A good death. Quality of death can be measured outside hospices.
Explore the source record for details and available documents.
Death↗
Biomedical subjects
M Thomas
Publications and source records attributed to M Thomas.
Single repeat deletion in ApoA-I blocks cholesterol esterification and results in rapid catabolism of delta6 and wild-type ApoA-I in transgenic mice.
The deletion mutation Delta6 apolipoprotein A-I lacks residues 143-164 or repeat 6 in the mature apoA-I protein. In vitro studies show this mutation dramatically reduces the rate of lecithin:cholesterol acyltransferase (LCAT) catalyzed cholesterol esterification. The present study was initiated to investigate the effect of this mutation on in vivo high density lipoprotein (HDL) cholesterol esterification and metabolism. Transgenic mice expressing human Delta6 apoA-I (TgDelta6 +/+) were created and then crossed with apoA-I knockout mice (-/-) to generate mice expressing only human Delta6 apoA-I (TgDelta6 -/-). Human Delta6 apoA-I was associated with homogeneous sized alpha-HDL, when wild-type mouse apoA-I was present (in TgDelta6 +/+ and +/- mice). However, in the absence of endogenous mouse apoA-I, Delta6 apoA-I was found exclusively in cholesterol ester-poor HDL, and lipid-free HDL fractions. This observation coincides with the 6-fold lower cholesterol ester mass in TgDelta6 -/- mouse plasma compared with control. Structural studies show that despite the structural perturbation of a domain extending from repeat 5 to repeat 8 (137-178), Delta6 apoA-I binds to spherical unilamellar vesicles with only 2-fold less binding affinity. In summary, these data show a domain corresponding to apoA-I repeat 6 is responsible for providing an essential conformation for LCAT catalyzed generation of cholesterol esters. Deletion of apoA-I repeat 6 not only blocks normal levels of cholesterol esterification but also exerts a dominant inhibition on the ability of wild-type apoA-I to activate LCAT in vivo.
Animals↗
What is your diagnosis? Kidney and ureteral injuries and subsequent adhesions and peritonitis in a dog hit by a car.
Explore the source record for details and available documents.
Accidents, Traffic↗
HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase.
The Discs Large (DLG) tumour suppressor protein is targeted for ubiquitin mediated degradation by the high risk human papillomavirus (HPV) E6 proteins. In this study we have used a mutational analysis of E6 in order to investigate the mechanism by which this occurs. We first show that the differences in the affinities of HPV-16 and of HPV-18 E6 proteins for binding DLG is reflected in their respective abilities to target DLG for degradation. A mutational analysis of HPV-18 E6 has enabled us to define regions within the carboxy terminal half of the protein which are essential for the ability of E6 to direct the degradation of DLG. Mutants within the amino terminal portion of E6 which have lost the ability to bind the E6-AP ubiquitin ligase, as measured by their ability to degrade p53, nonetheless retain the ability to degrade DLG. Significant levels of DLG degradation are also obtained using wheat germ extracts which lack E6-AP. Finally, we show that the transfer of the DLG binding domain onto the low risk HPV-6 E6 confers DLG binding activity to that protein and, most significantly, allows HPV-6 E6 to target DLG for degradation. These results indicate that E6 mediated degradation of DLG does not involve the E6-AP ubiquitin ligase and, in addition, shows that the high and low risk HPV E6 proteins most likely share a common cellular intermediary in the ubiquitin pathway.
Adaptor Proteins, Signal Transducing↗
DNA binding properties of novel distamycin analogs that lack the leading amide unit at the N-terminus.
First examples of distamycin (Dst) analogs which lack hydrogen bond donor or acceptor groups at the N-terminus have been synthesized. The first molecule of this series, which is a bispyrrole peptide, did not exhibit any detectable binding with double-stranded (ds) DNA. However, all other analogs did bind strongly to AT-rich sequences of ds-DNA, with the binding affinities increasing as a function of the number of repeating pyrrole carboxamide units. These results imply that a hydrogen bond donor or acceptor atom per se at the N-terminus is not a prerequisite for DNA binding in the case of pyrrole carboxamide-based Dst analogs. However, in the absence of H-bond donor or acceptor at the N-terminus, a minimum of three pyrrole carboxamide units is necessary for the onset of DNA binding. Beyond this minimum number, the binding affinity increases as a function of the number of pyrrole units, as a result of the greater availability of hydrogen bonding and van der Waals surface. Experiments with poly[d(G-C)] have shown that the presence of the N-terminus formamide group is not inevitable for GC binding of this class of molecules. The observation that the N-terminus formamide unit can be dispensed with suggests that these molecules, which are much easier to synthesize and functionalize, can be used in place of the conventional analogs of distamycin for the development of novel minor groove binders with extended sequence recognition properties.
Binding Sites↗
Effects of ceramide on apoptosis, proteoglycan degradation, and matrix metalloproteinase expression in rabbit articular cartilage.
Cartilage loss in osteoarthritis is characterized by matrix degradation and chondrocyte death. The lipid messenger ceramide is implicated in signal transduction of the catabolic cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as in apoptosis. The aim of this study was to examine the in vitro effects of ceramide on proteoglycan degradation, matrix-metalloproteinase (MMP) expression and activity, and chondrocyte apoptosis in rabbit articular cartilage. Cell-permeant ceramide C(2) stimulated proteoglycan degradation in cartilage explants starting from 3 x 10(-5) M, with 100% increase at the dose of 10(-4) M. This effect was probably due to MMPs since it was blocked by the MMP inhibitor batimastat. Furthermore, in isolated chondrocytes, C(2) stimulated the expression of MMP-1, 3, and 13 at the mRNA level, MMP activity, and MMP-3 production. Ceramide also caused chondrocyte apoptosis at doses ranging from 10(-5) to 10(-4) M. This study supports the hypothesis that ceramide might play a mediatory role in both matrix degradation and apoptosis in processes of cartilage loss such as those observed in osteoarthritis.
Animals↗
Physicians helping the underserved: the Reach Out program.
In the current health care environment of competition and market forces, concern has arisen that the classic principle of serving disadvantaged persons may not be fulfilled due to pressures from managed care. Reach Out, a $12 million national program of the Robert Wood Johnson Foundation, was developed to recruit leaders from among practicing physicians to organize projects to care for the uninsured and underserved. Physician volunteerism was a key component of all projects. Thirty-nine Reach Out projects were implemented and carried out across the United States, with average funding per project of $300000 distributed over a period of 4 years. Seven model types emerged, the most common of which, the free clinic and the referral network, accounted for two thirds of the total. At the program's conclusion, 199584 patients were enrolled and 11252 physicians recruited. Project execution was more complex than initially supposed, and major progress commonly was not evident until the third or fourth year, but at least two thirds of the projects are likely to continue with local support. With strong physician leadership and a funded administrative core, organized community efforts can develop and sustain an effective program. Programs such as Reach Out cannot solve the national problem of access to health care, but they can make a small but important impact on the number of uninsured and underserved persons without access to health care.
Altruism↗
Inactive matrix metalloproteinase 2 is a normal constituent of human glomerular basement membrane. An immuno-electron microscopic study.
Remodelling of the extracellular matrix requires tight control not only of matrix synthesis, but also of matrix degradation. Control of matrix degradation is achieved mainly through the matrix metalloproteinase (MMP) enzymes. In the glomerulus, MMP-2 and MMP-9 are believed to be particularly important, as they have activity against type IV collagen. This study has demonstrated by immuno-electron microscopy that most of the immunoreactivity for MMP-2 in the normal glomerulus is located within the glomerular basement membranes and mesangial matrix. mRNA for MMP-2 is also detectable in normal glomeruli, but the other main gelatinase, MMP-9, could not be localized by immuno-electron microscopy. In the normal glomerulus, it seemed likely that MMP-2 is present in an inactive form. To confirm this, in situ zymography was carried out using frozen sections of normal kidney. Baseline activity of normal kidney was relatively weak, but this was dramatically increased by chemical activation of metalloproteinases. The results imply that MMP-2, in an inactive form, is a normal constituent of the extracellular matrix and glomerular basement membranes. Activation would presumably render the matrix 'self-degrading'; membrane-bound MMPs (MT-MMPs) seem particularly likely to be involved in leukocyte penetration of basement membranes in inflammation.
Basement Membrane↗
Presentation of intravascular lymphomatosis as lumbosacral polyradiculopathy.
A 53-year-old man developed progressive sensory disturbance and weakness in the legs, sphincter disturbance, back pain, systemic symptoms, and pancytopenia. Electrophysiological tests indicated a widespread lumbosacral polyradiculopathy. Spinal magnetic resonance imaging and routine cerebrospinal fluid analysis showed minor nonspecific abnormalities. Bone marrow and liver biopsies showed hemophagocytosis; and polymerase chain reaction of cerebrospinal fluid, bone marrow, and serum suggested active infection with human herpesvirus-6. Autopsy revealed that his neurological symptoms resulted from intravascular lymphomatosis (angiotropic large cell lymphoma), a rare variant of lymphoma with predilection for the nervous system.
Diagnosis, Differential↗
Screening the 3' region of the polycystic kidney disease 1 (PKD1) gene in 41 Bulgarian and Australian kindreds reveals a prevalence of protein truncating mutations.
Screening for disease-causing mutations in the unique region of the polycystic kidney disease 1 (PKD1) gene was performed in 41 unrelated individuals with autosomal dominant polycystic kidney disease. Exons 34-41 and 43-46 were assayed using PCR amplification and SSCP analysis followed by direct sequencing of amplicons presenting variant SSCP patterns. We have identified seven disease-causing mutations of which five are novel [c.10634-10656del; c.11587delG; IVS37-10C>A; c.11669-11674del; c.13069-13070ins39] and two have been reported previously [Q4010X; Q4041X]. Defects in this part of the gene thus account for 17% of our group of patients. Five of the seven sequence alterations detected are protein-truncating which is in agreement with mutation screening data for this part of the gene by other groups. The two other mutations are in-frame deletions or insertions which could destroy important functional properties of polycystin 1. These findings suggest that the first step toward cyst formation in PKD1 patients is the loss of one functional copy of polycystin 1, which indirectly supports the "two-hit" model of cystogenesis where a second somatic mutation inactivating the normal allele is necessary to occur for development of the disease condition.
3' Untranslated Regions↗
Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in russian charcot-marie-tooth neuropathy patients; irina V. Mersiyanova, sookhrat M. Ismailov, alexandr V. Polyakov, elena L. Dadali, valeriy P. Fedotov, eva nelis, ann Lofgren, vincent timmerman, christine van broeckhoven, and oleg V. Evgrafov (Article was originally published in human mutation 15:340-347, 2000)
The authors wish to correct a mistake which occurred in the reporting of one of the mutations. The mutation in Cx32 Met34Lys is wrongly described as 100A>G. The correct description of the mutation should be 101T>A (Met34Lys).
Journal Article↗
Ectopic expression of maize knotted1 results in the cytokinin-autotrophic growth of cultured tobacco tissues.
The ectopic expression of knotted homologues has cytokinin-like effects on plant morphology. The functional relationship between knotted and cytokinins was investigated in cultures of leaf tissue established from tobacco (Nicotiana tabacum L. cv. Havana 425) plants transformed with the maize knotted1 (kn1) gene regulated by cauliflower mosaic virus 35S RNA expression signals. In contrast to leaf tissues of untransformed plants, leaf tissues of kn1 transformants were capable of sustained, cytokinin-autotrophic growth on auxin-containing medium and resembled the tobacco cytokinin-autotrophic mutants Hl-1 and Hl-2. The concentration of 18 cytokinins was measured in cultures initiated from leaves of three independent kn1 transformants and the Hl-1 and Hl-2 mutants. Although cytokinin contents were variable, the content of several cytokinins in Kn1, Hl-1 and Hl-2 tissue lines was at least 10-fold higher than that of wild-type tobacco tissues and in the range reported for other cytokinin-autotrophic tobacco tissues. These results suggest that the cytokinin-autotrophic growth of Kn1 lines could result from elevated steady-state levels of cytokinins.
Adenine↗
p53 tumour-suppressor gene in non-small-cell lung cancer with neoadjuvant therapy.
In a phase II study for optimizing therapeutic management of locally advanced non-small-cell lung cancer the prognostic and therapeutic relevance of the p53 status was investigated. Biopsy or mediastinoscopy samples, collected prior to neoadjuvant chemoradiotherapy and corresponding resection specimens, were analysed immunohistochemically (CM1 antiserum) for p53 accumulation and molecular biologically (polymerase chain reaction/single-strand conformation polymorphism) for p53 mutations. The results were correlated to the response to therapy (regression grade) and to the survival times. p53 accumulation was found in 41.7% (prior to neoadjuvant therapy) and in 40.0% (after surgery) of the tumours. p53 mutation was demonstrated in 45.4% (prior to neoadjuvant therapy) and in 46.4% (after surgery) of the investigated tumours. Neither before nor after therapy was any correlation to the survival times or to the response to therapy seen in the collective analysed. Thus, such investigations are not suitable for identifying patients with locally advanced non-small-cell lung cancer who might benefit, to different extents, from neoadjuvant therapy.
Adult↗
Minocycline-induced systemic adverse reaction with liver and bone marrow granulomas and Sezary-like cells.
Explore the source record for details and available documents.
Adult↗
Extrapulmonary tuberculosis in the northeastern suburbs of Paris: 141 cases.
Background: Big cities were particularly affected by tuberculosis in the 1990s. Methods: We studied 141 cases of extrapulmonary tuberculosis in patients not infected by HIV in the northeastern suburbs of Paris. Results: A total of 84 men and 57 women were included in the study. Their average age at diagnosis was 42.2 years. Some 73.6% of the patients were foreign-born. A total of 182 sites were identified in 141 patients. There was an association with pulmonary tuberculosis in 38 cases. The sites were: lymph node (48.9%), pleural (25.5%), skeletal (22.7%), genitourinary (5.7%), and meninges (5%). Unfavorable social conditions were frequently observed. The average duration of treatment was 10 months. Twenty-four adverse drug effects were noted. Sixty-eight strains of Mycobacterium tuberculosis were isolated. Five cases of primary resistance to at least one antituberculous drug and only one case of multidrug resistance were observed. Some 95.7% of the 93 patients who were not lost to follow up were cured. Conclusion: Independently of HIV infection, extrapulmonary tuberculosis is still present, particularly in the suburbs of big cities, where social conditions are poor. The significant number of patients lost to follow-up demands that measures be adapted for the therapeutic management of these patients.
Journal Article↗
Intolerance of osteosynthesis material: evidence of dichromate contact allergy with concomitant oligoclonal T-cell infiltrate and TH1-type cytokine expression in the peri-implantar tissue.
BACKGROUND: We report on a 37-year-old man without history of previous allergic disease who developed an aseptic intolerance reaction to a chromium-cobalt alloy, with local discomfort, loosening, and absence of fracture healing. Both in vivo and in vitro allergoimmunologic diagnostic tests were performed. METHODS: Patch testing was done with a European standard series. Specific serum IgE was measured by CAP-FEIA. In addition to immunohistology (APAAP method), peri-implantar tissue was further analyzed by PCR to determine T-cell-receptor-gamma rearrangement and thus the potential clonal (antigen-driven) T-cell repertoire. The actual tissue mRNA expression for IL-4, IL-6, and IFN-gamma was visualized by RT-PCR. RESULTS: Skin testing gave a delayed-type reaction to dichromate. Specific serum IgE to natural rubber latex and grass pollen was found--but without clinical symptoms. Immunohistology revealed a monocytic and dense T-cell infiltrate. The latter, instead of being random, showed an oligoclonal T-cell receptor rearrangement. In addition, there was TH1-type mediator expression (IL-6 and IFN-gamma, but not IL-4). CONCLUSIONS: Skin test, examination of peri-implantar tissue, and the prompt healing after replacement of the osteosynthesis material suggest an allergic reaction. PCR analysis of peri-implantar tissue can further help to identify and understand allergy-mediated implant intolerance reactions.
Adult↗
Molecular, serological and genetic studies on two new HLA-DRB1 alleles--HLA-DRB1*0704 and HLA-DRB1*1507.
Two new HLA-DRB1 alleles (DRB1*0704 and DRB1*1507) were detected during routine polymerase chain reaction (PCR)-based typing of two Caucasoid bone marrow panel donors due to apparent DRB1* "blanks" being associated with unexpected DRB4, DRB5 and DQB1 alleles. HLA-DRB1*0704 differed from DRB1*0701 by five consecutive nucleotides at positions 217 to 221 of exon 2 encoding two amino acids substitutions of tyrosine to asparagine at codons 77 and valine to tyrosine at codon 78. DRB1*1507 differed from DRB1*1501 by a single nucleotide at position 127 encoding an amino acid substitution of phenylalanine to tyrosine at codon 47. Their specificities were unequivocally assigned by serology as HLA-DR7 and DR15, respectively, and family and population studies allowed their likely HLA-A,B,C,DR,DQ and complement (Bf, C4A, C4B) bearing haplotypes to be identified. No further examples were found in 19,113 HLA-DR,DQ typed donors from the Welsh Bone Marrow Donor Registry indicating that both these alleles have a phenotype frequency of <0.01% and a gene frequency of <0.00003.
Alleles↗
Formation of functional tissue from transplanted adrenocortical cells expressing telomerase reverse transcriptase.
We report the first use of human telomerase reverse transcriptase (hTERT) expression in experimental xenotransplantation. Previously, we showed that bovine adrenocortical cells can be transplanted into severe combined immunodeficient (SCID) mice, and that these cells form functional tissue that replaces the animals' own adrenal glands. We cotransfected primary bovine adrenocortical cells with plasmids encoding hTERT, SV40 T antigen, neo, and green fluorescent protein. These clones do not undergo loss of telomeric DNA and appear to be immortalized. Two clones were transplanted beneath the kidney capsule of SCID mice. Animals that received cell transplants survived indefinitely despite adrenalectomy. The mouse glucocorticoid, corticosterone, was replaced by the bovine glucocorticoid, cortisol, in the plasma of these animals. The tissue formed from the transplanted cells resembled that formed by transplantation of cells that were not genetically modified and was similar to normal bovine adrenal cortex. The proliferation rate in tissues formed from these clones was low and there were no indications of malignant transformation.
Adrenal Cortex↗