Biomedical subjects
M J Harris
Publications and source records attributed to M J Harris.
Late-onset psychotic disorder, not otherwise specified: clinical and neuroimaging findings.
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Further genetic studies of the cause of exencephaly in SELH mice.
We have developed an inbred stock of mice called SELH that has a high frequency of the neural tube defect exencephaly at birth. A previous genetic study indicated that the exencephaly is due to two to three additive loci differing between SELH and a closely related normal strain, ICR/Bc, but this analysis was not designed to detect genetic maternal effects. Recently, we demonstrated that there is genetic polymorphism among normal mouse strains leading to differences in site of initiation of closure of the cranial neural tube. In the present study, an inbred substrain of SELH mice, with 24% exencephaly among embryos, was crossed with an unrelated normal strain, SWV/Bc, and the frequency of exencephaly in subsequent generations used to extend our understanding of the genetic cause of exencephaly in SELH mice. The purposes of the genetic studies reported here were twofold. First, based on the influence of genetic maternal effects on other genetically complex birth defects in mice, we hypothesized that the exencephaly of SELH mice would exhibit strong genetic maternal effects. This hypothesis was tested by comparisons among the four possible reciprocal backcrosses to SELH. The result was an overall frequency of 2.3% exencephaly in first backcross embryos with no difference among the four crosses and no evidence of genetic maternal effects. Second, the frequency of exencephaly recovered in the backcross and F1 embryos was compared with the previous genetic study and with various genetic models. The frequencies were similar to those obtained from the cross to ICR/Bc mice and were compatible with a hypothesis of additive gene action at a few loci.(ABSTRACT TRUNCATED AT 250 WORDS)
Self-fulfilling effects of stigmatizing information on children's social interactions.
The stigmatizing effects of negative expectancies were examined in observations of interactions between children with and without a behavior problem. Ss were 68 pairs of unacquainted boys in Grades 3-6. In each dyad, a normal boy was either told that his partner had a behavior problem or given no expectancy; this expectancy manipulation was crossed with the partner's actual diagnostic status with respect to hyperactivity. The perceivers' expectancy that their partner had a behavior problem as well as the actual diagnostic status of the target adversely affected the boys' interactions. Behavioral data suggest how the expectancies were communicated to the target. The processes underlying interpersonal expectancy effects and the ways in which a childhood stigma can act as a self-fulfilling prophecy are discussed.
Studies of a spontaneous lethal mutation at the albino locus in SELH/Bc mice.
We report a new mutation at the albino locus in SELH/Bc mice. The mutation arose spontaneously in a male mouse that appeared to be a somatic and germ line mosaic for a new albino (c) allele, provisionally named cBc. The mutation is a recessive lethal, causing embryonic death soon after implantation. We have shown that there is no detectable activity of the Mod-2 allele in cis with the mutation and conclude that the mutation is probably a deletion that includes the c locus, the Mod-2 locus, the intervening 2 cM, and at least one locus essential for postimplantation embryonic survival, either proximal to the c locus or distal to the Mod-2 locus. This new mutation is similar to most previously reported spontaneous mutations at the albino locus in that it arose in a somatic and germ line mosaic mutant animal but differs from them in that it is an embryonic lethal when homozygous and is apparently a deletion. SELH/Bc mice appear to have a high mutation rate. This lethal albino mutation that appears to be a postmeiotic deletion should be useful in the search for the mechanism of mutagenesis in SELH/Bc mice. It may also be useful in mapping essential genes in the c-locus region.
Cognitive deficits of patients with Alzheimer's disease with and without delusions.
OBJECTIVE: The goal of this investigation was to study the prevalence of delusions in Alzheimer's disease and to compare the performance of the delusional and nondelusional groups on a neuropsychological test battery. METHOD: The authors studied 107 patients with Alzheimer's disease and 51 age- and education-comparable normal subjects using a standardized psychiatric interview and a neuropsychological test battery. RESULTS: Thirty-seven patients with Alzheimer's disease had delusions with or without hallucinations. Patients with delusions were significantly more impaired than those without delusions (and the normal comparison group) on the Mini-Mental State examination; Blessed Information-Memory-Concentration Test; Dementia Rating Scale, especially its conceptualization and memory subtests; and a test of verbal fluency. The delusional group also tended to be somewhat more impaired than the nondelusional group on the modified Wisconsin Card Sorting Test and the similarities subtest of the Wechsler Adult Intelligence Scale-revised. CONCLUSIONS: Approximately one-third of patients with Alzheimer's disease had developed psychotic symptoms sometime after the onset of dementia. The presence of psychotic symptoms in Alzheimer's disease was associated with greater cognitive impairment, especially frontal/temporal dysfunction, and possibly with a more rapidly progressive dementia.
High incidence of tardive dyskinesia in older outpatients on low doses of neuroleptics.
We are conducting a prospective study of tardive dyskinesia (TD) in psychiatric patients over age 45, a large proportion of whom have had less than 1 month of total lifetime neuroleptic exposure. Patients are treated with the lowest effective dose of either haloperidol (usually 1-3 mg daily) or thioridazine (usually 25-75 mg daily). Patients are reexamined 1 month and 3 months after initial assessment and then at 3-month intervals. To date, a total of 68 patients (mean age 69.5 years) have been evaluated. Survival analysis showed a 27 percent cumulative incidence of TD (the 95% confidence interval being 14% to 40%) with 6 months of neuroleptic treatment in the study. The TD and non-TD patients did not differ on demographic and baseline clinical measures. Instrumental assessment showed that a greater proportion of TD patients had subclinical evidence of dyskinesia prior to the institution of neuroleptics, compared with non-TD patients.
Studies of the effect of retinoic acid on anterior neural tube closure in mice genetically liable to exencephaly.
Previously we have shown that all SELH/Bc mouse embryos close their anterior neural tubes by an abnormal mechanism and that 10-20% of SELH/Bc embryos are exencephalic. The purposes of these studies were (1) to observe the effects of retinoic acid on the frequency of exencephaly in SELH/Bc embryos; (2) to compare the SELH/Bc response with those of normal strains and of other neural tube mutants; and (3) to compare, between SELH/Bc and a normal strain (SWV/Bc), the effects of retinoic acid on morphology of the closing anterior neural tube. SELH/Bc was more liable to retinoic acid-induced exencephaly than were normal strains. After maternal treatment with 5 mg/kg retinoic acid on day 8.5 of gestation, 53% of SELH/Bc embryos had exencephaly, compared with 22% in ICR/Bc and 14% in SWV/Bc. When these results were transformed according to the assumptions of the developmental threshold model, the effects of genotype and retinoic acid appeared to be additive. Similar treatment on day 9 or 10 of gestation had little or no effect on the frequency of exencephaly in SELH/Bc mice. These results are similar to the reported responses of the curly-tail and Splotch mutants, where frequencies of spina bifida but not exencephaly were decreased. This pattern suggests that studies of effects of periconceptional vitamin treatment on risk of human neural tube defects should consider anencephaly and spina bifida separately. The study comparing the morphology of anterior neural tube closure in SELH/Bc and normal SWV/Bc embryos showed that retinoic acid delays the elevation of the mesencephalic neural folds. This results in a "stalling" of many embryos in the first steps of neural tube closure, with their neural folds remaining convex and splayed wide apart. The delay in fold elevation was superimposed on the different closure patterns of the two strains. The overall conclusion is that there is no nonadditive interaction in the parameters studied between retinoic acid treatment and the SELH/Bc genotype.
Normal mouse strains differ in the site of initiation of closure of the cranial neural tube.
The scanning electron microscopic study of day 9 embryos reported here documents differences among normal mouse strains in morphology of cranial neural tube closure. The site of initiation of contact and fusion of the cranial neural folds, previously defined as Closure 2 (Macdonald et al., '89), is located in the region of the junction between the forebrain (prosencephalon) and midbrain (mesencephalon) in three normal strains: LM/Bc, AEJ/RkBc, and ICR/Bc. However in a fourth normal strain, SWV/Bc, Closure 2 is initiated much further rostral, in the prosencephalic region. In addition, the anterior neuropore, rostral to Closure 2, closes late in ICR/Bc embryos, relative to the posterior progress of development of the Closure 2 seam. Initiation of closure from the most rostral end of the neural tube (Closure 3) appears to be relatively delayed in ICR/Bc embryos. We hypothesize that the observed genetic polymorphism in location of the first site of fusion between the cranial neural folds in normal mouse embryos may be one basis for differences among normal strains in liability to exencephaly induced by teratogens.
Deficit syndrome in older schizophrenic patients.
Previous studies have reported that a proportion of younger schizophrenic patients have the "deficit syndrome," with persistent "negative" symptoms not secondary to factors other than the disease process (e.g., depression). Yet, there is scant information on the deficit syndrome in older schizophrenic patients. We studied 46 schizophrenic patients over age 45. Seventeen met the criteria for the deficit syndrome as described by Carpenter et al. (1988), 20 were considered definite nondeficit patients, and 9 could not be classified. The deficit schizophrenic patients had a significantly higher total score on the Scale for the Assessment of Negative Symptoms but similar scores on scales for positive symptoms, depressive symptoms, and overall psychopathology as compared with nondeficit patients. The deficit patients also had a nonsignificantly greater impairment on the Halstead-Reitan Battery. One notable difference between our results and those of Carpenter et al. was in the prevalence of deficit syndrome. We found the prevalence (37%) to be significantly higher than that reported in younger patients (15%). Pending confirmation using larger sample sizes, the increased frequency of the deficit syndrome in our study could possibly be attributed to aging or a longer duration of illness in our subjects.
New-onset psychosis in HIV-infected patients.
BACKGROUND: Psychiatric symptoms and disorders are becoming increasingly evident in human immunodeficiency virus (HIV)-infected patients. As psychotic symptoms may be severe and require immediate behavioral management, the authors sought to determine the frequency and clinical characteristics of new-onset psychosis not obviously attributable to substance abuse or delirium in these patients. METHOD: The authors reviewed the English-language literature since 1981 by means of the Index Medicus and MEDLINE for reports of new-onset psychosis in HIV-infected patients and also examined the charts of 124 HIV-infected patients who had been followed up at the San Diego Veterans Affairs Medical Center since 1984. Cases of substance-induced psychosis and delirium were excluded. RESULTS: Results reflect a combination of cases from the authors' study and cases of new-onset HIV-associated psychosis reported in the literature (N = 31). Results of the initial neurologic evaluation, including computed tomography (CT) scan and examination of the CSF, were normal in a majority of patients (CT = 12 of 23 patients; CSF = 10 of 14 patients). Psychotic symptoms improved with neuroleptic treatment although side effects were frequently seen. In some patients (N = 12) psychosis was the presenting manifestation of HIV infection or acquired immunodeficiency syndrome. A proportion of patients (N = 7 [23%]), especially those with an abnormal CT and EEG at the time of presentation with psychosis, tended to have a relatively rapid deterioration in cognitive and medical status. Differences between studies in population and method made it impossible to determine the frequency of new-onset psychosis in the general HIV-infected population. CONCLUSIONS: A common clinical feature noted in new-onset psychosis in HIV-infected patients was acute or subacute onset of symptoms, which included delusions, hallucinations, bizarre behavior, mood or affective disturbances, and mild memory or cognitive impairment. The etiological association of the HIV infection to the psychosis is yet to be established.
Growing up and growing apart: a developmental meta-analysis of twin studies.
Developmental change in twin similarity was examined with age contrasts in a meta-analysis of twin studies from 1967 through 1985. Intraclass rs were coded from 103 papers that included data for monozygotic or dizygotic twins, or for both, on personality or intelligence variables. Analyses indicated that there was a general tendency for some intraclass rs to decrease with age. In other words, as twins grow up, they grow apart. There were also developmental differences associated with components of variance for heritability, the shared environment, and the nonshared environment. Mechanisms through which the nonshared environment may operate are discussed.
Primary biliary and pancreatic carcinoma after renal transplantation.
Renal transplant recipients have an increased risk of malignancies. We have described a 41-year-old man in whom adenocarcinoma of the gallbladder developed during the first year after renal transplantation. He also had a nonfunctioning pancreatic islet cell tumor during the fifth year after transplantation. He was the first known renal transplant recipient to be a long-term survivor of adenocarcinoma of the gallbladder.
Antipsychotics.
The multiple medical problems in the geriatric population complicate the issues of diagnosis and management of behavioral symptoms. Systematic evaluation of the etiology, course, and prognosis of behavioral and psychotic symptoms associated with dementia may clarify the indications for treatment. Further research is needed to evaluate effective adjuncts and alternatives to neuroleptic treatment in the demented elderly and to minimize medication side effects.
Disruption of pattern formation in palatal rugae in fetal mice heterozygous for First arch (Far).
The purpose of this study was to document the extent of disruption in the pattern of palatal rugae caused by the presence of one copy of the First arch mutation. The palatal ruga pattern was found to be disrupted in 86% of 15- to 17-day mouse fetuses that were heterozygous for the First arch mutation in the ICR/Bc strain, compared with 9% in ICR/Bc fetuses of normal (+/+) genotype. This new observation in First arch heterozygotes, together with the previously reported dominant effects of the First arch mutation, particularly the bifurcation of the maxillary nerve (100% in both BALB/cGaBc and ICR/Bc strains), the disruption of maxillary vibrissa pattern (80% in ICR/Bc), and the hemifacial deficiency (38% in ICR/Bc), has led us to redefine the First arch mutation as a semidominant, Far. Like the other defects caused by Far, the rugal defects are in tissue derived from the embryonic maxillary prominence. The rugal defects observed in +/Far palates were always asymmetrical and most often involved fragmentation and misalignment of two or more of rugae 4-7. The relatively large degree of variation in ruga pattern observed in fetuses of normal genotype suggests that it is a less well canalized trait than the normal pattern of maxillary vibrissae which varies only in a few very specific and minor ways. The First arch mutation, which in heterozygotes disrupts pattern formation in both palatal rugae and maxillary vibrissae, can be used to study genetic control of pattern formation in mammalian embryos.
The adrenal response to trauma, operation and cosyntropin stimulation.
Thirty-four patients who underwent abdominal or thoracic, or both, operation for injuries were studied. Serum and urinary cortisol levels were elevated perioperatively and returned to normal levels by the fourth postoperative day. Postoperative complication was associated with persistent elevation of levels of serum and urinary cortisol. Baseline serum cortisol levels correlated with Injury Severity Scores. Cosyntropin stimulation produced a significant rise in serum cortisol to a peak level of 47.4 +/- 10.2 (S.D.) micrograms per deciliter in patients after emergent operations for traumatic injury. Use of the cosyntropin stimulation test for the diagnosis of postoperative adrenal insufficiency can be extended to patients who undergo operation for traumatic injury.
The use of chloral hydrate in infancy.
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