Perceptions of causal attribution and attitudes to genetic testing among people with schizophrenia and their first-degree relatives.

Rapid advances in the genetics of psychiatric disorders mean that diagnostic and predictive genetic testing for schizophrenia risk may one day be a reality. This study examined how causal attributions for schizophrenia contribute to interest in a hypothetical genetic test. People with schizophrenia and first-degree relatives of people with schizophrenia were recruited through a schizophrenia research bank and mental health organisation. Semi-structured telephone interviews were conducted with 13 individuals with schizophrenia and 8 first-degree relatives. Transcripts were subjected to a qualitative analysis using the thematic analysis framework. Five themes were developed: (i) "It is like a cocktail", with most participants aware that both genetic and environmental factors contributed to causation, and many mentioning the positive impact of genetic causal explanations; (ii) "Knowledge is power" (i.e., in favour of genetic testing); (iii) Genetic testing provides opportunities for early intervention and avoiding triggers, with participants citing a wide range of perceived benefits of genetic testing but few risks; (iv) Views on reproductive genetic testing for schizophrenia risk with a few participants viewing it as "playing God" but not necessarily being against it; and (v) "It snowballs", whereby participants' understanding of genetics was sophisticated with most believing that multiple rather than single genes contributed to schizophrenia. In conclusion, many individuals had a sound understanding of the role of genetic testing if it were to become available, with evidence of insight into the role of multiple genes and the contribution of other risk factors that may interact with any inherited genetic risk.

Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: the role of CD4 coreceptor.

The interaction of the T cell receptor (TCR) with its cognate peptide-major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR-MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC-TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC-TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide-MHC complex. These peptide-MHC-IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo.

Analysis of the expression of peptide-major histocompatibility complexes using high affinity soluble divalent T cell receptors.

Understanding the regulation of cell surface expression of specific peptide-major histocompatibility complex (MHC) complexes is hindered by the lack of direct quantitative analyses of specific peptide-MHC complexes. We have developed a direct quantitative biochemical approach by engineering soluble divalent T cell receptor analogues (TCR-Ig) that have high affinity for their cognate peptide-MHC ligands. The generality of this approach was demonstrated by specific staining of peptide-pulsed cells with two different TCR-Ig complexes: one specific for the murine alloantigen 2C, and one specific for a viral peptide from human T lymphocyte virus-1 presented by human histocompatibility leukocyte antigens-A2. Further, using 2C TCR- Ig, a more detailed analysis of the interaction with cognate peptide-MHC complexes revealed several interesting findings. Soluble divalent 2C TCR-Ig detected significant changes in the level of specific antigenic-peptide MHC cell surface expression in cells treated with gamma-interferon (gamma-IFN). Interestingly, the effects of gamma-IFN on expression of specific peptide-MHC complexes recognized by 2C TCR-Ig were distinct from its effects on total H-2 Ld expression; thus, lower doses of gamma-IFN were required to increase expression of cell surface class I MHC complexes than were required for upregulation of expression of specific peptide-MHC complexes. Analysis of the binding of 2C TCR-Ig for specific peptide-MHC ligands unexpectedly revealed that the affinity of the 2C TCR-Ig for the naturally occurring alloreactive, putatively, negatively selecting, complex, dEV-8-H-2 Kbm3, is very low, weaker than 71 microM. The affinity of the 2C TCR for the other naturally occurring, negatively selecting, alloreactive complex, p2Ca-H-2 Ld, is approximately 1000-fold higher. Thus, negatively selecting peptide-MHC complexes do not necessarily have intrinsically high affinity for cognate TCR. These results, uniquely revealed by this analysis, indicate the importance of using high affinity biologically relevant cognates, such as soluble divalent TCR, in furthering our understanding of immune responses.

The association of a class of saltatory movements with microtubules in cultured cells.

Particulate structures in the cytoplasm of HeLa and other cultured cells in interphase undergo rapid individual linear displacements (long saltatory movements, LSM). By the use of time-lapse microscopy to locate saltating particles prior to fixation and histochemical examination of the cells, structures of several kinds have been shown to move in this manner. Elements that show LSM include lysosomes, pinosomes, ingested carbon particles, lipoidal granules, and unidentified particles that appear as bright objects in positive phase contrast. The pattern of movement of the particles suggests the presence of linear guiding elements radially disposed from the cytocenter (centriole region). The participation of microtubules in these movements is inferred from the observation that LSM cease after treatment with drugs which depolymerize microtubules, i.e., colchicine, Vinblastine, and podophyllin. The directions of the microtubules in the cytoplasm of HeLa cells found by electron microscopy are consistent with the aster-like configuration predicted from study of LSM. Further support for this arrangement of cytoplasmic microtubules is provided by light microscope observations of colchicine-sensitive radial arrays of acid phosphatase granules in the cytoplasm of some cell lines.

Assessment of alpha-1-antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. Physiological comparison of adult normal and heterozygous protease inhibitor phenotype subjects from a random population.

For plethysmographic studies of lung mechanics and measurement of pulmonary diffusing capacity, 62 subjects were drawn from a randomly selected population sample. Data obtained from the 24 subjects of heterozygous phenotype for alpha-1-antitrypsin deficiency (PiMZ) were compared by age group with data from 38 normal (PiM) subjects matched for sex, age, and smoking history. Comparison of mean values by age group for lung volumes, diffusing capacity, lung elastic recoil, maximum expiratory flow, and the occurrence of frequency dependence of dynamic compliance revealed no differences between phenotype groups. There was no evidence of an accelerated effect of aging among PiMZ subjects when compared with normal counterparts nor was there evidence of an increased effect of smoking. From these data it appears that the PiMZ phenotype per se is not a risk factor in the development of emphysema.

Isolation and characterization of human antibodies targeting human aspartyl (asparaginyl) beta-hydroxylase.

Over-expression of the enzyme human aspartyl (asparaginyl) beta-hydroxylase (HAAH) has been detected in a variety of cancers. It is proposed that upon cellular transformation, HAAH is overexpressed and translocated to the tumor cell surface, rendering it a specific surface antigen for tumor cells. In this work, twelve human single-chain Fv fragments (scFv) against HAAH were isolated from a human non-immune scFv library displayed on the surface of yeast. Five of the twelve were reformatted as human IgG1. Two of the five IgGs, 6-22 and 6-23, showed significant binding to recombinant HAAH in ELISA, tumor cell lines, and tumor tissues. The apparent dissociation constants of 6-22 and 6-23 IgG were 1.0 +/- 0.2 nM and 20 +/- 10 nM respectively. These two antibodies were shown to target different domains of HAAH, with 6-22 targeting the catalytic domain of HAAH and 6-23 targeting the N-terminal non-catalytic domain of HAAH. 6-22 IgG was further characterized, as it had high affinity and targeted the catalytic domain. 6-22 IgG alone does not exhibit significant cytotoxicity toward the tumor cells. However, 6-22 internalizes into tumor cells and can therefore be employed to deliver cytotoxic moieties. A goat anti-human IgG-saporin conjugate was delivered into tumor cells by 6-22 IgG and hence elicited cytotoxicity toward the tumor cells in vitro. These tumor-binding human antibodies can potentially be used in both diagnosis and immunotherapy targeting HAAH-expressing tumor cells.

Vasopressin, phorbol diesters and serum elicit choline glycerophospholipid hydrolysis and diacylglycerol formation in nontransformed cells: transformed derivatives do not respond.

REF52, a rat embryo cell line, and several transformed derivatives were used to examine the lipid-related events associated with agonist treatment (phorbol diesters, vasopressin, fetal bovine serum). Exposure of cells, prelabeled with [3H]glycerol, to TPA (12-O-tetradecanoylphorbol 13-acetate) resulted in 3-4-fold increase in the amount of intracellular diacyl[3H]glycerols as early as 10 min after treatment. Continued incubation (up to 60 min) revealed that the diacyl[3H]glycerol formed was under dynamic metabolic regulation as shown by the production of triacyl[3H]glycerols and free [3H]glycerol. Serum and vasopressin likewise induced the generation of intracellular diacyl[3H]glycerol, thereby illustrating that physiological agents provoke a similar reaction. In the three SV-40-transformed variants examined, the diacylglycerol generative-response to TPA, serum and vasopressin, was greatly diminished or totally absent. Experiments employing REF52 cells prelabeled with [3H]choline demonstrated that both TPA and vasopressin induce the hydrolysis of cellular choline-containing glycerophospholipids; this was measured by both a decrease in cell-associated phosphatidylcholine radioactivity and an increase in the production of water-soluble [3H]choline-containing metabolites in the culture medium. 92-97% of the tritium released to the medium was identified as [3H]choline. Vasopressin treatment of REF52 cells prelabeled with [3H]arachidonic acid elicited an increase of more than 11-fold in the amount of cellular diacyl[3H]glycerol and a concomitant release of arachidonic acid to the culture medium that was 12-fold higher than controls. These data demonstrate that tumor-promoting phorbol esters (agonists of protein kinase C), serum and vasopressin, increase the levels of cellular diacylglycerol by stimulating the hydrolysis of choline-containing glycerophospholipids. This agonist-directed mechanism is inoperable in transformed cells. Further, collateral with vasopressin-induced phosphatidylcholine hydrolysis, the cellular release of arachidonic acid occurs. The participation of these lipid-related responses in the signaling of agonist-directed events and their relation to cellular homeostasis is currently being explored.

An association of human congenital cardiac malformations and drinking water contaminants.

During an informal study in 1973 it was noted that approximately one third of patients with congenital heart disease lived in a small area in the Tucson Valley. In 1981 groundwater for a nearly identical area was found to be contaminated with trichloroethylene and to a lesser extent with dichloroethylene and chromium. Contamination probably began during the 1950s. Affected wells were closed after discovery of contamination. This sequence of events allowed investigation of the prevalence of congenital heart disease in children whose parents were exposed to the contaminated water area as compared with children whose parents were never exposed to the contaminated water area. The contaminated water area contained 8.8% of the Tucson Valley population and 4.5% of the labor force. Using their case registry, the authors interviewed parents of 707 children with congenital heart disease who, between 1969 and 1987, 1) conceived their child in the Tucson Valley, and 2) spent the month before the first trimester and the first trimester of the case pregnancy in the Tucson Valley. Two random dialing surveys showed that only 10.5% of the Tucson Valley population had ever had work or residence contact, or both, with the contaminated water area, whereas 35% of parents of children with congenital heart disease had had such contact (p less than 0.005). The prevalence of congenital cardiac disease (excluding syndromes, children with atrial tachycardia or premature infants with patent ductus arteriosus) in the Tucson Valley was 0.7% of live births and with syndromes was calculated to be 0.82%. The odds ratio for congenital heart disease for children of parents with contaminated water area contact during the period of active contamination was three times that for those without contact (p less than 0.005) and decreased to near unity for new arrivals in the contaminated water area after well closure. The proportion of infants with congenital heart disease as compared with the number of live births was significantly higher for resident mothers in the contaminated water area than for mothers with no exposure. No other environmental agent could be identified that was localized to the contaminated water area, but one could have been missed. The data show a significant association but not a cause and effect relation between parental exposure to the contaminated water area and an increased proportion of congenital heart disease among live births as compared with the proportion of congenital heart disease among live births for parents without contaminated water area contact.

Persistence and new onset of asthma and chronic bronchitis evaluated longitudinally in a community population sample of adults.

BACKGROUND: Some patients with chronic obstructive pulmonary disease may share the clinical characteristics of those with asthma; their disease is sometimes called "asthmatic bronchitis." Whether there is a difference between asthmatics who do and do not develop chronic bronchitis is not yet clear. We investigated whether asthma and chronic bronchitis may share some "allergic" phenotypes and whether asthmatic individuals who develop chronic bronchitis subsequently have steeper declines in lung function. METHODS: Known risk factors for decline in lung function were analyzed in a representative community population of adults followed up longitudinally since 1972 in Tucson, Ariz, in groups with persistent, newly developed, and past diagnoses of asthma and chronic bronchitis. We evaluated contributions of initial level of forced expiratory volume in 1 second (FEV1), reversibility with isoproterenol hydrochloride nebulized aerosol bronchodilator treatment, percentage of blood eosinophils to determine eosinophilia, and IgE level. RESULTS: The concurrence of chronic bronchitis and asthma is associated with a steeper decline in FEV1 than is asthma as the sole diagnosis. Asthmatics (those with persistent asthma with and without chronic bronchitis) had the greatest prevalence of increased reversibility with isoproterenol therapy and with eosinophilia. The prevalence of eosinophilia was also high in those with newly diagnosed chronic bronchitis without asthma; however, this was not the case in those with persistent chronic bronchitis without asthma. Larger bronchodilator responses were related to steeper declines in FEV1, both in persistent asthma and in chronic bronchitis. CONCLUSIONS: Bronchodilator response and eosinophilia are generally believed to be hallmarks of asthma. We show that these characteristics may be present in chronic bronchitis as well. The presence of a large (> 25%) bronchodilator response is associated with a steeper decline in FEV1.

The molar ratio of insulin to C-peptide. An aid to the diagnosis of hypoglycemia due to surreptitious (or inadvertent) insulin administration.

After beta-cell stimulation by carbohydrate or other secretagogues, insulin and C-peptide are secreted into the portal vein in a 1:1 molar ratio. A large fraction of endogenous insulin is cleared by the liver, whereas C-peptide, which is cleared primarily by the kidney and has a lower metabolic clearance rate than insulin, traverses the liver with essentially no extraction by hepatocytes. Hence, the molar ratio of insulin to C-peptide in peripheral venous blood (ICPR) should be less than 1.0 during fasting and feeding, unless exogenous insulin is introduced into the systemic circulation. Consequently, an ICPR in excess of 1.0 in a hypoglycemic patient argues persuasively for surreptitious or inadvertent insulin administration and against insulinoma (or sulfonylurea ingestion) as the cause of the hypoglycemia. This conclusion is supported by personal experience and by the literature.

Primary hyperepinephrinemia in patients without pheochromocytoma.

Clinical features of epinephrine release led to the finding of spontaneously elevated plasma epinephrine concentrations in five patients, in four of whom plasma norepinephrine concentrations were normal. Adrenal medullary hyperplasia was suspected in one patient, whose first cousin had multiple endocrine neoplasia type IIa, and in two others, all of whom have experienced relief from symptoms during propranolol or atenolol administration. The other two patients had unilateral adrenal cysts, with negative metaiodobenzylguanidine scans and no histological evidence of pheochromocytoma, but complete relief of symptoms by excision of the cysts. In one patient, Cushing's syndrome and associated hypertension, diabetes, and ischemic finger-tip ulceration all disappeared after surgery. It is concluded that spontaneous hyperepinephrinemic manifestations can be received by beta-blockers or, when an adrenal mass is present, by unilateral adrenalectomy even when the metalodobenzylguanidine test result is negative.

Risk factors associated with complaints of insomnia in a general adult population. Influence of previous complaints of insomnia.

BACKGROUND: Insomnia is a common complaint both in the general population and also in physician's offices. However, risk factors for the development of insomnia complaints have not been completely identified. METHODS: To identify population characteristics associated with increased prevalence of insomnia complaints, we surveyed a large general adult population in 1984 through 1985. We evaluated the relationship among current complaints of initiating and maintaining sleep and obesity, snoring, concomitant health problems, socioeconomic status, and documented complaints of difficulty with insomnia 10 to 12 years previously. RESULTS: The strongest risk factor for complaints of initiating and maintaining sleep was previous complaints of insomnia (odds ratio, 3.5). In addition, female gender (odds ratio, 1.5), advancing age (odds ratio, 1.3), snoring (odds ratio, 1.3), and multiple types of concomitant health problems (odds ratios, 1.1 to 1.7) were all risk factors associated with an increased rate of complaints of initiating and maintaining sleep. CONCLUSION: Complaints of insomnia tend to be a persistent or recurrent problem over long periods of time. Female gender, advancing age, and concomitant health problems also are important risk factors.

Testicular chromosomal mosaicism and infertility.

A healthy young man with azoospermia and no other endocrinological abnormalties was shown to have chromosomal mosaicism with the cytogenetic errors found only in testicular tissue. Three clones of cells were identified in both meiosis I and meiosis II by cytogenetic analysis of direct testicular smears. Peripheral blood karyotypes and buccal smear preparations revealed no abnormalities. It is postulated that the gonadal cytogenetic defects account for this patient's azoospermia. In addition, it is hypothesized that this type of incomplete spermatogenesis nonetheless produces sufficiet feedback material ("inhibin") so that FSH levels are not affected.

PIP: The study of a patient with testicular chromosomal mosaicism and inf ertility is reported. A healthy 27-year-old man with azoospermia and no other endocrinological abnormalities was shown to have chromosomal mosaicism with the cytogenetic errors found only in testicular tissue. 3 clones of cells were identified in both meiosis 1 and meiosis 2 by cytogenetic analysis of direct testicular smears. No abnormalities were revealed in peripheral blood karyotypes or buccal smear preparations. It is postulated that the gonadal cytogenetic defects account for the azoospermia in this patient and that this type of incomplete spermatogenesis produces sufficient feedback material ("inhibin") so that follicle stimulating hormone levels are not affected.

Divorce and the American teenager.

Divorce is woven into the fabric of today's American society, and parents and professionals alike are concerned about the effects of divorce on children of all ages. Research in this area is in its infancy, particularly research about how divorce effects teenagers, but research thus far has helped us to appreciate that divorce is difficult for children of all ages. This paper considers the effects of divorce on teenagers by drawing from existing research and clinical experiences with teenagers. The focus of this presentation is how teenagers feel when parents divorce and how they behave in response to divorce. The purpose of this focus is to provide those who interact with teenagers a greater understanding of how teenagers react to divorce.

Populations at risk: addressing health effects due to complex mixtures with a focus on respiratory effects.

Some individuals in the population may be sensitive or susceptible be to the effects of air pollutants. Such sensitivity may be to specific pollutants or classes of pollutants. However, sensitivity or susceptibility in some individuals can be to all irritants, but the sensitivity is likely to be response specific or organ specific. The U.S. Clean Air Act specifically recognizes that some individuals in the population are sensitive to air pollutants and indicates that such individuals need to be protected by air quality standards. It is usually difficult to determine the cause of sensitivity, though various biological mechanisms have been studied. Biological age may be a factor, with the young being most sensitive and susceptible to being affected. An example is the heightened bronchial lability and responsiveness in the very young that appears to disappear with growth. Susceptibility may be innate (e.g., genetic) and/or induced by events/exposures. Frequently, those with preexisting illnesses are part of the sensitive population because they may often respond, sometimes hyperrespond, to a pollutant exposure that may not affect most people. Asthmatics are excellent examples of individuals who were susceptible to the disease and, once inflicted, are susceptible to the effects of many environmental and nonenvironmental agents. Usually only a fraction of the general population will respond with heightened reactions at lower doses. Such individuals require special evaluation and attention in all exposure-response studies and risk assessments. Thus, the conditions defining populations at risk and the methodologies to discover and study them can be reviewed.

Methods to assess respiratory effects of complex mixtures.

This paper evaluates the influence of exposures on acute and chronic airway obstruction. Clinical, physiological, and immunological aspects are important in evaluating the effects of the pollutant exposures. Aspects of the exposure-response relationships important enough to record are those factors interactive with the pollutants (e.g., smoking and other personal/behavioral factors) and precursor conditions. To determine baseline status and study chronic effects, one uses standardized and modified health questionnaires and standardized pulmonary function. Confirmatory studies of responsive airways, potentially assessed first by diurnal peak flow, can be done using post-bronchodilator maximum expiratory flow volume curves and methacholine challenges. Immunoglobulin determinations for immunological status (a predisposing/susceptibility factor), allergy skin tests (for immediate hypersensitivity status), and blood counts (mostly for eosinophils) are also important. Other tests that could be performed include expired carbon monoxide and/or carboxyhemoglobin and methemoglobin (for smoking and combustion exposures). Measures of acute effects are symptomatic responses (by questionnaires and diaries), responses of the airways (as measured by spirometry and peak flows), and changes in medication usage or associated medical care (in diaries). Methodologies should also include discussions of protocols and analysis.

Utilization of data from human population studies for setting air quality standards: evaluation of important issues.

Epidemiological studies of community populations are highly relevant to the process of setting national ambient air quality primary standards, as criteria for those standards are the protection of human populations against adverse effects on health. Nevertheless, because of the difficulties of performing adequate community population studies of a quality commensurate with the needs of standard setting, the use of data derived from studies is problematic. This paper addresses the important issues of appropriate exposure assessment and health assessment, and discusses the problems of multiplex variables and colinearity as they are critical in assessments of exposure-effect relationships. It is concluded that a major problem in the use of data from such studies for standard setting is not necessarily one of scientific reliability or validity, but arises from the attempt of translating adequate science into policy decisions.

Prevalence rates of respiratory symptoms in Italian general population samples exposed to different levels of air pollution.

We surveyed two general population samples aged 8 to 64 living in the unpolluted, rural area of the Po Delta (northern Italy) (n = 3289) and in the urban area of Pisa (central Italy) (n = 2917). Each subject filled out a standardized interviewer-administered questionnaire. The Pisa sample was divided into three groups according to their residence in the urban-suburban areas and to outdoor air pollution exposure (automobile exhaust only or industrial fumes as well). Significantly higher prevalence rates of all the respiratory symptoms and diseases were found in Pisa compared with the Po Delta. In particular, rhinitis and wheezing symptoms were higher in all the three urban zones; chronic cough and phlegm were higher in the zone with the automobile exhaust and the additional industrial exposure. Current smoking was more frequent in the rural area, but the urban smokers had a higher lifetime cigarette consumption. Childhood respiratory trouble and recurrent respiratory illnesses were evenly distributed. Exposure to parental smoking in childhood and lower educational level were more frequent in Po Delta, whereas familial history of respiratory/allergic disorders and work and indoor exposures were more often reported in the city. Multiple logistic regression models estimating independently the role of the various risk factors showed significant odds ratios associated with residence in Pisa for all the symptoms but chronic phlegm. For example, those living in the urban-industrial zone had an odds ratio of 4.0 (4.3-3.7) for rhinitis and 2.8 (3.0-2.6) for wheeze with respect to those living in the Po Delta.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory symptoms related to smoking habits of family adults.

A study of the effects of family smoking habits on the symptoms of other family members has shown that symptoms of household members, especially children, are related to smoking habits within the households but are not significantly so when symptoms in adults are controlled.

Relationships between pulmonary function and changes in chronic respiratory symptoms. Comparison of Tucson and Cracow longitudinal studies.

Parallel analyses of data from two longitudinal studies, one in Poland and one in the United States, were performed to assess the relationships between pulmonary function and respiratory symptoms. Similar relationships were seen in the both cities using the same methods of analysis. The rate of FEV1 decline and its final level were related to the prior presence of attacks of breathlessness or to a syndrome that also included wheezing and diagnosed asthma. Initial FEV1 level was lower in subjects with dyspnea appearing during the follow-up than in the never-symptom group. These relationships were independent of smoking habits. The consistencies in the parallel analyses strengthen the relationships observed. In Tucson, Ariz, the FEV1 decline in smokers with persistent chronic cough was greater than that due to separate effects of the symptom and smoking. This suggests that chronic cough may be an indicator of an increased effect of tobacco smoke on pulmonary function.