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T Thomas

Publications and source records attributed to T Thomas.

At least 127 records · Page 7Linked to original sources
PubMed1999

Sequelae of abortion and relinquishment of child custody among women with major psychiatric disorders.

A growing number of women with major psychiatric disorders frequently consider the choice of abortion or relinquishment of the custody of children. Psychological reactions to abortion and relinquishment of custody were assessed and contrasted among 119 hospitalized women of M age 40 yr. and psychiatric patients. An original questionnaire was developed to assess emotional symptoms, psychiatric signs, attitudes, and satisfaction with the decision regarding the loss of a fetus or child. As hypothesized, reported sequelae of relinquishments of custody were rated as significantly more severe than sequelae of abortion. Dissatisfaction with choice, negative attitudes, religious affiliation, and involuntary removal of a child from custody were predictive of distress following abortion or relinquishment. The findings show that increased efforts are needed to help women with psychiatric difficulties cope with reproductive planning and losses.

Abortion, Induced↗
PubMed1999

Polyamine-fas interactions: inhibition of polyamine biosynthesis in MRL-lpr/lpr mice is associated with the up-regulation of fas mRNA in thymocytes.

MRL-lpr/lpr is a strain of mice that develops spontaneous signs of the autoimmune disease, systemic lupus erythematosus (SLE or lupus). The lpr (lymphoproliferation) defect has been identified as an insertion of an early transposon (ETn) derived sequence into the fas apoptosis gene. We studied the in vivo effects of difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), on the expression of fas in MRL-lpr/lpr mice as well as in congenic MRL- + / + and autoimmune NZB/W strains. Using Northern blot hybridization and reverse transcription polymerase chain reaction (RT-PCR), we found that DFMO treatment resulted in an increase in the expression of fas mRNA in the thymus of MRL-lpr/lpr mice. Using RT-PCR, we further found that the increased expression of fas was associated with the suppression of chimeric ETn/fas mRNA. With fractionated CD4 + and CD8 + T cells, we found a cell-specific effect of DFMO on chimeric ETn/fas expression in CD8 + cells. ETn/fas expression was detected in CD8+ T cells from untreated mice, but it was eliminated after DFMO treatment. HPLC analysis of polyamines showed depletion of putrescine and partial reduction of spermidine (35%) in DFMO-treated mice compared to controls. These results indicate that DFMO-mediated polyamine depletion is linked to the regulation of fas and chimeric ETn/fas in MRL-lpr/lpr mice. Elevated levels of polyamines in this strain, as found in earlier studies, may be associated with the progression of the autoimmune disease by altering the expression of fas gene or by facilitating the expression of chimeric ETn/fas. Our data also provide new mechanistic insights into the beneficial effects of DFMO on these mice.

Animals↗
PubMed1999

No exit? The effect of health status on dissatisfaction and disenrollment from health plans.

OBJECTIVE: To examine the implications of serious and chronic health problems on the willingness of enrollees to switch health plans if they are dissatisfied with their current arrangements. DATA SOURCE: A large (20,283 respondents) survey of employees of three national corporations committed to the model of managed competition, with substantial enrollment in four types of health plans: fee-for-service, prepaid group practice, independent practice associations, and point-of-service plans. STUDY DESIGN: A set of logistic regression models are estimated to determine the probability of disenrollment, if dissatisfied, controlling for the influence on satisfaction and disenrollment of age, race, education, family income and size, gender, marital status, mental health status, pregnancy, duration of employment and enrollment in the plan, number of alternative plans, and HMO penetration in the local market. Separate coefficients are estimated for enrollees with and without significant physical health problems. Additional models are estimated to test for the influence of selection effects as well as alternative measures of dissatisfaction and health problems. DATA COLLECTION: Data were collected through a mailed survey with a response rate of 63.5 percent; comparisons to a subsample administered by telephone showed few differences. PRINCIPAL FINDINGS: In group/staff model HMOs and point-of-service plans, only 12-17 percent of the chronically ill enrollees who were so dissatisfied when surveyed that they intended to disenroll actually left their plan in the next open enrollment period. This compared to 25-29 percent of the healthy enrollees in these same plans, who reported this level of dissatisfaction and 58-63 percent of the enrollees under fee-for-service insurance. CONCLUSIONS: Switching plans appears to be significantly limited for enrollees with serious health problems, the very enrollees who will be best informed about the ability of their health plan to provide adequate medical care. These effects are most pronounced in plans that have exclusive contracts with providers. We conclude that disenrollment provides only weak safeguards on quality for the sickest enrollees and that reported levels of dissatisfaction and disenrollment represent inaccurate signals of plan performance.

Adult↗
PubMed1999

Bisphosphonate effects in rat unloaded hindlimb bone loss model: three-dimensional microcomputed tomographic, histomorphometric, and densitometric analyses.

The effects of antiresorptive drugs on bone loss remain unclear. Using three-dimensional microtomography, dual X-ray/densitometry, and histomorphometry, we evaluated tiludronate effects in the bone loss model of immobilization in tail-suspended rats after 7, 13, and 23 days. Seventy-eight 12-week-old Wistar male rats were assigned to 13 groups: 1 baseline group, and for each time point, 1 control group treated with vehicle and three tail-suspended groups treated with either tiludronate (0.5 or 5 mg/kg) or vehicle, administered s. c. every other day, during the last week before sacrifice. In primary spongiosa (ISP), immobilization-induced bone loss plateaued after day 7 and was prevented by tiludronate. In secondary spongiosa (IISP), bone loss appeared at day 13 with a decrease in trabecular thickness and trabecular number (Tb.N) as assessed by three-dimensional microtomography. Osteoclastic parameters did not differ in tail-suspended rats versus control rats, whereas bone formation showed a biphasic pattern: after a marked decrease at day 7, osteoblastic activity and recruitment normalized at days 13 and 23, respectively. At day 23, the 80% decrease in bone mass was fully prevented by high-dose tiludronate with an increase in Tb.N without preventing trabecular thinning. In summary, at day 7, tiludronate prevented bone loss in ISP. After day 13, tiludronate prevented bone loss in ISP and IISP despite a further decrease in bone formation. Thus, the preventive effects of tiludronate in this model may be related to the alteration in bone modeling with an increase in Tb.N in ISP and subsequently in IISP.

Analysis of Variance↗
PubMed1999

Animal model of vascular inflammation.

Inflammatory mechanisms play a central role in the pathology of a variety of conditions ranging from atherosclerosis, arthritis, cancer and Alzheimer's disease. Under normal conditions the inflammatory response initiates protective actions, but triggers tissue damage under pathological conditions. Acute or chronic inflammation is mediated by nascent expression of a host of proteins such as the cytokines interleukins (IL), tumor necrosis factor (TNF), and interferons. Currently available in vitro or in vivo methods do not offer the specificity to probe the complex inflammatory cascade. We developed an animal model in which a single injection of the proinflammatory cytokines TNF-alpha and IL-1 beta in live rodents initiates a rapid inflammatory reaction which can be monitored by video microscopy and electron microscopy. This model exhibits the characteristic feature of inflammatory reaction such as adhesion and transmigration of leukocytes, and activation and degranulation of platelets and mast cells. This model is applicable to inflammatory processes in the peripheral and cerebral vasculature including the blood-brain barrier disruption in Alzheimer's disease. The animal model of inflammation reported here may prove to be a valuable tool in investigating the pathophysiology of a number of inflammatory diseases and identifying potential targets as well as agents for therapy.

Animals↗
PubMed1999

Amyloid-beta peptide induced inflammatory reaction is mediated by the cytokines tumor necrosis factor and interleukin-1.

A chronic inflammatory response possibly mediated by amyloid-beta (A beta) is believed to be a major factor in the pathology of Alzheimer's disease (AD). Recently, we demonstrated that in vivo administration of A beta produces an inflammatory response and vascular disruption as seen in the brains of AD patients. In an inflammatory response, leukocyte activation and extravasation involves cytokine production. Previous studies have indicated that immune interactions exist between the central nervous system and the peripheral immune mechanisms in AD. Increased levels of interleukin-1 beta (IL-1 beta) have been detected in brain tissue, cerebrospinal fluid, and blood/serum from AD patients. In addition, A beta stimulated the production of tumor necrosis factor-alpha (TNF-alpha) in brain astrocytes and murine monocytes. Using an animal model we investigated the role of the cytokines, TNF-alpha and IL-1 beta, in the A beta-induced inflammatory response. Adult male rats were perfused via an intra-aortic cannula with either A beta alone, interleukin-1 receptor antagonist (IL-1 ra) plus A beta, tumor necrosis factor-binding protein (TNF-bp) plus A beta or sterile saline. Serum analysis for TNF-alpha, IL-1 beta, A beta and NO showed a significant increase in TNF-alpha and A beta but not in IL-1 beta or NO after the injection of A beta. Control values for serum A beta averaged 1.6 ng/ml and in rats injected with A beta, 99.6% of this peptide was removed from the blood within 30 min. The mesenteric arterioles and venules were video recorded for 1-2 h and then processed for electron microscopy (EM). In rats given A beta alone there was extensive vascular disruption, including endothelial and smooth muscle damage with leukocyte adhesion and migration. Animals receiving either IL-1 ra or TNF-bp before A beta showed no in vivo leukocyte extravasation or vascular damage under EM. Therefore, the cytokines TNF-alpha and IL-1 beta seem to mediate the vascular disruption and inflammatory response initiated by A beta. Antagonism of these pro-inflammatory cytokines may offer new avenues for AD therapy.

Amyloid beta-Peptides↗
PubMed1999

Contribution of genetically modified mouse models to the elucidation of bone physiology.

The development over the last few years of genetically modified mouse models has provided a wealth of new information on the intimate cellular mechanisms involved in bone physiology. This article reviews some of the new insights gained into non-collagenous bone proteins. The bone matrix is no longer viewed as a passive support for bone cells, but rather as a key factor in the regulation of cell recruitment, proliferation, and differentiation. Studies using genetically modified mouse models have demonstrated the central importance of transcription factors such as Cbfa1, c-Fos, and c-Src in the differentiation of osteoblasts or osteoclasts from bone marrow stem cells. They have also allowed to identify the main cytokines involved in the regulation of bone cell activities, particularly in estrogen-deprived individuals. A discussion is provided in this article of the studies that identified the main communication pathway between osteoblasts and osteoclasts, in which the mediators are osteoprotegerin and its ligand, and that demonstrated the central position of these two factors in the regulation of osteoclast differentiation and activity.

Animals↗
PubMed1999

Estrogen protects peripheral and cerebral blood vessels from toxicity of Alzheimer peptide amyloid-beta and inflammatory reaction.

Due to increases in life expectancy, women are living 30 years or more beyond menopause. This has led to an increasing interest in the association between postmenopausal estrogen deficiency and degenerative diseases associated with aging such as cardiovascular disease, osteoporosis and dementia. Women are two times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. The mechanism underlying the protective action of estrogen in AD is under active investigation. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. This rodent model allows live videomicroscopic recording and electron microscopic analysis of peripheral vascular disruption and inflammatory reaction triggered by A beta. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. Estrogen also protected the cerebral blood vessels from endothelial dysfunction induced by A beta. This novel protective effect of estrogen against A beta cytotoxicity in peripheral and cerebral vasculature may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.

Aged↗
PubMed1998

Archaeal cold-adapted proteins: structural and evolutionary analysis of the elongation factor 2 proteins from psychrophilic, mesophilic and thermophilic methanogens.

To identify structural features important for low temperature activity in archaeal proteins, elongation factor 2 (EF-2) genes (aef2) were sequenced from psychrophilic, mesophilic and thermophilic methanogens. Scatter plots were used to compare evolutionary distances for EF-2 amino acid sequences vs. 16S-rRNA sequences from methanogens growing at diverse temperatures. The absence of a temperature bias for the rate of protein vs. nucleic acid evolution demonstrated the importance of comparing closely related proteins in order to identify changes indicative of thermal adaptation. Three-dimensional modelling of the new EF-2 sequences enabled the identification of amino acid residues that may be important for conferring low temperature activity and included greater structural flexibility produced by fewer salt bridges, less packed hydrophobic cores and the reduction of proline residues in loop structures.

Adaptation, Physiological↗
PubMed1998

L-deprenyl: nitric oxide production and dilation of cerebral blood vessels.

The monoamine oxidase-B inhibitor L-deprenyl (Selegiline) is effective in treating Parkinson's disease and possibly Alzheimer's disease. The neuroprotective property of L-deprenyl may be unrelated to the inhibition of monoamine oxidase-B. Since nitric oxide (NO) modulates activities including cerebral blood flow and memory, we examined the effect of L-deprenyl on NO. L-Deprenyl induced rapid increases in NO production in brain tissue and cerebral vessels. Vasodilation was produced by endothelial NO-dependent as well as NO-independent mechanisms in cerebral vessels. The drug also protected the vascular endothelium from the toxic effects of amyloid-beta peptide. These novel actions of selegiline may protect neurons from ischemic or oxidative damage and suggest new therapeutic applications for L-deprenyl in vascular and neurodegenerative diseases.

Amyloid beta-Peptides↗
PubMed1998

The bHLH factors, dHAND and eHAND, specify pulmonary and systemic cardiac ventricles independent of left-right sidedness.

dHAND and eHAND are basic helix-loop-helix transcription factors that play critical roles in cardiac development. The HAND genes have a complementary left-right cardiac asymmetry of expression with dHAND predominantly on the right side and eHAND on the left side of the looped heart tube. Here we show that although eHAND is asymmetrically expressed along the anterior-posterior and dorsal-ventral embryonic axes, it is symmetrically expressed along the left-right axis at early stages of embryonic and cardiac development. After cardiac looping, dHAND and eHAND are expressed in the right (pulmonary) and left (systemic) ventricles, respectively. The left-right (LR) sidedness of dHAND and eHAND expression is demonstrated to be anatomically reversed in situs inversus (inv/inv) mouse embryos; however, dHAND expression persists in the pulmonary ventricle and eHAND in the systemic ventricle regardless of anatomic position, indicating chamber specificity of expression. Previously we showed that dHAND-null mice fail to form a right-sided pulmonary ventricle. Here mice homozygous for the dHAND and inv mutations are demonstrated to have only a right-sided ventricle which is morphologically a left (systemic) ventricle. These data suggest that the HAND genes are involved in development of segments of the heart tube which give rise to specific chambers of the heart during cardiogenesis, rather than controlling the direction of cardiac looping by interpreting the cascade of LR embryonic signals.

Animals↗
PubMed1998

Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults.

OBJECTIVES: To assess whether antibiotic treatment for acute cough is effective and to measure the side effects of such treatment. DESIGN: Quantitative systematic review of randomised placebo controlled trials. DATA SOURCES: Nine trials (8 published, 1 unpublished) retrieved from a systematic search (electronic databases, contact with authors, contact with drug manufacturers, reference lists); no restriction on language. MAIN OUTCOME MEASURES: Proportion of subjects with productive cough at follow up (7-11 days after consultation with general practitioner); proportion of subjects who had not improved clinically at follow up; proportion of subjects who reported side effects from taking antibiotic or placebo. RESULTS: Eight trials contributed to the meta-analysis. Resolution of cough was not affected by antibiotic treatment (relative risk 0.85 (95% confidence interval 0.73 to 1.00)), neither was clinical improvement at re-examination (relative risk 0.62 (0.36 to 1.09)). The side effects of antibiotic were more common in the antibiotic group when compared to placebo (relative risk 1.51 (0.86 to 2.64)). CONCLUSIONS: Treatment with antibiotic does not affect the resolution of cough or alter the course of illness. The benefits of antibiotic treatment are marginal for most patients with acute cough and may be outweighed by the side effects of treatment.

Adult↗
PubMed1998

Characterization of the erythrocyte sodium-lithium countertransporter: limitations and assumptions of traditional and kinetic methodologies.

The present work examined the key elements featuring in the various methods used to characterize the erythrocyte sodium-lithium countertransport. Effects of medium composition on lithium efflux were investigated in 20 subjects. Mean lithium efflux (mmol Li/l RBC.h) into a 150 mM sodium medium was significantly higher than efflux into a revised sodium-rich medium (149 mM) containing 1 mM Mg (0.335 +/- 0.100 vs. 0.298 +/- 0.085 respectively; P < 0.03). Mean lithium efflux into sodium-free media where sodium had been entirely replaced by magnesium, was significantly lower than efflux into a choline-based medium containing only 1 mM magnesium (0.088 +/- 0.027 vs. 0.109 +/- 0.034 respectively; P = 0.03). Sodium-lithium countertransport activity and the transporter's kinetic profile were measured simultaneously in 35 subjects using traditional choline-based and kinetic methodologies. There was a significant correlation between countertransport activity and maximal rate of turnover (Vmax) (r = 0.62; P < 0.001); Vmax values were consistently greater than their corresponding countertransport activities (P < 0.001). On subdividing the subject group into tertiles based on the Michaelis-Menten constant (km) values (mM), < 75, 75-150 and > 150, the slopes of the regression lines for each group diminished progressively (0.64, 0.49 and 0.23 respectively), correlations within each group remained significant (P < 0.001, P < 0.001 and P < 0.02). No significant correlation was found between km values and countertransport activity (r = 0.035; P = NS). Increasing the number of points representing sodium concentrations within the range 0-150 mM, improved the confidence in the emerging estimates of Vmax and km obtained by linear transformation. Comparison of kinetic data derived using four different analytical methods (two linear transformations, a nonlinear regression and a statistical method), showed no significant differences between the estimates yielded for either Vmax (P = 0.88. NS) or km (P = 0.92, NS). This study has highlighted the critical roles of assay conditions and derivation techniques used when measuring sodium-lithium countertransport, emphasizing the need for standardization of the methodology.

Adult↗
PubMed1998

Efficiency assessment of the gene trap approach.

The trapping of genes in murine embryonic stem (ES) cells offers three features in one experimental approach: 1) analysis of the expression patterns of unknown genes by using a simple staining method, 2) rapid cloning of unknown genes, and 3) generation of mutant mouse lines. We performed a gene trap screen aimed at the discovery of new genes regulating embryonic development. We have processed 209 gene trap events for expression patterns in chimeric murine embryos. Randomly tested, beta-galactosidase-positive ES cell clones resulted in vivo in 35% gene trap events showing no beta-galactosidase activity, 39% gene trap events with ubiquitous beta-galactosidase activity, and 26% gene trap events showing beta-galactosidase activity restricted to specific cell types or organs. In vitro preselection reduced gene trap events with ubiquitous beta-galactosidase activity to 10% and increased the gene trap events with restricted beta-galactosidase activity to 64%, making the screening procedure for genes expressed in a restricted manner 2.5-fold more efficient. In five of the seven gene trap insertions into genes in which the expression pattern during embryogenesis was known, the beta-galactosidase marker gene reproduced faithfully the expression pattern of the trapped gene. 5'-Rapid amplification of cDNA ends (5'-RACE) of 28 gene trap events revealed 19 novel mouse genes, 8 known mouse genes, and 1 random transsplicing event. Twelve of the 25 mouse lines that crossed to homozygosity showed overt abnormalities. The genomic structure was investigated in four of these gene trap events, which caused obvious abnormalities. In all four cases, the splice-acceptor gene trap construct was inserted into an exon. One of the 13 gene trap events that did not result in overt abnormalities was examined for the presence of wild-type mRNA. Homozygous animals were found to produce normal levels of wild-type mRNA. Evidently, gene trapping does not always provide all three of the features mentioned above. In this paper, we discuss the efficiency of gene trapping and ways in which some problems may be overcome.

Animals↗
PubMed1998

Distribution of a murine protein tyrosine phosphatase BL-beta-galactosidase fusion protein suggests a role in neurite outgrowth.

We have generated a gene trap insertion into the protein tyrosine phosphatase-BL (PTP-BL) locus, which produces a fusion of the N-terminal half of PTP-BL with beta-galactosidase. During development, beta-galactosidase activity was seen in all epithelial cells: strong staining was observed in the stomach and kidney epithelium, the ependymal layer of the central nervous system, and the surface ectoderm. Particularly prominent beta-galactosidase activity was seen in the peripheral nervous system, which correlated with neurite outgrowth. In epithelial cells, staining was seen in the apical portion of the cells. In nerves, beta-galactosidase activity was associated with growth cones as well as with Schwann cells. This suggests that the amino-terminal portion of PTP-BL contains sequences sufficient to target the fusion protein to specific subcellular compartments. In situ hybridization with a PTP-BL probe demonstrated that all tissues in which beta-galactosidase activity was seen were genuine sites of expression of the PTP-BL gene, although differences in the stability of the PTP-BL protein and the PTP-BL-beta-galactosidase fusion protein may exist. The distribution of beta-galactosidase activity in the peripheral nervous system, together with the structure of the wild-type protein, suggests that this phosphatase may have a role in regulation of the cytoskeleton during the development of the peripheral nervous system.

Animals↗