Mudanças globais e desenvolvimento: importância para a saúde / Global changes and development: health importance

Neste artigo busca-se inventariar o estado atual das inter-relações entre mudanças ambientais globais e saúde, incluindo uma revisão do estado atual das ameaças de origem antrópica sobre a biodiversidade, trazendo o enfoque ecossitêmico como linha de pesquisa para a melhoria da qualidade de vida. Os processos de mudanças ambientais globais afetam a saúde humana, direta ou indiretamente, pontual ou regionalmente. Alterações na química da atmosfera, mudanças climáticas, degradação do solo, perda da biodiversidade, urbanização e grandes empreendimentos, escassez de água e poluições químicas de âmbito global podem ter consequências severas para o bem-estar humano, saúde e sobrevivência. A importância dessas mudanças para a saúde humana dependerá de quanto as populações são ou podem ser afetadas no futuro, do grau e amplitude dos impactos e das adaptações biológicas e das formas de mitigação e controle disponíveis. Vários programas têm sido desenvolvidos em todo o mundo, mas é preciso avançar em modelos conceituais, incluir as questões das mudanças ambientais globais na agenda científica e institucional brasileira, buscar modelos de desenvolvimento sustentável, criar mecanismos que interropam a perda da biodiversidade, minimizar o uso de poluentes e sensibilizar as pessoas para o possível esgotamento dos recursos naturais renováveis

In this article we intended to survey the current state of relationships between global environmental changes and health. It includes a revision of the current state of threats of anthropic origin on biodiversity, bringing an ecosystem approach as a field of research for the improvement of quality of life. Global environmental changes affect human health directly or indirectly, locally or regionally. Alterations in the chemistry of the atmosphere, climate changes, soil degradation, loss of biodiversity, urbanization and major development sites, shortage of water and chemical pollutants constitute driving forces that can have severe consequences for human well-being and health as well as, its survival. The importance of these changes for human health will depend on how populations may be affected in the future, the severity and magnitude of the impact, the possibility of biological adaptations, and the availability of strategies to mitigate and control. Several programs have been developed around the world. However, the Brazilian scientific and institutional agenda needs to move forward in conceptual models that include aspects related to global environmental changes, searching for models of sustainable development, and creating mechanisms that interrupt the loss of biodiversity, minimize the use of pollutants, establish awareness programs concerning the exhaustion of renewable natural resources.

Epidermal growth factor stimulates the synthesis of cell-attachment proteins in the human breast cancer cell line PMC42.

The human breast cancer cell line PMC42 responds to the addition of epidermal growth factor (EGF) by proliferation and increased frequency of attachment of cell-organoid structures to the culture vessel. Antibodies to fibronectin and laminin reacted strongly, by immunoperoxidase, with the membranes of cells from organoids that became adherent following addition of EGF. This reaction was weak with membranes of cells of non-adherent organoids in cultures containing EGF and was negative with membranes of cells of free-floating organoids from cultures without EGF. An increase in biosynthetic labelling with 35S-methionine was found in cell lysates and supernatants of PMC42 cells cultured in the presence of EGF compared with control cells grown without EGF. One-dimensional SDS-polyacrylamide gel electrophoresis and 2-dimensional NEPHGE-PAGE of labelled cell proteins showed increased synthesis of several cellular proteins and the appearance in EGF-treated cells of 2 proteins which were not detected in cells from control cultures lacking EGF. Immunoprecipitation experiments using antibodies to fibronectin and laminin with lysates of 35S-methionine labelled PMC42 cells cultured with EGF showed strong immunoprecipitation at Mr 200 and 400 with anti-laminin, and at Mr 200 and 96 with anti-fibronectin. These immunoprecipitates were blocked specifically by purified laminin or fibronectin, respectively. No immunoprecipitates were detected with these antibodies in lysates from cells grown without EGF. EGF thus stimulates increased adherence of cultured PMC42 cell-organoid structures together with increased membrane expression of the cell-adhesive proteins laminin and fibronectin. These effects may play a role in normal development and neoplastic behaviour of breast epithelia.

Development of monoclonal antibodies to the human breast carcinoma cell line PMC42.

In an attempt to identify antigens expressed during breast differentiation, three murine monoclonal antibodies, CIBr2, CIBr7, and CIBr18, were produced against the human pleomorphic breast carcinoma cell line PMC42. All three monoclonal antibodies reacted with previously undescribed antigenic determinants on the PMC42 cell line. Antibody CIBr18 reacted only with the immunizing cell line PMC42, whereas antibodies CIBr2 and CIBr7 showed minimal reactivity toward a panel of 34 human leukemia- and solid tumor-derived cell lines. The antigenic determinants detected by the three antibodies were distinct, and each showed variable expression in PMC42 monolayer and organoid cultures. The heterogeneity of staining seen on PMC42 cultures may reflect the fact that this cell line contains up to eight morphologically distinct cell types. Antigen expression correlated with cell type in some instances, whereas in other instances phenotypic subdivision within a cell type was apparent. Antigens recognized by antibodies CIBr7 and CIBr18 were characterized biochemically. In Western blotting, antibody CIBr7 identified a single band of an apparent molecular weight of 38,000 within PMC42 cell lysates. Sodium dodecyl sulfate-polyacrylamide gel analysis of polypeptides immunoprecipitated by antibody CIBr18 from [35S]methionine-labeled PMC42 cell lysates identified two glycoproteins of apparent molecular weights of 115,000 and 120,000, respectively. No biochemical data for the CIBr2 antigen are yet available. All three antigens were detected in human mammary epithelium and some non-breast tissues. The expression of these antigens in normal and neoplastic mammary epithelia is discussed in terms of antigen heterogeneity and changes in antigen expression upon conversion to the malignant state.

Lymphoma immunotyping by paraffin immunoperoxidase and cell suspension methods--a comparative study.

Immunoperoxidase staining incorporating an enzyme digestion step was performed on paraffin sections of 84 biopsy cases of lymphoproliferative disorders. Monoclonality was demonstrated in 100% of plasmacytomas and related tumours, and in 66% of non-Hodgkin's lymphomas. In 83% of lymphomas the immunoglobulin class was IgM and the light chain distribution was kappa 64% and lambda 36%. Polyclonality was found in 89% of cases of reactive lymphoid hyperplasia and within Reed-Sternberg cells in 55% of cases of Hodgkin's disease. Similar results were obtained by dispersed cell studies in 56 overlapping cases. The concordance rate between the two methods in 40 cases of non-Hodgkin's lymphoma was 67.5%. Reasons for the inconsistencies are discussed. Immunoperoxidase staining of enzyme digested paraffin sections is useful in the diagnosis of B cell lymphoproliferative disorders with a particular role in centres where cell suspension studies are not available or when there is no access to fresh tissue.

A monoclonal antibody CIBr17 recognizes a myoepithelium-specific antigen in human mammary gland.

A murine monoclonal antibody (MAb) CIBr17, raised against the human breast carcinoma cell line PMC42, reacts specifically with myoepithelial cells in normal human breast. This IgGl antibody recognizes a approximately 110kDa glycoprotein that is expressed on the cell surface and junctional membranes of PMC42 monolayer cultures. The CIBr17 antigen is present in two major glycosylated forms with approximate pls of 5.2 and 5.5 respectively in PMC42 cells. The tissue specificity of CIBr17 was assessed on frozen sections of PLP-fixed tissues by means of a 4-layer immunoperoxidase technique. CIBr17 has reacted with a variety of epithelium-derived tissues and some smooth muscle cells. Within many epithelial tissues, CIBr17 has demonstrated specific staining of particular epithelial cell types. Within normal breast and most benign breast lesions, antibody CIBr17 stained only myoepithelial cells. No staining of luminal epithelium, basement membranes or stromal elements was observed. In sclerosing adenosis, CIBr17 stained areas of pronounced myoepithelial differentiation, while in duct epitheliosis variable staining of proliferating cells was observed. In breast carcinomas, CIBr17 demonstrated variable antigen expression. In most tumors, CIBr17 either did not stain any tumor cells or stained only a small number of tumor cells spread randomly throughout the tumor. In several ductal carcinomas, however, CIBr17 stained the majority of tumor cells.

Biochemical characterization of the monoclonal antibody-defined ovarian carcinoma-associated antigen SGA.

The molecular nature of SGA, the ovarian-carcinoma-associated antigen defined by the MAb OM-1, has been determined. The cell-surface form of the SGA molecule is a glycoprotein with p1 less than 4.2, which on PAGE analysis has an apparent MW of approximately 360 kDa. This was the only OM-1-reactive species found on the cell surface. The apparent MW was unaffected by reducing conditions. The predominant cytoplasmic form of SGA is a non-glycosylated 170-kDa molecule with p1 6.5. Pulse-chase experiments were complicated by the extremely slow rate of SGA synthesis. However, the data indicate that the SGA molecule is synthesized as a 190-kDa protein, cleaved to yield a 170-kDa non-glycosylated intracellular form which is slowly glycosylated to the 360-kDa cell-surface species. Western blotting experiments revealed the presence of the 360-kDa glycosylated molecule in human ovarian cell culture supernatants.

Monoclonal antibody CI-panHu defines a pan-human cell-surface antigen unique to higher primates.

The murine monoclonal antibody CI-panHu reacts strongly with the cell surface of all human cells, including erythrocytes, tumour cells and HLA-A,B,C-negative cell lines. As such, this antibody defines the first pan-human cell-surface antigen reported. The antigenic determinant detected is associated with a protein doublet of 16,000 MW whose expression is restricted to cells from humans, apes and some species of Old World monkeys. Antibody reactivity is not diminished by routine fixation procedures, nor by paraffin-embedding, and the antigenic determinant is relatively protease-resistant. The use of this antibody as a positive control in immunoassays of human cells is discussed.

The sebaceous gland antigen defined by the OM-1 monoclonal antibody is expressed at high density on the surface of ovarian carcinoma cells.

A monoclonal antibody, designated OM-1, was raised against ovarian serous papillary cystadenocarcinoma (stage IV) cells. This antibody was found to react strongly with primary and metastatic ovarian serous cystadenocarcinomas and endometrioid carcinomas but the antigen detected was either absent or at very low levels in ovarian mucinous adenocarcinomas, clear cell carcinomas, benign serous and mucinous cystadenomas and Brenner tumours. The OM-1 antibody gave no detectable reaction with 93 other human tumours, including examples of breast and colon adenocarcinomas. In normal tissues the OM-1 antibody reacted with normal sebaceous gland cells, lung type II pneumocytes and placental syncytial trophoblasts. In the normal ovary OM-1 reactivity was confined to extremely weak staining of the surface epithelium. No reaction with any other ovarian cell type could be detected. No evidence of reaction with other normal cell populations present in 24 adult and seven foetal tissues was found. The antigen detected is compared with other ovarian tumour-associated antigens. The OM-1 antibody is likely to prove of value in the detection and diagnosis of ovarian carcinoma.

Two families of abl-related transcripts in human haematopoietic cells differing in their homology to v-abl.

The transforming gene of the Abelson murine leukaemia virus, v-abl, contains two open reading frames (orf). The 5' orf encodes a tyrosine-specific protein kinase while the 3' orf has the capacity to code for an 18,000 Mr protein. However, no 3' orf product has yet been identified. Using probes capable of distinguishing between the 5' and 3' orfs of v-abl, we have examined the abl-related transcripts present in human haematopoietic cells and leukaemia-derived cell lines, including the chronic myeloid leukaemia-derived cell line K562. Our results indicate that transcripts of 6 kb, 7 kb and 8 kb (kilobase, 10(3) base-pairs) show strong homology to v-abl 5' protein kinase-encoding orf sequences, but are devoid of any sequences from the v-abl 3' orf. In addition, transcripts of 5 kb, 3 kb, 1.6 kb and 1.4 kb, reacting with both 5' orf and 3' orf probes, were observed. The latter species, with coding sequences from both the tyrosine kinase and the putative 18,000 Mr protein, must be transcribed from the human c-abl gene as this is apparently the only human gene containing sequences homologous to the v-abl 3' orf. The 6 kb, 7 kb and 8 kb transcripts may arise either from the c-abl gene through differential splicing, or from one of the three other regions of the human genome with sequences homologous to the 5' orf of v-abl. Examination of genomic DNA from the K562 cell line revealed that the amplification of abl-related sequences, which is presumed to result in the elevated levels of the 8 kb transcript found in this cell line, does not involve sequences homologous to the v-abl 3' orf. This lends credence to the idea that the 8 kb transcript may derive from an abl-related gene other than c-abl. While the significance of the 3' orf of v-abl remains unknown, the data presented strongly suggest the existence of at least two distinct abl-related proteins in human haematopoietic cells.

Monoclonal anti-T-cell antibodies react with circulating myeloid leukemia cells and normal tissue macrophages.

Rabbit and monoclonal antibodies to human myeloid leukemia cells, monocytic leukemia cells and human thymocytes have shown the existence of common T-cell/myeloid/monocyte antigens. For this reason, the specificity of a series of monoclonal antibodies to human T-cells (OKT 1, 3, 4, 5, 6, 8, 9, 10; and NA1/34) was tested by immunofluorescence (cytofluorograph) and complement-mediated cytotoxicity against human myeloid leukemia and normal blood cells and leukemic cell lines. In addition, an immunohistological analysis of the specificity of OKT4, 9.3, Leu 3a, OKT3 and NA1/34 antibodies was performed using normal lymphoid tissues and a sensitive immunoperoxidase technique. Normal human peripheral blood mononuclear cells reacted with OKT3 ("pan T-cell", mean 54%), OKT4 ("helper T-cell", mean 35%) and OKT 5/8 ("suppressor T-cell", mean 18%) as previously reported. However, OKT3 reacted with the cell lines K562 (myeloid), RC2a and THP-1 (monocytoid) and U937 (macrophage) as well as with cells from 9/65 myeloid leukemia patients. OKT4 reacted with the cell lines HL60 (promyelocyte), RC2a and U937 and also with cells from 6/60 myeloid leukemia patients. OKT5 reacted with the cell lines K562 and THP-1. OKT1 ("pan T-cell") reacted with THP-1 and with myeloid and monocytic leukemia samples (5/32) as did OKT6 ("cortical thymocyte") (3/32). OKT10 ("common thymocyte") reacted with a range of leukemia cell lines (B-cell, pre- B-cell and macrophage) as well as 7/21 myeloid leukemia samples. In tissue sections Leu 3a, (9.3 and OKT4 to a lesser extent), stained paracortical lymphocytes, plus subcapsular and medullary macrophages, and dendritic cells present within the paracortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunity to melanoma associated antigens detected by both leukocyte adherence inhibition and antibody dependent cellular cytotoxicity assays.

Two different assays, leukocyte adherence inhibition (LAI) and antibody dependent cellular cytotoxicity (ADCC) have been used to measure the immune responses of 69 melanoma patients, 116 patients with other tumours and 64 normal controls to a number of melanoma and control antigens. Using the LAI test, melanoma patients were significantly more reactive (43-69% positive) than normal controls (7-32% positive) to membrane extracts from 3 to 6 melanoma cell lines, and 4 to 6 extracts of melanoma biopsy specimens. However, the proportion of patients with other tumours reacting with 3 of these extracts was similar to melanoma patients. Melanoma patients were more reactive to the melanoma extract than to extracts of normal skin, normal muscle and 2 breast cancer cell lines. ADCC tests were used to detect anti-melanoma antibodies in patient sera. Preferential reactivity by melanoma patients was detected towards only 2 of the 6 melanoma cell lines tested--53% of 55 melanoma sera reactive to LiBr compared with 28% of 79 sera from patients with other tumours and 17% of 29 normal sera (P less than 0.05); 42% of 31 melanoma sera reactive to MM127 compared with 18% of 22 sera from other tumour patients (n.s.) and 5% of 20 normal sera (P less than 0.005). Melanoma patients tested against a number of melanoma cell lines by ADCC or antigen extracts by LAI generally reacted with one or more, but not all of them. Thus, incomplete cross-reactivity between different melanomas was observed. There was no correlation between results of the same patient in the 2 tests.

Diagnostic information derived from immunotyping 1000 patients with leukemia and lymphoma.

Immunotyping analysis has been performed on cells from 1000 patients with leukemia or lymphoma using 14 markers of cell lineage or differentiation stage over a 4 yr period. Results showed considerable heterogeneity of cell type among these groups of malignant diseases not readily apparent by morphology and histochemistry. Immunotyping contributed additional diagnostic information in 30% of patients and should be a routine procedure in 8 disease categories. These are: acute leukemia, cell type not determined; acute lymphoblastic leukemia; lymphocytosis of undetermined origin; chronic myeloid leukemia-terminal blast crisis; chronic lymphocytic leukemia; malignant lymphoma-leukemic phase; Sézary syndrome, mycosis fungoides and chronic T cell leukemia; malignant lymphoma and lymphadenopathy- ? lymphoma. Immunotyping provided information on cell lineage and differentiation stage of major leukemic cell populations. Abnormal monoclonal proliferations of B lymphocytes and the presence of primitive cells amongst normally mature tissue cells were identified. Disturbances in normal lymphoid and monocytic cell populations in blood, marrow or tissues could also be demonstrated. Many of the reagents used in this period are now replaced by monoclonal antibody reagents to human lineage and differentiation antigens. These are expected to increase diagnostic usefulness of these techniques.

The effect of hexadimethrine bromide (polybrene) on the infection of the primate retroviruses SSV 1/SSAV 1 and BaEV.

Polybrene was shown to enhance the adsorption of simian sarcoma virus-simian sarcoma associated virus complex (SSV-1/SSAV-1) and baboon endogenous virus (BaEV) onto cells in culture. A 16- to 18-fold increased adsorption of both viruses occurred at 8 micrograms/ml polybrene within one hour after infection. The polybrene mediated adsorption was found to be inhibited by the addition of tri-sodium citrate to the culture medium, suggesting the involvement of electrostatic forces. This contention was further supported by the demonstration of temperature independence of the polybrene mediated interaction.

Children's brain tumour cells produce RNA particles with incomplete retrovirus characteristics.

Short-term cultures of cells from human rain tumours have been reported to synthesise RNA particles of density in the range characteristic of C type RNA retroviruses, with associated DNA polymerase activity. Fresh tumour cells obtained from 6 children with astrocytoma and 7 children with medulloblastoma, together with one sample of normal brain tissue and normal leukocytes from brain tumour patients were assayed by several characteristics for the primate retrovirus. 1 or 6 (17%) astrocytomas and 4 of 7 (57%) medulloblastomas released RNA particles which banded in sucrose gradients at a density of 1.16-1.18 g/cm3 together with a short segment of DNA, which was eliminated by prior ribonuclease treatment and two proteins of 28k and 16k daltons. These findings were compatible with the presence of a primate retrovirus. Immune coprecipitation of 125I-labelled proteins from the 1.16-1.18 g/cm3 gradient region failed to show any reactivity with antisera to p28 core antigens or the p70 reverse transcriptase antigens of simian sarcoma virus, baboon endogenous virus or Mason Pfizer virus. Assays for DNA polymerase activity in culture supernatant fluid showed only a low amount of activity with template preferences not characteristic of the retroviral reverse transcriptase enzyme.

Use of the antibody-dependent cellular cytotoxicity test to detect antibodies in sera of breast cancer patients.

Sera from 114 breast cancer patients, 53 patients with other tumors, and 29 healthy controls were tested for antibodies reactive in antibody-dependent cellular cytotoxicity tests against a new breast cancer cell line (PMC9), two well-documented cell lines (MCF-7 and BT-20), and two melanoma cell lines. Of the breast cancer sera, 47% reacted with PMC9, whereas 30% reacted with the melanoma cell lines (P less than 0.05). Only 22% of sera from other cancer patients and 21% of sera from healthy controls reacted with PMC9 (P less than 0.05). The reactivity of sera from breast cancer patients was related to clinical stage of disease. Absorption studies on sera showing reactivity to both PMC9 and melanoma cells showed that the antimelanoma reactivity could be removed leaving anti-PMC9 reactivity intact. This study demonstrated the presence of breast cancer-associated antibody to PMC9 but not MCF-7 or BT-20 in the sera of breast cancer patients.

Levamisole in patients with recurrent herpes infection.

The effect of the immunomodulating drug levamisole was tested in 33 patients with frequently recurring attacks of herpes labialis or herpes genitalis. All patients had suffered monthly recurrent attacks for at least six months, but were otherwise healthy. Patients were randomly allocated to receive levamisole tablets, 2.5 mg/kg orally, on two consecutive days each week for 26 weeks, or placebo tablets taken for a similar time. The tablets were reversed for a second consecutive six-month period. Seven of 21 patients (33%) with recurrent herpes genitalis infection showed complete response and 10 (47%) showed a partial response while receiving levamisole. Three of 21 patients (14%) showed a partial response on placebo. Six of 12 patients (50%) with herpes labialis showed complete or partial responses, with three partial responses on placebo. Frequent minor drug side effects were seen, and therapy was ceased in one patient. No episodes of leucopenia or agranulocytosis were encountered. Levamisole produces a significantly better reduction in frequency, duration and severity of herpes attacks than placebo, particularly after the initial eight weeks of administration.

Classification of childhood acute lymphocytic leukaemia using rabbit antisera to leukaemia cells and lymphoblastoid cell lines.

Leukaemic cells from seventeen untreated acute lymphocytic leukaemia (A.L.L.) patients have been typed at presentation with heteroantisera prepared in rabbits by complement mediated cytotoxicity. Reactivity with antisera has suggested a preliminary grouping of patients, in this study, into Null, pre-T (post-thymic T-cell precursor) and T-cell subtypes. The leukaemic cells have also been classified with the established markers, E-rosette receptor, surface immunoglobulin and C3 receptor as well as total white cell count at presentation. Anti NALM-1 (Null-lymphoblastoid cell line) serum reacted with cells from all childhood A.L.L. patients tested but could be made specific for cALL antigen of the common Null form of A.L.L. by further absorption or dilution. Antisera to membrane fractions from cells of high white cell count Null-A.L.L. patients reacted with cells of these patients as well as T-A.L.L. patients. Anti MOLT-4 (adult T-A.L.L. derived lymphoblastoid cell line) serum reacted only with cells of T-A.L.L. patients.