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D Elias

Publications and source records attributed to D Elias.

At least 19 recordsLinked to original sources
PubMed1999

[Neuro-endocrine tumors and von Hippel-Lindau disease. 3 cases].

BACKGROUND: Neuroendocrine tumors can occur in patients with hereditary syndromes predisposing to multiple endocrine neoplasia (MEN) and Von Hippel-Lindau disease (VHL). CASE REPORTS: We report the cases of three men with pheochromocytomas, one with an associated neuroendocrine tumor of the pancreas. In one case, diagnosis was suggested by the familial context of VHL in the patients father. In the two other cases, the bilateral character of the pheochromocytoma, and in one case the associated pancreatic neuroendocrine tumor led to the diagnosis of VHL. Systematic biological surveillance gave the diagnosis of contralateral pheochromocytoma in two cases. Search for associated tumoral lesions led to the diagnosis of hemangioblastoma of the cerebellum in two patients and pancreatic cyst in the third. No renal or retinal lesions were observed. Molecular study of the VHL gene evidenced point nonsense mutation of the gene in all three patients, involving codon 184 in two and codon 167 in the third (identical to the proband case). Systematic investigations in the families of the two other patients remains to be completed. CONCLUSION: The diagnosis of HVL disease should be suggested in case of familial pheochromocytoma and/or bilateral localizations, but also in case of neuroendocrine tumors of the pancreas associated with another cardinal lesion of the disease. Early screening and treatment of this potentially fatal disease is essential.

Adolescent↗
PubMed1999

The 60-kDa heat shock protein modulates allograft rejection.

Allograft rejection is a process of immune reactivity triggered by foreign transplantation antigens. We now demonstrate that the 60-kDa heat shock protein (hsp60), a molecule that is identical in the donor and the recipient, can regulate allograft immunity. In wild-type mice, hsp60 expression was greatly enhanced in allografts being rejected. By using MHC class II (Ealpha) promoter hsp60 transgenic mice either as donors of skin with enhanced expression of hsp60, or as allograft recipients with decreased hsp60 autoimmunity, we found that augmented expression of mouse hsp60 in the allograft accelerated its rejection, whereas reduced autoimmunity to mouse hsp60 in graft recipients delayed the process. Moreover, in nontransgenic mice, therapeutic administration of hsp60 or hsp60 peptides, known to modulate naturally occurring hsp60 autoimmunity, led to delayed allograft rejection. Thus, we demonstrate that hsp60 expression and hsp60 autoimmunity can influence and modify the immune response to foreign antigens. Hence, autoimmunity to self-hsp60 epitopes is not necessarily an aberration, but may serve physiologically and therapeutically to modulate foreign immunity.

Animals↗
PubMed1999

Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy.

Interleukin-2 (IL-2) has been shown to decrease cytochrome P450 (CYP) mRNAs and proteins in cultured rat hepatocytes, and IL-2 administration decreases CYPs in rats. Although high doses of IL-2 are administered to cancer patients, the effect on human CYPs has not yet been determined. Patients with hepatic metastases from colon or rectum carcinomas were randomly allocated to various daily doses of human recombinant IL-2 (from 0 to 12.10(6) units/m(2)). IL-2 was infused from day 7 to day 3 before hepatectomy and the conservation of a non-tumorous liver fragment in liquid nitrogen. Hepatic CYPs and monooxygenase activities were not significantly decreased in 5 patients receiving daily doses of 3 or 6 10(6) IL-2 units/m2, compared to 7 patients who did not receive IL-2. In contrast, in 6 patients receiving daily doses of 9 or 12 x 10(6) IL-2 units/m2, the mean values for immunoreactive CYP1A2, CYP2C, CYP2E1, and CYP3A4 were 37, 45, 60 and 39%, respectively, of those in controls; total CYP was significantly decreased by 34%, methoxyresorufin O-demethylation by 62%, and erythromycin N-demethylation by 50%. These observations suggest that high doses of IL-2 may decrease total CYP and monooxygenase activities in man.

Adenocarcinoma↗
PubMed1999

T cell proliferative responses of type 1 diabetes patients and healthy individuals to human hsp60 and its peptides.

T cell responses to peptide epitopes of the 60 kDa heat shock protein (hsp60) have been shown to play a role in the pathogenesis of type 1 insulin-dependent diabetes mellitus (IDDM) in mice. To test whether hsp60 autoimmunity might be involved in human type 1 diabetes, we studied T cell proliferative responses (stimulation index; SI) to intact human hsp60, to hsp60 peptides and to a recall antigen (tetanus toxoid) in 25 newly diagnosed type 1 diabetes patients, in 22 type 2 (non-insulin-dependent diabetes mellitus, NIDDM) patients, and in 25 healthy blood donors. There were no significant differences between the T cell responses of the three groups to tetanus toxoid. However, the responses to hsp60 of the type 1 diabetes group (median SI=5) were significantly greater (P<0. 01) than those of the type 2 group (median SI=1.67) and of the blood donors (median SI=1.7). Epitope mapping revealed significant responses to at least seven different peptides, with prevalent responses to the p277 peptide previously mapped in NOD mice and to peptide p32. Thus, newly diagnosed type 1 diabetes patients, similar to prediabetic and newly diabetic NOD mice, show heightened autoimmunity to hsp60 and hsp60 peptides.

Adolescent↗
PubMed1999

Inhibition of diabetes in NOD mice by idiotypic induction of SLE.

The present study was undertaken to investigate whether active induction of systemic lupus erythematosus (SLE) in non-obese diabetic (NOD) mice could affect their development of insulin-dependent diabetes mellitus (IDDM). NOD mice were immunized with a human IgM mAb carrying the 16/6 idiotype (MIV-7) or with control human IgM. The mice were bled monthly and tested for SLE-associated autoantibodies in the serum and for the presence of leukopenia, thrombocytopenia, proteinuria and immunoglobulin deposits in the kidneys. The development of diabetes was determined by a blood glucose level exceeding 15 mM on two consecutive weekly determinations and by the presence of insulitis in the pancreas. The NOD mice immunized with MIV-7 developed high and persistent levels of autoantibodies, including anti-DNA, anti-histones and anti-cardiolipin, untreated mice and those immunized with normal human IgM did not produce these autoantibodies. The MIV-7-immunized mice also manifested an elevated erythrocyte sedimentation rate, leukopenia, thrombocytopenia and significant proteinuria, as well as deposits of Ig in their kidney glomeruli. Thus, NOD mice immunized with MIV-7 developed both autoantibodies and clinical features of SLE. The MIV-7-treated mice, however, showed a significantly lower incidence of IDDM (25%vs. 90%, P<0.003), accompanied by amelioration of the insulitis. The present study indicates that the induction of SLE by idiotypic immunization can protect NOD mice from developing IDDM, pointing to the importance of immune dysregulation in shift from one autoimmune disease to another.

Animals↗
PubMed1999

[Total pelvic exenteration and rectal cancer. Apropos of 20 cases].

STUDY AIM: The report of a series of 20 patients with the aim of trying to specify the implications of pelvic exenteration for rectal cancer. PATIENTS AND METHODS: From 1986 to 1996, 20 total pelvic exenterations were performed for rectal adenocarcinoma. This retrospective study included locally extended carcinomas (n = 10), and recurrences (n = 10) after anterior resection (n = 7), and after abdominoperineal resection (n = 3). The subjects included 13 men and seven women with a mean age of 54 years (34-74 years). Complaints were major and serious: pain (n = 20), rectal syndrome (n = 17), recto-vesical fistula (n = 5) recto-vaginal fistula (n = 5), urinary infection (n = 13), and hematuria (n = 6). Preoperative radiotherapy was performed in 11 patients and preoperative radio chemotherapy in six. The surgical procedure included a total pelvic exenteration with perinectomy in 12 patients, and a total pelvic exenteration with preservation of levator ani and perineum in eight, associated in two cases with a partial resection of the sacrum, and in two other cases with partial hepatectomy for a single liver metastasis. Urinary diversion was a trans ileal ureterostomy in 17 patients and a direct double ureterostomy in three. RESULTS: The mean duration of surgery was 6 h. The mean preoperative blood loss was 1,200 L. Nine patients received blood transfusion. There was no postoperative mortality but in contrast, the morbidity rate was high with mainly urinary and digestive complications, pelvic sepsis and thromboembolic complications. After pathological examination, tumoral resections were classified R0 in 19 cases, and R1 in one. All tumors were T4 with tumoral invasion of the bladder (n = 15), prostate (n = 6), seminal vesicles (n = 4), ureter (n = 3), vagina (n = 7), urethra (n = 1), and sacrum (n = 1). Lymph node involvement was present in four patients. The 3 and 5 year actuarial survival rate was respectively 47 and 18%. Thirteen patients died of their cancer, nine from metastases, and four from local recurrence with a mean survival of 29 and 32 months respectively. Seven patients were alive at the time of this study, six without actual recurrence. CONCLUSIONS: In spite of its aggressive aspect, total pelvic exenteration seems justified in rectal carcinoma when extended to the urinary tract, when it causes major functional disorders, when there are no detectable metastases, and when the tumor has no posterior or lateral fixation. Local tumoral evolution can usually be controlled by pelvic exenteration but prolongation of survival is not demonstrated.

Adenocarcinoma↗
PubMed1999

During liver regeneration following right portal embolization the growth rate of liver metastases is more rapid than that of the liver parenchyma.

BACKGROUND: The relative growth rates of human liver metastases are not known. The aim of this study was to determine in humans the growth rate of liver parenchyma during regeneration and the growth rate of liver metastases during the same process. METHODS: Among 556 patients hepatectomized for a malignant lesion, 48 underwent preoperative selective right portal vein embolization to induce hypertrophy of the left lobe. Five cases were selected because a liver metastasis was present inside the regenerating left lobe. The volumes of the liver metastasis and left lobe were measured with a three-dimensional technique on pre-embolization and postembolization computed tomography (CT) or CT arterial portography. The median interval between the two measurements was 34 (range 28-40) days. RESULTS: An increase occurred in the volume of the liver metastasis and the left lobe in the four patients with functionally intact liver parenchyma, but not in the patient with an impaired parenchyma. The volumetric increase of the normal liver varied from 59 to 127 per cent, compared with 60 to 970 per cent for the liver metastases. The ratio between the growth rate of the left lobe and the liver metastasis varied from 1.0 to 15.6. The growth rates of two metastases in the left lobe of a single patient were different. CONCLUSION: In functionally intact liver parenchyma, during hepatic regeneration or hypertrophy, the growth rate of metastases is more rapid that that of the liver parenchyma. However, a wide variation in growth rate is observed between patients and between metastases.

Aged↗
PubMed1999

The pathogenicity of islet-infiltrating lymphocytes in the non-obese diabetic (NOD) mouse.

The aim of the present study was to investigate the pathogenic properties of islet-infiltrating lymphocytes related to the severity of the autoimmune destruction of islet beta-cells in the NOD mouse. We analysed the development of insulin-dependent diabetes mellitus (IDDM) produced by adoptive transfer of islet lymphocytes from NOD into NOD.scid mice. Here we show that the transfer was most effective when both CD4+ and CD8+ T cells were present in the infiltrate, but CD4+ T cells alone were sufficient to cause the disease. Islet lymphocytes from both females and males transferred diabetes effectively, but the severity of IDDM was higher when female islet lymphocytes were used. Unexpectedly, the sensitivity of male islets to beta-cell damage was greater than that of female islets. Treatment of NOD females with a peptide of heat shock protein (hsp)60, p277, known to protect NOD mice from IDDM, reduced the pathogenicity of the islet lymphocytes. In contrast, administration of cyclophosphamide to males, a treatment that accelerates the disease, rendered the islet lymphocytes more pathogenic. More severe disease in the recipient NOD.scid mice was associated with more interferon-gamma (IFN-gamma)-secreting islet T cells of the NOD donor. The disease induced by islet lymphocytes was strongly inhibited by co-transfer of spleen cells from prediabetic mice, emphasizing the regulatory role of peripheral lymphocytes. Thus, the cellular characteristics of the islet infiltrate and the pathogenicity of the cells are subject to complex regulation.

Adoptive Transfer↗
PubMed1999

A shared TCR CDR3 sequence in NOD mouse autoimmune diabetes.

T cells involved in autoimmune diseases have been characterized by the genetic elements used to construct their autoimmune TCR. In the present study, we sequenced the alpha and beta chains of the TCR expressed by a CD4(+) T cell clone, C9, functional in NOD mouse diabetes. Clone C9 can adoptively transfer diabetes or, when attenuated, C9 can be used to vaccinate NOD mice against diabetes. Clone C9 recognizes a peptide epitope (p277) of the 60 kDa heat shock protein (hsp60) molecule. We now report that the C9 TCR beta chain features a CDR3 peptide sequence that is prevalent among NOD mice. This CDR3 element is detectable by 2 weeks of age in the thymus, and later in the spleen and in the autoimmune insulitis. Thus, a TCR CDR3beta sequence appears to be a common idiotope associated with mouse diabetes.

Amino Acid Sequence↗
PubMed1999

Regulation of NOD mouse autoimmune diabetes by T cells that recognize a TCR CDR3 peptide.

NOD mice spontaneously develop type I diabetes resulting from autoimmune destruction of their insulin-producing beta cells. Among the self-antigens targeted by NOD autoimmune T cells is a peptide, p277, from the sequence of the 60 kDa heat shock protein (hsp60). Common to the anti-p277 T cell populations of NOD mice is an idiotope, C9, that spans the CDR3 region of the C9 TCR. We now report: (i) that the C9 idiotope peptide can be presented directly to anti-C9 anti-idiotypic T cells by C9 T cells, (ii) that spontaneous anti-C9 anti-idiotypic T cell activity falls as disease progresses, but immunization can activate the anti-idiotypic T cells to regulate the autoimmune process, (iii) that the anti-idiotypic T cells secrete IFN-gamma, but appear to control the disease by down-regulating the IFN-gamma produced by the pathogenic population of anti-p277 T cells, (iv) that intrathymic administration of the C9 idiotope peptide at 1 week of age can accelerate the disease, and (v) that administering the p277 target peptide can up-regulate the anti-idiotypic T cells and arrest the disease process. Thus, the development of NOD diabetes can be regulated by a balance between anti-idiotypic and anti-target peptide autoimmunity, and anti-idiotypic regulation can lead to changes in the cytokine secretion of the autoimmune T cells involved in the disease process.

Amino Acid Sequence↗
PubMed1999

[Sufentanil in balanced anesthesia: need to predict concentrations for dose optimization].

During balanced anaesthesia sufentanil may be difficult to use, as the required doses change over time depending on the patient and the noxious stimuli. Patient adjustment may be improved by using pharmacokinetic simulations that predict the concentration achieved in the body. In the first case report, sufentanil was given manually as repeated boluses, then by infusion. As haemodynamic status remained unstable, a simulation of the sufentanil concentration time course was started during the case. It showed that instability had pharmacokinetic explanation and allowed to determine the adequate sufentanil concentrations (0.30-0.40 ng.mL-1 + N2O + isoflurane 0.8-1 vol% for abdominal surgery). However, adjusting the doses manually required numerous human actions. In the second case, sufentanil was given as a computer-controlled infusion. The adequate concentrations were determined (0.15-0.20 ng.mL-1 + N2O + isoflurane 0.4 vol% for peripheral surgery in an aged cardiac patient). They were maintained with a limited number of human actions and resulted in satisfactory haemodynamic stability.

Aged↗
PubMed1998

Results of 136 curative hepatectomies with a safety margin of less than 10 mm for colorectal metastases.

BACKGROUND AND OBJECTIVES: It is now established that liver resection is beneficial for metastases from colorectal cancer. Nevertheless, a surgical margin estimated at less than 10 mm at preoperative imaging is considered an absolute contraindication to surgery by some, and a relative contraindication by others. The true impact of the width of the margin on the prognosis is unclear. METHODS: From 1984 to 1996, 196 patients underwent curative hepatectomy for liver metastases and were studied prospectively. Surgery was to be curative (or a complete R0 resection) and mortality was to be avoided. Of these 196 patients, 136 had surgical margins of less than 10 mm. Sixty-eight percent had multiple liver metastases and 15% had extrahepatic metastatic lesions. Clinical and pathological factors were studied specifically and a multivariate analysis was carried out. RESULTS: Overall 5-year survival rate of these 136 patients (taking into account postoperative mortality which attained 1.5%) was 27.8% and the disease-free survival was 22.9%. The surgical margin was 0 mm in 30 cases. The sole prognostic factor was the discovery of unsuspected (resectable) extrahepatic lesions at laparotomy (P < 0.001) ; the width of the free margin had no significant effect. However, in the multivariate analysis of prognostic factors for the entire series (269 hepatectomies), three powerful parameters were identified : (1) the curative nature of resection (P = 0.0007), (2) less than 20% of liver involvement (P = 0.002), and (3) a free margin exceeding 9 mm (P = 0.02). A correlation was found between narrow margins and extensive disease (high number of metastases, bilateral sites, and extended hepatectomy). There was also a greater likelihood of microscopic satellite lesions within 10 mm around the metastases. CONCLUSIONS: The prognostic impact of the width of the surgical margin should not be overestimated. Hepatectomy for liver metastases can procure long-term survival, even in patients with supposedly poor prognostic factors. Resection is justified as long as it is complete and the risks are minimal.

Aged↗
PubMed1998

Islet T cells secreting IFN-gamma in NOD mouse diabetes: arrest by p277 peptide treatment.

Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent (type 1) diabetes mellitus (IDDM) caused by T cells which destroy the insulin-producing islet beta-cells. Since cytokines are involved in this auto-immune beta-cell damage, we used an ELISPOT assay to enumerate the islet-associated T cells that secreted interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) or interleukin-4 (IL-4). We used mitogenic anti-CD3 antibody to activate all the T cells capable of responding, irrespective of their antigen specificity. We found that NOD females, more susceptible than males to IDDM, accumulated islet IFN-gamma producers more rapidly with age than did the males. Acceleration of male IDDM by cyclophosphamide led to a marked increase in IFN-gamma secreting islet T cells. In contrast, a decrease in IFN-gamma-producing islet T cells was associated with arrest of IDDM by administration of peptide p277 of the 60 kDa heat-shock protein (hsp60) to 12-week-old female NOD mice. The p277-treated mice later manifested a greater number of islets and fewer leukocytes per islet than did the mice treated with a bacterial hsp60 peptide. Thus, the development of diabetes could be correlated with the accumulation in the islets of T cells producing IFN-gamma, and destructive insulitis could be downregulated by the administration of a single peptide.

Age Factors↗
PubMed1998

Production and purification of a recombinant human hsp60 epitope using the cellulose-binding domain in Escherichia coli.

The heat shock protein hsp60 plays a functional role in insulin-dependent diabetes mellitus. The hsp60 epitope p277 (aa 437-aa 460) is effective in vaccinating mice against diabetes. A synthetic peptide gene (p277) that encodes the human hsp60 epitope was cloned to the 3' end of the cellulose-binding domain gene (cbd). CBD-p277 was overexpressed in Escherichia coli and purified on a cellulose column. A methionine at the C-terminal end of CBD enabled CNBr cleavage between CBD and p277. After CNBr cleavage, free CBD and residual uncleaved CBD-p277 were recovered by cellulose chromatography. The p277 peptide was further purified on a RPC-FPLC column. The molecular weight of the recombinant peptide was confirmed by electrospray mass spectrometry. The recombinant peptide was found to be biologically active in assays involving clone C9 T-cell proliferation, lymph-node cell proliferation, and antibody production. Thus the use of CBD as an affinity tag and the utilization of affordable cellulose matrices offers an attractive method for the production and purification of recombinant peptides.

Cell Division↗