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Biomedical subjects

M Grossman

Publications and source records attributed to M Grossman.

At least 127 records · Page 7Linked to original sources
PubMed1994

Molecular mechanisms of androgen action.

Androgens directly regulate a vast number of physiological events. These direct androgen effects are mediated by a nuclear receptor that exhibits four major functions or activities: steroid binding, DNA binding, transactivation, and nuclear localization. The SBD consists of a hydrophobic pocket of amino acids that exhibits high-affinity, androgen-specific binding. Based on studies of mutant AR, it appears that a number of different amino acids contribute to the steroid binding characteristics of the AR. The DNA binding domain confers sequence-specific binding to structures called androgen-responsive elements. The specificity of steroid binding and DNA binding provides a crucial basis for androgen-specific regulation of target genes. The nuclear localization signal shares homology with known nuclear localization signals and, coupled with the presence of androgens, is responsible for localizing the AR to the nucleus. The transactivation functions reside mostly in the NH2 terminus but the responsible domains are as yet poorly defined. Though the different domains can act as independent moieties, one domain can clearly alter the behavior of another domain. For instance, the SBD appears to inhibit the transactivating functions until steroid is bound and the amino terminus prevents DNA binding activity until steroid is bound. The relative ease of introducing mutations with polymerase chain reaction technology will facilitate further delineation of critical amino acids and domains responsible for the various activities of the AR. The recent cloning and characterization of AR promoters revealed that the AR genes are driven by a TATA-less promoter characteristics of housekeeping genes. Analysis of transcription rates, mRNA levels, and protein levels indicates that androgens and pkA and pkC pathways modulate expression of AR mRNA and protein. This indicates that the same signal pathways that interact to regulate androgen target genes also regulate the levels of AR in the target tissues. Surprisingly few androgen-regulated genes have been well characterized for the mechanisms by which androgen regulates the gene. The C(3), Slp, probasin, PSA, and hKLK2 genes have provided examples where androgens regulate transcription. Posttranscriptional regulation by androgens has been demonstrated for the SVP1, 2, 3, and 4 and AR genes. The mechanisms underlying posttranscriptional regulation are poorly defined but substantial progress has been made in defining the critical elements that mediate transcriptional effects of androgens. Transcriptional effects are mediated through binding of androgen-AR complexes to specific DNA sequences called AREs. Simple AREs such as those found in C(3) and kallikrein genes tend to be permissive in that GR and PR can also act through the same element.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgens↗
PubMed1994

Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.

An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in which the recipient is transplanted with autologous hepatocytes that are genetically corrected with recombinant retroviruses carrying the LDL receptor. We describe the treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver. She tolerated the procedures well and in situ hybridization of liver tissue four months after therapy revealed evidence for engraftment of transgene expressing cells. The patient's LDL/HDL ratio declined from 10-13 before gene therapy to 5-8 following gene therapy, improvements which have remained stable for the duration of the treatment (18 months). This represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.

Adult↗
PubMed1994

Gene therapy for cystic fibrosis using E1-deleted adenovirus: a phase I trial in the nasal cavity. The University of North Carolina at Chapel Hill.

Cystic fibrosis (CF) is an autosomal recessive disease that reflects mutations in the CFTR gene. Multiple mutations in this gene have been detected that lead to a protein (CFTR) that is abnormally metabolized, dysfunction, or both. The full spectrum of the activities of the gene product have not been defined, but it is clear that CFTR can act as a cAMP-regulated Cl- channel. This type of defect is consistent with the physiologic characterization of CF epithelia, which has revealed abnormalities in salt and water transport. In the lung, abnormalities in epithelial salt and water metabolism lead to abnormal mucociliary clearance. This defect in clerance represents a major failure of lung defense and leads ultimately to infection of the lung with Staphylococcus aureus, Pseudomonas aeruginosa, and other bacterial organisms. The chronic inflammatory response to this persistent intraluminal bacterial infection leads to protease-induced destruction of airway walls and finally, lung failure. More than 95% of CF patients die of lung disease. The clinical therapy of CF lung disease is limited to agents designed to promote clearance of secretions from the lung and antibiotics to treat the chronic bacterial infection. Recent laboratory demonstrations that introduction of the normal CFTR cDNA into CF cells corrects the ion transport defects of these cells has led to the hypothesis that gene therapy in the lung can be an effective, novel mode of therapy for this lung disease. The classic gene transfer vectors, e.g., retroviruses, appear to be not well suited for therapy of lung disease because of the low proliferation rate of airway epithelia in vivo. Recently, adenoviruses, which have a natural tropism for airway epithelia, have been genetically modified (E1-deleted) in an attempt to reduce potential toxicity of this virus and provide space for the CFTR cDNA. A series of in vitro studies have shown that this vector is highly efficient for transferring CFTR into airway epithelial cells in culture and correcting the CF defect. Further, studies in whole animals appear to indicate that this mode of gene transfer is associated with a low degree of toxicity. The present study is a dose-effect study designed to test for the safety and efficacy of E1-deleted recombinant adenovirus containing the CFTR cDNA under a CMV-beta-actin promoter in CF nasal epithelia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoviridae↗
PubMed1994

Evaluation of lymphadenopathy in children.

This chapter provides an approach to the evaluation of lymphadenopathy in children. Malignant etiologies, including HIV-associated malignancies are reviewed. In discussing infectious agents or causes of lymphadenopathy, particular emphasis is placed on chronic regional lymphadenopathy with a focus on new advances in cat-scratch disease and tuberculous and non-tuberculous mycobacterial lymphadenitis. After a suggested preliminary set of laboratory tests, biopsy is often necessary both for histologic and cultural investigation. Therapy must be specific and must follow an accurate diagnosis.

AIDS-Related Complex↗
PubMed1994

Photosensitivity as the presenting illness in four patients with human immunodeficiency viral infection.

BACKGROUND: A multitude of skin lesions have been reported in individuals with human immunodeficiency virus (HIV) infection. Some of them, eg, severe seborrheic dermatitis and herpes zoster infections, may predate the onset of the diagnostic criteria for the acquired immunodeficiency syndrome and may actually raise the suspicion of HIV infection in healthy-appearing individuals. We have recently evaluated four individuals who presented with a severe idiopathic photosensitivity of eczematous morphologic features who eventuated in a diagnosis of HIV seropositivity. Four individuals who presented with an eczematous eruption of sun-exposed skin were referred to the Environmental Dermatology Unit of Columbia-Presbyterian Medical Center (New York, NY) for evaluation of possible photosensitive disease. They were examined and underwent photobiological testing (minimal erythema dose testing and photopatch testing) to confirm and classify their suspected photosensitivity. OBSERVATIONS: All four patients fulfilled the criteria for chronic actinic dermatitis, a rare idiopathic photosensitivity characterized by debilitating, unremitting dermatitis with eczematous or lymphomalike histologic features and reproduction of lesions by small quantities of mid-wave UV-B radiation (290 to 320 nm). All four individuals were HIV seropositive and CD4 counts were markedly suppressed in all four. The photosensitivity predated the finding of seropositivity and the diagnosis of acquired immunodeficiency syndrome in all four patients. CONCLUSION: The presentation of healthy-appearing individuals with photodistributed dermatitis of unknown cause should alert the physician to the possibility of HIV infection.

Adult↗
PubMed1993

Therapeutic strategies for familial hypercholesterolemia based on somatic gene transfer.

Inherited dyslipidemias are important risk factors for the premature development of coronary artery disease. One example is an inherited deficiency of low density lipoprotein (LDL) receptors that leads to the syndrome familial hypercholesterolemia (FH). We have used FH as a model for developing new approaches for treating this group of disorders by somatic gene therapy. Experiments in animal models that led to the initiation of a clinical trial of homozygous FH will be presented in this review.

Animals↗
PubMed1993

The sum and substance of it: the appreciation of mass and count quantifiers in Parkinson's disease.

We performed three experiments in order to determine whether patients with Parkinson's disease (PD) have a sentence comprehension impairment. In the first experiment, we found that nondemented PD patients were impaired at matching a short sentence containing a mass or count quantifier (e.g., "Point to the jar with many") with one of four pictures. Patients erred by pointing to the incorrect mass or count type of substance, but pointed correctly to the large or small amount of a substance in the picture. In the second experiment, we asked the same PD patients to judge short sentences containing mass or count nouns modified by mass or count adjectives (e.g., *"The glass contains many milk"). PD patients were significantly impaired at detecting errors in the agreement between a noun and a quantifying adjective and errors in the appropriate use of the plural associated with a noun. A sentence completion task was performed in order to determine whether patients impaired on both sentence-picture matching and sentence judgment tasks are also compromised in their expression of quantifiers. Some patients impaired on both tasks also had difficulty expressing quantifiers, and it is these patients who may have difficulty performing grammatical computations. Other patients were selectively impaired in their sentence-picture matching or their sentence judgments, suggesting a performance deficit concerned with a particular task. We conclude that sentence comprehension impairments in PD are multifactorial in nature.

Adult↗
PubMed1993

Adenovirus-mediated correction of the genetic defect in hepatocytes from patients with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an inherited deficiency of LDL receptors that has been an important model for liver-directed gene therapy. We are developing approaches for treating FH that are based on direct delivery of recombinant LDL receptor genes to liver in vivo. As a first step towards this goal, replication-defective recombinant adenoviruses were constructed which contained either the lacZ gene or the human LDL receptor cDNA expressed from a beta-actin promoter. Primary cultures of hepatocytes were established from two patients with homozygous FH and one nonFH patient, and subsequently exposed to recombinant adenoviruses at MOIs ranging from 0.1 to 5. Essentially all of the cells expressed high levels of the transgene without demonstrable expression of an early or late adenoviral gene product; the level of recombinant-derived LDL receptor protein in transduced FH hepatocytes exceeded the endogenous levels by at least 20-fold. These studies support the utility of recombinant adenoviruses for efficient transduction of recombinant LDL receptor genes into human FH hepatocytes without expression of viral proteins.

Adenoviridae↗
PubMed1993

Determinants of interest rates on tax-exempt hospital bonds.

The aim of this paper is to examine the determinants of interest rates on tax-exempt hospital bonds. The results highlight the potential and actual roles of Federal and state policy in the determination of these rates. The shift to a Prospective Payment System under Medicare has subsidized the borrowing costs of some hospitals at the expense of others. The selection of underwriters by negotiation rather than by competitive bidding results in higher interest rates. The Federal tax act of 1986 raised the cost of hospital debt by encouraging bond issues to contain call features.

Capital Financing↗
PubMed1993

Retroviruses: delivery vehicle to the liver.

Liver-directed gene therapy holds great promise for the treatment of inherited metabolic disease. Two strategies have emerged. Ex vivo gene therapy involves the transplantation of autologous hepatocytes transduced with recombinant retroviruses while in culture. The feasibility of this approach has been demonstrated in several animal models, and a human trial has been initiated. An alternative strategy uses recombinant viruses to deliver the transgene directly to hepatocytes in vivo.

Animals↗
PubMed1993

Sex differences in intensity of emotional experience: a social role interpretation.

According to gender role theory, women's greater emotional intensity than men's stems from normative expectations for sex differences that arise as a result of men's and women's social roles. In the 1st experiment, endorsement of normative expectations for sex differences was associated with sex differences in Ss' own emotions: To the extent that they endorsed stereotypical differences between men and women, female Ss reported personally experiencing emotions of greater intensity and male Ss reported experiencing emotions of lesser intensity. The 2nd study manipulated expectations for responsiveness while Ss viewed a series of emotion-inducing slides. When instructions rendered normative expectations comparable for men and women, no sex differences were obtained in emotion self-reports. Furthermore, women evidenced more extreme electromyograph physiological responding than men, suggesting general sex differences in emotion that are not limited to self-report.

Attitude↗
PubMed1993

The significance of the relationship between a discipline and its practice.

In this paper, it is argued that the absence of conceptual consensus across the university and its sectors is largely responsible for the growing gap between the goals of the discipline and its practice. Both discipline and practice are defined, their symbiotic relationship explored, and specific strategies proposed, to enhance the development of the profession. In particular, the need for a shared conceptual framework which would transcend university and service structures to promote an academic practice is examined in addition to the benefits of instituting theoretically based daily rounds and journal club in the practice setting.

Education, Nursing, Baccalaureate↗
PubMed1993

Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: biological efficacy study.

We have evaluated the biological efficacy of E1-deleted adenoviruses in baboons for lung-directed gene therapy of cystic fibrosis (CF). The experimental design attempted to simulate a phase I clinical trial with animals receiving a single dose of virus to an isolated pulmonary segment. A total of 14 animals divided into four groups, each of which received escalating doses of virus, were used. Individual animals were necropsied 4 and 21 days after gene transfer and tissues were carefully surveyed for gene expression. Expression of the transgene was localized primarily to the area into which it was infused; the efficiency of recombinant gene expression and the abundance of transgene sequences were proportional to dose and both diminished with time. Transgene expression was found predominantly in alveolar cells with patches of expression in the proximal and distal airway. Analysis of adenoviral protein expression within transgene-expressing cells revealed infrequent expression of the E2a gene and no detectable expression of late genes (i.e., fiber protein). These results suggest that recombinant adenovirus can be used to transfer genes efficiently to the lung of nonhuman primates and that therapeutic strategies of cystic fibrosis may require repetitive administration with current vectors.

Adenoviridae↗