Discordant Twin Pairs Research Articles

Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles

Fewer than 5% of monozygotic (MZ) and dizygotic (DZ) twin pairs are clinically concordant for systemic sclerosis (SSc), yet the majority of MZ twins are concordant for antinuclear antibodies. To discover genetic versus nongenetic molecular pathways important to the pathogenesis of SSc, we compared global gene expression patterns in twins discordant for SSc. Total RNA from dermal fibroblasts of 15 discordant twin pairs (10 MZ and 5 DZ) and 5 normal controls were used in microarray analysis. Aberrantly expressed genes were confirmed using quantitative real-time reverse transcriptase-polymerase chain reaction. Lesional and nonlesional fibroblasts from SSc patients showed no significant differences in gene expression, while SSc patients had gene profiles that were significantly different from those of unaffected DZ twins and normal controls. Unaffected MZ twins, however, were not significantly different from SSc patients. Unsupervised hierarchical clustering segregated the fibroblast samples as originating from 2 major groups. Group A contained 5 discordant MZ twin pairs, 3 affected MZ twins, and 3 affected DZ twins. Group B contained all 5 normal population controls, all 5 healthy DZ twins, 2 discordant MZ twins, and 2 discordant DZ twin pairs. Normal fibroblasts incubated with serum from an SSc-affected patient or with serum from her unaffected MZ twin sister developed the increased expression of COL1A2, SPARC, and CTGF typically seen in SSc fibroblasts. These results demonstrate that dermal fibroblasts from SSc patients and from 40-50% of their genetically identical but clinically unaffected MZ twins exhibit a similar gene expression pattern which can be induced in normal fibroblasts by sera from both. Thus, a stronger genetic predisposition to SSc (than can be detected clinically) is apparent at the molecular level in skin fibroblasts.

Ovarian Transplantation In A Series Of Identical Twins Discordant For Ovarian Failure

To investigate the prospects for restoring spontaneous menstrual cycles and fertility by ovarian isotransplantation between monozygotic twin sisters. A series of 4 otherwise healthy monozygotic twins, where 1 had idiopathic premature menopause & the other had normal ovarian function. 4 pairs of monozygotic twins (aged 24, 25 and 38[n=2] years of age) requested ovarian transplantation from the fertile sister to their sibling who had premature ovarian failure (POF). 3 of the donor sisters had normal menstrual cycles and had completed their target family sizes of 2 or 3 children; a 25 y.o. twin donor had no children and was on oral contraception. All 4 prospective recipients had FSH levels > 90 mIU/ml, no menses for ≥10 years, and complete absence of ovarian follicles in ovarian biopsies. They were menopausal from ages 14, 15, 16, and 22 years. 2 of the twins underwent transplantation at age 24 and 38, and 2 are awaiting. One ovary was removed from the donor and cortical tissue was dissected ex vivo in Leibovitz-L15 medium at 4°C. Donor ovarian cortex was then sutured microsurgically into the recipient’s medulla via a mini-laparotomy. This procedure was outpatient, with prompt & uneventful recovery. Surplus tissue from the youngest twin-pair was cryopreserved for future use with a slow-freezing protocol using 1,2-propanediol & sucrose as cryoprotective agents. Ovarian tissues & peripheral blood from both women was cultured for analysis by karyotyping and analyzed by FISH for sex chromosome mosaicism. All twin-pairs were genetically fingerprinted, and DNA from the sterile sisters was tested for fragile X mutation. All the twin-pairs were confirmed by genetic fingerprinting to be homozygous, implying that immunosuppression was unnecessary for transplant survival. Histology confirmed that the recipient ovaries were sterile, whereas the donor ovaries contained numerous primordial and small growing follicles, consistent with the antral follicle counts obtained preoperatively by transvaginal ultrasound. Karyotypes were normal 46,XX and there was no expansion of CCG repeats in the FMR-1 gene. The first of the ovary transplant recipients menstruated lightly at 12 weeks postoperatively and conceived naturally with an intrauterine pregnancy at the next cycle (∼20 weeks postoperatively). At 22 weeks of pregnancy, ultrasound revealed a normal girl and, at the time of writing, the pregnancy is proceeding uneventfully at the 33rd week. The 2nd twin-pair has also undergone transplantation with similar genetic and histologic findings, and 2 additional pairs are awaiting the same procedure. Evidence we present elsewhere indicates that POF within discordant twin-pairs is less rare than expected. These first cases of ovarian tissue transplantation between women are made possible by virtue of a genetically identical twin willing to be a donor. There is a latent period of several months before ovulation is restored & the endocrine profile is normalized, but in our first case, conception occurred promptly thereafter & pregnancy was normal. If this success can be repeated, ovarian transplantation may provide an alternative to conventional egg donation for comparable patients, and it confirms the feasibility of natural conception after transplanting thawed ovarian tissue in cancer patients. Finally, ongoing molecular study of such twin-pairs may eventually shed light on the causes of premature ovarian failure.%3:45 p.m.

Behavioral Versus Genetic Correlates of Lipoproteins and Adiposity in Identical Twins Discordant for Exercise

Lipoprotein and weight differences between vigorously active and sedentary monozygotic (MZ) twins were used to (1) estimate the effects of training while controlling for genotype and (2) estimate genetic concordance (ie, similarity) in the presence of divergent lifestyles. Thirty-five pairs of MZ twins (25 male, 10 female) were recruited nationally who were discordant for vigorous exercise (running distances differed by > or =40 km in male and > or =32 km in female twins). The active twins ran an average (mean+/-SD) of 63.0+/-20.4 km/wk, whereas the mostly sedentary twins averaged 7.0+/-13.5 km/wk. The active twins had significantly lower body mass index (difference+/-SE, -2.12+/-0.57 kg/m2, P=0.0007) and significantly higher HDL cholesterol (0.14+/-0.04 mmol/L, P=0.004), HDL2 (2.71+/-1.04 U, P=0.01), and apolipoprotein (apo) A-I (0.10+/-0.03 g/L, P=0.004). Despite the difference in lifestyle, when adjusted for sex, the correlations between the discordant MZ twin pairs were significant (P<0.01) for HDL cholesterol (r=0.69), apoA-I (r=0.58), and HDL2 (r=0.67). There was no significant MZ twin correlation for body mass index (r=0.17). None of the active twins having an overweight twin were themselves overweight. Behavior (vigorous exercise) may reduce genetic influences on body mass index. In contrast, genetics (or shared environment) substantially influences HDL cholesterol and HDL subclasses, even in the presence of extreme behavioral differences. There may be greater individual control over moderate degrees of obesity, whereas low HDL cholesterol may be largely predetermined and less effectively treated by vigorous exercise.

Growth Restriction as a Determinant of Outcome in Preterm Discordant Twins

To estimate the influence of intrauterine growth restriction (IUGR) on the outcome of preterm discordant twins. Medical records of preterm twins born at 24-34 weeks of gestation between 1995 and 2000 were reviewed. Significant discordancy was defined as more than 15% difference in birth weight. Small for gestational age (SGA) was defined as birth weight less than 10th percentile, according to a twin-adjusted gestational age nomogram. The smaller twins of 96 discordant twin pairs were evaluated. The SGA-discordant group included the smaller twin of a discordant pair who was also SGA (n = 46); the appropriate-for-gestational-age (AGA)-discordant group included the smaller twin of a discordant pair who was appropriate for gestational age (n = 50). Maternal age, incidence of maternal hypertension, antenatal steroids, and gestational age at delivery were similar between groups. Delivery for suspected fetal compromise complicated significantly more pregnancies in the SGA-discordant group than in the AGA-discordant group (45.6% versus 16%, P = .005), as did respiratory distress syndrome (RDS) (37% versus 8%, P < .05) and intraventricular hemorrhage (21.7% versus 6%, P = .024). Mortality or severe neonatal morbidity (defined as severe RDS, intraventricular hemorrhage grades 3-4, or necrotizing enterocolitis) were significantly higher among neonates in the SGA-discordant group than in the AGA-discordant group (19.5% versus 6%, P = .04). The risk for major morbidity was 7.7-fold greater in the SGA-discordant than in the AGA-discordant group, adjusted for gestational age. Growth restriction in preterm discordant twins is associated with a 7.7-fold increased risk for major neonatal morbidity. Therefore, discordant twins with IUGR require closer monitoring than discordant twins without IUGR.

No evidence for heritability of Parkinson disease in Swedish twins.

Although several genes are implicated in Parkinson disease (PD), they explain only a small fraction of cases. The etiology of most cases is yet unknown. To evaluate heritability of PD in same-sexed and opposite-sexed twin pairs in the Swedish Twin Registry (STR). All twins in the STR born in 1950 or earlier and alive in 1998 (n = 50,150) were included. The authors screened 33,780 twins in 14,082 pairs for PD by telephone interviews and linked the STR to the Swedish Inpatient Discharge Register. Two hundred forty-seven twins with self-reported PD or a PD diagnosis in the Inpatient Discharge Register (called "possible PD") and 517 twins who reported parkinsonian symptoms or use of antiparkinsonian medication ("suspected parkinsonism or movement disorder") were identified. For possible PD, there were only two concordant pairs, both female dizygotic. Similarly, concordances were low in all zygosity groups when the definition of affected was expanded to include twins with suspected parkinsonism or movement disorder in addition to possible PD. Sex differences in the relative importance of genetic and environmental effects were indicated with a marginally larger familial component in women. The best-fitting structural equation model included only environmental components of variance. These results suggest that environmental factors are most important in the etiology of PD. Compared with other complex diseases, the importance of genetic effects in PD is notably low. The preponderance of discordant twin pairs provides an ideal material for studying environmental risk factors and potential genotype-by-environment interaction.

Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism.

The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype. The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments. Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects. These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.

Language activation in monozygotic twins discordant for schizophrenia.

In previous functional magnetic resonance imaging (fMRI) studies, participants with schizophrenia showed decreased language lateralisation, resulting from increased activation of the right hemisphere compared with controls. To determine whether decreased lateralisation and increased right cerebral language activation constitute genetic predispositions for schizophrenia. Language activation was measured using fMRI in 12 right-handed monozygotic twin pairs discordant for schizophrenia and 12 healthy right-handed monozygotic twin pairs who were twin pairs who were matched for gender, age and education. Language lateralisation was decreased in discordant twin pairs compared with the healthy twin pairs. The groups did not differ in activation of the language-related areas of the left hemisphere, but language-related activation in the right hemisphere was activation in the significantly higher in the discordant twin pairs than in the healthy pairs. Within the discordant twin pairs, language lateralisation was not significantly different between patients with schizophrenia and their co-twins. Decreased language lateralisation may constitute a genetic predisposition for schizophrenia.

Life dissatisfaction and subsequent work disability in an 11-year follow-up.

Mental disorders are associated with disability, but the long-term effects of low subjective well-being on work ability in general population are not known. In this study we investigated whether self-reported life dissatisfaction predicts work disability. A nationwide sample of Finnish twins aged 18-54 years (N = 22,136), unselected for health status responded to a health questionnaire with a four-item life satisfaction scale (range 4-20) covering interest, happiness, easiness and loneliness of life in 1975 and 1981. Cox regression for all subjects and conditional logistic regression for discordant twin pairs were used to compare the risk of subsequent work disability (N = 1200) (Nationwide Disability Register) between the dissatisfied and satisfied. Life dissatisfaction predicted subsequent (1977-87) work disability pension due to psychiatric and non-psychiatric causes among the healthy at baseline, and that due to psychiatric causes among the ill. After controlling for age, marital status, social class and health behaviour, these risks remained significant. Repeatedly reported (1975 and 1981) life dissatisfaction was strongly associated with increased (age-adjusted) risk of subsequent (1982-87) work disability due to psychiatric and also that due to non-psychiatric causes among the healthy. When twin pairs discordant for end-point disability status were analysed, risk differences related to life satisfaction were only slightly decreased, but they did not differ significantly between monozygotic and dizygotic pairs. Life dissatisfaction predicts subsequent work disability especially among the healthy.

Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia

Background Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected in gray or white matter volume change is not known. Methods Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. Results Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly in the monozygotic twin pairs. A decrease in gray matter was found in the patients compared with their co-twins and compared with the healthy twins. Conclusions The results suggest that the decreases in white matter volume reflect the increased genetic risk to develop schizophrenia, whereas the decreases in gray matter volume are related to environmental risk factors. Study of genes involved in the (maintenance) of white matter structures may be particularly fruitful in schizophrenia.

Neonatal mortality rates among growth-discordant twins, classified according to the birth weight of the smaller twin

Objective The purpose of this study was to evaluate neonatal mortality rates among discordant twins, classified according to the birth weight of the smaller twin. Study design We compared neonatal mortality rates among three groups of discordant twins (>25%), distinguished by the birth weight of the smaller twin being <10th, 10th to 50th, or >50th percentile. Results Among the 10,683 pairs of twins who were studied, the respective proportions of the three groups were 62.4%, 32.9%, and 4.7%. The neonatal mortality rate was significantly higher among pairs in which the smaller twin weighed <10th birth weight percentile (29. vs 11.1 and 11 per 1000; odds ratio, 2.7; 95% CI, 1.3, 5.7). This difference results from the higher mortality rates among the smaller but not among the larger twins. Conclusion Severely discordant twin pairs in whom the smaller twin is also small for gestational age are at an increased risk of neonatal death. Identification of this group is an imperative step in the management of birth weight discordance in twin gestations.

Does Participation in Leisure Activities Lead to Reduced Risk of Alzheimer's Disease? A Prospective Study of Swedish Twins

This study examined whether participation in leisure activities during early and middle adulthood was associated with reduced risk of Alzheimer's disease. The sample consisted of 107 same-sex twin pairs discordant for dementia and for whom information on leisure activities was self-reported more than 20 years prior to clinical evaluation. A factor analysis of these activities yielded three activity factors: intellectual-cultural, self-improvement, and domestic activity. Matched-pair analyses compared activities within the discordant twin pairs while controlling for level of education. For the total sample, participation in a greater overall number of leisure activities was associated with lower risk of both Alzheimer's disease and dementia in general. Greater participation in intellectual-cultural activities was associated with lower risk of Alzheimer's disease for women, although not for men.

Evidence of altered bone turnover, vitamin D and calcium regulation with knee osteoarthritis in female twins.

Osteoarthritis (OA) is a disorder of the whole synovial joint organ. There is growing evidence of the importance of bone turnover in OA, and human studies have demonstrated that the subchondral bone is metabolically active in OA. The aim of this study was to assess the relationships of radiographic knee OA with altered bone turnover and calcium regulation. We performed a matched and unmatched case-control study using twins assessed for OA. The subjects were 1644 female Caucasian twin pairs (266 monozygotic and 556 dizygotic) aged 24-79 yr from the St Thomas' UK Adult Twin Registry. Assays for measures of bone turnover [bone-specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline (DPD)] and calcium regulation [serum parathyroid hormone (PTH), 25-hydroxyvitamin D, serum calcium, serum magnesium and serum phosphate] were performed. The radiological features of knee OA were graded on a four-point scale (0-3) for osteophytes and a five-point scale (0-4) for Kellgren and Lawrence classification. Adjustment for age, body mass index (BMI) and relatedness was made. Conditional logistic regression analysis was also used to estimate the odds ratio (OR) and 95% confidence intervals (CI) for having radiological features of knee OA per standardized unit difference of serum variable between twins. Of the 1644 women studied, 474 (28.8%) had radiological evidence of knee osteophytes. There was evidence of increased bone turnover, increased PTH levels and decreased vitamin D levels in this group compared with those without osteophytes. No association was seen with joint space loss. After adjusting for age, BMI and relatedness, all of the differences disappeared except for a significant increase 10% in urinary DPD (P = 0.04). Discordant twin pair analysis (performed on a subgroup of 229 pairs) confirmed modest increases in bone resorption indicated by urinary DPD (OR 1.67, 95% CI 0.88-3.16) and a significant decrease in serum magnesium (OR 0.65, 95% CI 0.46-0.92) in the co-twins with OA. Bone resorption is increased in women with knee OA, consistent with metabolically active subchondral bone. However, bone formation, vitamin D and calcium regulation were not different after adjusting for age and BMI. The results suggest that bone resorption is increased in the presence of OA. Although we cannot clearly differentiate a cause or effect relationship, these results suggest that this is related to disease mechanisms and point to potential diagnostic or therapeutic avenues for bone resorption in OA.

A note on cluster headache in a population-based twin register.

Evidence of a familial risk factor in cluster headache is accumulating and studies of twin concordance may resolve family resemblance into genetic and environmental influences. The past literature on cluster headache in twins comprises a few case reports of concordant monozygotic pairs. Swedish twin pairs with a diagnosis of cluster headache were selected through a cross-match of national registers of twin births and hospitalizations. Seventeen discordant twin pairs were found, in which it was possible to verify cluster headache status in 11 complete pairs (two monozygotic, four dizygotic, and five unlike-sexed pairs). In both members of a female monozygotic pair, migraine without aura developed after birth of the first child and remitted by menopause, whereas post-menopausal development of chronic cluster headache occurred in only one of them. The importance of individual specific factors for cluster headache was demonstrated. However, to explain familial aggregation a larger sample of affected twin pairs is necessary.

Differential gene expression in CD8 + cells exhibiting noncytotoxic anti-HIV activity

Suppressive subtractive hybridization with polymerase chain reaction was used to identify the gene(s) associated with the CD8 + cell noncytotoxic anti-HIV response. The differences in gene expression profiles of CD8 + cells from a pair of discordant HIV-positive identical twins were studied. Forty-nine genes were identified as expressed at higher levels in the CD8 + cells from the infected twin that inhibited viral replication. The differential expression of these genes was then evaluated using Q-PCR to determine if this gene expression pattern is evident in CD8 + cells from other HIV-positive subjects showing this antiviral activity. Three genes, including one unknown, were found to have significantly increased expression in antiviral CD8 + cells.

The association between body height and coronary heart disease among Finnish twins and singletons.

An inverse association between body height and the incidence of coronary heart disease (CHD) has been observed. However, the mechanisms behind this association are still largely unknown. We will examine the role of genetic and familial factors behind the association in a large twin data set. The data were derived from the Finnish Twin cohort including 2438 singletons, 4073 monozygotic (MZ) twins, and 9202 dizygotic (DZ) twins aged 25-69 years at baseline in 1976. Incident CHD cases were derived from hospital discharge data and cause of death data between 1977 and 1995. Cox regression analysis and conditional logistic regression analysis were used. In population-level analyses no differences in the general risk of CHD between zygosity groups were found. The association between body height and CHD was similar between sexes and zygosity groups. When men and women in all zygosity groups were studied together an increased risk of CHD was found only among the shortest quartile (hazard ratio [HR] = 1.34, 95% CI: 1.14-1.57). Among the twin pairs discordant for CHD a suggestive increased risk for the shorter twin was seen among DZ twins (odds ratio [OR] = 1.19, 95% CI: 0.95-1.48) when men and women were studied together. An inverse association between body height and CHD was broadly similar between sexes and twin zygosity groups and was associated with short stature. Among discordant twin pairs we found a weak association among DZ twins but not MZ twins. This may suggest the role of genetic liability behind the association between body height and CHD.

Life events and depressiveness - the effect of adjustment for psychosocial factors, somatic health and genetic liability.

To study the nature of the relationship of life events with depressiveness. In 1990, 9947 Finnish adult twins aged 33-60 years participated in a questionnaire study, with no missing data on the analysed variables. The relationship between stressful life-events and depressiveness, based on Beck Depression Inventory (BDI) classified as normal, mild or moderate, was analysed using multinomial regression for all subjects with adjustment for the effect of age, sex, health status, social support, marital status, social class, and personality variables. These same factors were analyzed among 643 twin pairs discordant for depressiveness. High BDI score categories were strongly associated with stressful life events in all individuals and equally strongly within discordant twin pairs, both monozygotic and dizygotic. Poor somatic health and lack of social support also increased depressiveness. The effect of life events predicting depressiveness was independent of social support, somatic disease, sex and genetic liability.

The Influence of Genetics and Environmental Factors in the Pathogenesis of Acne: A Twin Study of Acne in Women

Acne is common and often leads to significant psychologic and physical morbidity. From clinical experience, acne appears to run in families; however, very few studies have investigated the genetic basis of this very common skin disease. A large twin study based on 458 pairs of monozygotic and 1099 pairs of dizygotic twins, all women with a mean age of 46 y was performed to investigate the relative contribution of genetic and environmental factors on the liability to acne. In addition, potential risk factors were assessed in twins with and without acne in a nested cross-sectional design. Fourteen percent of the twins reported a history of acne. Genetic modeling using acne scores showed that 81% (95% confidence interval 73-87%) of the variance of the disease was attributable to additive genetic effects. The remaining 19% was attributed to unique (i.e., unshared) environmental factors. Of the potential risk factors tested in 400 acne twins and 2414 unaffected twins, only apolipoprotein A1 serum levels were significantly lower in acne twins even after adjusting for age and weight. Family history of acne was also significantly associated with an increased risk. No significant differences were found between acne twins and nonacne twins for weight, body mass index, height, birth weight, hair thinning, reproductive factors as well as cholesterol, triglycerides, high-density lipoprotein, and glucose levels. The lower serum levels of apolipoprotein A1 in acne twins were also confirmed when analyzing acne discordant twin pairs. The evidence of a major genetic influence on acne should stimulate the search for potential genes that may lead to new therapeutic approaches.

Size-discordant twin pairs have higher perinatal mortality rates than nondiscordant pairs

Objective: The purpose of this study was to determine whether size-discordant twin pairs have worse perinatal mortality and neonatal morbidity rates than nondiscordant pairs and whether the smaller twins of discordant pairs have worse perinatal outcomes than the larger twins. Study Design: We conducted a population-based, retrospective analysis of linked birth certificates and fetal and infant death certificates for 9590 twin pairs who were born in the state of Washington from 1987 through 1999. The Cochran-Mantel-Haenszel test, Student t test, and McNemar test were among the tests used to assess statistical significance. Results: Discordant twin pairs had higher rates of perinatal mortality, neonatal mortality, and 5-minute Apgar scores of <7, even after stratification by gestational age. Discordant pairs had lower pair weights at each gestational age and were more likely to include small-for-gestational-age infants. Compared with the larger twins, the smaller twins of discordant pairs had higher rates of perinatal mortality. Conclusion: Discordant pairs had worse perinatal outcomes within each gestational age category. (Am J Obstet Gynecol 2002;187:1173-8)

Testing the NKT cell hypothesis of human IDDM pathogenesis.

Defects in IL-4-producing CD1d-autoreactive NKT cells have been implicated in numerous Th1-mediated autoimmune diseases, including diabetes, multiple sclerosis, rheumatoid arthritis, lupus, and systemic sclerosis. Particular attention has been focused on autoimmune insulin-dependent diabetes mellitus (IDDM) because nonobese diabetic (NOD) mice and humans with IDDM are both reported to express severe deficiencies in the frequency and Th2 functions of NKT cells. Furthermore, experimental manipulations of the NKT defect in the NOD mouse induced corresponding changes in disease. Taken together, these converging studies suggested a general role of NKT cells in natural protection against destructive autoimmunity. However, in previous reports the identification of NKT cells was based on indirect methods. We have now devised a direct, highly specific CD1d tetramer-based methodology to test whether humans with IDDM have associated NKT cell defects. Surprisingly, although we find marked and stable differences in NKT cells between individuals, our study of IDDM patients and healthy controls, including discordant twin pairs, demonstrates that NKT cell frequency and IL-4 production are conserved during the course of IDDM. These results contradict previous conclusions and refute the hypothesis that NKT cell defects underlie most autoimmune diseases.

Does marijuana use have residual adverse effects on self-reported health measures, socio-demographics and quality of life? A monozygotic co-twin control study in men.

To assess the effects of former heavy marijuana use on selected aspects of health. A monozygotic co-twin control design was used to compare the health of former heavy marijuana using male monozygotic twins to that of their co-twins who never used marijuana significantly. In-person survey and questionnaires. Fifty-six marijuana use discordant monozygotic twin pair members of the Vietnam Era Twin (VET) Registry. Current socio-demographic characteristics; current nicotine and alcohol use; life-time nicotine and alcohol abuse/dependence; past 5-year physical and mental health services utilization; and health-related quality of life. The mean number of days on which the marijuana user twin used marijuana in his life-time was 1085, while the non-marijuana user used marijuana a maximum of 5 days. Marijuana was last used a mean of 20 years previously. No significant differences were found between the former marijuana user twins and their siblings for current socio-demographic characteristics; current nicotine or alcohol use; life-time nicotine or alcohol abuse/dependence; past 5-year out-patient or emergency room visits, hospitalizations or medication use for medical problems; past 5-year mental health out-patient use or hospitalizations; or health-related quality of life. Previous heavy marijuana use a mean of 20 years earlier by a group of men who reported no other significant illicit drug use does not appear to be associated with adverse socio-demographic, physical or mental health adverse effects. The conclusions of the study are limited by possible participation and recall biases, relatively small sample size and the absence of a physical health examination.