

Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives

BACKGROUND: Previous work suggests that impairments in executive function and verbal memory in particular may persist in euthymic bipolar patients and serve as an indicator of genetic risk (endophenotype). METHOD: A systematic review of the literature was undertaken. Effects sizes were extracted from selected papers and pooled using meta-analytical techniques. RESULTS: In bipolar patients, large effect sizes (d>0.8) were noted for executive functions (working memory, executive control, fluency) and verbal memory. Medium effect sizes (0.5相似文献   

Increased risk for cancer in multiple myeloma patients and their first-degree relatives

Analyzing data of 125 multiple myeloma patients, the authors found a 40-fold increased tumor incidence among the patients and their first-degree relatives as compared to the average population. These tumors were the same as those usually found among Hungarians. There was no difference as to the patient's blood group antigens in the families of myeloma patients with or without other tumor. IgA-type disease was found to be relatively more frequent in the group of patients who had tumor besides myeloma. In a prospective study, authors could not find mutation of suppressor gene p53 in 14 patients and their 16 healthy first-degree relatives. This may indicate that there is no p53 suppressor gene alteration responsible for the high-risk condition for tumorgenesis in this population.     

Verbal fluency in patients with schizophrenia and affective psychoses and their first-degree relatives

BACKGROUND: Schizophrenic patients are known to have neuropsychological deficits including impaired verbal fluency, but it is not clear whether this latter deficit is: (a) a consequence of overall intellectual deficit; (b) shared with affective psychotic patients; or (c) shared by the relatives of schizophrenic patients; and (d) shared by the relatives of affective psychotic patients. METHODS: We administered Thurstone's Verbal Fluency Test to 45 schizophrenic patients and 72 of their relatives, and 30 affective psychotic patients and 53 of their relatives. Subjects were asked to generate as many words as possible beginning with the letters 'C' and 'S' and the total was taken as the dependent variable. Subjects also completed the National Adult Reading Test (NART) to provide a measure of (pre-morbid) IQ. RESULTS: Schizophrenic patients generated significantly fewer words than affective psychotic patients, however adjusting for NART this became non-significant. Schizophrenic (but not affective psychotic) patients generated significantly fewer words than their relatives; again adjusting for NART this became non-significant. Patients who had been exposed to obstetric complications (OC+) and those who had not (OC-) had similarly poor verbal fluency scores. Relatives of OC+ schizophrenic patients had superior verbal fluency than relatives of OC- schizophrenic patients and this remained significant after adjustment for NART. CONCLUSIONS: The results suggest that some families transmit impairment in verbal fluency as part of a pattern of lower overall IQ. However, in other families, relatives show largely normal neuropsychological function, and the poorer verbal performance of the schizophrenic member appears to have arisen secondary to his/her exposure to OCs.     

Expression of a common idiotype PR4 in the sera of patients with leprosy.

The sera of 187 patients from across the leprosy spectrum were screened for the expression of the PR4 idiotype, which was first identified on a human hybridoma-derived monoclonal antibody from a patient with leprosy and found to react with the Mycobacterium leprae phenolic glycolipid and a variety of polynucleotides. Sixty per cent (51 out of 85) of patients with lepromatous leprosy (LL), 66% (33 out of 49) with borderline lepromatous (BL) disease, 47% (14 out of 30) with borderline tuberculoid (BT) leprosy, and 56% (13 out of 23) of tuberculoid (TT) patients were found to have significantly elevated titres of the PR4 idiotype in their sera compared with endemic controls, irrespective of the presence or absence of endemic malaria. Sera from 52 patients with tuberculosis were also screened as a control for mycobacterial infection. The PR4 idiotype was significantly elevated in 37% (19 out of 52) of these patients. No correlation between idiotype and serum immunoglobulins IgG and IgM was found, indicating that the concentrations of idiotype levels in sera were not merely a reflection of changes in serum immunoglobulin levels. It is hypothesized that the expression of the PR4 idiotype is due to certain germline genes preferentially expressed rather than being the result of polyclonal B cell activation.     

A common idiotype expressed on a murine anti-Sm monoclonal antibody and antibodies in SLE sera.

A rabbit anti-idiotypic antiserum made against a murine monoclonal anti-Sm autoantibody (Y2) was used in a solid-phase radioimmunoassay to investigate idiotypic cross-reactivity among anti-Sm antibodies present in sera from patients with systemic lupus erythematosus. Sera from 25 of 51 SLE patients (49%) containing anti-Sm antibodies were positive for this Y2 idiotype compared to only one of 22 normal human sera. Nine of 28 SLE patients (32%) whose sera were anti-Sm negative were also positive for the Y2 idiotype in low titre. Binding was not due to rheumatoid factor-like activity but was specific for the Y2 determinant and could be eliminated by absorption with Y2 monoclonal antibodies. The anti-idiotypic antibody blocked the ability of 12 of 25 anti-Sm positive lupus sera to bind Sm. Conversely, Sm antigen inhibited the binding of anti-idiotypic antibody in nine of 12 lupus sera.     

Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their first-degree relatives

We evaluated the resting electroencephalogram (EEG) of 50 first-episode schizophrenia patients and 55 of their relatives, 31 first-episode bipolar patients and 35 of their relatives, and 113 nonpsychiatric subjects and 42 of their relatives. The frequency characteristics of the EEG showed moderate stability for a subgroup of these subjects (n= 106) who were tested twice, approximately 9 months apart. Both the schizophrenia and bipolar patients showed a generalized pattern of increased delta and theta and decreased alpha activity. The bipolar patients demonstrated additional right hemisphere activity that was not present among the schizophrenia patients and nonpsychiatric subjects, a finding consistent with hypotheses concerning nondominant hemisphere involvement in the regulation of elated mood. The schizophrenia patients' female relatives and/or relatives with affective disorders and the bipolar patients had significantly reduced peak alpha frequencies. This finding may be related to reduced information processing capacity among these subjects.     

Acoustic startle reflex in schizophrenia patients and their first-degree relatives: evidence of normal emotional modulation.

We investigated emotional disturbances in 36 schizophrenia patients, 48 of their first-degree relatives, and 56 controls to determine if abnormal affective startle modulation could be associated with genetic risk for schizophrenia. Both patients and relatives had a pattern of startle modulation indistinguishable from controls, with potentiated startle amplitude while viewing negative valence slides and attenuation while viewing positive slides. Patients with flat affect did not differ from those without in startle modulation or slide ratings. The patients and their relatives had lower pleasantness ratings of positive slides and the patients had higher pleasantness ratings of the negative slides than controls. The startle paradigm may not be useful for identifying individuals with a genetic liability for schizophrenia. The results suggest that low-level defensive and appetitive behaviors are unaffected in schizophrenia.     

Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives

Narcolepsy is a rare neurological sleep disorder affecting around 0.05% of the general population. Genetic factors are known to have an important role in narcolepsy. However, because of its very low prevalence, it is difficult to have groups of comparison between first-degree relatives and general population subjects in order to identify a specific spectrum of disorders in these families. Consequently, from 157 Italian patients with narcolepsy, 263 first-degree relatives were recruited, two refused to participate. These family members were compared with a matched group of 1071 subjects selected from a sample of 3970 subjects representative of the general population of Italy (46 million inhabitants). Finally, 68 spouses of narcoleptic patients were used to assess for possible role of environmental factors. All subjects were interviewed by telephone using the Sleep-EVAL system. Nineteen cases of narcolepsy were discovered among the first-degree relatives of 17 probands (10.8%). Compared with the general population subjects, the relative risk of narcolepsy among female first-degree relatives was of 54.4 and of 105.1 among male first-degree relatives. First-degree relatives were also at higher risk for idiopatic hypersomnia (OR: 23.0), obstructive sleep apnea syndrome (OR: 6.8), adjustment sleep disorder (OR: 4.0), insufficient sleep syndrome (OR: 7.0), circadian rhythm disorders (OR: 2.5), REM behavior disorder (OR: 4.4), and sleep talking (OR: 2.0). The vulnerability to sleep disorders is very high in first-degree relatives and the link with different expressivity and severity of hypersomnia can be confirmed.     

Anti-DNA idiotype- and anti-idiotype-specific T cell responses in patients with systemic lupus erythematosus and their first-degree relatives.

We examined the proliferative responses of T cells of patients with systemic lupus erythematosus (SLE), their first-degree relatives, and healthy donors, to a human monoclonal antibody that bears a common anti-DNA idiotype, 16/6 Id, and to a murine, 16/6 Id-specific, monoclonal antibody. Both 16/6 Id+ and 16/6 Id-specific antibodies were previously shown to be involved in the induction of experimental SLE in mice. Here we show that T cells of fewer SLE patients, as compared with healthy donors, could proliferate to both antibodies. The difference between T cell responses of patients and controls to the 16/6 was found to be significant. The proliferative responses of T cells of first degree relatives of SLE patients to the anti-16/6 Id were found to be significantly lower compared with the responses detected in healthy donors and in SLE patients. The responses of T cells of SLE relatives to the 16/6 Id were found to be lower than those of healthy donors, but this difference was not significant. The present study suggests a possible involvement of T cells, and specifically of idiotype and anti-idiotype specific T cells, in SLE.     

Peripheral T-cell subset imbalance in patients with vitiligo and in their apparently healthy first-degree relatives

Twenty-two patients with vitiligo had lesions stable for at least 1 year and 23 apparently healthy first-degree relatives were studied for T-cell subpopulations using monoclonal antibody technique. High levels of CD4+ lymphocytes and high CD4/CD8 ratios were found in both patients and their relatives, as compared with normal age-matched and sex-matched controls. This immunologic abnormality, together with the presence of autoantibodies previously reported in the apparently normal relatives, seems to be the hallmark of the disease. Further support of this interpretation comes from the observation that two out of the 23 apparently healthy relatives went on to develop vitiligo in a 2-year follow-up.     

Islet-cell antibodies (ICA-CFICA) and HLA genotypes in 107 IDD patients and their first-degree relatives

The prevalence of ICA and CFICA in relation to HLA-DR genotypes was analyzed in 107 insulin-dependent diabetic (IDD) patients with a duration of IDD ranging from onset to 30 years, and 247 nondiabetic first-degree relatives. In 46 patients tested at onset of IDD, the prevalence of ICA and of CFICA was 61 and 50%, respectively; with the longer duration of IDD, the prevalence of CFICA decreased more rapidly than that of ICA. No significant association was observed between ICA and any HLA allele in patients tested from onset till 2 years after onset. However, a higher prevalence of ICA was found in DR3 positive patients with a duration of IDD of more than 2 years (p less than 0.02). Among the healthy relatives, the prevalence of ICA was 7% in parents and 13% in siblings; one out of 101 siblings had CFICA. No association was found between ICA and any HLA marker. The presence of ICA in sibs was independent of the number of haplotypes they shared with the IDD proband: among the 13 ICA-positive healthy sibs, one shared 2 haplotypes, nine shared 1 haplotype and three shared no haplotype with the proband, which is not different from the random distribution.     

Pitted enamel hypoplasia in tuberous sclerosis patients and first-degree relatives

Thirty-six families with tuberous sclerosis (TS) including 49 affected persons and 68 apparently unaffected first-degree relatives were examined for dental abnormality. Fifty unrelated controls were similarly examined. Clinically observed multiple enamel pits (pitted enamel hypoplasia) were noted in 71% of persons with typical TS and in one out of 10 "atypical" cases. Enamel pits were rarely seen, and in small numbers only, in the control series, and they were rare in the otherwise apparently normal TS first-degree relatives. However, one parent and one half-sib of persons with typical TS, but themselves without other signs of TS, were found to have multiple enamel pits. Examination for pitted enamel hypoplasia should be made in all persons suspected of having TS and in all close relatives; enamel pits are a valuable clinical sign and may identify otherwise unsuspected carriers of the gene within the family.     

A breath-holding challenge in panic disorder patients,their healthy first-degree relatives,and normal controls

Our aim was to observe the induction of panic attacks (PA) symptoms by a breath-hold test in panic disorder (PD) patients as the Diagnostic and Statistical Manual for Mental Disorders 4th edition (DSM-IV) and their healthy first-degree relatives. We randomly selected 26 PD patients, 28 healthy first-degree relatives of probands with PD and 25 normal volunteers with no family history of PD. They were induced to breath-hold for as long as possible four times with a two-min interval between them. Anxiety scales were applied before and after the test. Using specific PA criteria, 46.1% (n=12) PD patients, 7.1% (n=2) first-degree relatives and 4.0% (n=1) control subjects had a PA after the test (chi(2)=7.82, df=2, P=0.023). There was no heart rate, anxiety levels or breath-hold time differences among the groups. In this breath hold challenge test PD patients were more sensitive to breath-hold than first-degree relatives and normal volunteers.     

Rheumatoid arthritis-associated antibodies in healthy first-degree relatives of RA patients

Rheumatoid arthritis (RA) affects approximately 1.5% of the population worldwide and 0.5–3.3% of the Mexican population. The presence of rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein (anti-CarP) antibodies has been described in populations at risk of RA development, such as first-degree relatives (FDR). Anti-CarP antibodies are present in RA patients (44%), FDR of RA patients (18%) and healthy controls (4.7%). Anti-CarP antibodies have not been described in FDR of the Mexican population. The objective of this study was to determine the prevalence of Rheumatoid Factors (RF) isotypes, ACPA and anti-CarP antibodies isotypes in FDR of RA patients. An observational, cross-sectional study, in an FDR of RA cohort, was performed. We measured IgA, IgG and IgM isotypes of RF, ACPA and anti-CarP antibodies. A total of 144 FDRs from 99 RA patients were enrolled. The prevalence of anti-CarP antibodies was 2.8% for IgA, 4.2% for IgG, whereas IgM was not detected. The serologic association was for RF/ACPA 4.48%, RF/anti-CarP 2.7%, FR 64.5%, ACPA 1.3%, ACPA/anti-CarP 0.69%, anti-CarP 3.4%, and no RF/ACPA/anti-CarP was observed. We found a low prevalence of anti-CarP antibodies in our cohort of FDR of RA patients, but the prevalence of ACPA and RF were higher than other cohorts previously reported.