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Biomedical subjects

R Lucas

Publications and source records attributed to R Lucas.

At least 55 records · Page 3Linked to original sources
PubMed1999

Composite cervicofacial flap for reconstruction of complex cheek defects.

The authors present the reconstructive technique for complex cheek defects using the composite cervicofacial flap and study the possibilities, advantages, disadvantages, and results that can be expected. The design follows the classic outline of Mustardé's flap. The skin is undermined for 2 cm anterior to the ear, then after incision of the superficial musculoaponeurotic system (SMAS), undermining is continued below the plane of the SMAS, level with the facial nerve branches. It is continued forward to the facial vessels, which give rise to branches that ensure the blood supply of this composite flap and contribute to its high reliability. In the cervical region, undermining is done beneath the platysma, which is transected transversely in the lower cervical region to allow good upward mobility and satisfactory transposition of the flap. The flap is adapted to the defect and the medial suture line is placed as near as possible to the medial limit of the cheek aesthetic unit. The authors carried out a retrospective study of 7 patients with complex facial reconstruction after excision of malignant lesions. The defects measured from 4x4 cm to 9x7 cm. In 4 patients excision included the periosteum, and in 1 patient excision involved the entire thickness and removed the entire anterior half of the cheek. In 4 patients reconstruction involved the cheek and eyelid. In spite of the advanced age of the patients (88, 69, 91, 67, 70, 82, and 59 years), there was no distal edge necrosis. The only complication was a single case of facial paresis, which resolved spontaneously. The results were considered very good in all 7 patients. The authors conclude that the composite flap increases the possibilities of the cervicofacial flap. It is more mobile, more reliable, thicker, and more adaptable. It can be used in complex cheek defects that involve the periosteum, or even in full-thickness defects. The quality of the results obtained using this flap represents a considerable advance in facial reconstruction.

Aged↗
PubMed1999

The endogenous balance of soluble tumor necrosis factor receptors and tumor necrosis factor modulates cachexia and mortality in mice acutely infected with Trypanosoma cruzi.

To better understand the role of tumor necrosis factor (TNF) during Trypanosoma cruzi infection in BALB/c mice, we have investigated the kinetics of circulating tumor necrosis factor (TNF), soluble TNF receptor 1 (sTNR1), and sTNFR2 levels, as well as the interactions between such factors, in relation to parasitemia, cachexia, and mortality of acutely infected animals. Our data show that the parasitemic phase of T. cruzi infection in mice is associated with high levels of circulating TNF and sTNFR2, resulting in the formation of cytokine-receptor complexes and some degree of neutralization of TNF bioactivity. Although sTNR2 levels always exceeded TNF levels, low sTNFR/TNF circulating ratios were associated with cachexia in all infected mice, whereas the lowest ratios were observed in dying animals harboring the highest parasitemia. We also studied the modulation of sTNFR/TNF ratios induced by anti-TNF antibodies administered to infected animals and their consequences on the outcome of the infection. The injection of anti-TNF monoclonal antibody (MAb) TN3 into infected mice resulted in a paradoxical overproduction of TNF (associated with a higher parasitemia), lowered the sTNFR/TNF circulating ratios, and considerably worsened cachexia and mortality of animals. Another anti-TNF MAb (1F3F3) decreased the in vivo availability of TNF as well as parasite levels and reduced cachexia. Altogether, such results highlight that, besides playing a beneficial role early in infection, TNF also triggers harmful effects in the parasitemic phase, which are limited by the in vivo simultaneous endogenous production of soluble receptors.

Acute Disease↗
PubMed1998

Multiple forms of angiostatin induce apoptosis in endothelial cells.

Angiostatin is a circulating inhibitor of angiogenesis generated by proteolytic cleavage of plasminogen. In this study we have used recombinant human and murine angiostatins (kringles 1-4) as well as native human angiostatin (prepared by elastase digestion of plasminogen [kringles 1-3] or by plasmin autocatalysis in the presence of a free sulfhydryl donor [kringles 1-4]). We report that angiostatin reduces endothelial cell number in a 4-day proliferation assay without affecting cell cycle progression into S-phase (as determined by bromodeoxyuridine labeling). This suggested that the reduction in cell number in the proliferation assay might in part be due to cytotoxicity. This was confirmed by the observation that ethidium homodimer incorporation (a measure of plasma membrane integrity) into endothelial cells was increased by angiostatin in a manner similar to that seen with tumor necrosis factor- (TNF-) and transforming growth factor-beta1 (TGF-beta1), both of which induce apoptosis in endothelial cells. In contrast to TNF- and TGF-beta1, angiostatin did not induce cytotoxicity in human MRC-5 fibroblast, rat smooth muscle, canine MDCK epithelial, or murine B16-F10 melanoma cell lines. Angiostatin-induced apoptosis was confirmed by endothelial cell nuclear acridine orange incorporation as well as by annexin V and TUNEL staining. These in vitro findings point to endothelial cell apoptosis as a mechanism for the antiangiogenic effect of angiostatin in vivo.

Angiostatins↗
PubMed1998

Both TNF receptors are required for direct TNF-mediated cytotoxicity in microvascular endothelial cells.

The conditions under which tumor necrosis factor-alpha (TNF) induces apoptosis in primary microvascular endothelial cells (MVEC) were investigated. In the absence of sensitizing agents, TNF induced apoptosis after 3 days of incubation in confluent MVEC. In contrast, upon addition of the transcriptional inhibitor actinomycin D (Act. D), confluence was no longer required and apoptosis occurred already after 16 h. To assess the role of either TNF receptor (TNFR) type in apoptosis, MVEC isolated from mice genetically deficient in TNFR1 (Tnfr1o mice) or TNFR2 (Tnfr2o mice) were incubated with TNF in the presence or absence of Act. D. Under sensitized conditions, Tnfr2o MVEC were lysed like controls, whereas Tnfr1o MVEC were completely resistant, indicating an exclusive role for TNFR1. In contrast, in the absence of Act. D, confluent monolayers of wild-type cells were lysed by TNF, but both Tnfr1o and Tnfr2o MVEC were resistant to TNF-mediated toxicity, indicating a requirement for both TNFR types. Overexpression of the anti-apoptotic protein bcl-xL in MVEC led to a protection against the direct, but not the sensitized cytotoxicity of TNF. In conclusion, in pathophysiologically relevant conditions, both TNFR appear to be required for TNF-induced apoptosis in MVEC.

Animals↗
PubMed1998

Caprine mucopolysaccharidosis-IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Several animal models have been developed for the mucopolysaccharidoses (MPSs), a group of lysosomal storage disorders caused by lysosomal hydrolase deficiencies that disrupt the catabolism of glycosaminoglycans (GAG). Among the MPS, the MPS-III (Sanfilippo) syndromes lacked an animal counterpart until recently. In this investigation of caprine MPS-IIID, the clinical, biochemical, morphological, and immunohistochemical studies revealed severe and mild phenotypes like those observed in human MPS III syndromes. Both forms of caprine MPS IIID result from a nonsense mutation and consequent deficiency of lysosomal N-acetylglucosamine 6-sulfatase (G6S) activity and are associated with tissue storage and urinary excretion of heparan sulfate (HS). Using special stains, immunohistochemistry, and electron microscopy, secondary lysosomes filled with GAG were identified in most tissues from affected goats. Primary neuronal accumulation of HS and the secondary storage of gangliosides were observed in the central nervous system (CNS) of these animals. In addition, morphological changes in the CNS such as neuritic expansions and other neuronal alterations that may have functional significance were also seen. The spectrum of lesions was greater in the severe form of caprine MPS IIID and included mild cartilaginous, bony, and corneal lesions. The more pronounced neurological deficits in the severe form were partly related to a greater extent of CNS dysmyelination. These findings demonstrate that caprine MPS IIID is a suitable animal model for the investigation of therapeutic strategies for MPS III syndromes.

Animals↗
PubMed1998

Effects of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha on Trypanosoma cruzi trypomastigotes.

We have previously shown that the addition of exogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) to nonactivated mouse peritoneal macrophages (MPM) limits Trypanosoma cruzi infections in vitro (E. Olivares Fontt and B. Vray, Parasite Immunol. 17:135-141, 1995). Lower levels of infection were correlated with a higher level of production of tumor necrosis factor alpha (TNF-alpha) in the absence of nitric oxide (NO) release. These data suggested that GM-CSF and/or TNF-alpha might have a direct parasitocidal effect on T. cruzi trypomastigotes, independently of NO release. To address this question, T. cruzi trypomastigotes were treated with recombinant murine GM-CSF (rmGM-CSF), recombinant murine TNF-alpha (rmTNF-alpha), or both cytokines in a cell-free system. Treatment with rmGM-CSF but not rmTNF-alpha caused morphological changes in the parasites, and most became spherical after 7 h of incubation. Both cytokines exerted a cytolytic activity on the trypomastigotes, yet the trypanolytic activity of rmTNF-alpha was more effective than that of rmGM-CSF. Viable rmGM-CSF- and rmTNF-alpha-treated parasites were less able to infect MPM than untreated parasites, and this reduction in infectivity was greatest for rmGM-CSF. Treatments with both cytokines resulted in more lysis and almost complete inhibition of infection. The direct parasitocidal activity of rmTNF-alpha was inhibited by carbohydrates and monoclonal antibodies specific for the lectin-like domain of TNF-alpha. Collectively, these results suggest that cytokines such as GM-CSF and TNF-alpha may directly control the level of T. cruzi trypomastigotes at least in vitro and so could determine the outcome of infection in vivo.

Animals↗
PubMed1998

Metabolic-cytokine responses to a second immunological challenge with LPS in mice with T. gondii infection.

Injection of 10 cysts of Toxoplasma gondii (Me49 strain) into Swiss Webster mice results in 1) an acute phase of infection lasting for 2-3 wk, characterized by weight loss, and 2) a chronic phase in which surviving mice show either partial weight recovery (Gainers) or persistent, although stable, cachexia (Nongainers). In response to a second immunological stimulation with lipopolysaccharide (LPS) in the chronic phase of the infection, it is shown that 1) the increase in energy expenditure was more prolonged in both groups of infected mice than in controls, 2) the intensity and duration of hypophagia were also differently affected with Nongainers > Gainers > controls, and 3) the infected mice had higher serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-10 and a lower ratio of IL-10 to TNF-alpha than controls. In contrast, serum IL-4 increased to the same level in all three groups. Evaluation of the permeability of the blood-brain barrier by intravenous injection of Evans blue revealed a marked staining in the brain of only the infected Nongainers. Taken together, these results indicate that, in mice with chronic toxoplasmosis, a second nonspecific challenge (with LPS) exacerbates the hypophagic and hypermetabolic states, the latter being associated with hyperresponsiveness in TNF-alpha and IL-10 production. Furthermore, the greater exacerbation of the hypophagic state in mice showing persistent cachexia may be due to a preexisting higher permeability of the blood-brain barrier, which would allow a greater access of plasma-borne cytokines and/or other neuroimmunologically active substances to the central nervous system.

Animals↗
PubMed1998

Unilateral parathyroid exploration.

Unilateral neck exploration (UNE) for primary hyperparathyroidism can be done with the same excellent results as bilateral neck exploration (BNE) with decreased operative time and postoperative complications with a good preoperative localization study. One hundred six charts were reviewed retrospectively in patients operated on between May 1989 and October 1996 with primary hyperparathyroidism. Seventy-seven of these patients had preoperative ultrasounds (US) performed by a radiologist interested in parathyroid ultrasonography. UNE was performed if the operative findings were consistent with the US and a normal gland was identified on the same side. If a normal gland was not identified on the initial side or there was a question of hyperplasia a BNE was performed. Forty-six of the 77 patients had UNE, and 31 had BNE. Sixty-nine of these patients were found to have accurate US. Based on these results there is a 90 per cent accuracy rate for US performed by an interested radiologist. Comparing operative times between patients with UNE and BNE, there was a statistical difference (P = 0.001). Complications were also recorded in each group. Patients with UNE had a 22 per cent complication rate, whereas patients with BNE had a 45 per cent complication rate. This difference was statistically significant (P = 0.04) (Fisher's exact test). The majority of complications were asymptomatic and symptomatic hypocalcemia. Two patients in the BNE group experienced transient hoarseness. The advantages of UNE include reduced morbidity, decreased operative time and avoidance of scarring in the contralateral neck. In the total study population (n = 106), 99 patients (93.4%) had a single adenoma. An accurate, noninvasive, low-cost preoperative localization study is necessary to practice UNE for primary hyperparathyroidism. Parathyroid US, done by an interested radiologist, with a 90 per cent accuracy rate, meets all these criteria.

Adenoma↗
PubMed1998

[An experimental study of a new bidirectional distraction appliance].

The goals of mandibular distraction are to restore a normal length but also a normal shape to the hypoplastic mandible. These two goals are related to the elongation vector which is itself related to the location of the cortictomy and of the device. Other factors influence this elongation vector. So it is impossible to precisely predict the elongation vector. With the monodirectional distraction device no modification can be made during the distraction time. With a bidirectional distraction device offering the possibility to modulate the angulation between the two elongation rods it is possible to adjust the elongation vector during distraction. Precise distraction gap modeling is possible. This is particularly important to correct anterior open-bite. This device was tested on animals (pigs).

Animals↗
PubMed1998

Unilateral lobectomy for Hurthle cell adenoma.

Considerable controversy exists regarding the ability to predict the biologic behavior of Hurthle cell tumors. Some have found the clinicopathologic criteria used to differentiate benign from malignant lesions to be unreliable and have advocated total thyroidectomy for all Hurthle cell neoplasms. From January 1980 to December 1995, 39 patients had surgery for Hurthle cell tumors of the thyroid. The surgical pathologic findings were reviewed by an experienced pathologist (JP). Eight patients had histologic findings of capsular or vascular invasion consistent with carcinoma and had total thyroidectomy. Four of these patients had postoperative evidence of residual disease and were treated by radiation ablation. No evidence of invasion was found in 31 patients diagnosed with Hurthle cell adenoma. Twenty-three of these patients had unilateral lobectomy; total thyroidectomy was done in the remaining 8 patients, 5 of whom were found to have an associated papillary carcinoma at the time of operation. There were no operative deaths or significant morbidity. Twenty-two adenomas (71%) were found in females, whereas males had malignant tumors in 6 of 8 cases (P = 0.025). The mean age of adenoma patients is 54.1 years, and that of the carcinoma patients is 55.8 years. Mean size of benign tumors was 2.8 cm and of malignant tumors 4.1 cm (P = 0.04). Four of seven (57%) carcinomas were larger than 4 cm as compared with 6 of 30 (20%) adenomas (P = 0.069). Follow-up has ranged from 1 month to 15 years, with a mean of 3.2 years. There have been no deaths, and no patients with Hurthle cell adenoma have had evidence of recurrence or metastases during follow-up. Our data suggest that carcinoma patients tend to be male and tumor size is larger. An association was found when trying to predict malignancy by using 4 cm as a threshold size. We conclude that pathologic evidence of capsular or angioinvasion can accurately differentiate benign from malignant tumors. Unilateral thyroid lobectomy is adequate therapy for the treatment of Hurthle cell adenoma, with total thyroidectomy reserved for those patients with histologically proven carcinoma.

Adenoma, Oxyphilic↗
PubMed1998

[Secondary rhinoplasty for unilateral cleft lip and palate. Review of the literature and 50 clinical cases].

The nasal sequelae of unilateral cleft lip and palate are almost always present: more or less severe deformities, essentially consisting of nostril deformity and deviated septum. After an anatomical study of nasal deformities and the consequences of the primary procedures of cheiloplasty or cheilorhinoplasty, the authors review all of the most satisfactory technical aspects of secondary proposed in the literature. Five clinical cases illustrate the therapeutic strategy and the results.

Adult↗
PubMed1998

[Posterior thoracic reconstruction with latissimus dorsi flap after partial amputation of the latissimus dorsi muscle for sarcoma of the back. Report of four cases].

Malignant fibrous histiocytomas (MFH) arising from the subcutaneous tissues of the posterior thoracic wall require wide, but usually non-transfixing, resection to ensure adequate resection margins, the only way to reduce the local recurrent rate. Due to its size and position, the Latissimus dorsi muscle usually requires partial amputation. However, its vascular anatomy allows it to be used as a musculocutaneous flap of the residual muscle to fill the defects created. Four clinical cases are reported. This technique reduces the complication rate and simplifies the postoperative course.

Adult↗
PubMed1997

Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position.

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.

Administration, Oral↗
PubMed1997

Specific uptake of tumor necrosis factor-alpha is involved in growth control of Trypanosoma brucei.

Trypanosoma brucei is lysed by tumor necrosis factor-alpha (TNF-alpha) in a dose-dependent way, involving specific binding of the cytokine to a trypanosomal glycoprotein present in the flagellar pocket of the parasite. TNF-alpha-gold particles are endocytosed via coated pits and vesicles and are directed towards lysosome-like digestive organelles. The specific uptake of the cytokine by the parasite results in a developmentally regulated loss of osmoregulatory capacity. TNF-alpha specific lysis is prevented when lysis assays are performed at a temperature <26 degrees C, despite uptake of the cytokine. Inhibition of lysis is also observed when a lysosomotropic agent is added during the first 2 h of incubation. Both monomorphic and pleomorphic trypanosomes are lysed but only when isolated during the peak of parasitaemia. Lysis is not observed with early infection stage parasites or procyclic (insect-specific) forms. Anti-TNF-alpha treatment of T. brucei-infected mice reveals a dramatic increase in parasitaemia in the blood circulation, the spleen, the lymph nodes, and the peritoneal cavity. These data suggest that in the mammalian host, TNF-alpha is involved in the growth control of T. brucei.

Amino Acid Sequence↗
PubMed1997

Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria.

Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1null) mice, which were as susceptible as wild-type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-gamma was found between infected wild-type and Tnfr1null or Tnfr2null mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1null mice-both of which developed CM-whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2null mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1null or Tnfr2null mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 up-regulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

Animals↗
PubMed1997

TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria.

The microvascular endothelial cell (MVEC) is a major target of inflammatory cytokines overproduced in conditions such as sepsis and infectious diseases. We addressed the direct and indirect effects of tumor necrosis factor (TNF) on endothelial cells that can be relevant for the pathogenesis of septic shock, with particular attention to the acute respiratory distress syndrome (ARDS) and to cerebral malaria (CM). To identify functional and phenotypical changes occurring in MVEC during sepsis, we isolated these cells from the lungs of patients who died of ARDS. The constitutive expression of ICAM-1 and, to a lesser extent, VCAM-1, CD14, and TNFR2 were significantly increased on MVEC isolated from ARDS patients compared with control MVEC, whereas ELAM-1 and TNFR1 were not increased. We found that lung MVEC from ARDS patients present a procoagulant profile and a higher production capacity of interleukin-6 (IL-6) and IL-8 when compared with those from controls. As in pulmonary MVEC derived from ARDS patients, the only TNFR type found up-regulated in brain microvessels during CM was TNFR2. This increase in TNFR2 expression only occurred in CM-susceptible mice at the onset of the neurological syndrome. We therefore investigated the role of TNFR2 in the development of this brain pathology by comparing the incidence of CM in wild-type and TNF receptor knock-out mice. Unexpectedly, the genetic deficiency in TNFR2, but not in TNFR1, conferred protection against CM and its associated mortality. No ICAM-1 up-regulation was detected in the brain of Tnfr2 knockout mice, indicating a close correlation between protection against CM-associated brain damage, absence of TNFR2, and absence of ICAM-1 up-regulation in the brain. Our results in ARDS and CM indicate a specific up-regulation of TNFR2, but not of TNFR1, on lung and brain MVEC, respectively. This increased expression leads to a reduced sensitivity toward TNFR1-mediated phenomena, such as the sensitized TNF cytolytic activity on lung MVEC. In contrast, the sensitivity toward TNFR2-mediated effects, such as ICAM-1 induction by membrane-bound TNF, is increased on brain and lung MVEC expressing increased levels of TNFR2. Therefore, the ICAM-1-inducing effect, rather than the direct cytotoxicity of inflammatory cytokines, such as TNF, appears to be crucial in ARDS and CM-induced endothelial damage, and TNFR2 seems to play an important role in this activity in vivo.

Acute Disease↗
PubMed1997

Respective role of TNF receptors in the development of experimental cerebral malaria.

The respective role of the two receptors of TNF in experimental cerebral malaria (CM) was investigated. During CM, a significant upregulation of TNF-receptor 2 (TNFR2), but not of TNFR1, was found in brain microvessels of susceptible, but not resistant mice. Mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from CM, while TNFR1-deficient (Tfnr1null) mice were as susceptible as wild-type mice. The protection of Tnfr2null mice could be explained by their absence of ICAM-1 upregulation and leukocyte sequestration, known to occur in brain microvessels of CM-susceptible animals.

Animals↗