Biomedical subjects

R Freedman

Publications and source records attributed to R Freedman.

At least 91 records · Page 5Linked to original sources

PubMed1995

Normalization of the auditory P50 gating deficit of schizophrenic patients after non-REM but not REM sleep.

Diminished suppression of the P50 response to repeated auditory stimuli is one example of a deficit in elementary sensory processing in schizophrenia. Normal subjects suppress the response to the second of two paired auditory stimuli. Although normal suppression is occasionally observed in schizophrenic patients, it generally disappears with subsequent testing. We have previously reported that slow wave sleep (SWS) transiently normalized suppression in schizophrenic patients and that the degree of suppression was positively correlated with the depth of SWS attained. We hypothesized that schizophrenic patients may have a defect that causes a neuronal mechanism to fail after brief use and that its activity can be restored by a transient period of inactivity. The present study examined whether this effect of sleep in schizophrenic patients is specific to SWS or is due to nonspecific factors involved in any period of unconsciousness. After baseline recordings, 10 schizophrenic subjects were allowed a period of sleep until they attained rapid-eye-movement (REM) sleep. They were awakened at the end of the REM period, and postsleep recordings were obtained. REM-stage sleep failed to normalize suppression in any of the schizophrenic subjects. P50 suppression was subsequently assessed after a period of non-REM (NREM) sleep. Subjects who reached stage-2 sleep did demonstrate a transient correction in auditory gating. These results replicate our previous findings and suggest that the sleep effect is specific to NREM sleep. A desensitized nicotinic receptor that is resensitized during cholinergic inactivity in NREM sleep is one possible mechanism for this effect.

Adult↗

PubMed1995

Glutamate receptor subtype expression in human postmortem brain tissue from schizophrenics and alcohol abusers.

Antibodies to functional AMPA/kainate (GluR1, GluR2, GluR3), and kainate binding sites (GluR5-7) were used as probes to characterize and quantitate glutamatergic receptor subtypes in human post-mortem brain tissue from schizophrenic subjects and non-psychotic control subjects, which included normal controls and subjects with a previous history of alcohol abuse. Crude membrane fractions from human hippocampi and cingulate cortices were fractionated by SDS-PAGE, electrotransferred to nitrocellulose, and probed for the various glutamate receptor subtypes. Western blots were developed with chemiluminescence and the images analyzed by densitometry. Significant reductions were observed in the hippocampal immunoreactivity of both GluR2 and GluR3 AMPA/kainate receptor subtypes in schizophrenic subjects compared to the entire group of non-psychotic control subjects. No significant changes were observed in schizophrenic hippocampal GluR1 and GluR5 receptor subtypes or in levels of the structural control proteins, NCAM and tau. Significant increases were observed for GluR2 and GluR3 in the hippocampi of subjects with alcohol abuse histories when compared to the non-psychotic normal control group. When subjects with alcohol abuse histories were removed from the non-psychotic control pool, schizophrenics were no longer statistically different from the remaining normal controls. An analysis of GluR2 and GluR3 immunoreactivity in the cingulate cortex revealed no changes in these receptor subtypes among any of the groups. No alterations were observed in the immunoreactivity of these various proteins due to confounding factors such as age, sex, postmortem interval, or smoking history, except in the cingulate cortex were GluR3 receptor subtype levels were significantly reduced in the brains of smokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

The activity of hippocampal interneurons and pyramidal cells during the response of the hippocampus to repeated auditory stimuli.

Interneurons and pyramidal cells were identified electrophysiologically in the hippocampus of anesthetized rats. Paired tones were presented 500 ms apart, and the resulting neuronal response was compared to differences in the amplitude of an auditory evoked potential (N40) elicited by each of the tones. Generally, the N40 elicited in response to the second tone is less than the response to the first. Pyramidal cells exhibited their most pronounced activation within 40 ms after the first tone. The post-stimulus discharge activation of interneurons was less than the pyramidal cells, but activation of different interneurons occurred at various times throughout the interval between the two tones. The presence or absence of suppression of N40 amplitude in the paired stimulus paradigm correlated with differences in the auditory response of both the interneurons and pyramidal cells. The activity of interneurons in relationship to gating of hippocampal auditory response is discussed.

Acoustic Stimulation↗

PubMed1995

Genetic polymorphism of the alpha 2-adrenergic receptor is associated with increased platelet aggregation, baroreceptor sensitivity, and salt excretion in normotensive humans.

It is likely that a number of independent heritable traits, each encoded by a singular gene, contribute to pathologic elevations in blood pressure in humans. Genetic polymorphisms of individual genes may result in intermediate phenotypes which, by themselves, do not raise blood pressure, but, coupled with environmental or epistatic forces, contribute to the prevalence of human hypertension. The gene for the alpha 2-adrenergic receptor encoded by chromosome 10 (C10 A2AR) is polymorphic, and Southern blotting with a cDNA probe following restriction enzyme digest of this gene results in fragments of either 6.3 kb or 6.7 kb in size. We reported an association between homozygosity for the 6.3 kb allele and hypertension in blacks. Blacks with hypertension also have an increased risk for thrombotic stroke, increased baroreceptor sensitivity, and decreased sodium excretion. We noted that the C10 A2AR, which modulates norepinephrine release in blood-pressure-regulating regions of the brain, is also expressed on platelets and in the kidney. We postulated that functional changes associated with the C10 A2AR gene polymorphism could be responsible for increased baroreceptor sensitivity, epinephrine-mediated platelet aggregation, and decreased sodium excretion in some individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1995

Regional zinc staining in postmortem hippocampus from schizophrenic patients.

Schizophrenia-associated deficits in learning and memory have been associated with a decrease in the volume of the hippocampus, but the specific nature of the neuronal deficit remains unknown. Many critical afferent pathways in the hippocampus contain ionic zinc. Alterations of these pathways could be manifest as a decrease in ionic zinc levels within hippocampal afferent pathways. This possibility was examined in postmortem hippocampal tissue taken from schizophrenic patients, patients with other psychiatric disorders and matched, non-mentally ill subjects using a modified Timm's silver staining method. The three groups exhibited similar patterns of zinc staining within the hippocampal formation as well as similar levels of zinc within the mossy fiber projection system. A greater prevalence of zinc staining within the inner molecular layer of the dentate gyrus was observed in female as compared to male donors and in older as compared to younger donors. The results of the present study demonstrate that loss of ionic zinc within the hippocampus does not appear to be part of the pathology of schizophrenia.

Adolescent↗

PubMed1995

Search for a schizophrenia susceptibility gene on chromosome 18.

Nine multiplex schizophrenia families were genotyped with 15 microsatellite markers mapping to the short and long arm of chromosome 18. Assuming either autosomal dominant or recessive inheritance evidence of linkage was not found. In addition, the non-parametric sib pair test did not reveal significant evidence of linkage.

Chromosome Mapping↗

PubMed1995

Effects of sound intensity on a midlatency evoked response to repeated auditory stimuli in schizophrenic and normal subjects.

Inhibitory gating of response to repeated stimuli is demonstrated by several event-related potentials, including the auditory P50 wave. The present study examined the effects of variation in sound intensity on this phenomenon in schizophrenics and normal subjects. Paired clicks, 500 ms apart, were presented 50 dB above threshold to 10 normal subjects and 10 schizophrenics. The normal subjects demonstrated significantly more decrement of response to the second stimulus than did the schizophrenics. When the sounds were noticeably louder(70 dB above threshold), no such difference was observed. Rather, both groups had similarly diminished gating of response. A significant difference between schizophrenics and normal subjects was also observed when the sounds were 30 dB above threshold, but the difference was smaller than that at 50 dB. At any stimulus intensity, concomitant eye movements led to loss of gating of P50 in the normal subjects.

Acoustic Stimulation↗

PubMed1995

Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer.

PURPOSE: To determine the activity of carboplatin in patients with ovarian cancer who progressed on taxane (paclitaxel or docetaxel) therapy. PATIENTS AND METHODS: Thirty-three patients with ovarian cancers refractory to platinum and taxane therapy were treated with single-agent carboplatin reinduction once the disease progressed on a taxane. The starting dose of carboplatin was 300 mg/m2 at 28-day intervals. RESULTS: Patients were a median age of 56 years (range, 31 to 80), had a median Zubrod performance status of 1 (range, 0 to 2) and had received a median of three prior chemotherapy regimens (range, two to eight) and one pretaxane platinum regimen (range, one to three). Twenty-six patients had a platinum-free interval of at least 12 months at the time of posttaxane re-treatment with carboplatin. There were seven of 33 (21%) partial responses, with a median duration of 7+ months (range, 2+ to 12+). Responses were noted only in patients with at least a 12-month platinum-free interval and an initial sensitivity to a taxane. The therapy was well tolerated and neurotoxicity was absent. CONCLUSION: A subset of patients with platinum-refractory disease that initially responded to a taxane and who eventually have a platinum-free interval of at least 1 year may respond to carboplatin reinduction. This finding may be secondary to paclitaxel or docetaxel therapy that leads to the reversal of platinum resistance, or the prolonged platinum-free interval permits the loss of resistance to platinum by the tumor. Carboplatin reinduction should be considered in the treatment of patients whose ovarian cancer progresses after an initial sensitivity to a taxane and who had a prolonged platinum-free interval.

Adult↗

PubMed1995

Temperature gradient gel electrophoresis analysis of the beta-NGF gene in schizophrenia.

Methods for localizing functional polymorphisms in candidate genes are important for the elucidation of pathogenesis in complex diseases such as schizophrenia and manic depression. Temperature gradient gel electrophoresis (TGGE), a variant of denaturing gradient gel electrophoresis (DGGE), can detect single-base mutations in a specified region of double-stranded DNA. This technique has been evaluated for use with polymerase chain reaction (PCR)-generated DNA fragments containing either transitional (A to G) or transversional (T to A) mutations. Single-base mutations of both types are detectable in PCR fragments up to 500 bp long. This method was then used to examine the coding region of the beta-nerve growth factor (NGF) gene for polymorphisms in PCR-generated DNA fragments derived from lymphocyte DNA of subjects with schizophrenia and normal subjects. No single-base mutations in sequence coding for the mature beta-NGF peptide were found in any of the subjects who were examined. If DNA sequence information is available for PCR primer design, TGGE detection of DNA polymorphisms can be used to rapidly determine whether or not a defect in a gene of interest contributes to the pathophysiology of the illness.

DNA Mutational Analysis↗

PubMed1995

Long-term effects of neuromuscular rehabilitation of chronic facial paralysis.

Although chronic facial dysfunction can be improved with neuromuscular biofeedback therapy, it is uncertain whether this improvement is maintained after such therapy ends, or whether post-therapy, home exercise programs optimize this improvement. We aimed to clarify these issues. Post-therapy facial function, in 38 previously treated patients, was blindly assessed using the House grading system, 1 to 41 months after ending therapy. Results were compared with pre-therapy function. It was found that post-therapy function was better than pre-therapy function in most patients (40%), it was worse in some (26%), and was unchanged in the rest. This surprising result occurred because, although most patients who recently stopped therapy (1 to 6 mo) had improved significantly, the longer other patients were out of therapy, the more they had tended to deteriorate, particularly those who had been practicing. Results suggested that unsupervised, post-therapy, home exercise programs may be detrimental, and that new post-therapy programs may be required to maintain the benefits of regular therapy.

Adolescent↗

PubMed1994

Influence of protein disulfide isomerase (PDI) on antibody folding in vitro.

The role of eucaryotic protein disulfide isomerase (PDI) in the folding and reoxidation of proteins in vitro was investigated using an antibody Fab fragment as a model substrate, since PDI is known to participate in the disulfide bond formation of immunoglobulins in vivo. PDI has no effect on the folding of the Fab fragment with intact disulfide bonds, suggesting that, at least in this system, PDI is not able to influence the folding process in a chaperone-like manner. Instead, the role of PDI is limited to disulfide bond formation as demonstrated for the folding of the denatured and reduced Fab fragment. Here, PDI influences the yield of reactivation enormously with a maximum effect at about stoichiometric amounts of PDI and Fab. Furthermore, PDI changes the redox dependence of the reaction. In the presence of PDI, formation of the correct disulfide bonds is possible at higher oxidizing conditions compared to the spontaneous reaction. The requirements both for stoichiometric amounts of PDI and for the presence of PDI during the first seconds of refolding suggest that there is a kinetic competition between rapid structure formation of the antibody domains and interaction of PDI with cysteine residues in the folding protein.

Animals↗

PubMed1994

Genomic scan for genes predisposing to schizophrenia.

We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than -2.0 at theta = 0.0, 101 DNA markers gave lod scores less than -2.0 at theta = 0.05, while 5 DNA loci produced maximum lod scores greater than 1: D4S35, D14S17, D15S1, D22S84, and D22S55. Of the DNA markers yielding lod scores greater than 1, D4S35 and D22S55 also were suggestive of linkage when the Affected-Pedigree-Member method was used. The families were then genotyped with four highly polymorphic simple sequence repeat markers; possible linkage diminished with DNA markers mapping nearby D4S35, while suggestive evidence of linkage remained with loci in the region of D22S55. Although follow-up investigation of these chromosomal regions may be warranted, our linkage results should be viewed as preliminary observations, as 35 unaffected persons are not past the age of risk.

Adolescent↗

PubMed1994

Analysis of chromosome 22 markers in nine schizophrenia pedigrees.

Previous results of a genome-wide survey for schizophrenia susceptibility genes in nine multiplex families indicated a possible region of linkage on chromosome 22. We therefore tested for linkage using ten highly polymorphic chromosome 22 DNA markers. Lod score analyses were suggestive of linkage for several markers on the distal end of the chromosome; however, no lod score exceeded 3 assuming either autosomal dominant or autosomal recessive transmission. The highest lod score was 2.09 (theta = 0.10) for marker D22S276 under autosomal recessive inheritance. Based on simulation analyses, this result is unlikely to represent a false positive. Analyses using information from affected individuals only resulted in reduced lod scores, with a maximum of 1.40 (theta = 0.05) for D22S276 assuming autosomal recessive inheritance. Two nonparametric methods, sib pair analysis and the Affected-Pedigree-Member method, also yielded suggestive but inconclusive findings; results were positive, but strict thresholds of significance were not met. Additionally, we tested one candidate gene, the Arylsulfatase A gene, located in the region of 22q13.31-qter. Results were again inconclusive, though the DNA marker available for this gene was a 2-allele RFLP with heterozygosity of 0.5, and therefore not maximally informative. Further investigation of this chromosomal region and this and other candidate genes may be warranted.

Adolescent↗

PubMed1994

Spectroscopy of Mars from 2.04 to 2.44 micrometers during the 1993 opposition: absolute calibration and atmospheric vs mineralogic origin of narrow absorption features.

We present moderate-resolution (lambda/delta lambda = 300 to 370) reflectance spectra of Mars from 2.04 to 2.44 micrometers that were obtained at UKIRT during the 1993 opposition. Seven narrow absorption features were detected and found to have a Mars origin. By comparison with solar and Mars atmospheric spectra, five of these features were attributed all or in part to Mars atmospheric CO2 or CO(2.052 +/- 0.003, 2.114 +/- 0.002, 2.150 +/- 0.003, 2.331 +/- 0.001, and 2.357 +/- 0.002 micrometers). Two of the bands (2.331 +/- 0.001 and 2.357 +/- 0.002 micrometers) appear to have widths and depths that are consistent with additional, nonatmospheric absorptions, although a solar contribution cannot be entirely ruled out. Two other weak bands centered at 2.278 +/- 0.002 and 2.296 +/- 0.002 micrometers may be at least partially mineralogic in origin. The data provide no conclusive identification of the mineralogy responsible for these absorption features. However, examination of terrestrial spectral libraries and previous moderate spectral resolution mineral studies indicates that the most likely origin of these features is either (bi)carbonate or (bi)sulfate anions in framework silicates or (Fe, Mg)-OH bonds in sheet silicates. If the bands are caused by phyllosilicate minerals, then an explanation must be found for the extremely narrow widths of the cation-OH features in the Mars spectra as compared to terrestrial minerals.

Astronomy↗

PubMed1994

Role of growth factors in degeneration and regeneration in the central nervous system; clinical experiences with NGF in Parkinson's and Alzheimer's diseases.

Neurotrophin-mediated mechanisms are integral to development and maintenance of the adult central nervous system. Neurotrophin expression has been shown to change rapidly in response to many different types of neuronal stress such as excitotoxic injury, mechanical lesions, epileptogenesis and ischemia. It therefore appears as if they are not only to be regarded as target-derived trophic factors in the classical sense, but also as providers of local trophic support and neuronal protection. These discoveries suggest that neurotrophins or compounds with neurotrophin-like actions might become useful in developing new treatment strategies, not only for neurodegenerative diseases, but also for other diseases and injuries to the nervous system including stroke.

Alzheimer Disease↗

PubMed1994

A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia: I. Comparisons with healthy control subjects and neuroleptic-treated/unmedicated pairs analyses.

Recent hypotheses and findings indicate that measurements of interactions between cerebrospinal fluid (CSF) biogenic amine systems, rather than measurement of CSF biogenic amine metabolites, better correlate with clinically important findings in schizophrenia. To test hypotheses, we used a recent technological advance in high performance liquid chromatography with electrochemical detection and combined it with multivariate statistical analyses to study biogenic amine concentrations in CSF in schizophrenia. This approach enabled the study of the interactions of several metabolites of each of the three major neurotransmitter pathways (dopaminergic, noradrenergic, and serotonergic) to test existing hypotheses regarding the neurobiochemical basis of schizophrenia. Twenty biogenic amines, their metabolites, and other compounds from 24 medication-free schizophrenic patients and 12 normal control subjects were simultaneously measured using a recently developed technique of gradient high performance liquid chromatography coupled with a 16-channel electrochemical array detector. After covariation for storage time, results of a stepwise discriminant function analysis comparing the control and patient groups identified tryptophan, tryptophol, and epinephrine as discriminating variables. Hotelling's paired T2 test from a subgroup of schizophrenic patients studied while they were and were not receiving neuroleptic treatment did not yield any significant differences between subgroups. A discussion of the findings and a comparison with previous studies of CSF biogenic amines in schizophrenia are presented.

Adult↗

PubMed1994

A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia: II. Correlations with psychopathology.

As part of a multidimensional study of cerebrospinal fluid biogenic amine metabolites in schizophrenia, the relationship between neurochemical measures and psychopathology assessed using the Psychiatric Symptom Assessment Scale (PSAS) was analyzed. In a group of 20 unmedicated patients, 3,4-dihydroxyphenylacetic acid (DOPAC) was a predictor of symptom severity in a stepwise multiple regression model. Values of 3-hydroxykynurenine and metanephrine in the unmedicated state predicted clinical response in a stepwise multiple regression model, as measured by improvement in PSAS mean item score following 6 weeks on a standard dose of neuroleptic. In a subgroup of 14 patients in whom both off- and on-medication concentrations of cerebrospinal fluid biogenic amines and metabolites were measured, change in 3-hydroxykynurenine predicted clinical outcome in a multiple regression model. These findings point toward the need to examine the role of the kynurenine pathway of tryptophan metabolism in the pathophysiology of schizophrenia.

Adult↗

PubMed1994

Neuronal development in embryonic brain tissue derived from schizophrenic women and grafted to animal hosts.

The distribution of schizophrenia in families supports the hypothesis of heritable risk factors in schizophrenia, but there is as yet no identification of an inherited neurobiological defect. Human embryonic brain tissue fragments, derived from first trimester abortions, can be transplanted into rat hosts, where they continue neuronal development and are accessible for neurobiological investigation. Hippocampal transplants derived from three schizophrenic women and a larger series of normal women have been studied. If there are heritable neuronal defects associated with schizophrenia, a proportion of the transplants from schizophrenic women would be expected to carry these defects. The transplants from the first two schizophrenic women showed profound abnormalities in survival and growth, compared to the series of transplants from normal women. The transplants from the third schizophrenic woman showed normal growth and development, as well as typical histological and electrophysiological features. The data must be regarded as preliminary, because of the small number of subjects that have been studied. However, they are consistent with the transmission of a defect in neuronal development to some of the offspring of schizophrenic women, a possibility consistent with other studies of the pathogenesis of schizophrenia. The mechanism of the defect in development remains to be identified.

Adult↗