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Biomedical subjects

D Lerner

Publications and source records attributed to D Lerner.

At least 19 recordsLinked to original sources
PubMed2001

The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy.

Stress-induced mitogen-activated protein kinase (MAP) p38 is activated in various forms of heart failure, yet its effects on the intact heart remain to be established. Targeted activation of p38 MAP kinase in ventricular myocytes was achieved in vivo by using a gene-switch transgenic strategy with activated mutants of upstream kinases MKK3bE and MKK6bE. Transgene expression resulted in significant induction of p38 kinase activity and premature death at 7-9 weeks. Both groups of transgenic hearts exhibited marked interstitial fibrosis and expression of fetal marker genes characteristic of cardiac failure, but no significant hypertrophy at the organ level. Echocardiographic and pressure-volume analyses revealed a similar extent of systolic contractile depression and restrictive diastolic abnormalities related to markedly increased passive chamber stiffness. However, MKK3bE-expressing hearts had increased end-systolic chamber volumes and a thinned ventricular wall, associated with heterogeneous myocyte atrophy, whereas MKK6bE hearts had reduced end-diastolic ventricular cavity size, a modest increase in myocyte size, and no significant myocyte atrophy. These data provide in vivo evidence for a negative inotropic and restrictive diastolic effect from p38 MAP kinase activation in ventricular myocytes and reveal specific roles of p38 pathway in the development of ventricular end-systolic remodeling.

Animals↗
PubMed2001

The Mdm-2 amino terminus is required for Mdm2 binding and SUMO-1 conjugation by the E2 SUMO-1 conjugating enzyme Ubc9.

Covalent attachment of SUMO-1 to Mdm2 requires the activation of a heterodimeric Aos1-Uba2 enzyme (ubiquitin-activating enzyme (E1)) followed by the conjugation of Sumo-1 to Mdm2 by Ubc9, a protein with a strong sequence similarity to ubiquitin carrier proteins (E2s). Upon Sumo-1 conjugation, Mdm2 is protected from self-ubiquitination and elicits greater ubiquitin-protein isopeptide ligase (E3) activity toward p53, thereby increasing its oncogenic potential. Because of the biological implication of Mdm2 sumoylation, we mapped Ubc9 binding on Mdm2. Here we demonstrate that Ubc9 can associate with Mdm2 only if amino acids 40-59 within the N terminus of Mdm2 are present. Mdm2 from which amino acids 40-59 have been deleted can no longer be sumoylated. Furthermore, addition of a peptide that corresponds to amino acids 40-59 on Mdm2 to a sumoylation reaction efficiently inhibits Mdm2 sumoylation in vitro and in vivo. In UV-treated cells Mdm2 exhibits reduced association with Ubc9, which coincides with decreased Mdm2 sumoylation. Our findings regarding the association of Ubc9 with Mdm2, and the effect of UV-irradiation on Ubc9 binding, point to an additional level in the regulation of Mdm2 sumoylation under normal growth conditions as well as in response to stress conditions.

3T3 Cells↗
PubMed2001

Photodegradation of cassava and corn starches.

The baking expansion properties of sour cassava starch (Polvilho azedo) are attributable to photochemical starch degradation induced by heterolactic fermentation after sun-drying. This study investigated the effects of UV irradiation on the different structural levels of cassava starch as compared to those of corn starch and dextrins. Photosensitive compounds excited at 360 and 290 nm in cassava starch were photodegraded when starch was exposed to sunlight or 360 nm irradiation. UV irradiation depolymerized cassava and corn starches, inducing modifications due, at least in part, to a mechanism involving free radicals. Lactic acid was also photodegraded. Photodegradation induced by UV absorption could have been due to fluorescent chromophores found in starches and nonfluorescent chromophores present in glucosidic units.

Cooking↗
PubMed2001

Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease.

We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 x 107 CD3+ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m(2)/4 days and melphalan 70 mg/m(2)/2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n = 4), MDS (n = 1), ALL (n = 3), CML (n = 3) and multiple myeloma (n = 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n = 3), acute GVHD (n = 3), chronic GVHD (n = 1) and disease relapse (n = 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day +30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear.

Adolescent↗
PubMed2001

The Work Limitations Questionnaire.

OBJECTIVE: The objective of this work was to develop a psychometrically sound questionnaire for measuring the on-the-job impact of chronic health problems and/or treatment ("work limitations"). RESEARCH DESIGN: Three pilot studies (focus groups, cognitive interviews, and an alternate forms test) generated candidate items, dimensions, and response scales. Two field trials tested the psychometric performance of the questionnaire (studies 1 and 2). To test recall error, study 1 subjects were randomly assigned to 2 different questionnaire groups, a questionnaire with a 4-week reporting period completed once or a 2-week version completed twice. Responses were compared with data from concurrent work limitation diaries (the gold standard). To test construct validity, we compared questionnaire scores of patients with those of healthy job-matched control subjects. Study 2 was a cross-sectional mail survey testing scale reliability and construct validity. SUBJECTS: The study subjects were employed individuals (18-64 years of age) from several chronic condition groups (study 1, n = 48; study 2, n = 121) and, in study 1, 17 healthy matched control subjects. MEASURES: Study 1 included the assigned questionnaires and weekly diaries. Study 2 included the new questionnaire, SF-36, and work productivity loss items. RESULTS: In study 1, questionnaire responses were consistent with diary data but were most highly correlated with the most recent week. Patients had significantly higher (worse) limitation scores than control subjects. In study 2, 4 scales from a 25-item questionnaire achieved Cronbach alphas of > or = 0.90 and correlated with health status and self-reported work productivity in the hypothesized manner (P < or = 0.05). CONCLUSIONS: With 25 items, 4 dimensions (limitations handling time, physical, mental-interpersonal, and output demands), and a 2-week reporting period, the Work Limitations Questionnaire demonstrated high reliability and validity.

Adult↗
PubMed2001

Allogeneic transplantation for patients with advanced acute leukemia: a single center retrospective study of 92 patients.

Allogeneic transplantation is a well recognized treatment strategy of leukemia. However, its use in advanced leukemia patients is a subject of some debate especially when donors are not HLA-identical siblings because of the toxicity and cost of the procedure. We reviewed retrospectively the outcome of patients (pts) who received allogeneic transplantation for advanced acute leukemia in our center between 09/86 and 11/97. Thirty-six pts (study group) who lacked a matched sibling donor received partially matched related donor (n=14: PMRD group) or matched unrelated donor transplantation (n=22: MUD group). Fifteen pts had AML and 21 ALL. Seventeen pts (47%) were in CR>1, 13 pts (36%) had refractory disease and six pts (17.7%) were in untreated relapse. The outcome was compared to that of 56 patients (AML: 45.5 %, ALL: 55.5 %, CR>1: 49.9 %, refractory disease: 37.5 %, untreated relapse 19.6 %) who received allogeneic transplantation from a matched sibling donor (control group). Various conditioning regimens and GVHD prophylaxis were used. The actuarial incidence of grade II to IV acute GVHD was significantly higher in the study group (57%) than in the control group (34%) (p=0.047). The actuarial risk of relapse at three years was 21% +/- 22% in the study group versus 65% +/- 16% in the control group (p= 0.04). The actuarial probability of transplant-related mortality at 3 years is 64 +/- 16% for the study group and 25 +/- 11% for the control group (p=0.001). The leading cause of death in the study group was infection (30%) followed by acute GVHD and relapse. Relapse was the major cause of death in the control group (54%), followed by infection, interstitial pneumonia, veno-occlusive disease and GVHD. The OS and probability of leukemia-free survival at 3 years were 28 % +/- 15% (95% CI) and 27% +/- 15% (95% CI) in the study group. The overall survival and probability of LFS at 3 years were respectively 28 +/- 12% (95% CI) and 23 +/- 12% (95% CI) in the control group (p = 0.08 and p=0.11 respectively). In multivariate analysis, transplant-related mortality was higher in the study group (p=0.04) and lower if both donor and recipient were seronegative for CMV (p=0.007). OS was significantly higher for seronegative couples (p=0.0001), and when CR was achieved before BMT (p=0.0022). These results suggest that all efforts in this field should be directed on lowering the transplant related mortality for non geno-identical transplants and the relapse rate in geno-identical transplants.

Actuarial Analysis↗
PubMed2000

Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma.

Chronic airway eosinophilia is associated with allergic asthma and is mediated in part by secretion of IL-5 from allergen-specific Th2 lymphocytes. IL-5 is a known maturation and antiapoptotic factor for eosinophils and stimulates release of nascent eosinophils from bone marrow into the peripheral circulation. An antisense oligonucleotide found to specifically inhibit IL-5 expression in vitro was observed to significantly reduce experimentally induced eosinophilia in vivo, in both the murine OVA lung challenge and allergic peritonitis models. Intravenous administration resulted in sequence-dependent inhibition of eosinophilia coincident with reduction of IL-5 protein levels, supporting an antisense mechanism of action. Potent suppression of lung eosinophilia was observed up to 17 days after cessation of oligonucleotide dosing, indicating achievement of prolonged protection with this strategy. Furthermore, sequence-specific, antisense oligonucleotide-mediated inhibition of Ag-mediated late phase airway hyperresponsiveness was also observed. These data underscore the potential utility of an antisense approach targeting IL-5 for the treatment of asthma and eosinophilic diseases.

Adjuvants, Immunologic↗
PubMed2000

Characterizing non-linearity in the cochlear microphonic using the instantaneous frequency.

In this paper, we examine the non-linearity of mechano-electric transduction in the cochlea by computing the instantaneous frequency (IF) of the cochlear microphonic (CM) in response to sinusoidal stimuli. In contrast to a linear system which yields a constant IF when driven with a sinusoid, the IF of the CM varied during one period of oscillation. This variation was not symmetric, but differed for positive and negative slopes of the CM. Administration of tetrodotoxin to eliminate neural activity indicated that the variation of the IF was not due to neural contamination. Moreover, comparing the IF of the stimulus to that of the CM indicated that the IF was not due to non-linearity in the acoustic signal. Signal frequency, signal level and acoustic trauma altered the IF. A cochlear model of the CM was developed to determine the influence of the saturation of hair-cell receptor currents and vector summation on the IF. Results indicated that these factors could not fully account for the variation in the IF. We conclude that the variation in IF within one period of cochlear partition vibration indicates that the mechanical and/or electrical oscillations which produce the CM differ from those of a linear system.

Acoustic Stimulation↗
PubMed1999

Validation of a migraine work and productivity loss questionnaire for use in migraine studies.

Migraine symptoms and therapy side effects cause significant functional disability that can result in work and productivity losses. Effective, well-tolerated migraine therapy with rapid onset of relief could decrease work and productivity losses. The Migraine Work and Productivity Loss Questionnaire (MWPLQ) evaluates the impact of migraine and migraine therapy on paid work. Data from a randomized, open-label extension study were collected over 3 months. Migraineurs were randomized to either rizatriptan (5HT1B/1D receptor agonist) or their usual migraine therapy. Data were analyzed from 164 patients who experienced at least one work-related migraine. Internal consistency (Cronbach's alpha) for the work difficulty domains ranged from 0.80 to 0.95. Work loss and work difficulty were moderately correlated (r = 0.39-0.58) with migraine severity and functional ability. Differences were found favoring rizatriptan for absenteeism (1.3 vs 2.4 h), effectiveness at work (62% vs 49%), and difficulty with work-related tasks (p < 0.01). The MWPLQ demonstrated favorable measurement characteristics in this study and could be an important research tool for future evaluations of migraine-related work disability.

Absenteeism↗
PubMed1998

Purification, crystallization, and preliminary X-ray crystallographic data analysis of small heat shock protein homolog from Methanococcus jannaschii, a hyperthermophile.

A gene coding for a small heat shock protein homolog from the hyperthermophilic methanogenic Archaeon Methanococcus jannaschii was cloned. This gene was overexpressed in Escherichia coli harboring rare codon tRNAs and its protein purified and crystallized. Crystals displayed the space group R3 with unit cell dimensions a = b = 171.46 A and c = 102.13 A in a hexagonal axis setting. These crystals grew in one week and diffracted to 3.2 A resolution. The presence of eight molecules in the asymmetric unit gives a Vm value of 2.2 A3/Da and a solvent content of 44% by volume. The 24-molecule complex is generated from a subunit by a combination of crystallographic threefold symmetry and three types of noncrystallographic symmetries (a two-, a three-, and a fourfold).

Archaeal Proteins↗
PubMed1998

(R)(+)-N-propargyl-1-aminoindan (rasagiline) and derivatives: highly selective and potent inhibitors of monoamine oxidase B.

(+)-N-Propargyl-1-aminoindan (rasagiline) and a series of derivatives have been synthesized and screened for monoamine oxidase inhibitory activity. Rasagiline and several analogues were found be highly selective and potent inhibitors of the B form of the enzyme in contrast to the levorotatory enantiomer which was not active. The results indicate that rasagiline has potential for the treatment of Parkinson's Disease. This compound is currently under development for that indication.

Animals↗
PubMed1998

Relationship of job strain and iso-strain to health status in a cohort of women in the United States.

OBJECTIVE: This study examined the relationships of job strain and iso-strain psychosocial work-environment exposures to health status in a cohort of working women in the United States. METHODS: In a cross-sectional survey, 33689 women responded to the Karasek job content and the MOS SF-36 health status questionnaires. The psychosocial work-environment exposures were characterized using the job strain and iso-strain frameworks. Health status was assessed with the following 6 scales: physical functioning, vitality, freedom from pain, mental health, role limitations due to physical health, and role limitations due to emotional health. RESULTS: When compared with active work, high-strain work (high job demands and low job control) was associated with lower vitality, mental health, higher pain, and increased risks of both physical and emotional role limitations. Iso-strain work (high strain and low work-related social support) increased the risks further. Job insecurity was also associated with lower health status. CONCLUSIONS: The analyses supported the hypothesis that the psychosocial work environment is an important determinant of health status among working women. The findings suggest that incorporating social conditions at work into the measurement of psychosocial work-environment exposure improves the identification of high-risk work arrangements.

Adult↗
PubMed1996

Bacterial leakage in endodontics: an improved method for quantification.

A new method for studying leakage of root fillings using the bacterium Pseudomonas fluorescens ATCC 13525 is described. The presence of the microorganism is detected by fluorimetry and can thus be used to measure the depth of penetration from the root apex toward the crown of the tooth. This system, applied to a number of methods of root canal filling, showed that procedures involving compaction of the gutta-percha gave a more effective seal than the use of a paste sealer with uncondensed gutta-percha. There was no statistically significant difference between the leakage results from the lateral, vertical, and thermomechanical condensed techniques.

Dental Leakage↗
PubMed1995

Cardiovascular magnetic resonance imaging goes beyond anatomy.

Magnetic resonance imaging (MRI) provides noninvasive functional information as well as a three-dimensional anatomic display of the cardiovascular system. MRI of protons, phosphorus, or sodium nuclei is currently being investigated to characterize cardiovascular pathology, and the potential benefits of paramagnetic contrast agents are becoming apparent. Finally, techniques to quantitate blood flow, vascular pressures, chamber volumes, ventricular ejection fractions, and cardiac output are being developed.

Contrast Media↗
PubMed1994

B-CLL in PLL transformation associated with hypercalcemia.

A 64-year-old woman is reported with Stage I (Rai) chronic lymphocytic leukaemia (CLL), in whom hypercalcemia developed when an increased proportion of prolymphocytic cells characterized a transformation of CLL in prolymphocytoid leukaemia (CLL/PL). Although hypercalcemia is more frequently found in T-cell leukaemia associated with human T lymphotropic lymphocyte type I, scattered reports indicate that patients with B-CLL can also be affected with this metabolic disturbance. The case described here, progressed with an indolent course of CLL for 26 months, when she was admitted with a very aggressive disease characterized by a high WBC count, splenomegaly and hypercalcemia. Despite an effort to achieve a clinical remission, she failed treatment and death was attributed to unresponsive hypercalcemia. The mechanism of hypercalcemia in such cases is unclear as no parathyroid adenoma or second malignant tumor was found ante mortem. This electrolytic disturbance would appear to be a direct consequence of the transforming leukaemia and a possible mechanism involving a secreted humoral factor that could lead to altered calcium metabolism.

Antigens, CD↗
PubMed1994

Family physicians and first-trimester abortion: a survey of residency programs in southern California.

INTRODUCTION: Since abortion has become a focus of increased public attention, it is important to assess family physicians' attitudes and scope of training regarding this outpatient procedure. METHODS: Residents and faculty at eight southern California family practice residency programs were surveyed about their views on first-trimester abortion, and about their interest in training to perform the procedure. RESULTS: While 62.5% of respondents believed abortion to be an appropriate procedure for family physicians to perform, only 19.5% had performed an abortion during the past year. Attitudes about situations in which abortion should be available to women were not associated with age, gender, or ethnicity. Religion of the respondents, however, was significantly associated with attitudes toward abortion. Of respondents without personal objections to the procedure, those who perceived the performance of abortion as appropriate for family physicians were significantly more likely to be interested in further training (48.2%) than those who did not perceive it as appropriate (18.2%, P = .0147). This perception of appropriateness was affected by whether or not a respondent had been offered training; those who had been offered training in abortion were 8.5 times more likely to believe it to be an appropriate procedure for family physicians to perform (P = .0001). CONCLUSION: If the number of family physicians providing abortions is to be increased, residency programs must offer abortion training as a more fully recognized part of the family medicine curriculum.

Abortion, Induced↗