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Biomedical subjects

J Halpern

Publications and source records attributed to J Halpern.

At least 19 recordsLinked to original sources
PubMed1996

The CRKL adaptor protein transforms fibroblasts and functions in transformation by the BCR-ABL oncogene.

The CRKL adaptor protein was recently identified as a substrate for the BCR-ABL tyrosine kinase in patients with chronic myelogenous leukemia, but its function is unknown. Here we report that CRKL is phosphorylated when overexpressed, activates RAS and JUN kinase signaling pathways, and transforms fibroblasts in a RAS-dependent fashion. We examined the potential role of CRKL in BCR-ABL function by deleting the CRKL binding site in BCR-ABL. This mutant BCR-ABL protein shows a 50% reduction in fibroblast transforming activity. The GRB2 adaptor protein has previously been implicated in this pathway, presumably linking BCR-ABL to RAS. To address the relative roles of CRKL and GRB2 in this system, we compared BCR-ABL mutants with defects in binding to one or both adaptors. Whereas each single mutant showed a 2-3-fold loss in transforming activity, the double mutant showed a 15-fold reduction, suggesting that GRB2 and CRKL both contribute to BCR-ABL transformation. These results demonstrate the oncogenic potential of CRKL and provide functional evidence that CRKL plays a role in fibroblast transformation by BCR-ABL in conjunction with other adaptor proteins.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia.

Using chronic myelogenous leukemia (CML) as a model, we tested the hypothesis that cytokine-independent growth of leukemia cells results from aberrant activation of cytokine signaling pathways. The STAT5 (signal transducer and activator of transcription) protein, which is activated transiently in normal myeloid cells by cytokines such as GM-CSF (granulocyte-macrophage colony stimulating factor), was constitutively activated in cell lines derived from CML patients, even in the absence of GM-CSF. STAT5 was also activated in primary mouse bone marrow cells acutely transformed by the CML-specific BCR-ABL oncogene, but not by the serine kinase oncogene v-MOS. Reconstitution experiments in non-hematopoietic cells show that STAT5 activation by BCR-ABL occurs independent of cytokines. Results using BCR-ABL mutants which specifically uncouple connections to known signal transduction pathways show that STAT5 activation is kinase dependent and correlates directly with ability to confer cytokine independent growth in hematopoietic cells. BCR-ABL also activates JAK kinases, which may provide a mechanism for STAT activation. These findings are consistent with a role for STAT5 in hematopoietic transformation by BCR-ABL.

Animals↗
PubMed1996

Evaluating pressure ulcer occurrence in long-term care: pitfalls in interpreting administrative data.

Administrative databases for long-term care frequently collect information on fixed dates of the calendar year, rather than for entire episodes of care. Patients discharged or dying prior to an evaluation date are lost to follow-up. We used one such database, the VA Patient Assessment File, to examine pressure ulcer occurrence in long-term care. Clinical studies have established that most pressure ulcers develop during the first several weeks following admission. In these data, however, pressure ulcer development was less common in patients assessed within 2 months following admission, as compared to those examined at 3 to 6 months. This finding appears to be related to the selective discharge of patients, which makes these patient populations noncomparable. These results highlight that care must be exercised when interpreting results obtained from such administrative data.

Aged↗
PubMed1996

The measurement of quality of care in the Veterans Health Administration.

The Veterans Health Administration (VHA) is committed to continual refinement of its system of quality measurement. The VHA organizational structure for quality measurement has three levels. At the national level, the Associate Chief Medical Director for Quality Management provides leadership, sets policy, furnishes measurement tools, develops and distributes measures of quality, and delivers educational programs. At the intermediate level, VHA has four regional offices with staff responsible for reviewing risk management data, investigating quality problems, and ensuring compliance with accreditation requirements. At the hospital level, staff reporting directly to the chief of staff or the hospital director are responsible for implementing VHA quality management policy. The Veterans Health Administration's philosophy of quality measurement recognizes the agency's moral imperative to provide America's veterans with care that meets accepted standards. Because the repair of faulty systems is more efficient than the identification of poor performers, VHA has integrated the techniques of total quality into a multifaceted improvement program that also includes the accreditation program and traditional quality assurance activities. VHA monitors its performance by maintaining adverse incident databases, conducting patient satisfaction surveys, contracting for external peer review of 50,000 records per year, and comparing process and outcome rates internally and when possible with external benchmarks. The near-term objectives of VHA include providing medical centers with a quality matrix that will permit local development of quality indicators, construction of a report card for VHA's customers, and implementing the Malcolm W. Baldrige system for quality improvement as the road map for systemwide continuous improvement. Other goals include providing greater access to data, creating a patient-centered database, providing real-time clinical decision support, and expanding the databases.

Cardiac Surgical Procedures↗
PubMed1995

Designing a cost-effective clinical trial.

Researchers and administrators must decide which clinical trials are worth doing and how many subjects are needed for a trial. We calculated sample size considering the costs of implementing the results of the trial and the trial costs using (1) Neyman-Pearson methods and (2) a Bayesian cost-benefit method. We illustrate these methods in a clinical trial sponsored by the National Institutes of Health that compares two levels of blood urea nitrogen clearance by haemodialysis for patients with end-stage renal disease. When applied to evaluations of research proposals, these methods may help researchers to decide whether to begin a study, and, if so, how many subjects to enrol in it. These methods should be especially useful for large studies intended to inform health policy.

Bayes Theorem↗
PubMed1995

Reactogenicity and immunogenicity of a three-component acellular pertussis vaccine administered as the primary series to 2, 4 and 6 month old infants in the United States.

Five hundred and fifty-seven infants received either an acellular pertussis (DTaP) vaccine containing pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) or one of two commercially available whole-cell pertussis (DTP) vaccines at 2, 4 and 6 months. One month after the third immunization, IgG antibody values to pertussis toxoid, filamentous hemagglutinin and PRN were significantly greater following DTaP than either DTP (P < 0.05). When reactions within 48 h after all three doses of vaccine were combined, fever 101 degrees, > or = moderate fussiness, > or = moderate pain, swelling 10 mm, and erythema 10 mm occurred less often after DTaP compared with DTP-Connaught (P < 0.001). The same adverse events were also less after DTaP compared with DTP-Lederle (P < 0.05), except for erythema 10 mm. This three-component DTaP vaccine produced fewer adverse events and greater antibody values to PT, FHA and PRN in comparison with either licensed DTP vaccine when given as the primary series.

Adhesins, Bacterial↗
PubMed1995

Long-term survival after histologic transformation of low-grade follicular lymphoma.

PURPOSE: To describe the course of patients following histologic transformation (HT) from low-grade follicular lymphoma to intermediate- or high-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were identified from data bases in the Division of Oncology and the Department of Surgical Pathology. HT was defined as the conversion of a follicular small cleaved-cell or follicular mixed small cleaved-cell and large-cell lymphoma to a diffuse large-cell, diffuse mixed small cleaved-cell and large-cell or any high-grade lymphoma. RESULTS: We analyzed the clinical course of 74 low-grade lymphoma patients with histologically proven transformation occurring from 1965 to 1988. The median time from diagnosis to HT was 66 months, and the median age at HT was 58 years. The median duration of survival after transformation was 22 months. Anatomic extent of disease at HT (limited v extensive, P = .01), prior chemotherapy (none v any, P = .01), and response to therapy (complete v partial or none, P = .005) at time of HT were identified as significant predictors of survival after HT in backward-selection Cox regression analysis. Thirty patients attained a complete response to therapy at HT. They had a median survival duration of 81 months after HT. CONCLUSION: A subset of patients with HT from low-grade follicular lymphoma to intermediate- or high-grade lymphoma enjoys relatively long-term survival. Patients with limited disease and no previous exposure to chemotherapy have the most favorable prognosis.

Adult↗
PubMed1995

Loss of vision.

Assessment of the patient with vision loss includes measurement of visual acuity, examination of the pupil, a finger-counting confrontation field examination, and an ophthalmoscopic examination. Opticokinetic testing is useful when functional blindness is being considered. A scheme is presented to use these findings to arrive at the anatomic level of this dysfunction. A differential diagnosis can then be generated. Some specific disorders causing vision loss are presented by anatomic location.

Blindness↗
PubMed1994

Specific antibodies against the Zn(2+)-binding domain of clostridial neurotoxins restore exocytosis in chromaffin cells treated with tetanus or botulinum A neurotoxin.

Although tetanus and botulinum A neurotoxins are ineffective in cultured chromaffin cells, they will inhibit carbachol-induced release of noradrenaline provided they gain access to the cytosol either through artificial pores generated in the plasma membrane or by binding to incorporated exogenous gangliosides. The block of exocytosis persists for weeks followed by a slow recovery of cell function. When specific anti-botulinum A toxin antibodies are introduced into cells through pores after manifestation of the block by botulinum A neurotoxin, restoration of exocytotic function is accelerated and fully reestablished within 4 days. The same time course of restoration is seen with anti-tetanus toxin antibodies in cells poisoned by tetanus toxin. Since the light chains of the toxins are enzymatically active, we have introduced polyclonal and monoclonal anti-light chain antibodies into the cytosol. Of all light chain antibodies tested, only those directed against the peptide homologous to the zinc-binding sequence, which is present in both neurotoxins, restored exocytosis regardless of which toxin caused the block. These results indicate that the zinc-binding domain is directly involved in the interaction of the light chains with their substrates and that the toxins have to be present continuously to maintain the block.

Adrenal Medulla↗
PubMed1994

Clear cell epithelial-myoepithelial carcinoma arising in pleomorphic adenoma of the lacrimal gland.

BACKGROUND: A 63-year-old man had an 8-year history of painless proptosis, which had noticeably increased over the last 2 months. A mass was palpable in the left lateral canthus. Computed tomographic studies showed a globular mass with small foci of calcification involving the lacrimal gland. After an incisional biopsy, a histologic diagnosis of clear cell epithelial-myoepithelial carcinoma was made and an orbital exenteration was performed. FINDINGS: Results of histologic examination of the mass showed a partially encapsulated, clear cell epithelial-myoepithelial carcinoma with an associated pleomorphic adenoma (benign mixed tumor). Immunohistochemical studies disclosed strong immunoreactivity to cytokeratin (AE1/AE3), epithelial membrane antigen, S-100 protein, and alpha-actin. CONCLUSION: Although a clear cell myoepithelial carcinoma rarely has been reported in association with a pleomorphic adenoma of the submandibular gland, to the authors' knowledge, this combination has never been reported in the lacrimal gland, nor has a clear cell epithelial-myoepithelial carcinoma ever been reported in this anatomic location. The differential diagnosis of lesions with prominent clear cells involving the lacrimal gland is extensive and includes clear cell variants of acinic cell carcinoma and oncocytoma, mucoepidermoid carcinoma, and others.

Adenocarcinoma, Clear Cell↗
PubMed1994

Follicular large-cell lymphoma: intermediate or low grade?

PURPOSE: To evaluate the benefit of anthracycline-based chemotherapy, identify prognostic factors, and determine the value of the International Prognostic Factors Index for patients with follicular large-cell (FLC) lymphoma. PATIENTS AND METHODS: This retrospective study includes 96 patients with FLC lymphoma treated at Stanford University Medical Center between 1969 and 1991. Fifty-five patients received doxorubicin plus cyclophosphamide-containing chemotherapy regimens, 21 patients received other chemotherapy regimens, 15 patients received radiotherapy only, and five patients received no initial therapy. Thirty-four patients had stage I or II disease and 62 patients had stage III or IV disease. RESULTS: With a median follow-up duration of 5.2 years (range, 1 to 18), the actuarial 5- and 10-year overall survival rates were 75% and 54%, with actuarial 5- and 10-year freedom from progression (FFP) rates of 53% and 42%, respectively. Patients treated with chemotherapy regimens that contained both doxorubicin and cyclophosphamide had a superior actuarial 10-year FFP rate (55% v 25%, P = .06) and overall survival rate (65% v 42%, P = .04) compared with patients treated with other chemotherapy regimens. Only one patient treated with doxorubicin plus cyclophosphamide relapsed after 3 years. In the multivariate analysis, discordant lymphoma and treatment with chemotherapy regimens not containing both cyclophosphamide and doxorubicin predicted for worse FFP and overall survival rates. In addition, poor performance status and increasing areas of diffuse histology predicted for a worse survival, while anemia and male sex predicted for a worse FFP. The age-specific International Index was useful in predicting outcome; however, few patients with FLC lymphoma had high-risk features. CONCLUSION: The plateau in FFP implies that patients with FLC lymphoma enjoy sustained remissions after standard anthracycline-based chemotherapy. FLC lymphoma should continue to be approached as an intermediate-grade lymphoma with curative intent.

Actuarial Analysis↗
PubMed1994

HIV-1 syncytium-inducing phenotype, virus burden, codon 215 reverse transcriptase mutation and CD4 cell decline in zidovudine-treated patients.

The variable rate of disease progression in HIV-1-infected patients treated with zidovudine may be related to certain viral characteristics, such as, antiviral drug resistance, virus burden, and viral syncytium-inducing (SI) capacity. Thirty-two HIV-1-infected patients treated with zidovudine (mean of 34 months) were studied to determine the relationship of SI phenotype and the codon 215 pol gene mutation (a marker of zidovudine resistance) to virus burden and CD4 cell decline. Patients with SI strains and the codon 215 mutation in their proviral DNA had a 54% decline in CD4 cells and a virus burden of 21,480 proviral DNA copies/10(6) CD4 cells. In contrast, patients with non-SI (NSI) strains and wild-type at codon 215 had a 10% increase in CD4 cells and had a viral burden 1/46 that of patients with SI and the 215 mutation. Among patients with NSI strains, changes in CD4 cells depended on the presence of the codon 215 mutation (-160 CD4 cells/microliters), compared with those wild-type at codon 215 (+28 CD4 cells/microliters) (p < 0.01). There was a concordant rise in virus burden between proviral DNA and plasma HIV RNA depending on HIV phenotype and genotype. Using multiple linear regression, SI phenotype and the codon 215 mutation were found to independently predict CD4 cell decline and increased virus burden in zidovudine-treated patients.

CD4-Positive T-Lymphocytes↗
PubMed1994

Probability of gene identity by descent: computation and applications.

Two genes at a given locus are identical by descent (IBD) if both have been inherited from a common ancestor. We present an algorithm for computing the probabilities of all IBD relationships among the genes of pedigree members. We show how to use these probabilities to calculate the probability of any combination of genotypes or phenotypes for the pedigree members. Applications to linkage analysis and genetic counseling are illustrated with examples. The algorithm also can be used to calculate the generalized kinship coefficients proposed by others.

Algorithms↗
PubMed1994

A class of tests for linkage using affected pedigree members.

We describe a class of nonparametric tests for linkage between a marker and a gene assumed to exist and to govern susceptibility to a disease. The tests are formed by assigning a score to each possible pattern of marker allele sharing (identity-by-descent) among affected pedigree members, and then averaging the scores over all patterns compatible with the observed marker genotype and genealogical relationship of the affected members. Different score functions give different tests. One function, which examines marker allele similarity across pairs of affected pedigree members, gives a test similar to that of Fimmers et al. (1989, in Multipoint Mapping and Linkage Based on Affected Pedigree Members: Genetic Analysis Workshop, R. C. Elston, M. A. Spence, S. E. Hodge, and J. W. MacCluer (eds), 123-128; City: Alan R. Liss). A second function examines allele similarity across arbitrary subsets, not just pairs, of affected members. The resulting test can be more powerful than the one based solely on pairs of affected members. The approach has several advantages: it does not require knowledge of the mode of disease inheritance; it does not require unambiguous determination of identity-by-descent at the marker; it does not suffer from variability due to chance allele similarity among affected members who are unrelated, such as spouses; it allows marker genotypes of unaffected members to contribute information on allele sharing among the affected; it permits calculation of exact P-values. Computational requirements limit the tests to many pedigrees with few (< 16) affected members.

Alleles↗
PubMed1993

Poor survival of black patients in carcinoma of the endometrium.

PURPOSE: To compare the prognostic factors and survivals of black and white patients with endometrial carcinoma. METHODS AND MATERIALS: A retrospective study was undertaken of a total of 290 patients with endometrial carcinoma who were treated similarly at the Health Science Center at Brooklyn and Kings County Hospital Center from 1975 and 1990. One hundred and thirty-six of 290 (47.2%) were black and 135/290 (46.9%) were white. Well-known prognostic factors affecting endometrial carcinoma were studied in black and white group of patients. Their overall survival and comparison of survival in each prognostic group were also estimated using multi-variate analysis. RESULTS: Fifty-four percent of white patients had Stage I disease, compared to 45.9% in black patients. In Stage II, 51.6% were white and 48.4% were black, and in Stage III, 88.89% were black and 11.1% were white patients (p = 0.034). Fifty six percent Grade 1 patients were white and 44% were black. In Grade 2, 53.3% were white and 46.7% were black and in Grade 3 disease, 70.5% were black and 29.5% were white (p = 0.008). Up to the inner third of myometrial invasion had occurred in 60.6% of white patients and 39.4% in black patients. The middle third of the myometrium was invaded in 60.7% of white patients, and 39.3% of black patients. Thirty-seven percent of outer third of myometrial invasion was found in white patients and 63% in black patients (p = 0.038). Seventy-two percent of positive lymph nodes were found in black patients and 28.0% in white patients (p = 0.01). Sixty-one percent of patients with positive peritoneal cytology were black as compared to 38.7% in white patients (p = 0.017). The overall ten-year corrected survival for white and black patients was 72% and 40%, respectively (p = 0.0003). Survivals comparisons, when stratified by race and each prognostic group, showed statistically significant overall survival differences in favor of white patients. CONCLUSION: Black patients with endometrial carcinoma have poor survival. Low socio-economic status (SES) would not explain these findings. More research is required to determine the cause of poor survival in black patients with endometrial carcinoma.

Adult↗