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J Kaplan

Publications and source records attributed to J Kaplan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Antitumor activity of cationic lipid complexed with immunostimulatory DNA.

We previously reported that treatment of intraperitoneal tumors with complexes of cationic lipid and noncoding plasmid DNA leads to the development of a specific, cytotoxic T-cell response correlating with the rejection of established tumor cells as well as subsequent tumor re-challenge. Here, focusing on an intraperitoneal AB12 mesothelioma model, we show that the anticancer effects of the lipid:DNA complex are associated with DNA containing immunostimulatory CpG motifs. Complexes prepared with cationic lipid and bacterial plasmid DNA, Escherichia coli genomic DNA fragments, or synthetic immunostimulatory CpG oligodeoxynucleotides provided a substantial survival benefit, whereas eukaryotic DNA and methylated bacterial DNA had little or no therapeutic activity. Alternative inflammatory stimuli such as thioglycolate, poly(I:C), and incomplete or complete Freund's adjuvant failed to reproduce the antitumor activity obtained with the lipid:DNA complex. The innate immune response triggered by lipid:DNA complexes led to the development of a systemic immune response against tumor cells that allowed animals to reject tumors not only at the intraperitoneal treatment site, but also at a distal subcutaneous site. These data demonstrate that immunostimulatory DNA complexed with cationic lipid is a potent inducer of innate and adaptive immune responses against tumor cells and represents a potentially useful tool in the immunotherapy of cancers for which tumor-associated antigens have not been identified.

Animals↗
PubMed2001

Hemogen is a novel nuclear factor specifically expressed in mouse hematopoietic development and its human homologue EDAG maps to chromosome 9q22, a region containing breakpoints of hematological neoplasms.

We cloned a novel murine gene, designated Hemogen (hemopoietic gene), which was sequentially expressed in active hematopoietic sites and downregulated in the process of blood cell differentiation. Hemogen transcripts were specifically detected in blood islands, primitive blood cells and fetal liver during embryogenesis, and then remained in bone marrow and spleen in adult mice. Immunostaining demonstrated that Hemogen was a nuclear protein. We also identified a human homologue of Hemogen, named EDAG, which was mapped to chromosome 9q22, a leukemia breakpoint. Like Hemogen, EDAG exhibited specific expression in hematopoietic tissues and cells. Taken together, these data are consistent with Hemogen and EDAG playing an important role in hematopoietic development and neoplasms.

Amino Acid Sequence↗
PubMed2001

Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys.

Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.

Animals↗
PubMed2001

Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. So far, six LCA loci have been mapped but only 4 out of 6 genes have been identified. A genome-wide screen for homozygosity was conducted in seven consanguineous families unlinked to any of the six LCA loci. Evidence for homozygosity was found in two of these seven families at the 14q11 chromosomal region. Two retinal specific candidate genes were known to map to this region, namely the neural retina leucine zipper (NRL) and the retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1). No mutation of the NRL gene was found in any of the two families. Thus, we determined the complete exon-intron structure of the RPGRIP1 gene. RPGRIP1 encompasses 24 coding exons, nine of which are first described here with their corresponding exon-intron boundaries. The screening of the gene in the two families consistent with linkage to chromosome 14q11 allowed the identification of a homozygous null mutation and a homozygous missense mutation, respectively. Further screening of LCA patients unlinked to any of the four already identified LCA genes (n=86) identified seven additional mutations in six of them. In total, eight distinct mutations (5 out of 8 truncating) in 8/93 patients were found. So far this gene accounts for eight out of 142 LCA cases in our series (5.6%).

Amino Acid Sequence↗
PubMed2001

Soluble intercellular adhesion molecule-1 as a predictor of early adverse events in patients with chest pain compatible with myocardial ischemia.

STUDY OBJECTIVE: Inflammation plays an important role in acute coronary syndromes, and some evidence indicates that patients with a more pronounced vascular inflammatory response have a poorer outcome. Soluble intercellular adhesion molecule-1 (sICAM-1) is a specific marker for vascular endothelial cell activation. The aim of this study was to investigate the prognostic value of plasma sICAM-1 levels in patients with acute chest pain compatible with myocardial ischemia. METHODS: This prospective study was conducted at 2 urban university medical centers. The study cohort consisted of 119 consecutive patients with chest pain in whom myocardial ischemia was suspected clinically at presentation. Patients with conditions that affect sICAM-1 levels were ineligible. Cardiac troponin I (cTnI), C-reactive protein, and sICAM-1 levels were assayed at presentation to the emergency department. The primary end point was the occurrence of a serious cardiac event (death, nonfatal acute myocardial infarction, coronary revascularization) in the hospital. RESULTS: Although sICAM-1 levels tended to be higher in patients with a serious cardiac event, there was no significant association. In contrast, a cTnI level greater than 0.2 ng/mL was a powerful predictor of an in-hospital serious cardiac event (odds ratio 16.3, 95% confidence interval [CI] 4.7 to 55.9; P <.0001). Soluble ICAM-1 levels of more than 260 ng/mL at presentation had a sensitivity for predicting a serious cardiac event of 63% (95% CI 46% to 81%) but a specificity of only 47% (95% CI 38% to 57%). CONCLUSION: In a heterogeneous population of patients with chest pain compatible with myocardial ischemia, elevated sICAM-1 levels are poor predictors of an individual patient suffering a serious cardiac event in the hospital.

Adult↗
PubMed2001

Familial focal segmental glomerulosclerosis.

There is increasing recognition of the importance of genetic factors in the development of focal segmental glomerulosclerosis and related proteinuric disorders. Recently, four genes have been identified which, when defective, cause focal segmental glomerulosclerosis or nephrosis. All of these genes appear to be important in the maintenance of glomerular podocyte function. However, not all cases of familial nephrosis or proteinuria are explained by defects in these genes.

Actinin↗
PubMed2001

Proton and metal ion-dependent assembly of a model diiron protein.

DF1 is a small, idealized model for carboxylate-bridged diiron proteins. This protein was designed to form a dimeric four-helix bundle with a dimetal ion-binding site near the center of the structure, and its crystal structure has confirmed that it adopts the intended conformation. However, the protein showed limited solubility in aqueous buffer, and access to its active site was blocked by two hydrophobic side chains. The sequence of DF1 has now been modified to provide a very soluble protein (DF2) that binds metal ions in a rapid and reversible manner. Furthermore, the DF2 protein shows significant ferroxidase activity, suggesting that its dimetal center is accessible to oxygen. The affinity of DF2 for various first-row divalent cations deviates from the Irving-Willliams series, suggesting that its structure imparts significant geometric preferences on the metal ion-binding site. Furthermore, in the absence of metal ions, the protein folds into a dimer with concomitant binding of two protons. The uptake of two protons is expected if the structure of the apo-protein is similar to that of the crystal structure of dizinc DF1. Thus, this result suggests that the active site of DF2 is retained in the absence of metal ions.

Amino Acid Sequence↗
PubMed2001

Prediction of hyperkalemia in dogs from electrocardiographic parameters using an artificial neural network.

OBJECTIVE: To predict severe hyperkalemia from single electrocardiogram (ECG) tracings. METHODS: Ten conditioned dogs each underwent this protocol three times: Under isoflurane anesthesia, 2 mEq/kg/hr of potassium chloride was given intravenously until P-waves were absent from the ECG and ventricular rates decreased > or =20% in < or =5 minutes. Serum potassium levels (K(+)) were measured at regular intervals with concurrent digital storage of lead II of the surface ECG. A three-layer artificial neural network with four hidden nodes was trained to predict K(+) from 15 separate elements of corresponding ECG data. Data were divided into a training set and a test set. Sensitivity, specificity, and diagnostic accuracy for recognizing hyperkalemia were calculated for the test set based on a prospectively defined K(+) = 7.5. RESULTS: The model produced data for 189 events; 139 were placed in the training set and 50 in the test set. The test set had 37 potassium levels at or above 7.5 mmol/L. The neural network had a sensitivity of 89% (95% CI = 75% to 97%) and a specificity of 77% (95% CI = 46% to 95%) in recognizing these. The positive likelihood ratio was 3.87. Overall accuracy of this model was 86% (95% CI = 73% to 94%). Mean (+/-SD) difference between predicted and actual K(+) values was 0.4 +/- 2.0 (95% CI = -0.2 to 1.0). CONCLUSIONS: An artificial neural network can accurately diagnose experimental hyperkalemia using ECG parameters. Further work could potentially demonstrate its usefulness in bedside diagnosis of human subjects.

Animals↗
PubMed2001

Finding the underserved: directions for HIV care in the future.

The demographic, behavior, and background characteristics of 4,804 participants in 17 national demonstration projects for HIV medical and/or psychosocial support services were coded for an index of "service need" or possible under-representation in the traditional healthcare system. Fifteen items were coded including status as a person of color, lack of private insurance, unemployment/disability, problem drinking, crack cocaine use, heroin use, other illicit drug use, less than 12 years of education, criminal justice system involvement, children requiring care while the patient receives services, sex work, being the sex partner of an injection drug user, unstable housing, primary language not English, and age less than 21 or over 55 years. Most (87.7%) of the program participants had four or more of these factors present. Through CHAID modeling, those groups with the highest levels of service need and vulnerability were identified. These data suggest that these projects, designed to attract and serve individuals potentially underrepresented in the health services system, had in fact achieved that goal. Implications of the changing demographics of the HIV epidemic for the health service delivery system are discussed.

Adult↗
PubMed2001

Bracketing wires for preoperative breast needle localization.

OBJECTIVE: The purpose of this study was to evaluate the outcomes of bracketing wire placement during preoperative breast needle localization. SUBJECTS AND METHODS: We prospectively examined mammograms of 1057 consecutive lesions that had preoperative needle localization and surgical excision and classified the lesions according to Breast Imaging Reporting and Data System (BI-RADS) final assessment categories. Bracketing wires, defined as multiple wires placed to delineate the boundaries of a single lesion, were used in 103 (9.7%) of 1057 lesions. Medical records, imaging studies, and histologic findings in these 103 lesions were reviewed. RESULTS: Of 103 bracketed lesions, median lesion size was 3.5 cm (range, 1.5-9.5 cm). Ninety-three lesions (90.3%) contained calcifications; 65 lesions (63.1%) were BI-RADS category 5 (highly suggestive of malignancy); and 33 lesions (32.0%) were percutaneously proven cancers. The median number of wires placed was two (range, 2-5). Surgical histologic findings were carcinoma in 75 lesions (72.8%), atypical hyperplasia in eight lesions (7.8%), and benign in 20 lesions (19.4%). Of 42 calcific lesions that were bracketed and had postoperative mammograms available for review, complete removal of suspicious calcifications was accomplished in 34 (81.0%). Of 75 cancers that were bracketed, clear histologic margins of resection were obtained in 33 (44.0%). CONCLUSION: Bracketing wires were used during preoperative needle localization primarily for larger calcific lesions that were proven cancers or were highly suggestive of malignancy (BI-RADS category 5). Bracketing wires may assist the surgeon in achieving complete excision of calcifications, but bracketing wires do not ensure clear histologic margins of resection.

Adult↗
PubMed2001

Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to leber congenital amaurosis (LCA).

PURPOSE: Leber congenital amaurosis (LCA) is the earliest and the most severe form of all inherited retinal dystrophies. In 1996, the current investigators ascribed the disease in families linked to the LCA1 locus on chromosome 17p13.1 to mutations in the photoreceptor-specific guanylyl cyclase (retGC-1) gene. So far, 22 different mutations, of which 11 are missense mutations, have been identified in 25 unrelated families. This is a report of the functional analyses of nine of the missense mutations. METHODS: cDNA constructs were generated that contained the retGC-1 missense mutations identified in patients related to the LCA1 locus. Mutants were expressed in COS7 cells and assayed for their ability to hydrolyze guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). RESULTS: All mutations lying in the catalytic domain showed a complete abolition of cyclase activity. In contrast, only one mutation lying in the extracellular domain also resulted in a severely reduced catalytic activity, whereas the others showed completely normal activity. CONCLUSIONS: More than half the mutations identified in patients related to the LCA1 locus are truncating mutations expected to result in a total abolition of retGC-1 activity. Concerning missense mutations, half of them lying in the catalytic domain of the protein also result in the complete inability of the mutant cyclases to hydrolyze GTP into cGMP in vitro. In contrast, missense mutations lying in the extracellular domain, except one affecting the initiation codon, showed normal catalytic activity of retGC-1. Nevertheless, considering that all patients related to the LCA1 locus displayed the same phenotype, it can be assumed that all missense mutations would have the same dramatic consequences on protein activity in vivo as truncation mutations.

Animals↗
PubMed2001

[Age-related macular degeneration and genetics].

Age related macular degeneration (AMD) is the main cause of blindness after age 55 in western countries. These last past years, several lines of evidence such as familial aggregation or twin studies suggested a genetic component in AMD. However, the late onset of the disease and the fact that AMD is a polygenic and multifactorial disease are the main limiting factors for linkage studies. Gene candidate strategy allowed the exclusion of several genes (VMD2, RDS, TIMP3) and lead to the implication of two genetic factors: the apoE gene (involved in the transport of lipids) and the ABCR gene (involved in Stargardt macular dystrophy). Concerning the apoE gene, a lower frequency of the epsilon 4 alleles carriers was observed in the exudative AMD population compared with controls, supporting the idea of a role of the apoE gene in exudative AMD with drusen. These results, together with ultrastructural studies, suggest that allele epsilon 4 is a protective factor for drusen and thus for AMD. For the ABCR gene, several studies and a large multicentric study definitively show that some heterozygous mutations are predisposing factors for AMD, in a polygenic and multifactorial model.

Humans↗
PubMed2000

The yeast gene MSC2, a member of the cation diffusion facilitator family, affects the cellular distribution of zinc.

The sequence of the yeast gene YDR205W places it within the family of cation diffusion facilitators: membrane proteins that transport transition metals. Deletion of YDR205W was reported to result in an increase in unequal sister chromatid recombination and was named meiotic sister chromatid recombination 2 (MSC2; Thompson, D. A., and Stahl, F. W. (1999) Genetics 153, 621-641). We report here that a msc2 strain shows a phenotype of decreased viability in glycerol-ethanol media at 37 degrees C. Associated with decreased growth is an abnormal morphology typified by an increase in size of both cells and vacuoles. Addition of extracellular Zn2+ completely suppresses the morphological changes and partially suppresses the growth defect. Regardless of the concentration of Zn2+ in the media, the msc2 strain had a higher Zn2+ content than wild type cells. Zinquin staining also revealed that msc2 had a marked increase in fluorescence compared with the wild type, again reflecting an increase in intracellular Zn2+. The deletion strain accumulated excess Zn2+ in nuclei-enriched membrane fractions, and when grown at 37 degrees C in glycerol-ethanol media, it showed a decreased expression of Zn2+-regulated genes. The expression of genes regulated by either Fe2+ or Cu2+ was not affected. An epitope-tagged Msc2p was localized to the endoplasmic reticulum/nucleus. These results suggest that Msc2p affects the cellular distribution of zinc and, in particular, the zinc content of nuclei.

Carrier Proteins↗
PubMed2000

Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.

CONTEXT: Occasionally, 2 or more major neurodegenerative diseases arise simultaneously. An understanding of the genetic bases of combined disorders, such as amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), will likely provide insight into mechanisms of these and related neurodegenerative diseases. OBJECTIVE: To identify loci that contain genes whose defects cause ALS. DESIGN: A genome-wide linkage analysis of 2 data sets from an ongoing study begun in the mid-1980s at 4 university research centers. SUBJECTS: An initial subset of 16 families (549 people) potentially informative for genetic analysis, in which 2 or more individuals were diagnosed as having ALS, identified from a Boston data set of 400 families and 4 families potentially informative (244 people) subsequently identified from a Chicago data set of more than 300 families to test a hypothesis based on findings from the Boston families. MAIN OUTCOME MEASURES: Linkage calculations assuming autosomal dominant inheritance with age-dependent penetrance (a parametric logarithm-of-odds [lod] score of 1.0 or greater required for further study of a potential locus); crossover analysis involving the ALS-FTD locus. RESULTS: In a set of families in which persons develop both ALS and FTD or either ALS or FTD alone, a genetic locus that is linked to ALS with FTD located between markers D9S301 and D9S167 was identified on human chromosome 9q21-q22. Families with ALS alone did not show linkage to this locus. Crossover analysis indicates this region covers approximately 17 cM. CONCLUSION: These data suggest that a defective gene located in the chromosome 9q21-q22 region may be linked to ALS with FTD. JAMA. 2000;284:1664-1669.

Aged↗
PubMed2000

Evaluation of clinical parameters to predict Mycobacterium tuberculosis in inpatients.

BACKGROUND: Respiratory isolation has been recommended for all patients with suspected tuberculosis (TB) to avoid transmission to other patients and health care personnel. In implementing these guidelines, patients with and without TB are frequently isolated, significantly increasing hospital costs. The objective of this study was to derive a clinical rule to predict the need for respiratory isolation of patients with suspected TB. METHODS: To identify potential predictors of the need for isolation, 56 inpatients with sputum cultures positive for TB were retrospectively compared with 56 controls who were isolated on admission to the hospital based on clinically suspected TB but whose sputum cultures tested negative for TB. Variables analyzed included TB risk factors, clinical symptoms, and findings from physical examination and chest radiography. RESULTS: Multivariate analysis revealed that the following factors were significantly associated with a culture positive for TB: presence of TB risk factors or symptoms (odds ratio [OR], 7.9 [95% confidence interval (CI), 4.4-24.2]), a positive purified protein derivative tuberculin test result (OR, 13.2 [95% CI, 4.4-40.7]), high temperature (OR, 2.8 [95% CI, 1.1-8.3]), and upper-lobe disease on chest radiograph (OR, 14.6 [95% CI, 3.7-57.5]). Shortness of breath (OR, 0.2 [95% CI, 0.12-0.53]) and crackles noted during the physical examination (OR, 0.29 [95% CI, 0.15-0.57]) were negative predictors of TB. A scoring system was developed using these variables. A patient's total score of 1 or higher indicated the need for respiratory isolation, accurately predicting a culture positive for TB (98% sensitivity [95% CI, 95%-100%]; 46% specificity [95% CI, 33%-59%]). CONCLUSION: Among inpatients with suspected active pulmonary TB, a prediction rule based on clinical and chest radiographic findings accurately identified patients requiring respiratory isolation.

Adult↗
PubMed2000

Phemx, a novel mouse gene expressed in hematopoietic cells maps to the imprinted cluster on distal chromosome 7.

Phemx (Pan hematopoietic expression) is a novel murine gene expressed in developmentally regulated sites of hematopoiesis from early in embryogenesis through adulthood. Phemx is expressed in hematopoietic progenitors and mature cells of the three main hematopoietic lineages. Conceptual translation of the murine Phemx cDNA predicts a 25-kDa polypeptide with four hydrophobic regions and several potential phosphorylation sites, suggestive of a transmembrane protein involved in cell signaling. The PHEMX protein is structurally similar to tetraspanin CD81 (TAPA-1), a transmembrane protein involved in leukocyte activation, adhesion, and proliferation. Phemx maps to the distal region of chromosome 7, a segment of the mouse genome that contains a cluster of genes that exhibit genomic imprinting. However, imprinting analysis of Phemx at the whole organ level shows that it is biallelically expressed, suggesting that mechanisms leading to monoallelic expression are not imposed at this locus. The human PHEMX ortholog is specifically expressed in hematopoietic organs and tissues and, in contrast to murine Phemx, undergoes alternative splicing. The unique mode and range of Phemx expression suggest that it plays a role in hematopoietic cell function.

Alleles↗
PubMed2000

Prevalence of mutations associated with reduced antiretroviral drug susceptibility among human immunodeficiency virus type 1 seroconverters in the United States, 1993-1998.

To assess the prevalence of mutations associated with decreased antiretroviral drug susceptibility, specimens were tested from persons infected with human immunodeficiency virus (HIV) during 1993-1998. Subjects were drug naive and were attending sexually transmitted disease clinics in 6 US cities. All were enrolled consecutively and had tested negative for HIV during the 2 years before enrollment. Plasma specimens from patients having >/=1 reverse transcriptase (RT) or primary protease mutation were tested phenotypically with a recombinant virus assay. Of 99 patients, 6 (6%) had mutations associated with zidovudine resistance, 2 (2%) had mutations associated with nonnucleoside RT inhibitor resistance, and 1 (1%) had a primary protease mutation. Overall, the prevalence of resistance-associated primary mutations was 5%, although high levels of decreased drug susceptibility (IC(50)s >/=10 times that of a reference virus) were observed in just 1%. These findings confirm the transmission of these mutations to drug-naive persons.

Adolescent↗