Biomedical subjects

S W Lewis

Publications and source records attributed to S W Lewis.

At least 19 recordsLinked to original sources

PubMed2006

Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

OBJECTIVES: To determine the clinical and cost-effectiveness of different classes of antipsychotic drug treatment in people with schizophrenia responding inadequately to, or having unacceptable side-effects from, their current medication. DESIGN: Two pragmatic, randomised controlled trials (RCTs) were undertaken. The first RCT (band 1) compared the class of older, inexpensive conventional drugs with the class of new atypical drugs in people with schizophrenic disorders, whose current antipsychotic drug treatment was being changed either because of inadequate clinical response or owing to side-effects. The second RCT (band 2) compared the new (non-clozapine) atypical drugs with clozapine in people whose medication was being changed because of poor clinical response to two or more antipsychotic drugs. Both RCTs were four-centre trials with concealed randomisation and three follow-up assessments over 1 year, blind to treatment. SETTING: Adult mental health settings in England. PARTICIPANTS: In total, 227 participants aged 18-65 years (40% of the planned sample) were randomised to band 1 and 136 (98% of the planned sample) to band 2. INTERVENTIONS: Participants were randomised to a class of drug. The managing clinician selected the individual drug within that class, except for the clozapine arm in band 2. The new atypical drugs included risperidone, olanzapine, quetiapine and amisulpride. The conventional drugs included older drugs, including depot preparations. As in routine practice, clinicians and participants were aware of the identity of the prescribed drug, but clinicians were asked to keep their participating patient on the randomised medication for at least the first 12 weeks. If the medication needed to be changed, the clinician was asked to prescribe another drug within the same class, if possible. MAIN OUTCOME MEASURES: The primary outcome was the Quality of Life Scale (QLS). Secondary clinical outcomes included symptoms [Positive and Negative Syndrome Scale (PANSS)], side-effects and participant satisfaction. Economic outcomes were costs of health and social care and a utility measure. RESULTS: Recruitment to band 1 was less than anticipated (40%) and diminished over the trial. This appeared largely due to loss of perceived clinical equipoise (clinicians progressively becoming more convinced of the superiority of new atypicals). Good follow-up rates and a higher than expected correlation between QLS score at baseline and at follow-up meant that the sample as recruited had 75% power to detect a difference in QLS score of 5 points between the two treatment arms at 52 weeks. The recruitment to band 2 was approximately as planned. Follow-up assessments were completed at week 52 in 81% of band 1 and 87% of band 2 participants. Band 1 data showed that, on the QLS and symptom measures, those participants in the conventional arm tended towards greater improvements. This suggests that the failure to find the predicted advantage for new atypicals was not due to inadequate recruitment and statistical power in this sample. Participants reported no clear preference for either class of drug. There were no statistically significant differential outcomes for participants entering band 1 for reasons of treatment intolerance to those entering because of broadly defined treatment resistance. Net costs over the year varied widely, with a mean of 18,850 pounds sterling in the conventional drug group and 20,123 pounds sterling in the new atypical group, not a statistically significant difference. Of these costs, 2.1% and 3.8% were due to antipsychotic drug costs in the conventional and atypical group, respectively. There was a trend towards participants in the conventional drug group scoring more highly on the utility measure at 1 year. The results for band 2 showed an advantage for commencing clozapine in quality of life (QLS) at trend level (p = 0.08) and in symptoms (PANSS), which was statistically significant (p = 0.01), at 1 year. Clozapine showed approximately a 5-point advantage on PANSS total score and a trend towards having fewer total extrapyramidal side-effects. Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals (p < 0.05). Net costs of care varied widely, but were higher than in band 1, with a mean of 33,800 pounds sterling in the clozapine group and 28,400 pounds sterling in the new atypical group. Of these costs, 4.0% and 3.3%, respectively, were due to antipsychotic drug costs. The increased costs in the clozapine group appeared to reflect the licensing requirement for inpatient admission for commencing the drug. There was a trend towards higher mean participant utility scores in the clozapine group. CONCLUSIONS: For band 1, there is no disadvantage in terms of quality of life and symptoms, or associated costs of care, over 1 year in commencing conventional antipsychotic drugs rather than new atypical drugs. Conventional drugs were associated with non-significantly better outcomes and lower costs. Drug costs represented a small proportion of the overall costs of care (<5%). For band 2, there is a statistically significant advantage in terms of symptoms but not quality of life over 1 year in commencing clozapine rather than new atypical drugs, but with increased associated costs of care. The results suggest that conventional antipsychotic drugs, which are substantially cheaper, still have a place in the treatment of patients unresponsive to, or intolerant of, current medication. Further analyses of this data set are planned and further research is recommended into areas such as current antipsychotic treatment guidance, valid measures of utility in serious mental illness, low-dose 'conventional' treatment in first episode schizophrenia, QLS validity and determinants of QLS score in schizophrenia, and into the possible financial and other mechanisms of rewarding clinician participation in trials.

Adolescent↗

PubMed2004

The evolution of insight, paranoia and depression during early schizophrenia.

BACKGROUND: How insight, paranoia and depression evolve in relation to each other during and after the first episode of schizophrenia is poorly understood but of clinical importance. METHOD: Serial assessments over 18 months were made using multiple instruments in a consecutive sample of 257 patients with first episode DSM-IV non-affective psychosis. Repeated measures of paranoia, insight, depression and self-esteem were analysed using structural equation modelling, to examine the direction of relationships over time after controlling for confounds. RESULTS: Depression was predicted directly by greater insight, particularly at baseline, and by greater paranoia at every stage of follow-up. Neither relationship was mediated by self-esteem, although there was a weak association of lower self-esteem with greater depression and better insight. Paranoia was not strongly associated with insight. Duration of untreated psychosis and substance use at baseline predicted depression at 18 months. CONCLUSIONS: In first-episode psychosis, good insight predicts depression. Subsequently, paranoia is the strongest predictor. Neither effect is mediated by low self-esteem. Effective treatment of positive symptoms is important in preventing and treating low mood in early schizophrenia.

Adult↗

PubMed2003

Right-hemisphere encephalopathy in elderly subjects with schizophrenia: evidence from neuropsychological and brain imaging studies.

RATIONALE: Cognitive impairment is a recognised feature of schizophrenia. Elderly patients with early-acquired schizophrenia are seriously affected, with a proportion of them showing clinically significant dementia, not accounted for by any recognized degenerative processes common in this age group, such as Alzheimer's disease. Progression of cognitive deficits is described in elderly institutionalised patients, but disputed amongst community dwelling subjects. The pattern of cognitive deficits in this age group is not yet clearly defined, although there is some evidence that it differs from that in Alzheimer's disease. There is little evidence of any underlying specific brain abnormality. OBJECTIVES: To characterize the neuropsychological deficits in elderly schizophrenia patients and distinguish them from those in Alzheimer's disease. To establish the presence of underlying structural brain abnormality using MRI. METHODS: Twenty-eight elderly schizophrenia patients with onset before the age of 45 years carried out neuropsychology tests. Twelve scored in the dementia range and were compared with 16 equally impaired patients with early Alzheimer's disease. Thirteen of the schizophrenia patients consented to brain MRI. The imaging data were analysed using a newly developed automated method of measuring CSF volume distributions and compared with data from 30 age-matched normal controls. RESULTS: The schizophrenia group was more impaired on visuo-spatial tasks than the Alzheimer's group but less impaired on corresponding verbal tasks, despite similar overall cognitive impairment. The MR scans revealed right-sided enlargement of ventral CSF spaces in the schizophrenia patients especially in the posterior third, and this correlated with their impaired performance on visuo-spatial tasks. CONCLUSIONS: The results suggest that right hemisphere impairment underlies the specific profile of cognitive impairment in elderly patients with schizophrenia.

Aged↗

PubMed2003

Health beliefs link to duration of untreated psychosis and attitudes to later treatment in early psychosis.

BACKGROUND: Health beliefs influence health behaviours and have been shown to influence outcomes in a variety of illnesses, treatments and preventative interventions. AIMS: We aimed to measure health beliefs in first episode psychosis with the hypotheses that their structure would resemble that in physical illness (diabetes) and would correlate with prior duration of untreated psychosis and later attitudes to treatment. METHOD: The Multidimensional Health Locus of Control scale was used in a sample of 50 people with schizophrenia during the first episode and at 18-month follow-up, 51 diabetic controls and 51 normal controls. RESULTS: Schizophrenia patients, both at first episode and 18 months later, had a pattern of health beliefs that was similar to those of the patients with diabetes and significantly different to the normal controls. There were significant associations between internal locus of control score and short DUP, and between external locus of control score and a positive attitude to medication as measured by the Drug Attitudes Inventory. CONCLUSIONS: Health beliefs in first episode schizophrenia correlate with determinants of outcome.

Adolescent↗

PubMed2002

The cost-effectiveness of clozapine: a controlled, population-based, mirror-image study.

A retrospective cohort study, with a mirror-image design, was used to measure inpatient service utilization in 63 consecutive patients started on clozapine from a geographical catchment area compared to a control group matched for previous inpatient service use. An intent-to-treat analysis, including those patients (n = 28) who discontinued clozapine during the study period, showed a significant reduction in number of admissions and total time spent in hospital in the 2 years following clozapine initiation compared to the previous 2 years and to the follow-up period in the control group. This translated into a reduction of 7,300 pounds in hospitalization costs per patient started on clozapine, over the 2-year period. In those patients who continued clozapine treatment for the whole of the 2-year period, there was a two-thirds reduction in number of admissions and total time spent in hospital compared to no change in the clozapine discontinuers. These findings suggest that clozapine is a clinically and cost-effective intervention for severe schizophrenia in routine clinical settings.

Adult↗

PubMed2002

Randomised controlled trial of early detection and cognitive therapy for preventing transition to psychosis in high-risk individuals. Study design and interim analysis of transition rate and psychological risk factors.

BACKGROUND: There is interest in the possibility of indicated prevention of psychosis. There is a strong case for using psychological approaches to prevent transition to psychosis in high-risk patients. AIMS: To identify individuals at high risk of transition to psychosis, and psychological characteristics relevant to the development of psychosis in this group. METHOD: The design of a randomised controlled trial of cognitive therapy for the prevention of psychosis in people at high risk (meeting operational criteria of brief or attenuated psychotic symptoms, or first-degree family history with functional decline) is outlined. The first patients recruited are compared with non-patient samples on cognitive and personality factors; an interim analysis of transition rate is reported. RESULTS: Cases (n = 31) were recruited mainly from primary care. Of the 23 high-risk patients monitored for 6-12 months, 5 (22%) made the transition to psychosis. The high-risk group scored significantly higher than non-patients on measures of schizotypy, metacognitive beliefs and dysfunctional self-schemas (sociotropy). CONCLUSIONS: The findings validate the methods of identifying individuals at high risk of experiencing a psychotic episode. Compared with non-patient controls, the cases showed dysfunctional metacognitive beliefs and self-schemas.

Adult↗

PubMed2001

Randomized controlled trial of motivational interviewing, cognitive behavior therapy, and family intervention for patients with comorbid schizophrenia and substance use disorders.

OBJECTIVE: Comorbidity of substance abuse disorders with schizophrenia is associated with a greater risk for serious illness complications and poorer outcome. Methodologically sound studies investigating treatment approaches for patients with these disorders are rare, although recommendations for integrated and comprehensive treatment programs abound. This study investigates the relative benefit of adding an integrated psychological and psychosocial treatment program to routine psychiatric care for patients with schizophrenia and substance use disorders. METHOD: The authors conducted a randomized, single-blind controlled comparison of routine care with a program of routine care integrated with motivational interviewing, cognitive behavior therapy, and family or caregiver intervention. RESULTS: The integrated treatment program resulted in significantly greater improvement in patients' general functioning than routine care alone at the end of treatment and 12 months after the beginning of the study. Other benefits of the program included a reduction in positive symptoms and in symptom exacerbations and an increase in the percent of days of abstinence from drugs or alcohol over the 12-month period from baseline to follow-up. CONCLUSIONS: These findings demonstrate the effectiveness of a program of routine care integrated with motivational interviewing, cognitive behavior therapy, and family intervention over routine psychiatric care alone for patients with comorbid schizophrenia and alcohol or drug abuse or dependence.

Adolescent↗

PubMed2000

Childhood schizotypy and positive symptoms in schizophrenic patients predict schizotypy in relatives.

BACKGROUND: Schizotypy is one phenotypic expression of the familial-genetic liability to schizophrenia, but its precise relationship to frank psychotic symptoms remains unclear. We, therefore, set out to examine the relationships between (a) premorbid personality in schizophrenic patients, (b) the psychopathology they showed, and (c) schizotypal traits in their relatives. METHOD: Ninety consecutively admitted schizophrenic patients were interviewed with the Present State Examination (PSE). Their mothers were interviewed concerning their childhood personality and social adjustment, and 121 of their well relatives were evaluated with three different schizotypal scales. Factor analyses were carried out on (a) the nine main psychotic symptoms from the patients' PSE interview, and on (b) the schizotypal features derived from the scales completed by the first-degree relatives. Correlation coefficients were calculated between premorbid personality traits, and factor scores in probands and in relatives. RESULTS: No relationship was found between childhood schizoid-schizotypal personality traits and any particular dimension of psychopathology in patients. The positive syndrome in patients was correlated with higher scores for relatives on the three schizotypy scales, but did not predict any specific pattern of schizotypy in the relatives. Premorbid schizoid-schizotypal traits were also correlated with schizotypy in the relatives. CONCLUSIONS: Schizotypy in relatives has a familial relationship with schizoid-schizotypal traits in the childhood, and with positive symptoms during the illness, of schizophrenic patients.

Adolescent↗

PubMed2000

Determination of morphine, oripavine and pseudomorphine using capillary electrophoresis with acidic potassium permanganate chemiluminescence detection.

A simple and robust capillary electrophoresis chemiluminescence detection system for the determination of morphine, oripavine and pseudomorphine is described, based upon the reaction of these analytes with acidic potassium permanganate in the presence of sodium polyphosphate. The reagent solution was contained in a quartz detection cell which also held both the capillary and the anode. The resultant chemiluminescence was monitored directly using a photomultiplier tube mounted flush against the base of the detection cell. To ensure that no migration of the permanganate anion occurred, the anode was placed at the detector end whilst the electroosmotic flow was reversed by the addition of hexadimethrine bromide (0.001% m/v) to the electrolyte. The three analytes were separated counter to the electroosmotic flow via their interaction with alpha-cyclodextrin. The methodology realised detection limits (3 x S/N) of 2.5 x 10(-7) M for both morphine and oripavine and 5 x 10(-7) M for pseudomorphine. The relative standard deviations of the migration times and the peak heights for the three analytes ranged from 0.6 up to 0.8% and from 1.5 up to 2.1%, respectively.

Electrophoresis, Capillary↗

PubMed2000

Causes and consequences of duration of untreated psychosis in schizophrenia.

BACKGROUND: It is unclear what determines duration of untreated psychosis (DUP) in schizophrenia and why long DUP predicts poor outcome. AIMS: First, to test the hypothesis that specific patterns of symptoms and social functioning acting before treatment prolong DUP. Second, to clarify the mechanisms linking DUP with recovery after treatment. METHOD: Two hundred and forty-eight consecutive first admissions with schizophrenia were interviewed to assess DUP, symptoms and social functioning at admission, and symptoms were re-assessed after 6-12 weeks. RESULTS: Median DUP was 12 weeks. Long DUP was predicted by poor insight, social isolation and preserved coping skills, but not by demographic factors. Even allowing for all these variables, long DUP predicted poor outcome. CONCLUSIONS: Longer DUP results partly from a pattern of symptoms and social functioning which reduces concern by the sufferer and relevant others. DUP's relationship to outcome is strongest in the initial months of psychosis. This has implications for targeting early intervention.

Adolescent↗

PubMed1999

Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm.

BACKGROUND: Infants born very preterm (<33 weeks) are at increased risk of neurocognitive deficits. Their neurodevelopmental outcome up to age 8 years can be predicted by neonatal ultrasonography, but little is known of their later function. We investigated the effect of very preterm birth on brain structure and neurocognitive and behavioural functioning in adolescence. METHODS: A cohort of 105 infants born before 33 weeks of gestation in 1979-80 had ultrasonographic scans at University College Hospital, London, and were prospectively examined at 1, 4, and 8 years. At age 14-15 years, 72 of those who remained in UK (cases) and 21 age-matched full-term controls underwent brain magnetic resonance imaging (MRI), as well as neurological, cognitive, and behavioural assessment. MRI images were assessed by two neuroradiologists unaware of ultrasonographic findings or case or control status. FINDINGS: Of the 72 cases, 40 had unequivocally abnormal MRI and 15 had equivocal scans. Of the 21 controls, one had abnormal and five equivocal MRI. Abnormalities of ventricles, corpus callosum, and white matter were especially common in cases. More brain lesions were identified by MRI than by neonatal ultrasonography. The cases had significantly more reading, adjustment, and neurological impairments than controls, but their behaviour was significantly related to MRI abnormality. INTERPRETATION: Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans.

Adolescent↗

PubMed1999

Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.

BACKGROUND: Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. METHODS: A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. RESULTS: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. CONCLUSIONS: Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.

Adult↗

PubMed1998

Saccadic eye movements in families multiply affected with schizophrenia: the Maudsley Family Study.

OBJECTIVE: Family studies have shown that abnormalities of smooth pursuit eye movement are increased in the adult relatives of schizophrenic probands as well as in the probands themselves. More recently, an inability of schizophrenic subjects to inhibit reflexive saccades reliably has been shown. This study aimed to test the hypothesis that the latter dysfunction is part of the extended schizophrenia phenotype. METHOD: With the use of infrared oculography, measurements of reflexive saccades and antisaccades were undertaken in 29 probands with schizophrenia, 50 of their nonpsychotic first-degree relatives, and 38 unrelated healthy volunteers. RESULTS: Probands, relatives, and healthy subjects showed no overall differences in the generation of reflexive saccades. However, in the antisaccade task, probands showed more saccadic distractibility when they were required to inhibit reflexive saccades. Analysis of corrective saccades showed that this was not due to failed comprehension or motivation. Relatives of the probands with high saccadic distractibility showed a higher distractibility rate than relatives of the probands with normal distractibility. Across all subjects, females showed a higher rate of distractibility errors than males. CONCLUSIONS: The ability to suppress reflexive saccades is an objective neurocognitive measure that is impaired in schizophrenic patients and in a proportion of their biological relatives. This antisaccade abnormality may be a vulnerability marker in a subset of schizophrenic patients and their families.

Adult↗

PubMed1998

Treatment of schizophrenia in childhood and adolescence.

This paper reviews the management of schizophrenia occurring during childhood and adolescence. It considers the clinical features of the disorder particular to its early onset before providing a practical framework for assessment and treatment based upon a critical review of the available literature. A multi-modal approach to treatment encompassing the individual and their family is adopted with the roles of pharmacological, psychological, and environmental interventions all considered. The place of the newer "atypical" antipsychotic agents and the likelihood that they will soon become the first-line drugs of choice is particularly discussed.

Adolescent↗

PubMed1997

Focal signal hyperintensities in schizophrenia.

The presence of focal signal hyperintensities on MRI images of the brain was compared in 48 schizophrenic patients, 26 patients with bipolar disorder and 34 healthy controls. Significantly larger areas of brain were affected by focal signal hyperintensities, particularly in the frontal lobes, in the schizophrenic group compared to the bipolar group and the controls. Although the bipolar group had more such foci than controls, this difference did not reach statistical significance.

Adult↗

PubMed1997

Effects of antipsychotic medication on electromyographic responses to transcranial magnetic stimulation of the motor cortex in schizophrenia.

OBJECTIVE: To assess the effect of antidopaminergic antipsychotic medication on the electromyographic (EMG) responses of thenar muscles to transcranial magnetic stimulation (TMS) of the motor cortex in schizophrenic patients. METHODS: A group of nine drug naive schizophrenic patients was compared with a group of nine schizophrenic patients established on neuroleptic medication. Surface EMG recordings were made from the thenar muscles while patients maintained a weak isometric voluntary contraction. TMS was applied using a 9 cm circular stimulating coil centred over the vertex. The EMG responses to up to 50 magnetic stimuli were rectified and averaged. RESULTS: There was no difference in threshold TMS strength for eliciting compound motor evoked potentials (cMEPs), or in their latency, in drug naive and medicated patients. In some patients the silent period (SP) was clearly made up of two parts and the percentage of control levels of voluntary EMG was measured in each component. During the early component of the SP there was a weaker (P<0.05) suppression of EMG in the medicated patients (mean 73.9 (SEM) 5.5% of control levels) compared with the drug naive patients (54.7 (SEM) 7.3% of control levels). This resulted in the latency of maximum suppression of voluntary EMG being longer (P<0.05) in the medicated patients (38.3 (2.4) ms) than in the drug naive patients (28.2 (0.7) ms). During the late component of the SP voluntary EMG was reduced to similar levels (P>0.05) in both medicated (48.2 (7.7)% of control levels) and drug naive (58 (7.8)% of control levels) patients. CONCLUSION: The results are discussed with reference to the disrupted inhibition seen in the early part of the SP in Parkinson's disease and drug induced parkinsonism. The future uses of motor responses to TMS as a marker for the status of antipsychotic medication are considered.

Adult↗

PubMed1996

Determination of morphine in process streams by sequential injection analysis with chemiluminescence detection.

A procedure for the determination of morphine in process streams by sequential injection analysis based on the chemiluminescence reaction of morphine with acidic potassium permanganate in the presence of sodium hexametaphosphate is presented. The chemiluminescence emission has been monitored using an in-house detection system which consisted of a fibre optic flowthrough cell and a sensitive, low dark current, photomultiplier tube. The calibration graph (range 2 x 10(-8) to 1 x 10(-4) mol/l) was not linear over the entire range of concentration, with a polynomial equation of best fit of y = 1.0 x 10(15) x(3) - 2.2 x 10(11) x(2) + 1.3 x 10(7) x - 8.3. The calibration function approximates linearity over the concentration range 2.5 x 10(-6) to 3.0 x 10(-5) mol/l where the slope of the log-log plot is 1.09 +/- 0.16. The detection limit was estimated at about 10(-8) mol/l from the response of the lowest calibration standard (2.5 x 10(-8) mol/l) which gave a signal to noise ratio of 3 : 1. Although the structurally related codeine did not interfere significantly the results suggest that this method may be susceptible to matrix effects, dependent on the location of sampling from the process stream.

Journal Article↗

PubMed1996

Family history of autoimmune diseases in psychosis.

The mothers of 101 psychotic patients and 116 normal controls were interviewed using a semi-structured questionnaire designed to determine the presence or absence of autoimmune disorders in first degree relatives of the probands. Thyrotoxicosis and insulin-dependent diabetes mellitus were significantly more common in the relatives of the psychotic patients than in the control relatives; in particular thyrotoxicosis was more frequent in the mothers of patients (11%) than the mothers of controls (2.6%). None of the examined characteristics of the patients, including RDC-diagnosis, family history of psychosis, age at onset of psychosis and winter birth, was predictive of thyrotoxicosis and insulin-dependent diabetes mellitus in relatives.

Adolescent↗