Surgical moulages.
Explore the source record for details and available documents.
Dermatologic Surgical Procedures↗
Biomedical subjects
D Wallach
Publications and source records attributed to D Wallach.
Daily multidrug therapy for leprosy; results of a fourteen-year experience.
Between 1980 and 1994, 67 new or relapsing leprosy patients were treated by daily administered multidrug regimens. Tuberculoid patients (23 TT/BT) received either bitherapy [rifampin + dapsone or clofazimine (RMP + DDS or CLO)] or tritherapy [RMP + DDS and/or CLO and/or ethionamide (ETH)] until clinical cure. Lepromatous patients (44 BB/BL/LL) received tritherapy (RMP + DDS and/or CLO and/or ETH) at least until bacteriological negativity. Of the 23 tuberculoid patients only one patient (5%) was cured at 6 months and about 70% needed between 6 and 24 months of treatment to obtain clinical cure (mean 19.5 months). In the 44 lepromatous patients, the achievement of bacteriological negativity was significantly linked to the initial bacterial index (BI), and it occurred after 2 to 7 years (mean 66.5 months) of multidrug therapy (MDT). The average BI decrease per year was 1.1+ during the first year, 0.9+ the second year, and then < 0.5+ per year. Reactional states significantly (p < 0.01) influenced the BI course: reversal reactions (RR) accelerated while erythema nodosum leprosum (ENL) delayed the BI decrease. Three of the 23 (13%) tuberculoid and 19 of the 44 (43%) lepromatous patients (p < 0.02) exhibited a RR and 18 of 44 (41%) lepromatous patients had ENL during MDT. A late RR (LRR) was observed in 1 (5%) and 6 (17%) of our tuberculoid and lepromatous patients, respectively, and 3 (8%) of our lepromatous patients suffered post-MDT ENL. No confirmed relapse has been observed within a follow-up period of 6 months to 7 years and 3 months [59 person-years at risk (PYR)] for TT/BT patients and of 4 months to 5 years and 10 months (100 PYR) for BB/BL/LL patients. When compared to the recommended WHO/MDT, it appears that daily MDT does not increase the clinical or the bacteriological cure rates either at 6 months in paucibacillary tuberculoid patients or at 2d years in multibacillary lepromatous patients. Moreover, as does the WHO/MDT, our regimens show a high frequency of reactional states both during and after treatment. This fact constitutes the main new problem of the actual treatment of leprosy.
Adolescent↗
[The concept of neutrophilic disease].
Explore the source record for details and available documents.
Humans↗
Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.
Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that result in cell death. Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homology to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades.
Adaptor Proteins, Signal Transducing↗
A potential mechanism of "cross-talk" between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other.
The p55 tumor necrosis factor (TNF) receptor and Fas/APO1 induce cell death via distinct regions in their intracellular domains. Three cytoplasmic proteins that bind to these receptor regions have been identified recently. One, MORT1 (also called FADD), binds to Fas/APO1 but not to p55-R; another, TRADD, binds to the p55 TNF receptor but not to Fas/APO1; and the third, RIP, binds weakly to both receptors. The regions within these proteins that are involved in binding to the receptors and the receptor regions to which they bind share a common sequence motif, that of the "death domain." This study shows that the death domain motifs in MORT1, TRADD, and RIP bind effectively to each other, a mode of binding that may allow "cross-talk" between the functional expression of the p55 TNF receptor and Fas/APO1.
Adaptor Proteins, Signal Transducing↗
Long-term protection against the effects of tumour necrosis factor by controlled delivery of the soluble p55 TNF receptor.
Chronic inflammatory diseases are associated with increased soluble tumour necrosis factor (TNF) receptor concentrations in serum. To obtain such an increase, we implanted mice with ethylene vinyl-acetate or poly (lactic-co-glycolic) acid copolymers containing human soluble p55 TNF receptor. Copolymers containing rather small amounts of the receptor (about 20 micrograms) maintained prolonged increases in serum receptor concentrations. Mice implanted with these copolymers were effectively protected against lethal wasting and from arthritis resulting from chronic exposure to TNF. These findings suggest that the increased production of soluble TNF receptors in chronic inflammatory diseases counteracts deleterious effects of TNF, and suggest a therapeutic application for the natural forms of the receptors in such diseases.
Animals↗
Soluble tumor necrosis factor receptors and interleukin-6 levels in patients with severe preeclampsia.
OBJECTIVE: To investigate whether serum and amniotic fluid (AF) levels of soluble tumor necrosis factor receptors and interleukin-6, markers of immune activation and endothelial dysfunction, are altered in patients with severe preeclampsia. METHODS: Plasma was collected before induction of labor, at delivery, and postpartum from 19 patients with severe preeclampsia. Amniotic fluid was also obtained in early labor from these patients. Similar samples were obtained from an antepartum control group matched for gestational age and a term control group without preeclampsia. All plasma and AF samples were assayed for p55 and p75 soluble tumor necrosis factor receptors and for interleukin-6 by specific enzyme-linked immunoassays. Levels in preeclamptic patients and the control groups were compared. RESULTS: Levels of both receptors were significantly elevated in AF and all maternal plasma samples except those collected 24 hours postpartum for patients with preeclampsia relative to levels in controls. Interleukin-6 was detected more frequently and in higher concentrations in the plasma collected before labor for preeclamptic patients compared with controls, but no difference was noted in interleukin-6 detection rates or plasma concentrations at delivery. Conversely, AF concentrations of interleukin-6 were significantly reduced in patients with preeclampsia. CONCLUSION: The increased levels of soluble tumor necrosis factor receptors found in patients with severe preeclampsia may represent a protective response to increased tumor necrosis factor activity and be a marker for immune activation. Increased interleukin-6 concentrations in maternal plasma before labor suggest the involvement of this cytokine as well in the altered immune response and its contribution to endothelial cell dysfunction.
Adult↗
Suicide by order: some open questions about the cell-killing activities of the TNF ligand and receptor families.
That leukocytes can produce proteins with cell-killing activities has been known for almost 30 years (Granger GA, Kolb EP. J Immunol 1968, 101; Ruddle NH, Waksman BH. J Exp Med 1968, 128, 1267-1279; Carswell EA, Old LJ, Kassel S, Green S, Fiore N, Williamson B. Proc Natl Acad Sci USA 1975, 72, 3666-3670). However, it is only recently that the nature of this cell killing activity has become clear. What appeared initially to be merely a toxic effect of the leukocyte-produced proteins (hence their initial name, 'lymphotoxins') has turned out to represent a new kind of biological mechanism, whose understanding required a radical change of concepts concerning the ways in which the life and death of the cell are controlled. The leukocyte-produced 'toxic' proteins turned out to act, not through any toxic feature of the proteins themselves, but by activating destructive mechanisms that pre-exist within the target cell. Their action thus represents a way by which one cell can dictate suicide to another. Within the last few years more has been learnt about their mechanisms of action than was learnt throughout the two preceding decades. Nevertheless, many questions still remain unresolved. The purpose of this exposition is to spell out some of these open questions.
Adaptor Proteins, Signal Transducing↗
Inhibition of tumor necrosis factor alpha (TNFalpha) activity in rat brain is associated with cerebroprotection after closed head injury.
We recently demonstrated that closed head injury (CHI) in the rat triggers the production of tumor necrosis factor alpha (TNFalpha) in the contused hemisphere. Other investigations have shown that this cytokine plays a role in the inflammatory response following trauma. The present study was designed to determine whether inhibition of TNFalpha production or activity affects the development of cerebral edema as well as neurological dysfunction and hippocampal cell loss after CHI. To this end, we used two pharmacological agents, each acting via a different mechanism: pentoxifylline (PTX), which attenuates the production of TNFalpha, and tumor necrosis factor binding protein (TBP), a physiological inhibitor of TNFalpha activity. Both agents significantly lessened peak edema formation at 24 h and facilitated the recovery of motor function for < or = 4 days postinjury. In addition, TBP attenuated disruption of the blood-brain barrier and protected hippocampal cells. PTX significantly lowered the brain TNFalpha level (by approximately 80%), and TBP completely abolished the activity of recombinant human TNF when they were added at the same time in the in vitro bioassay. We suggest, therefore, that a decrease in TNFalpha level or the inhibition of its activity is accompanied by reduced brain damage.
Animals↗
[History of the treatment of syphilis with mercury: five centuries of uncertainty and toxicity].
Explore the source record for details and available documents.
History, Early Modern 1451-1600↗
[The treatment of syphilis with mercury: an exemplary therapeutic history].
Prior to the first use of penicillin against syphilis in 1943, mercury had a prominent position in the medical practice despite a tremendous toxicity and a questionable efficiency. In fact, during 450 years mercury remained the guarantee of efficacy. The modalities of use increased, the durations of treatment lengthened without any evidence of a worsening morbidity. This history of an exceptional duration seems to be a good example of the weight of tradition or habit in the medical practice, of the importance of the constraints supported by the patients, of the necessity and the difficulties to evaluate the treatments without error.
History, 15th Century↗
High levels of soluble p55-TNF receptors in seminal and prostatic fluids of normal and infertile men.
PURPOSE: To study the role of tumor necrosis factor (TNF) in the male reproductive systems by examining the occurrence, source, and possible functional significance of soluble TNF receptors in seminal fluids of normal and infertile men. MATERIALS AND METHODS: Concentrations of soluble TNF receptors (p55-sTNF-R and p75-sTNF-R) were measured by ELISA in human sera, seminal fluids, prostatic fluid and fluid obtained from an epididymal spermatocele. RESULTS: The level of p55-sTNF-R in seminal fluids of normospermic men was approximately equal to 20-fold higher than in normal serum (13.9 +/- 6.9 ng./ml. versus 0.7 +/- 0.2 ng./ml.). In contrast, p75-sTNF-R, which occurs in serum at amounts higher than p55-sTNF-R, was almost indiscernible in the seminal fluids (<0.18 +/- 0.28 ng./ml. versus 1.9 +/- 0.6 ng./ml. in sera). Concentrations of p55-sTNF-R in seminal fluids of oligoasthenospermic and azoospermic men were similar to those of normospermic men (15.6 +/- 8.5 ng./ml. and 14.9 +/- 6.5 ng./ml., respectively). Higher p55-sTNF-R concentrations were found in prostatic fluids and first split ejaculates (39.8 +/- 1.2 ng./ml. and 32 +/- 1.7 ng./ml., respectively), while second split ejaculates and the fluid from an epididymal spermatocele were found to contain p55-sTNF-R at lower levels (10.8 +/- 1 ng./ml. and 1 ng./ml., respectively). CONCLUSIONS: These findings suggest intense local biosynthesis of p55-sTNF-R in the prostate occurring independently of spermatogenesis. Possible functional implications are: 1) shielding of spermatozoa from the inhibitory effect of TNF in the female reproductive tract; 2) a role for TNF in the normal physiology of the prostate; and 3) blocking TNF-mediated immune response in the prostate, which may have bearings on the development of prostatic hypertrophy or cancer.
Antigens, CD↗
Exploring cell death mechanisms by analyzing signaling cascades of the TNF/NGF receptor family.
The ability of ligands of the tumor necrosis factor (TNF) family to induce death of cells independently of new protein synthesis provides a unique approach to molecular analysis of programmed cell death mechanisms. Sequential analysis of the protein-protein interactions by which these receptors signal, allows identification of specific molecules that participate in the cell death process and unequivocal definition of cause-effect relationships between them. Several receptors of this family, with structurally unrelated intracellular domains, have the ability to trigger cell death. some intracellular proteins that bind to the receptors and participate in the induction of their effects have been identified. Association of the Fas/APO1-interacting protein MORT1/FADD with the p55 TNF receptor-interacting protein TRADD, and the association of both MORT1/FADD and TRADD with a third protein, RIP, provide potential cross-talk mechanisms between Fas/APO1 and the p55 TNF receptor. TRAF2, a cytoplasmic protein that binds to the p75 TNF receptor, as well as to several other receptors of the TNF/NGF family, also binds to TRADD, thus further extending the range of receptors of this family that can share common signaling mechanisms. The N-terminal part of MORT1/FADD binds to a protease of the CED3/ICE family, MACH alpha. Activation of MACH alpha by the TNF/NGF receptors appears to be the most upstream enzymatic activity in the cascade of signaling for cell death.
Adaptor Proteins, Signal Transducing↗
A decade of accumulated knowledge and emerging answers. The 6th international congress on TNF Rhodes, Greece. May 1996.
Explore the source record for details and available documents.
Animals↗
Increased expression of tumor necrosis factor-alpha receptors in the brains of patients with AIDS.
Tumor necrosis factor (TNF)-alpha has been shown to be increased in brain tissue of AIDS patients and may function as a mediator of cerebral damage. We initiated a study to determine the cellular localization and degree of protein and mRNA expression of the two specific TNF-alpha receptors (TNF-Rs), p55 and p75, in brain tissues from AIDS patients. Cerebral white matter obtained at autopsy from 13 AIDS patients, 10 unhealthy controls, and 4 healthy controls was evaluated. Double-label immunohistochemistry revealed prominent up-regulation of p55 and p75 TNF-Rs on activated macrophages and microglial cells in all AIDS patients; no increased staining was found on astrocytes. Staining was most prominent in patients with opportunistic infection of the brain and in microglial nodules of patients with HIV encephalitis. Brain tissues also showed increased expression of interleukin (IL)-1 beta, IL-6, and TNF-alpha, cytokines known to up-regulate the TNF-Rs. Increased staining for TNF-Rs was also found in patients with multiple sclerosis, chronic cerebral edema, and radiation necrosis but not in an asymptomatic HIV-positive patient without AIDS. Reverse transcriptase polymerase chain reaction performed on adjacent sections from five AIDS patients revealed up-regulation from normal for p55 in all patients and for p75 in three patients. The up-regulation of both TNF-Rs in AIDS suggests that macrophages and microglial cells may be important in amplifying the TNF-alpha response.
AIDS Dementia Complex↗
A protein related to a proteasomal subunit binds to the intracellular domain of the p55 TNF receptor upstream to its 'death domain'.
A novel protein that binds specifically to the intracellular domain of the p55 tumor necrosis factor (TNF) receptor was cloned by two-hybrid screening of a HeLa cell cDNA library. Data bank searches revealed high sequence similarity of the protein (55.11) to yeast, nematode and plant proteins, whose functions are yet unknown. Significant similarity was also found between 55.11 and SEN3, the yeast equivalent of the p112 subunit of the 26S proteasome. Deletion analysis showed that the protein binds to the p55 receptor upstream to the region involved in induction of cell death.
Amino Acid Sequence↗
A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.
Signaling for cell death by Fas/APO1 occurs via a distinct region in its intracellular domain. This region contains a conserved sequence motif, the death domain motif, that is also found in the intracellular domains of the p55 tumor necrosis factor receptor and the low affinity nerve growth factor receptor, as well as in the regulatory domain of the ankyrins. A novel protein that specifically binds to the death domain of Fas/APO1 but not to Fas/APO1 molecules with a loss of function point mutation occurring in lprcg mice was cloned by a two-hybrid screen of a HeLa cells' cDNA library. The cloned protein itself contains a death domain motif, and this region binds to the death domain of Fas/APO1, while the region upstream to the death domain prompts self-association of the protein. Induced expression of the protein results in ligand-independent triggering of cytotoxicity, suggesting that it is involved in cell death induction by Fas/APO1.
Adaptor Proteins, Signal Transducing↗
Self-association of the "death domains" of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects.
Signaling by the p55 tumor necrosis factor (TNF) receptor and by the structurally related receptor Fas/APO1 is initiated by receptor clustering. Data presented here and in other recent studies (Wallach, D., Boldin, M., Varfolomeev, E. E., Bigda, Y., Camonis, H.J. and Mett, I. (1994) Cytokine 6, 556; Song, H.Y., Dunbar, J.D., and Bonner, D.B. (1994) J. Biol. Chem. 269, 22492-22495) indicate that part of that region within the intracellular domains of the two receptors that is involved in signaling for cell death, as well as for some other effects (the "death domain", specifically self-associates. We demonstrate also the expected functional consequence of this association; a mere increase in p55 TNF receptor expression, or the expression just of its intracellular domain, is shown to trigger signaling for cytotoxicity as well as for interleukin 8 gene induction, while expression of the intracellular domain of Fas/APO1 potentiates the cytotoxicity of co-expressed p55 TNF receptor. These findings indicate that the p55 TNF and Fas/APO1 receptors play active roles in their own clustering and suggest the existence of cellular mechanisms that restrict the self-association of these receptors, thus preventing constitutive signaling.
Antigens, Surface↗