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Biomedical subjects

M Lucas

Publications and source records attributed to M Lucas.

At least 55 records · Page 3Linked to original sources
PubMed2001

Antibody therapy of acute and chronic leukemias.

The development of antibody-based therapies for the treatment of both acute and chronic leukemias have undoubtedly been one of the most important advances in the treatment of leukemia. The importance of these novel agents lies not only in their unique mechanisms of action, but also their improved side effect profile which allows patients of advanced age or with significant co-morbid medical conditions to receive potentially beneficial therapies. Advances in therapeutic applications of monoclonal antibodies have come from a greater understanding of the biological characteristics of the antibody, as well as the target antigen, both of which impact the potential efficacy of a particular antibody. In the following review we will discuss the clinical development and potential roles of monoclonal antibodies in the treatment of both acute and chronic leukemias.

Acute Disease↗
PubMed2001

Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.

Mutations in the Kritl gene have been recently discovered as the cause of hereditary cerebral cavernous angioma. We sought the possibility that de novo, noninherited mutations of Kritl also cause cavernous angioma. A patient with two cerebral malformations carries a heterozygous deletion of two base pairs (741delTC) in exon VI of the Kritl gene. The deletion initiates a frameshift mutation that, 23 amino acids downstream, encodes a TAA stop triplet replacing a CAT triplet of histidine at exon VII (H271X). Magnetic resonance images of the parents were normal, neither parent carries the 741delTC mutation, and both bear the wild-type sequence of exon VI. These findings document a de novo germline mutation in Kritl gene that causes cerebral cavernous malformations.

Brain Neoplasms↗
PubMed2001

Changes in glucocorticoid and mineralocorticoid hormone levels due to compensation for ileostomy losses.

BACKGROUND: The Ileo-Pouch-Anal-Anastomosis (IPAA) is the standard restorative procedure for Ulcerative Colitis and Familial Adenomatous Polyposis (FAP). IPAA may lead to considerable losses of fluids, especially in association with a protective loop ileostomy. AIM: The aim of this study was to investigate adrenal mechanisms in the regulation of volume homeostasis immediately after IPAA and protective ileostomy. METHODS: For that purpose, 20 patients out of our patient population with elective IPAA with ileostomy participated in this study between 1993 and 1997. In all patients, routine laboratory tests and gluco- and minealocorticoid hormone measurements were performed preoperatively and 10 days after operation. RESULTS: These blood analyses indicated functional hyperaldosteronism immediately after IPAA. Significantly elevated levels of Aldosterone (36.4 +/- 25.1 ng/dl) and 18-OH-Corticosterone ( 173 +/- 11.3 ng/dl) were found. Among hormones with glucocorticoid effects, blood levels of Cortisol (10.4 +/- 4.8 microg/dl) were significantly elevated, while 11-Desoxycortiosterone (13.9 +/- 8.4 ng/dl) and Corticosterone (0.8 +/- 0.6 microg/dl) were not significantly elevated. Serum electrolytes remained unchanged. CONCLUSIONS: Our results indicate that hormones with mineralocorticoid effects play a predominant role in the compensation of ileostomy losses after IPAA.

Adaptation, Physiological↗
PubMed2000

Sequence analysis of two cosmids from the right arm of the Schizosaccharomyces pombe chromosome II.

We report the complete sequence of two cosmids, SPBC19C7 (34815 bp insert, Accession No. AL023859) and SPBC15D4 (33203 bp insert, Accession No. AL031349), localized on chromosome II of the S. pombe genome. Twelve open reading frames (ORFs) were identified in SPBC19C7 and 16 in SPBC5D4. Two known genes were found on each cosmid: cyr1 and uve1 on SPBC19C7, encoding adenylate cyclase and a UV-endonuclease, respectively, and gpt and pho2 on SPBC15D4, encoding an N-acetylglucosamine-1-phosphate transferase and a4-nitrophenylphosphatase, respectively. Five ORFs similar to known proteins were found on SPBC19C7, and six on SPBC15D4. They include putative genes for a ubiquitin protein ligase, a prolyl-tRNA synthetase, a tRNA splicing endonuclease, a voltage-gated chloride channel, a mannosyl transferase, a kinesin-like protein, a histone transcriptional regulator, an N-acetyltransferase, a cystathionine gamma-synthase and a TFIID subunit. Two ORF products of SPBC15D4 do not have clear homologues: one encodes a putative transcriptional regulator with a binuclear zinc domain and the other a protein with six transmembrane domains. Two ORFs from SPBC15D4 are similar to unknown ORFs, one from Saccharomyces cerevisiae and the other from Caenorhabditis elegans. Finally, two ORFs of SPBC19C7 and six of SPBC15D4 correspond to orphan genes. The frequent occurrence of introns and the short and degenerated intron-exon boundaries consensus sequences significantly complicated ORF predictions. Two potential ORF-free regions spanning several kb were predicted, and a clustering of ORFs transcribed in the same orientation was observed.

Amino Acid Sequence↗
PubMed2000

Sequence analysis of two cosmids from Schizosaccharomyces pombe chromosome III.

We report the complete sequence of two cosmids, SPCC895 (38457 bp insert, EMBL Accession No. AL035247) and SPCC1322 (42068 bp insert, EMBL Accession No. AL035259), localized on chromosome III of the Schizosaccharomyces pombe genome. Fourteen Coding DNA sequences (CDSs) were identified in SPCC895 and 17 in SPCC1322. Two known genes were found in each cosmid: map2 and gms1 on SPCC895, encoding the mating type P-factor precursor and an UDP-galactose transporter, respectively, and bub1 and ade6 in SPCC1322, encoding a protein kinase and a phosphoribosylaminoimidazole carboxylase, respectively. The fission yeast K RNA gene has been localized to SPCC895. Three ribosomal proteins have been predicted among these two cosmids. Nine CDSs similar to known proteins were found on SPCC895, and seven on SPCC1322. They include putative genes for an uridylate kinase, a proteasome catalytic component, an ion transporter, a checkpoint protein, a translation initiation protein, a SNARE complex protein, a protein involved in cytoskeletal organization, a spindle pole body-associating protein, pre-mRNA splicing factor RNA helicase, a 3'-5' exonuclease for RNA 3' ss-tail, an UTP-glucose-1-phosphate uridylyltransferase, a leukotriene A(4) hydrolase, a member of the RanBP7-importin beta-Cse1p superfamily, a Ca(++)-calmodulin-dependent serine/threonine protein kinase and a prohibitin antiproliferative protein. One CDS is predicted to be an integral membrane protein. One CDS from SPCC895 is similar to a CDS of unknown function from Saccharomyces cerevisiae and three from SPCC1322 are similar to CDSs of unknown function from Candida albicans, S. cerevisiae and Sz. pombe, respectively. Finally, one CDS of SPCC895 and three of SPCC1322 correspond to orphan genes.

Amino Acid Sequence↗
PubMed2000

Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients.

OBJECTIVE: To describe the demographic, clinical, and laboratory features and natural history of patients with systemic sclerosis sine scleroderma (ssSSc), and to compare them with those of patients with SSc and limited cutaneous involvement (IcSSc). METHODS: The University of Pittsburgh Scleroderma Databank served as the data source. Patients were divided into those who had no skin thickening (ssSSc) and those who had skin thickening only distal to elbows or knees and/or of the face (IcSSc) during their disease course. These two groups were compared with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. Chi-square and Student's t-test analyses were performed, and Fisher's exact test was used as appropriate. RESULTS: Of 555 consecutive patients without diffuse cutaneous SSc, 48 (9%) had ssSSc and 507 (91%) had IcSSc. The ssSSc patients had a mean total disease duration of 18.6 years (15.1 years before study entry and 3.5 years of followup after study entry), and had not developed IcSSc or another connective tissue disease. Other than the absence of skin thickening, the ssSSc group had no significant differences in individual internal organ involvements, laboratory features, serum autoantibody type, or survival rate compared with patients with IcSSc. Within the category of lung involvement, patients with ssSSc had a significantly greater frequency of dyspnea with mild exertion or at rest, and a tendency toward reduced carbon monoxide diffusing capacity (<70% of predicted normal) and primary pulmonary arterial hypertension. Patients with IcSSc had significantly more frequent individual manifestations of digital pitting scars, digital-tip ulcers, telangiectasia, and calcinosis than those with ssSSc, in part related to increased time of observation. Puffy fingers and finger joint contractures were detected significantly more often in IcSSc patients. CONCLUSION: Systemic sclerosis sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a distinct or separate disorder.

Adolescent↗
PubMed2000

Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients.

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.

Adult↗
PubMed2000

Serum endothelial adhesion molecules levels correlate with lesion burden in multiple sclerosis patients treated with interferon beta-1b.

The levels of serum-soluble intracellular adhesion molecule-1 and soluble endothelial-leukocyte adhesion molecule-1, and the Gadolinium-enhanced T1-weighted MRI were studied in a group of patients with relapsing-remitting multiple sclerosis treated with interferon beta-1b and compared to a non-treated control group. The levels of serum-soluble intracellular adhesion molecule-1 and soluble endothelial-leukocyte adhesion molecule-1 increased, after three months treatment, as compared to baseline and the non-treated MS patients. A significant correlation was found in the treated group between serum-soluble endothelial-leukocyte adhesion molecule-1 and the lesion area in the Gadolinium-enhancing (T2 weighted scan) MRI.

Adult↗
PubMed2000

Fibre-type distribution and subcellular localisation of alpha and beta enolase in mouse striated muscle.

Enolase is a dimeric glycolytic enzyme exhibiting tissue specific isoforms. During ontogenesis, a transition occurs from the embryonic alphaalpha towards the specific alphabeta, and betabeta isoforms in striated muscle. Immunocytochemical analyses on transverse sections of adult mouse gastrocnemius muscle, allowed us to compare the expression of alpha and beta subunits to that of myosin heavy chain (MHC) isoforms. Levels of beta immunoreactivity followed the order IIB > IIX > IIA > I. This gradient parallels the ATPase activity associated to MHC isoforms, indicating that the expression of beta enolase in myofibres is finely regulated as a function of energetic requirements. By contrast, variations in alpha immunolabelling intensity appeared independent of fibre types. Longitudinal muscle sections exhibited a striated pattern of alpha immunoreactivity. Confocal microscopy analyses demonstrated that alpha was localised at the M band. Most beta immunoreactivity was diffuse all over the sarcoplasm. However, some beta immunoreactivity was striated and localized at both Z and M bands. Thus, betabeta enolase could participate to multi-enzyme complexes present at the I band, and involved with local ATP production. Our results support the notion that isozymes differ in their ability to interact with other macromolecules, thus segregating to different subcellular sites where they would respond to specific functional demands.

Animals↗
PubMed2000

Protective effect of allopurinol in the renal ischemia--reperfusion in uninephrectomized rats.

The effect of allopurinol (an inhibitor of xanthine oxidase) on oxidative stress, renal dysfunction, and histologic alterations was evaluated during the renal ischemia--reperfusion in uninephrectomized rats. Renal malondialdehyde and serum creatinine levels significantly increased after renal ischemia--reperfusion. However, the pretreatment with allopurinol demonstrated a protector effect in these parameters. Renal ischemia--reperfusion provoked a significant renal damage in the operated group. Tubular atrophy and interstitial fibrosis were attenuated by allopurinol when given prior to the surgery. In our study, allopurinol had a strong tendency to exert a beneficial effect during renal ischemia--reperfusion in uninephrectomized rats.

Allopurinol↗
PubMed2000

Contrasting effects of HSP72 expression on apoptosis in human umbilical vein endothelial cells and an angiogenic cell line, ECV304.

The effect of overexpression of heat shock protein (HSP)72 on apoptosis induced by different stimuli in human umbilical vein endothelial cells (HUVECs) and the angiogenic cell line, ECV304, was studied. Transient overexpression of HSP72 was achieved using an adenoviral vector (Advhsp72) and apoptosis was induced by heat shock, tumour necrosis factor (TNF)-alpha with cycloheximide (CHX), lipopolysaccharide (LPS) with TNF-alpha and verocytotoxin (VT). Apoptosis induced by heat shock was reduced by HSP72 expression. However, HSP72 expression in HUVECs increased apoptosis induced by TNF-alpha/CHX, LPS and VT measured by flow cytometric analysis of propidium iodide (PI)-stained permeabilized cells. In contrast, apoptosis in ECV304 induced by the same stimuli was reduced by HSP72 expression. No difference was seen in cells transduced with a control adenoviral vector expressing beta-galactosidase. These data imply that induction of HSP72 in cells modulates responses to apoptotic stimuli, but that the nature of the response varies with the cell type. However, it is clear that in situations where apoptosis may be part of a pathological process, HSP72 induction, for example by reperfusion injury, may exacerbate the process.

Adenoviridae↗
PubMed2000

Successful surgical treatment of haemophilic pseudotumour, filling the defect with hydroxyapatite.

A preliminary report is made on the use of hydroxyapatite for surgical procedure of pseudotumour, a rare but serious complication of the bleeding diathesis in patients with inherited bleeding disorders. Surgical or percutaneous treatment and refilling with fibrin sealant is shown to be a successful therapy in a 19-year-old male with severe haemophilia B. The pseudotumour, in the upper pad of the left leg, was filled with hydroxyapatite after surgery. We suggest that the use of hydroxyapatite is a new and useful option in the surgical treatment of haemophilic pseudotumour.

Adult↗
PubMed2000

Induction by interleukin 6 of G(s)-coupled prostaglandin E(2) receptors in rat hepatocytes mediating a prostaglandin E(2)-dependent inhibition of the hepatocyte's acute phase response.

Prostanoids, that are released from nonparenchymal liver cells in response to proinflammatory stimuli, are involved in the regulation of hepatic functions during inflammation. They exert their effects on their target cells via heptahelical receptors in the plasma membrane. For the 5 prostanoids prostaglandin E(2) (PGE(2)), prostaglandin F(2alpha), prostaglandin D(2) (PGD(2)), prostacyclin, and thromboxane A(2) there exist 8 receptors that are coupled to different heterotrimeric G proteins. These receptors are expressed differentially in the 4 principal liver cell types, i.e., hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells. It was intriguing, that the messenger RNA (mRNA) of none of the G(s)-coupled prostanoid receptors (DP-R, EP2-R, EP4-R, and IP-R) that can attenuate the inflammatory reaction were present in hepatocytes. The current study shows that the expression of the G(s)-coupled prostanoid receptors EP2-R, EP4-R, and DP-R, but not the IP-R, was efficiently and rapidly up-regulated by treatment of hepatocytes in vitro or rats in vivo with the key acute phase cytokine interleukin 6 (IL-6). In IL-6-treated hepatocytes PGE(2) in turn attenuated the IL-6-induced alpha(2)-macroglobulin formation via a cyclic adenosine monophosphate (cAMP)-dependent signal chain. The data indicate that an IL-6-mediated induction of the previously not expressed EP2-R and EP4-R on hepatocytes might establish a prostanoid-mediated feedback inhibition loop for the attenuation of the acute phase response.

Acute-Phase Reaction↗
PubMed2000

Thyroid hormones differentially modulate enolase isozymes during rat skeletal and cardiac muscle development.

During muscle development, an isozymic transition of the glycolytic enzyme enolase occurs from the embryonic and ubiquitous alphaalpha-isoform to the muscle-specific betabeta-isoform. Here, we demonstrate a stimulatory role of thyroid hormones on these two enolase genes during rat development in hindlimb muscles and an inhibitory effect on the muscle-specific enolase gene in cardiac muscle. In hindlimb muscles the ubiquitous alpha-transcript level is diminished by hypothyroidism, starting at birth. On the contrary, the more abundant muscle-specific beta-transcript is insensitive to hypothyroidism before establishment of the functional diversification of fibers and is greatly decreased thereafter. Our data support the hypothesis of a role of thyroid hormones in coordinating the expressions of contractile proteins and metabolic enzymes during muscle development. The subcellular localization of isoenolases, established here, is not modified by hypothyroidism. Our results underline the specificity of action of thyroid hormones, which modulate differentially two isozymes in the same muscle and regulate, in opposite directions, the expression of the same gene in two different muscles.

Animals↗
PubMed2000

Role of ET(A) receptors in the regulation of vascular reactivity in rats with congestive heart failure.

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ET(A)-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo (n = 24) or LU (50 mg. kg(-1). day(-1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of L-NNA, whereas contraction induced by ET(B) receptor (receptor B) stimulation was increased (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ET(B)-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ET(A) blockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.

Animals↗
PubMed2000

The effects of allopurinol in hepatic ischemia and reperfusion: experimental study in rats.

BACKGROUND/AIMS: Some studies have shown that postischemic hepatic dysfunction is mainly due to oxygen free radicals that are generated by xanthine oxidase. The present study was undertaken to determine the effect of allopurinol, an inhibitor of xanthine oxidase, on oxidative stress, liver injury and histologic alterations induced by hepatic ischemia-reperfusion in rats. METHODS: One hundred and sixty Wistar rats were used and divided into three groups. Group 1: sham operation; group 2: 50 min of ischemia followed by 1 h of reperfusion, and group 3: pretreatment with allopurinol and 50 min of ischemia followed by 1 h of reperfusion. The effect of allopurinol was evaluated by plasma levels of alanine aminotransferase and aspartate aminotransferase, histopathologic studies, and lipid peroxidation measured by the thiobarbituric acid reactive substances method and chemiluminescence initiated by tert-butyl hydroperoxide technique. RESULTS: Ischemia followed by reperfusion promoted an increase in lipid peroxidation of the hepatic cells when compared to the sham-operated group (p<0.05). This increase was attenuated in the group treated with allopurinol (p< 0.05). Allopurinol also showed a protective effect on hepatocellular necrosis (p<0.05), and the plasma levels of liver enzymes returned earlier to the normal range in rats pretreated with allopurinol in comparison to those that did not receive the drug (p<0.05). CONCLUSIONS: Allopurinol exerted a protective effect on hepatic ischemia and reperfusion in rats. The administration of this drug prior to liver operations should be considered to be submitted to trials in humans.

Alanine Transaminase↗