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Biomedical subjects

B Fernandes

Publications and source records attributed to B Fernandes.

At least 19 recordsLinked to original sources
PubMed1998

Dominantly transmitted beta-thalassemia arising from the production of several aberrant mRNA species and one abnormal peptide.

We describe a dominantly inherited beta-thalassemia intermedia phenotype observed in a five-generation Portuguese family. Carriers are characterized by moderate anemia, hypochromia, microcytosis, elevated hemoglobin (Hb)A2 and HbF levels, splenomegaly, hepatomegaly, and inclusion bodies in peripheral red blood cells after splenectomy. The molecular basis of this condition is a small deletion within the 5' consensus splicing sequence of the second intron of the beta-globin gene, IVS-II-4,5 (-AG). Reticulocyte RNA studies performed by reverse transcription-polymerase chain reaction (RT-PCR) and primer extension analysis showed three abnormally processed transcripts, which, upon sequencing, were shown to correspond to (1) skipping of exon 2, and (2) activation of two cryptic splice sites (between codons 59/60, and at IVS-II-47). In vitro translation studies of these patients' reticulocyte RNA have shown that at least one of these aberrant mRNA species is translated into an abnormally elongated peptide whose cytotoxic properties could, in part, be causing the atypical dominant mode of inheritance observed in this family. We suggest that this elongated beta chain is unable to combine with an alpha-globin chain to form a functional Hb molecule. Its degradation would, then, exhaust the proteolytic defense mechanism of the erythroid precursors, leading to inefficient proteolysis of the free alpha chains in excess.

Amino Acid Sequence↗
PubMed1998

Preoperative autologous blood deposition in support of gynaecological repair procedures.

Autologous blood transfusion was evaluated in gynaecological repair procedures including abdominal/ vaginal hysterectomy with vaginal repair, post-hysterectomy vaginal suspension and fixation, uni/bilateral salpingo-oophorectomy with vaginal colpopexy and sling procedures. A total of 247 autologous units were collected from 95 patients at the regional blood centre with 1-3 units (mean 2-6 units) deposition from each patient. One hundred and ninety of all collected units were transfused (collection/transfusion ratio = 1.3). Of these patients, 86 (90.5%) received autologous blood; 12 (13%) being transfused with 1 unit, 44 (46%) with 2 units and 30 (32%) with 3 units. Two of these patients received additional homologous blood. The average preoperative haemoglobin level was 119 g L-1 and average post-operative haemoglobin level was 105 gL-1. The post-operative Hb level was used as a retrospective indicator for the requirement for blood transfusion. The results show that overall 75% of patients had post-operative haemoglobin levels < or = 110 and 33% of patients with Hb levels < 100, respectively. These results suggest that preoperative autologous blood deposition may be appropriate in the patients undergoing reconstructive gynaecological repair procedures since there was a high rate of usage of autologous blood and low post-operative haemoglobin in a significant proportion of patients.

Adult↗
PubMed1997

Physiologic human T-cell responses to OKT3 in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse model.

BACKGROUND: Our goal was to study physiologic responses of human T lymphocytes to OKT3 in the human peripheral blood lymphocyte-severe combined immunodeficiency (hu-PBL-SCID) mouse model. METHODS: SCID mice were pretreated with anti-asialo-GM1 (alpha-ASGM1) and radiation, then engrafted with human peripheral blood lymphocytes (PBLs). Seven to 14 days after engraftment, when most human T cells in the spleen of these mice are CD3+/CD4+ and CD3+/CD8+, mice were treated with OKT3 or control antibody. Mice were killed for histopathologic examination, for flow cytometric assessment of the engrafted human lymphocytes, and for analysis of human tumor necrosis factor-alpha serum levels. RESULTS: Intravenous injection of 5 microg of OKT3 resulted in early antigenic modulation of engrafted human T lymphocytes, with the emergence of CD3-/CD4+ and CD3-/CD8+ cells in the spleen of hu-PBL-SCID mice. There was an increase in the serum concentration of human tumor necrosis factor-alpha within 4 hr after OKT3 injection, suggesting early T-cell activation. Antigenic modulation and activation of the human lymphocytes in the spleen was followed by their depletion within 24 hr. This human T-cell response to OKT3 in hu-PBL-SCID mice is analogous to the response in humans treated with OKT3 and in BALB/c mice injected with an anti-murine CD3 monoclonal antibody. Graft-versus-host disease in the mice was abrogated by OKT3 treatment, and OKT3-treated mice lived longer than controls. Histopathologic studies showed clearance of lymphocytic infiltration in the liver and lungs of OKT3-treated mice. CONCLUSIONS: These findings provide further evidence of functional human immune T cells in the hu-PBL-SCID mouse. This model may have useful applications in the study of transplantation immunology.

Animals↗
PubMed1997

Regional cancer cytogenetics: a report on 1,143 diagnostic cases.

The results of studies from a regional cancer cytogenetics diagnostic service are reported. In a 10-year period, 1,143 marrow samples from patients with newly diagnosed leukemia and myelodysplastic syndrome were referred. Successful studies were completed on 992 cases (87%). Among all referred cases, the rates of detection of cytogenetically abnormal clones were 95% for chronic myelogenous leukemia (CML), 54% for acute lymphoblastic leukemia (ALL), 51% for acute myeloid leukemia (ANLL), and 43% for myelodysplastic syndrome (MDS). Of 169 cases of CML studied, 90.5% bore the standard Philadelphia chromosome (Ph), 3.55% had an unusual Ph, and 5.33% were Ph-negative. Among the 59 cases of cytogenetically abnormal MDS, common abnormalities observed were trisomy 8 and changes resulting in loss of material from the long arm of chromosomes 5 and 7, and 20q-. Of the 168 abnormal ANLL, there was a strikingly non-random pattern of aneuploidy, with monosomy 7 and trisomy 8 predominating. Common structural changes observed were changes resulting in loss of material from the long arm of chromosomes 5 and 7, trisomy 8, rearrangements of 11q23, t(15;17), t(8;21), rearrangements of 12q13 and 3q, inversion 16, trisomy 11, Ph, trisomy 21, t(6;9) and t(1;22). The differences between adult and pediatric findings were minor, with the exception of chromosome 5 abnormalities, which were common among adults with ANLL but rare in the pediatric cases. There were 273 ALLs with abnormal cytogenetic findings. There was preferential gain of chromosomes 21, X, 14, 6, 4, 18, 17, and 10 (in decreasing order of frequency) in leukemic clones. Of the 193 ALLs with structural changes, many fell into-well-defined categories with established correlations to FAB subtypes. Common changes in ALL were rearrangements of 9p, 12p, 6q, TCR loci, 11q23, Ig loci, and 8q24, and duplication of 1q, Ph, i(17q), t(1;19), i(9q) and dic(9;12). The detailed documentation of the cytogenetic findings in this relatively large, single-institution study will likely facilitate the further characterization of rare, primary cytogenetic changes associated with leukemias and MDS. From a managed health care perspective, regional cancer cytogenetic services may be cost-effective alternatives to single-institution laboratories.

Adult↗
PubMed1995

Functional characterization of the prostanoid DP receptor in human myometrium.

Spontaneous contractile activity of strips of human myometrium obtained from non-pregnant donors at the time of hysterectomy was inhibited by the selective prostanoid DP receptor agonists BW 245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin) and ZK110841 ((5Z,13E)-(9R,11R,15S)-9 beta-chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18,19, 20-pentanor-5,13-prostadienoic acid) with pEC50 values of 8.4 and 7.3 respectively but prostaglandin D2 produced a biphasic effect. In the presence of the TP receptor antagonist L670596 ((-)-6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid), contractile activity induced by the FP receptor agonist, cloprostenol ([1R-[1 alpha(Z),2 beta(1E,3R),3 alpha,5 alpha]]-7-[2-[4-(3- chlorophenoxy)-3-hydroxy-7-butenyl]-3,5-dihydroxycyclopentyl]-5-he ptenoic acid), was inhibited by BW 245C (pEC50 = 7.5), ZK110841 (pEC50 = 6.7) and prostaglandin D2 (pEC50 = 6.3). Under these conditions both prostaglandin J2 and 9 alpha,11 beta-prostaglandin F2 were inhibitory partial agonists. All compounds were antagonized by the selective DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)h ydantoin), but the pKB values were both concentration-dependent (pKB versus BW 245C at 10 nM = 9.1, at 50 nM = 8.3) and agonist-dependent (pKB at 10 nM versus BW 245C = 9.1, versus ZK110841 = 7.4). Both agonist and antagonist potencies support the existence of DP receptors in human myometrium. The concentration and agonist dependence of the action of BW A868C suggests that putative DP receptor agonists relax human myometrium by more than one mechanism. These observations may be explained by the existence of subtypes of DP receptor in human myometrium.

Adult↗
PubMed1995

Angiopeptin (BIM23014C) inhibits vascular smooth muscle cell migration in vitro through a G-protein-mediated pathway and is associated with inhibition of adenylyl cyclase and cyclic AMP accumulation.

Angiopeptin (AP: BIM23014C), a cyclic analogue of the peptide hormone somatostatin, inhibits intimal hyperplasia after balloon angioplasty. This inhibition has been attributed to a direct inhibitory effect on smooth muscle cell (SMC) proliferation. However, the SMC that proliferate in the intima and contribute to intimal hyperplasia arrive there by migrating from the injured media, suggesting that SMC migration may also play an important role in this process. Indeed, in the experiments we describe, AP inhibited the migration of rat aortic SMC cells (RA-SMC) in response to type I collagen, the predominant form of collagen in the vessel media, and did so dose dependently. RA-SMC migration was inhibited 70% in the presence of AP 100 nM. RA-SMC adhesion to type I collagen in these conditions was not inhibited, suggesting that AP does not interfere with RA-SMC recognition of type I collagen; instead, it blocks subsequent signaling events that are necessary for RA-SMC migration in response to type I collagen. AP inhibited the forskolin-stimulated accumulation of cyclic AMP by RA-SMC (35% at 30 nM). In addition, pertussis toxin (PT), which blocks Gi-mediated inhibition of adenylyl cyclase, blocked the inhibitory effect of AP on cyclic AMP (cAMP) accumulation and also blocked the inhibitory effect of AP on RA-SMC migration. These findings suggest that the inhibitory effect of AP on intimal hyperplasia is due at least in part to its effects on SMC migration and that these effects are mediated by a Gi-dependent pathway and may involve inhibition of adenylyl cyclase and cAMP accumulation.

Adenylate Cyclase Toxin↗
PubMed1994

A phase I study of swainsonine in patients with advanced malignancies.

Swainsonine, an alpha-mannosidase inhibitor which blocks Golgi oligosaccharide processing, represents a new class of compounds that inhibit both rate of tumor growth, and metastasis, in murine experimental tumor models. In this first phase I study, the quantitative and qualitative toxicities of swainsonine have been studied in patients given a continuous i.v. infusion over 5 days, repeated at 28-day intervals. Dose levels were escalated in increments of 100 micrograms/kg/day from 50-550 micrograms/kg/day. Nineteen patients with both solid tumor and hematological malignancies were given a total of 31 courses. Hepatotoxicity, particularly in patients with liver metastases, was the dose-limiting toxicity. The maximum tolerated dose (MTD) and the recommended starting dose (MTD -1 level) were 550 and 450 micrograms/kg/day, respectively. Common side effects included edema, mild liver dysfunction, a rise in serum amylase, and decreased serum retinol. Acute respiratory distress syndrome possibly precipitated by swainsonine resulted in a treatment-related death in a patient with significant pretreatment hepatic dysfunction. One patient with head and neck cancer showed > 50% shrinkage of tumor mass for 6 weeks after treatment. Two patients with lymphangitis carcinomatosis on chest X-ray noted improvement in cough and shortness of breath during the infusion of swainsonine and for 1 week thereafter. Clearance and serum half-life for swainsonine were determined to be approximately 2 ml/h/kg, and 0.5 day, respectively. Golgi oligosaccharide processing, a putative anticancer target for swainsonine was inhibited in peripheral blood lymphocytes as evidenced by a marked decrease in leukoagglutinin binding after 5 days of treatment. Oligomannosides in patient urine increased 5-to 10-fold over the 5 days of treatment, indicating that tissue lysosomal alpha-mannosidases were also blocked by swainsonine. Urine oligomannoside accumulation reached steady state at 3 days, approximately 1 day after serum drug levels reached steady state. The fraction of HLA-DR-positive cells in peripheral blood lymphocytes increased following 5 days of swainsonine treatment, an effect similar to that observed for peripheral blood lymphocytes from normal subjects cultured with swainsonine. No significant changes in CD3, CD4, CD8, CD16, and CD25 were observed. Swainsonine produces minimal toxicity when administered i.v. to cancer patients at dosages that inhibit both Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. Detection of hepatic metastases or liver enzyme abnormalities prior to treatment predict for more significant toxicity.

Adult↗
PubMed1994

Primary non-Hodgkin's lymphoma of bone. A clinicopathologic study.

BACKGROUND: This study relates our experience in the diagnosis and treatment of a rare clinical entity, non-Hodgkin's primary lymphoma of bone. METHODS: Seventeen cases of patients with primary lymphoma of bone diagnosed and treated at a single institution between 1975 and 1992 are reviewed. Ten patients received combined-modality therapy, consisting of an anthracycline-containing combination chemotherapy (CT) regimen, followed by adjuvant radiotherapy (RT) to the primary site of disease. Five patients were treated with CT alone; one patient received RT alone; and one patient was treated with CT after emergency RT for spinal cord compression. RESULTS: Thirteen patients presented with Stage I disease, two with Stage II; and two with Stage IV disease (multiple bony sites only). Thirteen patients had an intermediate-grade diffuse large cell lymphoma; two had an intermediate-grade mixed small and large cell lymphoma; and two had a high-grade lymphoma (one immunoblastic and one small non-cleaved cell lymphoma). The overall response rate was 94% (18% complete response, 58% partial response 1, and 18% partial response 2). Thirteen patients are alive and disease-free at a median of 29 months; 10 of these received CT+RT, and 3 received CT alone. Three patients have died; one of these received CT+RT and one CT alone, and one relapsed immediately after CT. One patient, who was initially treated with RT and then with CT+RT after relapse, was lost to follow-up 40 months from the start of treatment. CONCLUSIONS: Because experience in the literature suggests a 50% distant relapse rate in primary lymphoma of bone treated with RT alone, our policy is to treat all patients with combined-modality therapy (CT+RT). However, only a Phase III randomized, controlled clinical trial will determine whether CT+RT is superior to either modality alone.

Adolescent↗
PubMed1992

Increased expression of highly branched N-linked oligosaccharides terminating in N-acetylglucosamine residues in neoplastic and sclerodermal chicken fibroblasts.

Although neoplastic cells often show a shift towards the expression of larger N-linked oligosaccharides compared to their normal counterparts, little consideration has been given to the possibility that these changes might be a more general phenomenon characteristic of certain neoplastic and non-neoplastic proliferative disorders. Terminal N-acetylglucosamine (GlcNAc) cluster antigen (TGCA) is an immunoreactive epitope(s) of highly branched N-linked oligosaccharides terminating in GlcNAc residues. Here we have compared the expression of this antigen in normal, neoplastic and sclerodermal chicken fibroblasts by immunomorphological methods. TGCA was detectable in only a few, if any, fibroblasts of normal chicken skin or those cultured from chicken embryos. In contrast, the antigen appeared in 15 to 30% of chicken embryo fibroblasts transformed with avian sarcoma viruses and about 50% of neoplastic fibroblasts of both Rous sarcoma virus-induced fibrosarcomas and carcinogen-induced transplantable fibrosarcomas. Significantly, TGCA was also found in most activated fibroblasts in the skin of chickens with hereditary scleroderma. These results indicate that increased expression of highly branched N-linked oligosaccharides terminating in GlcNAc residues is characteristic of both neoplastic and sclerodermal chicken fibroblasts. Investigation of this phenomenon may thus provide insight into biochemical pathways involved in neoplastic transformation and pathogenesis of a number of non-neoplastic proliferative connective tissue disorders such as scleroderma. Moreover, changes in the expression of TGCA-positive oligosaccharides (or their modified biochemical counterparts in mammalian species) may have considerable value for diagnosis of several connective tissue diseases.

Acetylglucosamine↗
PubMed1992

Effects of interferon-alpha therapy on serum and liver HBV DNA in patients with chronic hepatitis B.

The aim of this study was to evaluate the effect of interferon-alpha therapy on serum and liver HBV DNA in 20 patients with chronic hepatitis B and to correlate the presence or absence of HBV DNA with the clinical response. There were 11 responders and all lost HBV DNA from the serum. Ten of the 11 were followed for 36 months following IFN treatment and remained well with absence of HBeAg and HBV DNA from the serum and with normal ALT. Five also lost HBsAg. HBV DNA became undetectable in the liver of nine of 10 of these patients in whom liver tissue was available for study. HBV DNA persisted in the liver of seven of nine nonresponders and was not detected in two in spite of the presence of HBV DNA and HBeAg in the serum of these two patients. We conclude that IFN may induce long remissions in patients with chronic hepatitis B with loss of HBV DNA from the serum and that occasionally HBV DNA may persist in the liver of such patients.

Adult↗
PubMed1991

Beta 1-6 branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia.

Malignant transformation of murine and human cells is commonly associated with increased--GlcNAc beta 1-6Man alpha 1-6Man beta--branching in asparagine-linked oligosaccharides. Somatic mutations and drugs which block expression of the beta 1-6 branched oligosaccharides are potent inhibitors of tumor cell invasion and metastasis in animal models. This suggests that the oligosaccharides are required for metastasis to occur and therefore their increased presence in primary tumors may be diagnostic of metastatic disease. Although antibodies to the beta 1-6 branched portion of the oligosaccharides are not available, a plant lectin leukoagglutinin (L-PHA) has been shown to bind specifically to this structure. L-PHA lectin histochemistry was performed on paraffin sections of human breast and colon tissues. All breast carcinomas and epithelial hyperplasia with atypia showed significantly increased L-PHA staining compared to fibroadenomas and hyperplasia without atypia. In histological sections of colon, adenomas showed a small but significant increase in L-PHA staining compared to normal colonic epithelium, while carcinomas showed greatly increased reactivity. In addition, Dukes stage C tumors showed higher levels of L-PHA staining than stage A tumors. These results demonstrate that L-PHA-reactive beta 1-6 branched N-linked oligosaccharides are consistently increased in neoplasias of human breast and colon and that the level of L-PHA staining correlates with the pathological staging of the diseases.

Adenofibroma↗
PubMed1991

Unusual findings in two patients with acquired deletions of the long arm of chromosome 5 (5q-).

Two patients with acquired deletions of the long arm of chromosome 5 (5q-) are presented and discussed. For both, clinical and other laboratory tests are highly atypical of patients with haematological malignancy characterized by 5q-. These unusual presentations of the 5q- anomaly further emphasize the heterogeneity of clinical presentations associated with this acquired chromosomal abnormality.

Aged↗
PubMed1989

Immunohistochemical study of ontogeny and phylogeny of a terminal N-acetylglucosamine cluster antigen.

In this work an immunohistochemical method was used to study the ontogeny and phylogeny of a terminal N-acetylglucosamine (GlcNAc) cluster antigen which is an epitope(s) of highly branched N-linked oligosaccharides terminating in GlcNAc residues. The ontogenic studies demonstrated that expression of the antigen is developmentally regulated in lymphocytes, epithelial cells of endodermal origin and kidney mesangial cells of the chicken. The antigen was found in several other avian species studied, namely, the Japanese quail, duck, goose and turkey. Furthermore, the distribution of the antigen in all these species was similar. In adult animals, it was found in bursal and thymic lymphocytes, macrophages, spleen reticulum cells, epithelial cells of the intestine and bronchioles and capillary endothelial cells. The antigen was also detected in epithelial cells of the gastrointestinal tract of several lower vertebrates studied: the amphibian (frog), reptile (chameleon) and fish (rainbow trout). It was undetectable in various organs of the human, African green monkey, calf, pig, rat and guinea-pig, but was found in the intestinal epithelial cells of ten mouse strains. It is likely that biosynthetic processing leading to the formation of highly branched N-linked glycans terminating in GlcNAc residues is conserved during evolution in birds and other lower vertebrates.

Acetylglucosamine↗
PubMed1989

Intraoperative ultrasound in the conservative resection of testicular neoplasms.

In a series of approximately 400 patients investigated for oligospermia 4 had small testicular tumors demonstrated by high resolution real-time ultrasound. The lesions ranged in size from 3 to 6 mm., were clinically impalpable and were demonstrated on repeated sonograms. Exploration was done in all 4 patients with the aid of intraoperative high resolution ultrasound. This procedure allowed for conservative resection of the tumor with preservation of the testicle. The pathological diagnosis in all cases was benign Leydig cell tumor.

Adult↗
PubMed1988

Chicken mucin-cross-reactive antigen.

We have previously described a chicken heterophile antigenic determinant (CHAD-1) shared by Mycobacterium smegmatis and chicken tissues. We then demonstrated that CHAD-1 is present on several chicken glycoproteins and that its immunoreactive domains are highly branched asparagine-linked oligosaccharides terminating in N-acetylglucosamine residues. In the present study, we have shown that CHAD-1 is also expressed by mucin purified to homogeneity from a soluble mucus of chicken intestine. Another antigen found on chicken mucin is a chicken mucin-cross-reactive antigen (CMCRA). Antisera to this antigen were produced by immunization of rabbits with an enriched preparation of CHAD-1 isolated from the bursa of Fabricius. These antisera were absorbed with Mycobacterium smegmatis (to block the anti-CHAD-1 antibody) and with chicken serum, and then used for immunoperoxidase staining of chicken tissue sections for CMCRA. The latter antigen was detected in most medullary cells of the bursa, in epithelial cells and Hassal's corpuscles of the thymus, and in mucus-producing cells of the intestine, esophagus, trachea, and bronchi. Using Western immunoblot analysis, we demonstrated that CMCRA is expressed by a number of polypeptides extracted from bursal lymphoid cells. These polypeptides could not be detected in extracts of thymus, spleen, peripheral blood or bone marrow mononuclear cells.

Animals↗
PubMed1988

Granulocyte precursors are the principal cells in bone marrow that stimulate allospecific cytolytic T-lymphocyte responses.

Mouse bone marrow cells were fractionated and enriched for functional activity as stimulators of allospecific cytolytic T-lymphocyte (CTL) responses in vitro. The relevant stimulator cells were enriched sequentially in the low-density fraction of bone marrow, its 2-hr adherent and 18-hr non-adherent fractions and in the FcR-negative fraction of 18-hr non-adherent cells. The functionally enriched cell population contained over 90% granulocyte precursors by ultrastructural analysis. The results indicate that granulocyte precursors are the principal cells in bone marrow that stimulate alloreactive T-cell responses.

Animals↗
PubMed1986

Novel heterophile chicken antigen: immunohistochemical localization using antisera to Mycobacterium smegmatis and possible association with lymphocyte maturation.

A novel heterophile antigen shared by Mycobacterium smegmatis and chicken tissues was demonstrated by the indirect immunoperoxidase method using antisera raised in rabbits immunized with a complete Freund's adjuvant containing killed Mycobacterium smegmatis as an immunostimulating component. This antigen was strongly expressed in medullary lymphocytes of the thymus and bursa of Fabricius, but was undetectable in lymphoid cells of the cortical regions of these organs. Only a few lymphocytes stained positively for the antigen in T- and B-cell areas of the spleen. These data suggest that the heterophile antigen is associated with the intrathymic and intrabursal maturation of chicken lymphocytes. The antigen was also detected in some nonlymphoid cells. It was not found in sheep erythrocytes, human and rat tissues or in killed bacillus Calmette--Guerin.

Animals↗