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Biomedical subjects

J Lazar

Publications and source records attributed to J Lazar.

At least 19 recordsLinked to original sources
PubMed2003

Olfactory adventures of elephantine pheromones.

Understanding the linkage between behaviour of mammals in their natural environment and the molecular basis of their sensory modalities presents challenges to biologists. Our olfactory investigations that involve the largest extant land mammal, the elephant, offer some clues of how these events mesh in sequence. Proboscideans have developed a sophisticatedly organized society and they rank with primates and cetaceans with respect to cognitive abilities. Our studies of discrete, quantifiable pheromone-elicited behaviours demonstrate that Asian elephants utilize their olfactory senses during fundamental, life-strategy decisions, including mate choice, female bonding and male hierarchical sorting. How biologically relevant odorants traverse mucous interfaces to interact with cognate odorant receptors remains a basic question in vertebrate olfaction. We have partially tracked the molecular odour reception trail of behaviourally distinct pheromones, ( Z )-7-dodecenyl acetate and frontalin (1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane), using approaches developed for insect studies and taking advantage of the extensive, highly mucoidal olfactory and vomeronasal systems that permit detailed investigations of pheromone-binding proteins. We have combined studies of quantifiable responses and behaviours with biochemical and biophysical investigations of the properties of protein-ligand complexes, their sequential pathways and associated protein-ligand fluxes. In the delineation of these sequential integrations of behavioural, biochemical and molecular events, we have discovered novel spatial and temporal adaptations in both the main olfactory and vomeronasal systems.

Acetates↗
PubMed2001

IgG autoantibodies in patients with anti-epiligrin cicatricial pemphigoid recognize the G domain of the laminin 5 alpha-subunit.

Anti-epiligrin cicatricial pemphigoid (AECP) is a mucosal-predominant, subepithelial blistering disease characterized by IgG anti-basement membrane autoantibodies to laminin 5 (alpha3beta3gamma2). This and prior studies found that autoantibodies from most patients recognize the alpha-subunit of this laminin isoform. Accordingly, sera from 10 representative patients were tested against prokaryotic recombinants of this polypeptide in epitope mapping studies. cDNAs spanning the full length of the alpha-subunit were generated by PCR, directionally cloned into the pGEX-4T-3 vector, and expressed as glutathione-S-transferase fusion proteins of appropriate size and immunoreactivity. Sera from 9 of 10 AECP patients immunoblotted fusion proteins corresponding to subdomains G2, G3, G4, and G5 at the carboxyl terminus of the laminin 5 alpha-subunit. Serum from 1 patient (and that from normal volunteers) showed no reactivity to any fusion proteins; no sera bound recombinant glutathione-S-transferase alone. Immunoadsorption of patient sera with fusion proteins corresponding to the G domain substantially reduced basement membrane autoantibody titers. IgG from patients with this form of cicatricial pemphigoid recognize the portion of laminin 5 thought to play a key role in promoting keratinocyte adhesion to epidermal basement membrane.

Autoantibodies↗
PubMed2001

Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant.

Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain magnetic resonance imaging showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T3 and free T4 levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). These are the highest TH levels reported for a heterozygous RTH patient. A T3 stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient's genomic DNA by PCR identified a single base deletion in exon 10 of her TRbeta gene that resulted in a frameshift and early stop codon. This, in turn, encoded a truncated receptor that lacked the last 20 amino acids. Cotransfection studies showed that the mutant TR was transcriptionally inactive even in the presence of 10(-6) M T3 and had strong dominant negative activity over the wild-type receptor. It is likely that the severely defective TRbeta mutant contributed to the extreme RTH phenotype and resistance in our patient.

Bone Development↗
PubMed2000

Discrimination of pheromone enantiomers by two pheromone binding proteins from the gypsy moth Lymantria dispar.

The gypsy moth, Lymantria dispar, uses (7R, 8S)-cis-2-methyl-7, 8-epoxyoctadecane, (+)-disparlure, as a sex pheromone. The (-) enantiomer of the pheromone is a strong behavioral antagonist. Specialized sensory hairs, sensillae, on the antennae of male moths detect the pheromone. Once the pheromone enters a sensillum, the very abundant pheromone binding protein (PBP) transports the odorant to the sensory neuron. We have expressed the two PBPs found in gypsy moth antennae, PBP1 and PBP2, and we have studied the affinity of these recombinant PBPs for the enantiomers of disparlure. To study pheromone binding under equilibrium conditions, we developed and validated a binding assay. We have addressed the two major problems with hydrophobic ligands in aqueous solution: (1) concentration-dependent adsorption of the ligand on vial surfaces and (2) separation of the protein-bound ligand from the material remaining free in solution. We used this assay to demonstrate for the first time that pheromone binding to PBP is reversible and that the two PBPs from L. dispar differ in their enantiomer binding preference. PBP1 has a higher affinity for the (-) enantiomer, while PBP2 has a higher affinity for the (+) enantiomer. The PBP from the wild silk moth, Antheraea polyphemus (Apol-3) bound the disparlure enantiomers more weakly than either of the L. dispar PBPs, but Apol-3 was also able to discriminate the enantiomers. We have observed extensive aggregation of both L. dispar PBPs and an increase in pheromone binding at high (>2 microM) PBP concentrations. We present a model of disparlure binding to the two PBPs.

Alkanes↗
PubMed1999

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Animals↗
PubMed1999

Utility of intracardiac echocardiography (ICE) in electrophysiology: ICEing the CAKE (catheter ablation knowledge enhancement).

PURPOSE: Previous studies have demonstrated the utility of intracardiac echocardiography (ICE) during electrophysiologic procedures including radiofrequency catheter ablation. The purpose of this study was to analyze the initial learning experience with ICE during invasive electrophysiologic procedures. METHODS: During a 1-month ICE trial, patients scheduled for radiofrequency catheter ablation underwent concurrent imaging using a 9 French, 9 MHz catheter in the right atrium proximal to important endocardial structures and diagnostic/ablation catheters. The procedure length, fluoroscopy and ICE times were systematically recorded during each procedure. In addition, the images were analyzed and recorded and their utility was evaluated after each case. A case control analysis was also performed. RESULTS: Seven patients underwent ICE (as part of an ICE trial period) during their electrophysiology study between July 21 and August 13, 1998. This study demonstrated the utility of ICE in identifying radiofrequency catheter tip stability and intracardiac and endocardial structures, including the crista terminalis, coronary sinus, and foramen ovale. CONCLUSION: ICE contributes to the electrophysiology arsenal for both diagnostic and therapeutic procedures. In particular, this technique demonstrated a decrease in fluoroscopy time as compared to a case control population. This technique limits radiation to the patient and operator. In addition, endocardial structures, which may be pivotal in diagnosing and treating cardiac arrhythmias, were easily identified. Radiofrequency catheter stability can also be assessed with this technique.

Adult↗
PubMed1998

New polyazaporphine chemistry for the origin of life.

Molecular orbital spectral predictions suggest that 2,5,7,10,12,15,17,20-octaaza-21H, 23H-porphine has a visible spectral range closely matching that of chlorophyll-a. Since the octaazaporphine is, in its core, a simple derivative of an (HCN)12 oligomer, this fact, together with its spectral properties, would suggest that it occupies a high rank as a primordial porphinic solar energy transducer for photochemistry essential to life's formation. The demonstration that the mass 324 hexahydrooctaazaporphine is formed in protic media by the cyclotetramerization of imidazol-4-aminohydroxonium ion or the derived nitrenium ion, and that a mass 318 species consonant with that of the Huckel aromatic octaazaporphine is observed in the course of these studies, strongly supports the proposed octaazaporphine synthesis in a prebiotic hydrocyanic acid milieu.

Chlorophyll↗
PubMed1997

Active repression by thyroid hormone receptor splicing variant alpha2 requires specific regulatory elements in the context of native triiodothyronine-regulated gene promoters.

Structural requirements for the inhibitory action of thyroid hormone receptor splicing variant alpha2 (TR alpha2) on T3/TRbeta1-mediated transactivation were investigated in native promoters of two T3-regulated genes: the brain-specific myelin basic protein (MBP) and the housekeeping malic enzyme (ME). T3/TRbeta1 transactivation of MBP256-chloramphenicol acetyl transferase (CAT) and ME315-CAT constructs was inhibited and unaffected by TR alpha2, respectively. In electrophoretic mobility shift assays, TR alpha2 bound MBP-thyroid response element (TRE) as a monomer but failed to interact with ME-TRE. Mutations of ME-TRE allowed TR alpha2 binding but not inhibition of T3/TRbeta1-mediated transactivation. In the context of the MBP promoter, replacement of MBP-TRE with ME-TRE or exchange of MBP TATA-like box with the ME GC-rich region spanning the transcription start site abolished TR alpha2 dominant negative action. Simultaneous introduction of both MBP-TRE and MBP TATA-like box in the context of ME promoter, however, triggered TR alpha2 inhibition of T3/TRbeta1 transactivation, indicating that these regulatory elements are necessary, but not individually sufficient, to mediate TR alpha2 dominant negative activity. Functional studies at low TR alpha2/TRbeta1 ratios revealed that binding to TRE facilitates TR alpha2 dominant negative action while prevention of DNA interaction by altering TR alpha2 P-box structure preserved TR alpha2 inhibitory effect, although with lower potency. In conclusion, the results suggest that, in native promoters of T3-regulated genes, a dual molecular mechanism, with DNA-binding dependent and DNA-binding independent components, underlies TR alpha2 dominant negative activity.

Animals↗
PubMed1995

The N-terminal region (A/B) of rat thyroid hormone receptors alpha 1, beta 1, but not beta 2 contains a strong thyroid hormone-dependent transactivation function.

In this study we have investigated the role of the N-terminal region of thyroid hormone receptors (TRs) in thyroid hormone (TH)-dependent transactivation of a thymidine kinase promoter containing TH response elements composed either of a direct repeat or an inverted palindrome. Comparison of rat TR beta 1 with TR beta 2 provides an excellent model since they share identical sequences except for their N termini. Our results show that TR beta 2 is an inefficient TH-dependent transcriptional activator. The degree of transactivation corresponds to that observed for the mutant TR delta N beta 1/2, which contains only those sequences common to TR beta 1 and TR beta 2. Thus, TH-dependent activation appears to be associated with two separate domains. The more important region, however, is embedded in the N-terminal domain. Furthermore, the transactivating property of TR alpha 1 was also localized to the N-terminal domain between amino acids 19 and 30. Using a coimmunoprecipitation assay, we show that the differential interaction of the N terminus of TR beta 1 and TR beta 2 with transcription factor IIB correlates with the TR beta 1 activation function. Hence, our results underscore the importance of the N-terminal region of TRs in TH-dependent transactivation and suggest that a transactivating signal is transmitted to the general transcriptional machinery via a direct interaction of the receptor N-terminal region with transcription factor IIB.

3T3 Cells↗
PubMed1995

Public reporting of performance measures in home care.

BACKGROUND: In 1992 DependiCare Home Health, Inc (Broadview, Ill), a 62-employee home medical equipment/respiratory therapy (HME) business in the Chicago metropolitan area, discovered that managed care organizations need quantifiable data from vendors in the form of measurements or outcomes. In response to this need, DependiCare developed its "Under the Microscope" program. This program provides quarterly reports (starting in April 1994) on service efficiency, patient satisfaction, and outcome statistics to referral sources, including physicians, discharge planners, and hospital executives. MEASUREMENTS: Performance measures, which represent information from DependiCare's internal operations, can be viewed as the company's quarterly report card. Areas reported on include target-time performance, same-day and under-two-hour delivery, patient (and referral source) satisfaction, equipment breakdown, and fillrate statistics. Outcome statistics include discontinuation of service by diagnosis and number of months on oxygen by diagnosis. USE OF RESULTS: Measurements help to identify weaknesses that need to be addressed by organizational or operational changes, as well as to uncover strengths that can be capitalized on for sales and marketing. Hospital-based discharge planning departments, a substantial referral source, most often use the Under the Microscope program to justify referring patients to DependiCare. Little is known about managed care customers' use of the data. CONCLUSIONS: In the long term, an integrated, automated way to track individual patients across the continuum of care from the physician, to the hospital, and to home care is needed. A centralized database of patient experience, including outcomes, could assist in health care decision making.

Capitation Fee↗
PubMed1994

A role for intronic sequences on expression of thyroid hormone receptor alpha gene.

We have cloned and characterized the organization of the rat thyroid hormone receptor alpha (THR) gene. Multiple transcription start sites were mapped by RNA primer extension analyses. The promoter of the rat THR alpha gene does not contain a TATA or CAAT box. Deletion analyses of the 5' region of THR alpha gene and transfection assays, using NIH3T3 and NG108-15 cells, revealed that the sequences from -137 to +205 (+205 resides in the first intron) are necessary for efficient expression of this gene. This region contains two positively acting elements, the sequence -137 to -60 upstream from the major start of transcription and three copies of an AGG sequence located in the first intron. In contrast, two octamer-binding motifs in the first intron function as the negative regulatory elements. Gel mobility shift assays showed that the purine-rich sequence and the octamer-binding motifs bind to a protein(s) present in NIH3T3 and NG108-15 cells, the recipients in transient transfection assays. Genomic sequence comparison of THR alpha and beta revealed the presence of the purine-rich track in both genes, while the octamer-binding motifs were found only in the alpha gene. These results might explain the differential regulation of THR alpha and beta gene expression previously noted.

3T3 Cells↗
PubMed1994

The stability of tachistoscopic measures of hemispheric specialization.

Two-week test-retest reliabilities were determined for two tachistoscopic tasks, consonant-vowel-consonant trigrams and dot location, in 48 right-handed university students. Both visual field and laterality scores were examined. Analysis of variance showed no significant main effects or interactions of session for either task, indicating stability of mean performance and laterality scores. Likewise, grouping subjects as "high" or "low" by median laterality scores showed concordance across sessions for both tasks. Test-retest correlations were moderately high for all verbal task measures and for visual field scores for the dot location test. However, laterality indices for dot location showed low stability despite comparable within-session reliabilities of laterality scores for the two tasks. These findings suggest stability of group means and subgroups for verbal and dot location tachistoscopic measures. However, the degree to which individual scores are predictable from one session to the next differs between the two tasks.

Adult↗
PubMed1993

Early thyroid hormone treatment in rats increases testis size and germ cell number.

By means of in vivo and in vitro approaches, we studied the effect of thyroid hormone on postnatal development of rat testis. T3 treatment in neonatal rats is associated with an increase of testis size of about 60%, compared to coeval controls. Increased number of both Sertoli and germ cells and enlarged diameter of seminiferous cords were found in hyperplastic testes. In the T3-treated group, TSH serum levels were low and a slight increase of FSH was found. In vitro treatment of neonatal testis fragments by 10(-7) M T3 for 3 days increased the number of gonocytes (P < 0.001 vs control) and decreased the percentage of degenerating germ cells (P < 0.001 vs control). In the adult testis, both in vivo and in vitro treatments with thyroid hormone did not induce morphological modifications, thus demonstrating that the critical window of thyroid hormone effectiveness coincides with the prepuberal period. Since thyroid hormone stimulates Sertoli cells to secrete growth factors and nutrients for germ cell development, we suggest that the increased testicular size and germ cell number following the T3 treatment is mediated by a direct hormonal effect on the somatic cell of the seminiferous epithelium.

Animals↗
PubMed1992

[Structural basis of appendiceal function in rabbits].

Enzymo-, immuno- and lactin-histochemical methods were used to study the structure of the rabbit appendix wall. The value of some structural components in the function of this part of the intestine is discussed. Some findings were documented electronmicroscopically. In addition to its resorptive function, the rabbit appendix is equipped with a potent defense mechanism against adverse environmental effects of the appendix content. Individual structures of this defensive barrier are closely characterized with regard to cellular equipment and possibilities of its morphological identification.

Animals↗