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Biomedical subjects

M Goodman

Publications and source records attributed to M Goodman.

At least 127 records · Page 7Linked to original sources
PubMed1997

The complete sequences of the galago and rabbit beta-globin locus control regions: extended sequence and functional conservation outside the cores of DNase hypersensitive sites.

The locus control region (LCR) of mammalian beta-globin genes covers at least 17 kb at the 5' end of the gene cluster and has been implicated in chromatin domain opening, enhancement, and insulation from neighboring sequences. Functional dissection of the LCR has defined the minimal cores for four of the five major DNase hypersensitive sites (HSs) that mark this regulatory region. To examine fully the patterns of conserved sequences in the mammalian homologs to the beta-globin LCR, we determined the complete DNA sequence of the galago beta-globin LCR and completed previously unsequenced regions of the rabbit LCR. Simultaneous alignment of these sequences with the human, goat, and mouse LCRs revealed conserved sequences (phylogenetic footprints) detected using three largely independent methods. The most highly conserved segments are found both within the HS cores and in some but not all regions flanking the cores. These results argue for an extended pattern of well-conserved sequences, many of which lie outside the minimal cores, and we show that a key sequence required for domain opening by the region including HS3 maps about 1 kb 5' to the minimal core. Differential phylogenetic footprints, containing sequences conserved in nonhuman mammals but not in humans, are found primarily around HS3, consistent with some species-specific differences in function that may be important for differences in hemoglobin switching during development.

Animals↗
PubMed1997

Activation signals regulate heat shock transcription factor 1 in human B lymphocytes.

We previously showed that the ability of human B lymphocytes to elicit a cytoprotective heat shock response when confronted by heat or other stresses was dependent upon the state of cell activation. This was unexpected, considering the highly conserved nature of the heat shock response and the widely held belief that all nonmutated mature cells were capable of eliciting a heat shock response when stressed. To elucidate the mechanism by which activation primes B cells to respond to stresses, we examined heat shock transcription factor 1 (hHSF1) in B cells since this factor appears to be solely responsible for stress-induced transcription of heat shock genes in human cells. In the current report, we show that hHSF1-DNA binding complexes are undetectable in extracts of unactivated B cells. In fact, hHSF1 protein is not constitutively expressed in unactivated B cells, nor is its synthesis stress-inducible. However, following activation, hHSF1 can be found in either a transcriptionally active or an inactive state, depending upon whether the cell has been stressed or not. Thus, activation pathways play an important role in enabling B cells to survive and function properly in the context of physiologic stresses by regulating hHSF1.

B-Lymphocytes↗
PubMed1997

Assessment of the Massachusetts Medicaid managed Behavioral Health Program: year three.

This evaluation of the third year of the Massachusetts Medicaid managed Mental Health/Substance Abuse Program showed that overall utilization increased slightly and expenditures were nearly the same in FY1994 compared to FY1993; however, they were lower for disabled members. Providers believed that access to care, utilization, and quality of care were the same or better than a year earlier and that the clinical review process was improved. Client severity was higher. Aftercare planning improved but gaps in services persisted. Integration of care improved. Administrative and management problems continued. Lessons for similar, more recent initiatives are discussed.

Adult↗
PubMed1997

Molecular evolution of cytochrome c oxidase subunit IV: evidence for positive selection in simian primates.

Cytochrome c oxidase (COX) is a multi-subunit enzyme complex that catalyzes the final step of electron transfer through the respiratory chain on the mitochondrial inner membrane. Up to 13 subunits encoded by both the mitochondrial (subunits I, II, and III) and nuclear genomes occur in eukaryotic organisms ranging from yeast to human. Previously, we observed a high number of amino acid replacements in the human COX IV subunit compared to mouse, rat, and cow orthologues. Here we examined COX IV evolution in the two groups of anthropoid primates, the catarrhines (hominoids, cercopithecoids) and platyrrhines (ceboids), as well as one prosimian primate (lorisiform), by sequencing PCR-amplified portions of functional COX4 genes from genomic DNAs. Phylogenetic analysis of the COX4 sequence data revealed that accelerated nonsynonymous substitution rates were evident in the early evolution of both catarrhines and, to a lesser extent, platyrrhines. These accelerated rates were followed later by decelerated rates, suggesting that positive selection for adaptive amino acid replacement became purifying selection, preserving replacements that had occurred. The evidence for positive selection was especially pronounced along the catarrhine lineage to hominoids in which the nonsynonymous rate was first faster than the synonymous rate, then later much slower. The rates of three types of "neutral DNA" nucleotide substitutions (synonymous substitutions, pseudogene nucleotide substitutions, and intron nucleotide substitutions) are similar and are consistent with previous observations of a slower rate of such substitutions in the nuclear genomes of hominoids than in the nuclear genomes of other primate and mammalian lineages.

Amino Acid Sequence↗
PubMed1997

Sensitivity and specificity of the neonatal brain-stem auditory evoked potential for hearing and language deficits in survivors of extracorporeal membrane oxygenation.

OBJECTIVE: We determined the sensitivity and specificity of neonatal brain-stem auditory evoked potentials (BAEP) as markers for subsequent hearing impairment and for developmental problems found later in infancy and childhood. METHODS: BAEP studies were performed before discharge in infants treated with extracorporeal membrane oxygenation (ECMO), and two specific abnormalities were analyzed: elevated threshold and delayed central auditory conduction. Behavioral audiometry was repeated during periodic follow-up until reliable responses were obtained for all frequencies, and standardized developmental testing was also conducted. The sensitivity and specificity of an elevated threshold on the neonatal BAEP for detecting subsequent hearing loss, and the relationship of any neonatal BAEP abnormality to language or developmental disorders in infancy, were calculated. RESULTS: Test results for 46 ECMO-treated infants (57.5%) were normal, and those for 34 infants (42.5%) were abnormal, with either elevated wave V threshold, prolonged wave I-V interval, or both on neonatal BAEP recordings. Most significantly, 7 (58%) of the 12 children with subsequent sensorineural hearing loss had left the hospital after showing normal results on threshold tests. There was no significant difference in the frequency of hearing loss between subjects with abnormal (5/21, or 24%) and those with normal BAEP thresholds (7/59, or 12%; Fisher Exact Test, p = 0.28). Therefore the sensitivity of neonatal BAEP testing for predicting subsequent hearing loss was only 42%. Neonatal BAEP specificity for excluding subsequent hearing loss was 76%. In contrast, on language development testing, 19 children demonstrated receptive language delay. Of these children, 12 (63%) had abnormal neonatal BAEP recordings and 7 (37%) had a normal BAEP threshold, normal central auditory conduction test results, or both (p = 0.04). CONCLUSIONS: Neonatal BAEP threshold recordings were of limited value for predicting subsequent hearing loss common in ECMO-treated survivors. However, an abnormal neonatal BAEP significantly increased the probability of finding a receptive language delay during early childhood, even in those with subsequently normal audiometry findings. Because neonatal ECMO is associated with a high risk of hearing and receptive language disorders, parents should be counseled that audiologic and developmental follow-up evaluations in surviving children are essential regardless of the results of neonatal BAEP testing.

Acoustic Impedance Tests↗
PubMed1997

Rat renal allograft tolerance is associated with local TGF-beta and absence of IL-2r expression within chimeric immunocytic foci.

Tolerance was induced in Lewis (LEW) rat renal allograft recipients of Brown Norway kidneys by multiple pretransplant donor-blood transfusions and prior limited cyclosporine A. Rat renal allograft tolerance was associated with the induction of systemic donor T cells (10%), an early phase of nonspecific suppressor-cell generation, followed by maturation of systemic antigen-specific suppressor cells, and renal cellular infiltrates that develop long-term in situ in the kidney graft model. It was hypothesized that these infiltrates represent chimeric immunocytic foci that are locally regulated via a TGF-beta-dependent mechanism. Both immunohistochemical staining and digital image analysis for cellular and extracellular TGF-beta, IL-2 receptor (CD25), and the BN Class I-MHC marker (OX-27) were performed. Control rejecting (REJ) kidneys did not demonstrate any differences with respect to levels of infiltrating immunocyte area vs long-term surviving (TOL) kidneys (3.9% vs 4.5%, P = .303). Immunostaining with the BN Class I MHC marker (OX-27) demonstrated high levels of chimerism within immunocyte foci of the tolerant grafts (OX-27 BN+immunocytes 49.0% +/- 5.1%). In situ cellular IL-2 receptor (CD25) expression was demonstrated in REJ kidney infiltrates but not within TOL immunocytic infiltrating foci, when measured as percent of total lymphocytes (REJ = 5.0% vs TOL = 0.4%, P = .031). Conversely, TGF-beta expression was significantly higher in immunocytes of TOL kidneys when measured as the number of DAB chromogen-staining pixels per total immunocyte area (TOL = .076 vs REJ = .047, P = .003). In conclusion, these results suggested that stable mixed immune chimerism (SMIC) plays an important role in DST-CyA-induced tolerance in situ. SMIC-induced tolerance may involve a local TGF-beta-dependent mechanism that is associated with in situ TGF-beta (+) and IL-2r (-) immunocytes.

Animals↗
PubMed1997

The relationship between personality and quality of life in persons with schizoaffective disorder and schizophrenia.

The goal of this study was to examine the effects of personality traits as measured by the NEO-PI on the quality of life (QOL) of persons with schizoaffective disorder and schizophrenia. The premise of this research is that personality traits may be important in shaping one's outlook and satisfaction with life. In a prior pilot study, personality traits were measured in persons with schizoaffective disorder and schizophrenia. In this study, the relationship between QOL and specific personality domains as assessed by the NEO-PI were studied in 21 patients. Global QOL as measured by the Lehman QOL instrument was positively correlated with Extroversion (E) and Agreeableness (A), and negatively correlated with the domain of Neuroticism (N). Global satisfaction scores were not correlated with ratings of psychoticism, paranoia or depression. These data suggest that even in psychotic conditions such as schizoaffective disorder or schizophrenia, intrapsychic factors influence one's sense of QOL. In addition, these data suggest that personality variables may differentially affect patients' satisfaction and QOL with different treatment settings.

Adult↗
PubMed1997

Molecular evolution of cytochrome c oxidase: rate variation among subunit VIa isoforms.

Cytochrome c oxidase (COX) consists of 13 subunits, 3 encoded in the mitochondrial genome and 10 in the nucleus. Little is known of the role of the nuclear-encoded subunits, some of which exhibit tissue-specific isoforms. Subunit VIa is unique in having tissue-specific isoforms in all mammalian species examined. We examined relative evolutionary rates for the COX6A heart (H) and liver (L) isoform genes along the length of the molecule, specifically in relation to the tissue-specific function(s) of the two isoforms. Nonsynonymous (amino acid replacement) substitutions in the COX6AH gene occurred more frequently than in the ubiquitously expressed COX6AL gene. Maximum-parsimony analysis and sequence divergences from reconstructed ancestral sequences revealed that after the ancestral COX6A gene duplicated to yield the genes for the H and L isoforms, the sequences encoding the mitochondrial matrix region of the COX VIa protein experienced an elevated rate of nonsynonymous substitutions relative to synonymous substitutions. This is expected for relaxed selective constraints after gene duplication followed by purifying selection to preserve the replacements with tissue-specific functions.

Amino Acid Sequence↗
PubMed1997

Urethane-protected N-carboxyanhydrides (UNCAs) as unique reactants for the study of intrinsic racemization tendencies in peptide synthesis.

We have established that urethane-protected N-carboxyanhydrides (UNCAs) are uniquely suited for the study of intrinsic racemization tendencies in peptide synthesis. The UNCA allows epimerization only by the direct enolization pathway (Proton abstraction from the alpha-carbon) and does not decompose upon epimerization. A protocol employing the quantitative separation and analysis of enantiomeric N-protected amino acid derivatives by chiral HPLC has been developed to measure the intrinsic rate of racemization of UNCAs under widely varying reaction conditions. The influence of the tertiary amine structure, UNCA side chain structure, and solvent were studied. The same protocol was employed to study the intrinsic rate of racemization of N-protected activated amino acid intermediates generated via 'onium-type' activating reagents. We have shown that the trends influencing the intrinsic rate of racemization of UNCAs are maintained under the conditions of in situ activations, and are consistent with the trends found in classical studies in the literature. The results are relevant to peptide synthesis both in solution and on solid phase. The intrinsic rate of racemization for any type of activation with any tertiary amine can be measured by this protocol.

Amino Acids↗
PubMed1997

Conformational analysis of potent sweet taste ligands by nuclear magnetic resonance, computer simulations and X-ray diffraction studies.

Four potent sweet-tasting molecules, N-(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methylester 1 (7000 times more potent than sucrose), N-(3,3-dimethylbutyl)-L-aspartyl-D-valine (S)-alpha-ethylbenzylamide 2 (3000 time more potent than sucrose), L-aspartyl-D-valine (R)-alpha-methoxymethylbenzylamide 3 (1350 times more potent than sucrose and L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide 4 (2500 times more potent than sucrose) were studied by 1H NMR and computer simulations. These flexible molecules adopt multiple conformations in solution. The "L-shaped" structure, which we believe to be responsible for sweet taste is accessible to all four compounds in solution. Extended conformations with the AH and B-containing moieties in the +y-axis and the hydrophobic group X pointing in the y-axis have also been observed for all four sweeteners. For compounds 1 and 3, the solid-state conformations were determined by X-ray diffraction studies. These results demonstrate that compounds 1 and 3 adopt an "L-shaped" structure even in the crystalline state. The extraordinary potency of the N-alkylated compound 1 compared with the unsubstituted Asp-Phe-OMe may be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the "L-shaped" structure.

Computer Simulation↗
PubMed1997

Predictors of psychosocial adjustment in patients with implantable cardioverter defibrillators.

Predictors of psychological distress/adjustment were examined in 25 patients following placement of ICDs. Patients completed a demographic questionnaire and a standardized questionnaire of psychological symptoms (i.e., Symptom Checklist-90 Revised; SCL-90-R). The number of discharges categorized by the patient as inappropriate and appropriate were also ascertained. The number of ICD discharges categorized as inappropriate and diminished levels of physical activity (r = 0.53 and 0.63, P < 0.01, respectively) did significantly relate to overall psychological distress. In addition, after controlling for age and prior psychiatric and physical health status through a stepwise multiple regression analysis, the occurrence of ICD discharges categorized as inappropriate and diminished physical activity continued to significantly predict overall psychological distress (R2 = 0.41, P < 0.01). However, the number of ICD discharges categorized as appropriate did not significantly predict overall psychological distress. The results of this investigation suggest that further refinement of the ICD could reduce the risk of exposure to potential psychological distress, and an analysis of prior and anticipated patient physical activity levels should be a factor when calibrating minimum ICD discharge threshold levels.

Activities of Daily Living↗
PubMed1997

Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex.

The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.

Cerebral Cortex↗
PubMed1997

The impact of managed care on Massachusetts mental health and substance abuse providers.

Medicaid managed care programs are becoming more widespread. To investigate the clinical, organizational, and financial impacts on service providers, a stratified, random sample of providers in the Massachusetts Managed Mental Health/Substance Abuse Program were surveyed by phone in Years 3 and 4 of the initiative. Providers reported that they were making widespread clinical changes such as more use of group, brief, and episodic therapies. They were increasing utilization review, Total Quality Management, and outcomes measurement. They were increasing in size, affiliating with other agencies, and providing a greater range of services. They were preparing for capitation. Compared to before the program and a year earlier, about 40 percent of providers were doing better financially and a quarter were doing worse. The study documents the hypothesis that a widespread and continuing transformation is taking place in response to managed care.

Cost Control↗
PubMed1997

Identification of pre-gamma-globin.

A pre-gamma-globin species was identified by high performance liquid chromatography in platyrrhine primates. Although pre-gamma-globin has not been observed in human hemoglobin, its identification in platyrrhine hemoglobin was facilitated by the functional inactivation of one of the duplicated gamma-globin genes in platyrrhines, which simplified the high performance liquid chromatography elution pattern. Part, but not all, of the pre-gamma was glutathionyl gamma 2-globin, and matrix-assisted laser desorption/ionization mass spectrometry was used to demonstrate that the glutathionyl residue was located on cysteine 93. As this residue is invariant in primates, it is predicted that the formation of glutathionyl gamma-globin will be seen in all primate hemoglobins under appropriate conditions.

Amino Acid Sequence↗