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Biomedical subjects

E Friedman

Publications and source records attributed to E Friedman.

At least 163 records · Page 9Linked to original sources
PubMed1997

Exclusion of the phosphoinositide-specific phospholipase C beta 3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1.

The predisposing genetic defect in multiple endocrine neoplasia type 1 has been assigned to chromosomal region 11q13. Our previous attempts to identify the MEN1 gene have resulted in the isolation of the phospholipase C beta 3 gene from the actual region. PLCB3 plays an important role in signal transduction and, moreover, shows loss of expression in some endocrine tumors, in accordance with a putative tumor suppressor gene function, and thus appears to be an excellent candidate for MEN1. We have therefore undertaken screening for constitutional mutations in individuals from MEN1 families. Several sequence alterations have been discovered, none of them however fulfilling the criteria for a disease-related mutation. We can now exclude PLCB3 from candidacy as the MEN1 gene.

Chromosome Mapping↗
PubMed1997

A missense mutation in ColA1 in Jewish Israeli patient with mild osteogenesis imperfecta, detected by DGGE.

Osteogenesis imperfecta (OI) underlies germline mutations in either Col1A1 or Col1A2. Here we describe, for the first time, the use of the denaturing gradient gel electrophoresis (DGGE) technique for mutation analysis of the Col1A1 gene. By employing this technique, we identified a point mutation in a young Jewish Israeli patient with mild OI. The missense mutation, a G to A alteration at position 888, result in a Gly to Arg substitution at codon 79. Furthermore, the patient's mother, who was clinically labeled as OI based solely on the fact that she has blue sclera, was found not to carry this mutation in two different tissues. We suggest that blue sclera alone should not be used as a parameter for the diagnosis of OI, and that DGGE can be effectively used for mutation analysis of the Col1A1 gene.

Adult↗
PubMed1997

No founder effect detected in Jewish Ashkenazi patients with fragile-X syndrome.

Several studies on small homogenous populations suggested that fragile-X syndrome originated from a limited number of founder chromosomes. The Israeli Jewish population could serve as an adequate model for tracing a founder effect due to the unique ethnic makeup and traditional lifestyle. Furthermore, a common haplotype for Jewish Tunisian fragile X patients was recently reported. To test for a similar occurrence in the Jewish Ashkenazi population, we performed haplotype analysis of 23 fragile-X patients and 28 normal chromosomes, all Jewish Ashkenazi, using microsatellite markers within and flanking the FMR-1 gene: FRAXAC1, FRAXAC2, and DXS548. The combined triple-marker analysis identified a wide range of diverse haplotypes in patients and controls, with no distinct haplotype prevalent in the patient group. Our data suggest that no common ancestral X chromosome is associated with the fragile-X syndrome in the Israeli Jewish Ashkenazi patient population studied. These findings are in contrast to other reports on founder effect associated with fragile-X syndrome in distinct European as well as Jewish Tunisian populations. On this basis, a more complex mechanism for the development of fragile-X syndrome in the Jewish Ashkenazi population should be considered.

Europe↗
PubMed1997

A hemodynamic model of the pathogenesis of age-related macular degeneration.

The clinical message of this editorial is that age-related macular degeneration may be a vascular disorder. It may be a manifestation of the hemodynamic consequence of the process of lipoid infiltration that, when it involves other organs such as those of the cardiovascular or cerebrovascular systems, is called atherosclerosis. The hemodynamic model presented here postulates that in age-related macular degeneration, the increase in resistance to the flow of blood in the choroid is caused by an age-related and diet-related decrease in the compliance of the sclera. It proposes that the form of age-related macular degeneration produced may depend on the relative resistances of the ophthalmic and cerebral circulations. A decrease in perfusion, leading to the atrophic form of age-related macular degeneration, is the outcome if the resistance of the cerebral circulation is relatively lower than that of choroid. Conversely, a relatively greater increase in the increase in the hydrostatic pressure in the choroidal vessels, leading to the exudative form of the disorder.

Blood Flow Velocity↗
PubMed1997

New evidence for neurotransmitter influences on brain development.

The early appearance of monoamine systems in the developing mammalian CNS suggests that they play a role in neural development. We review data from two model systems that provide compelling new evidence of this role. In one model system-in utero exposure to cocaine-specific and robust alterations are seen in dopamine-rich areas of the cerebral cortex, such as the anterior cingulate cortex: D1 receptor-G protein coupling is greatly reduced, the GABAergic system is altered and pyramidal dendrites undergo excessive growth. In a second model system-a transgenic mouse line in which the gene that encodes monoamine oxidase A (MAOA) is disrupted, resulting in excessively high 5-HT levels-barrels fail to form in the developing somatosensory cortex. Both models reveal the effects of very early manipulation of monoamines on forebrain development, and the long-term anomalies that persist into adulthood.

Animals↗
PubMed1997

Cardiovascular reactivity to a naturally occurring stressor: development and psychometric evaluation of a psychophysiological assessment procedure.

Three studies were conducted to examine the feasibility, reactive effects of assessment, stability, sampling parameters, and sensitivity of an assessment procedure designed to measure cardiovascular responses to a discrete, naturally occurring, and replicatable stressor--university course examinations. Undergraduate students monitored their blood pressure and heart rate several times during one or two classroom examinations and for several class sessions preceding each examination. Classroom examinations were generally associated with significant increases in subjective measures of distress and cardiovascular measures. Reactive effects of assessment and other sources of error were minimized and responses were reasonably stable over time. These results support the potential utility, validity, and cost-efficiency of this methodology for assessing cardiovascular reactivity to naturally occurring stressors.

Adolescent↗
PubMed1997

A mouse model for the learning and memory deficits associated with neurofibromatosis type I.

Neurofibromatosis type I (NF1) is one of the most commonly inherited neurological disorders in humans, affecting approximately one in 4,000 individuals. NF1 results in a complex cluster of developmental and tumour syndromes that include benign neurofibromas, hyperpigmentation of melanocytes and hamartomas of the iris. Some NF1 patients may also show neurologic lesions, such as optic pathway gliomas, dural ectasia and aqueduct stenosis. Importantly, learning disabilities occur in 30% to 45% of patients with NF1, even in the absence of any apparent neural pathology. The learning disabilities may include a depression in mean IQ scores, visuoperceptual problems and impairments in spatial cognitive abilities. Spatial learning has been assessed with a variety of cognitive tasks and the most consistent spatial learning deficits have been observed with the Judgement of Line Orientation test. It is important to note that some of these deficits could be secondary to developmental abnormalities and other neurological problems, such as poor motor coordination and attentional deficits. Previous studies have suggested a role for neurofibromin in brain function. First, the expression of the Nf1 gene is largely restricted to neuronal tissues in the adult. Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signalling. Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients. Here, we show that the Nf1+/- mutation also affects learning and memory in mice. As in humans, the learning and memory deficits of the Nf1+/- mice are restricted to specific types of learning, they are not fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning.

Acoustic Stimulation↗
PubMed1997

Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes.

OBJECTIVE: von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN2) are autosomal dominant cancer syndromes. In both conditions, phaeochromocytoma is a prominent feature. It has recently been suggested that phaeochromocytoma can be the presenting and sole clinical manifestation of these multi-organ syndromes. The aim of this study was to ascertain the incidence of VHL and MEN2 among patients with sporadic phaeochromocytoma by mutational analysis. PATIENTS: Twenty-seven unrelated patients with biochemically and/or anatomically proven sporadic phaeochromocytoma were evaluated. DESIGN AND MEASUREMENTS: Constitutional DNA obtained from the patients was analysed by single stranded conformational analysis (SSCP) for mutations within the VHL gene coding sequence and by denaturing gradient gel electrophoresis (DGGE) for predominant mutations in exons 10, 11 and 16 of the RET proto-oncogene. The incidence of patients positive for either VHL or RET germline mutations was assessed. RESULTS: Twenty-six of 27 patients had normal SSCP patterns in all three VHL gene exon segments and only one patient, with an atypical clinical presentation, had an aberrant pattern in exon 3 which upon DNA sequencing was shown to harbor a G to A transversion mutation at nucleotide 695. All patients had normal RET exon 10, 11 and 16 DGGE migration patterns. CONCLUSION: Most, if not all, patients with typical unilateral sporadic phaeochromocytoma do not have von Hippel-Lindau disease or MEN2. Thus, clinical and/or molecular investigation for von Hippel-Lindau disease and MEN2 in this patient population does not appear to be indicated.

Adolescent↗
PubMed1997

Managed care and medical education: hard cases and hard choices.

As managed care becomes more and more dominant in U.S. health care, it is coming into conflict with medical education. There are historical reasons for this: medical education traditionally excluded physicians who chose to work in health plans, and for profit managed care has tended to avoid subsidizing medical education. In order to improve the climate, three changes are necessary: medical education must understand the tense history of discord between the two; distinctions must be made between responsible and irresponsible managed care plans; and medical educators should not assume they own the moral high ground. Arrogance, a gross oversupply of physicians and especially specialists, scandals and fraud, an often callous attitude toward the poor, and other sins can be laid at medical education's door. The worse threat for both sides is that the public and payers could simply abandon both, leading to underfunding for health professions education, a society that does not trust its health care system, and the loss of superb teaching organizations. To prevent this, managed care and medical education should work together to solve several difficult problems: how to shrink the medical education infrastructure; how to report honestly the uses to which medical education funds are put; and how to identify and end irresponsible behavior on the part of health plans and medical education entities alike. If the two sides can exercise leadership in these areas, they will be able to protect and enhance the singular place of honor that medical education holds in this society.

Academic Medical Centers↗
PubMed1997

Pediatric aerodigestive foreign body injuries are complications related to timeliness of diagnosis.

Foreign body (FB) injury from aspiration or ingestion is a common pediatric health problem. Diagnosis relies on clinical judgment plus medical history, physical examination, and radiographic evaluation. A multi-institutional review of 1269 FB events revealed that 85% were correctly diagnosed following a single physician encounter. However, 15% of the children had an elusive diagnosis (>1 week), despite previous evaluation. Delays in diagnosis were seven times more likely to occur in aspirations than in ingestions. Secondary injuries (e.g., pneumonia and atelectasis) occurred in 13% of airway FBs but in only 1.7% of esophageal FBs. Plain radiographs were used in 82% of children, and special studies (e.g., fluoroscopy) in only 7%. We conclude that diagnosis of FB injury in children is frequently achieved at the initial evaluation but that continued surveillance by follow-up visits to health care facilities from parents and other caretakers is important, to reduce pulmonary injuries.

Adolescent↗
PubMed1997

D1-like dopaminergic activation of phosphoinositide hydrolysis is independent of D1A dopamine receptors: evidence from D1A knockout mice.

Accumulated evidence suggests that dopamine and dopamine D1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought to be linked to adenylyl cyclase, has also been proposed to couple to phospholipase C. However, a number of studies have suggested that this signaling pathway is mediated via a distinct D1-like dopamine receptor. We tested whether the D1A site plays a role in stimulating phosphoinositide hydrolysis by using the dopamine D1A-deficient mutant mice as a test model. Results show that although D1 dopamine receptor-mediated product on of cAMP is completely absent in membranes of D1A-deficient mice, D1 receptor-mediated accumulation of inositol phosphate is identical in tissues of mutant and wild-type animals. Furthermore, the coupling of [3H]SCH23390 binding sites in striatal or frontal cortex membranes to G alpha s is markedly reduced, although coupling of [3H]SCH23390 binding sites to G alpha q was unaltered in tissue taken from D1A mutant mice compared with control animals. These results clearly demonstrate that dopaminergic stimulation of inositol phosphate formation is mediated by a D1 dopamine receptor subtype that is distinct from the D1A receptor that activates adenylyl cyclase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

An efficacy-dependent effect of cardiac overexpression of beta2-adrenoceptor on ligand affinity in transgenic mice.

In previous studies, it was shown that the overexpression of beta2-adrenoceptor (beta2AR) in the hearts of transgenic mice (Tg) leads to agonist-independent activation of adenylate cyclase and enhanced myocardial function. Here, we measured the physical coupling of beta2AR and Gs by evaluating the coimmunoprecipitation of beta2AR and Gs and the ligand binding properties of beta2AR in the hearts of Tg mice to investigate the details of the interaction among ligand, receptor, and G protein. The following results were obtained: (i) coimmunoprecipitation of beta2AR and Gs was increased in the absence of agonist in Tg mice compared with the control animals. This demonstrates directly the increased interaction between unliganded beta2AR and Gs, which is consistent with increased background cAMP production and cardiac function in the hearts of Tg mice. (ii) Guanosine-5'-(beta,gamma-imido)triphosphate abolished the association of beta2AR/Gs in the immunoprecipitate. (iii) The affinities for ligands that show agonist (isoproterenol, clenbuterol, and dobutamine), neutral antagonist (alprenolol and timolol), and negative antagonist (propranolol and ICI 118551) activities in this experimental system were increased, not changed and decreased, respectively, in Tg mice compared with the controls. (iv) This efficacy-dependent alteration in ligand affinities was still observed in the presence of a guanosine-5'-(beta,gamma-imido)triphosphate concentration that abolishes beta2AR/Gs coupling. This suggests that the altered beta2AR binding affinities in Tg mice are not due to the increased interaction between beta2AR and Gs. These data cannot be explained by using ternary, quinternary, two-state extended ternary, or cubic ternary complex models. We therefore discuss the results using a "two-state polymerization model" that includes an isomerization step for the conversion of receptor between an inactive and an active form (denoted as R and R*, respectively) and a polymerization of the active state (R*n). The simplest form of this model (i.e., noncooperative dimerization of the receptor) is found to be consistent with the experimental data.

Adrenergic beta-Agonists↗
PubMed1997

Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta.

Previous studies showed that alpha-adrenoceptor (AR) stimulation with norepinephrine is more potent at eliciting contraction in aortas from 1-month-old Fischer 344 rats than from older rats and that this response is mediated by alpha 1b- and alpha 1d-AR subtypes in 1-month-old rats. We examined the G proteins responsible for alpha 1-AR-mediated contractile response and inositol phosphate accumulation in the aortas of 1-month-old Fischer 344 rats. Pertussis toxin (PTX) treatment (2.5 micrograms/ml for 4 hr) of aortic rings partially inhibited phenylephrine (PHE)-stimulated contraction and inositol phosphate accumulation, suggesting the involvement of PTX-sensitive and -insensitive G proteins. Specific antisera directed against G alpha q and G alpha o but not G alpha s and G alpha i precipitated specific alpha 1-AR binding sites labeled with 2-[beta-(4-hydroxy-3-[125I]iodophenyl)ethylaminomethyl]tetralone. The number of 2-[beta-(4-hydroxy-3-[125I]iodophenyl)ethylaminomethyl]tetralone binding sites precipitated by G alpha proteins was increased by activating membrane alpha 1-ARs with PHE. Moreover, PHE stimulated the palmitoylation of G alpha q and G alpha o, and this response was blocked by the alpha 1-AR antagonist prazosin. Characterization of the alpha 1-AR subtypes that couple to G proteins indicates that although aortic alpha 1a-, alpha 1b-, and alpha 1d-ARs were associated with G alpha q, alpha 1b-AR was also linked to G alpha o. These results suggest that alpha 1-ARs mediate the contractile response in rat aorta by coupling to both Gq protein and the PTX-sensitive G(o) protein.

Animals↗
PubMed1997

Desensitization of norepinephrine receptor function is associated with G protein uncoupling in the rat aorta.

Infusion of norepinephrine (NE) in rats results in desensitization of NE-mediated aortic contraction and a reduction (55% at 1 and 10 microM) in NE-stimulated vascular inositol phosphate accumulations. The functional responses to angiotensin II (ANG II) were also reduced in the tissues of NE-infused animals. alpha 1-Adrenoceptor number determined by 2-[beta-(4-hydroxy-3-[125I]iodophenyl)-ethylaminomethyl]-tetralone ([125I]HEAT) binding and levels of G alpha or G beta proteins measured by immunoblot analyses were not changed in the aortic membranes of NE-infused animals. To determine whether desensitization is associated with receptor-G protein uncoupling, agonist-stimulated palmitoylation of G alpha proteins was measured. NE infusion decreased phenylephrine (1 microM)-stimulated [3H]palmitate incorporation into Gq alpha, Gs alpha, and Gi alpha proteins and ANG II (10 microM)-stimulated palmitoylation of Gq alpha and Gi alpha in aortic membranes. Phenylephrine- and ANG II-stimulated guanosine 5'-O-(3-[35S]thiotriphosphate) binding to Gq alpha was also decreased in the aortas of NE-infused animals. These results show that an infusion of NE causes heterologous desensitization of the contractile and inositol phosphate accumulation responses in the rat aorta and that these changes are mediated by an uncoupling of receptors from their G proteins.

Adrenergic alpha-Antagonists↗
PubMed1997

Ubiquitous expression of a cloned murine thymopoietin cDNA.

Thymopoietin (TP) was originally isolated as a 5-kD 49-aa protein from bovine thymus and was subsequently observed to affect T-cell differentiation and function. We report here the molecular cloning of a murine TP cDNA. The 2,514 bp fragment contains a 630 bp open reading frame that encodes for 210 aa, highly homologous to the first 220 aa of the human TP beta and TP gamma isoforms and to bovine TP. Southern blot analysis of genomic DNA revealed that in mouse, calf and human TP is encoded by a single genomic locus. Recently, it was found that one of the TP isoforms designated TP beta is a homologous protein to the lamina-associated polypeptide 2 (LAP2), which is thought to play an important role in the regulation of nuclear architecture by binding lamin B1 and chromosomes in a manner regulated by phosphorylation during mitosis. In this study we report the TP expression at the transcription level in 17 murine and rat tissues of different origins and 18 lymphoid and nonlymphoid cell lines. The assessment of TP mRNA expression by S1-nuclease protection assays and in situ hybridizations revealed that its expression is not exclusive to thymus, but rather ubiquitous, higher in lymphatic tissues, but also in other cells characterized with a high rate of proliferation. TP was also shown to be expressed in athymic and old animals, lacking a functional thymus gland. Further in situ hybridization studies revealed that within the thymus, the highest levels of TP mRNA are noted at the cortex. These results suggest a possible role for TP in proliferation and cell cycle control.

Amino Acid Sequence↗
PubMed1997

A novel polymorphism in the coding region of the vasopressin type 2 receptor gene.

Nephrogenic diabetes insipidus (NDI) is a rare disease characterized by renal inability to respond properly to arginine vasopressin due to mutations in the vasopressin type 2 receptor (V2(R)) gene in affected kindreds. In most kindreds thus far reported, the mode of inheritance follows an X chromosome-linked recessive pattern although autosomal-dominant and autosomal-recessive modes of inheritance have also been described. Studies demonstrating mutations in the V2(R) gene in affected kindreds that modify the receptor structure, resulting in a dys- or nonfunctional receptor have been described, but phenotypically indistinguishable NDI patients with a structurally normal V2(R) gene have also been reported. In the present study, we analyzed exon 3 of the V2(R) gene in 20 unrelated individuals by direct sequencing. A C-->T alteration in the third position of codon 331 (AGC-->AGT), which did not alter the encoded amino acid, was found in nine individuals, including two unrelated patients with NDI. Taken together, these observations emphasize the molecular heterogeneity of a phenotypically homogeneous syndrome.

Diabetes Insipidus, Nephrogenic↗
PubMed1997

Childhood abuse as a risk for partner abuse among women in methadone maintenance.

This study examines the relationship between childhood abuse and partner abuse among a sample of predominantly African-American and Hispanic women, who were patients in methadone clinics in Harlem and the South Bronx. A structured questionnaire addressing demographics, psychosocial and physical health characteristics, depression, childhood abuse, and domestic violence was administered to 151 women. Over half of the women (60%, n = 98) reported lifetime physical, life-threatening, or sexual abuse by a spouse or boyfriend. Multiple logistic regression analysis was used to assess the associations between childhood physical abuse and abuse by a spouse or boyfriend and between childhood sexual abuse and abuse by a spouse or boyfriend. After controlling for potential confounders, women who reported childhood physical abuse were almost nine times more likely to report having been abused by a spouse or boyfriend (OR = 8.74, CI, = 3.25 to 23.57). Women who reported childhood sexual abuse were almost four times more likely to report having been abused by a spouse or boyfriend (OR = 3.93, CI = 1.46 to 10.59). Depression and need for social support were significantly associated with partner abuse, while current heroin use was inversely associated with partner abuse. The high rate of domestic violence and the strong association between childhood and partner abuse found in this study suggest areas for intervention in chemical dependency among women.

Adult↗