• Tuberculosis and Respiratory Diseases
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• v.41 no.4
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• pp.339-353
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• 1994

Background : The p53 gene codes for a DNA-binding nuclear phosphoprotein that appears to inhibit the progression of cells from the G1 to the S phase of the cell cycle. Mutations of the p53 gene are common in a wide variety of human cancers, including lung cancer. In lung cancers, point mutations of the p53 gene have been found in all histological types including approximately 45% of resected NSCLC and even more frequently in SCLC specimens. Mutant forms of the p53 protein have transforming activity and interfere with the cell-cycle regulatory function of the wild-type protein. The majority of p53 gene mutations produce proteins with altered conformation and prolonged half life; these mutant proteins accumulate in the cell nucleus and can be detected by immunohistochemical staining. But protein overexpression has been reported in the absence of mutation. p53 protein overexpression or gene mutation is reported poor prognostic factor in breast cancer, but in lung cancer, its prognostic significance is controversial. Method : We investigated the p53 abnormalities by nucleotide sequencing, polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP), and immunohistochemical staining. We correlated these results with each other and survival in 75 patients with NSCLC resected with curative intent. Overexpression of the p53 protein was studied immunohistochemically in archival paraffin- embedded tumor samples using the D07(Novocastra, U.K.) antibody. Overexpression of p53 protein was defined by the nuclear staining of greater than 25% immunopositive cells in tumors. Detection of p53 gene mutation was done by PCR-SSCP and nucleotide sequencing from the exon 5-9 of p53 gene. Result: 1) Of the 75 patients, 36%(27/75) showed p53 overexpression by immunohistochemical stain. There was no survival difference between positive and negative p53 immunostaining(overall median survival of 26 months, disease free median survival of 13 months in both groups). 2) By PCR-SSCP, 27.6%(16/58) of the patients showed mobility shift. There was no significant difference in survival according to mobility shift(overall median survival of 27 in patients without mobility shift vs 20 months in patients with mobility shift, disease free median survival of 8 months vs 10 months respectively). 3) Nucleotide sequence was analysed from 29 patients, and 34.5%(10/29) had mutant p53 sequence. Patients with the presence of gene mutations showed tendency to shortened survival compared with the patients with no mutation(overall median survival of 22 vs 27 months, disease free median survival of 10 vs 20 months), but there was no statistical significance. 4) The sensitivity and specificity of immunostain based on PCR-SSCP was 67.0%, 74.0%, and that of the PCR-SSCP based on the nucleotide sequencing was 91.8%, 96.2% respectively. The concordance rate between the immunostain and PCR-SSCP was 62.5%, and the rate between the PCR-SSCP and nucleotide sequencing was 95.3%. Conclusion : In terms of detection of p53 gene mutation, PCR-SSCP was superior to immunostaining. p53 gene abnormalities either overexpression or mutation were not a significant prognostic factor in NSCLC patients resected with curative intent. However, patients with the mutated p53 gene showed the trends of early relapse.

• Tuberculosis and Respiratory Diseases
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• v.45 no.6
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• pp.1265-1276
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• 1998

Background : Nitric oxide(NO) is an endogenously produced free radical that plays an important role in regulating vascular tone, inhibition of platelet aggregation and white blood cell adhesion to endothelial cells, and host defense against infection. The highly reactive nature of NO with oxygen radicals suggests that it may either promote or reduce oxidant-induced cell injury in several biological pathways. Oxidant injury and interactions between pulmonary vascular endothelium and leukocytes are important in the pathogenesis of acute lung injury, including acute respiratory distress syndrome(ARDS). In ARDS, therapeutic administration of NO is a clinical condition providing exogenous NO in oxidant-induced endothelial injury. The role of exogenous NO from NO donor or the suppression of endogenous NO production was evaluated in oxidant-induced endothelial injury. Method : The oxidant injury in cultured rat lung microvascular endothelial cells(RLMVC) was induced by hydrogen peroxide generated from glucose oxidase(GO). Cell injury was evaluated by $^{51}$chromium($^{51}Cr$) release technique. NO donor, such as S-nitroso-N-acetylpenicillamine(SNAP) or sodium nitroprusside(SNP), was added to the endothelial cells as a source of exogenous NO. Endogenous production of NO was suppressed with N-monomethyl-L-arginine(L-NMMA) which is an NO synthase inhibitor. L-NMMA was also used in increased endogenous NO production induced by combined stimulation with interferon-$\gamma$(INF-$\gamma$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), and lipopolysaccharide(LPS). NO generation from NO donor or from the endothelial cells was evaluated by measuring nitrite concentration. Result : $^{51}Cr$ release was $8.7{\pm}0.5%$ in GO 5 mU/ml, $14.4{\pm}2.9%$ in GO 10 mU/ml, $32.3{\pm}2.9%$ in GO 15 mU/ml, $55.5{\pm}0.3%$ in GO 20 mU/ml and $67.8{\pm}0.9%$ in GO 30 mU/ml ; it was significantly increased in GO 15 mU/ml or higher concentrations when compared with $9.6{\pm}0.7%$ in control(p < 0.05; n=6). L-NMMA(0.5 mM) did not affect the $^{51}Cr$ release by GO. Nitrite concentration was increased to $3.9{\pm}0.3\;{\mu}M$ in culture media of RLMVC treated with INF-$\gamma$ (500 U/ml), TNF-$\alpha$(150 U/ml) and LPS($1\;{\mu}g/ml$) for 24 hours ; it was significantly suppressed by the addition of L-NMMA. The presence of L-NMMA did not affect $^{51}Cr$ release induced by GO in RLMVC pretreated with INF-$\gamma$, TNF-$\alpha$ and LPS. The increase of $^{51}Cr$ release with GO(20 mU/ml) was prevented completely by adding 100 ${\mu}M$ SNAP. But the add of SNP, potassium ferrocyanate or potassium ferricyanate did not protect the oxidant injury. Nitrite accumulation was $23{\pm}1.0\;{\mu}M$ from 100 ${\mu}M$ SNAP at 4 hours in phenol red free Hanks' balanced salt solution. But nitrite was not detectable from SNP upto 1 mM The presence of SNAP did not affect the time dependent generation of hydrogen peroxide by GO in phenol red free Hanks' balanced salt solution. Conclusion : Hydrogen peroxide generated by GO causes oxidant injury in RLMVC. Exogenous NO from NO donor prevents oxidant injury, and the protective effect may be related to the ability to release NO. These results suggest that the exogenous NO may be protective on oxidant injury to the endothelium.

• Journal of Preventive Medicine and Public Health
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• v.20 no.1 s.21
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• pp.165-203
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• 1987

This project was a service-cum-research effort with a quasi-experimental study design to examine the health benefits of an integrated Family Planning (FP)/Maternal & Child health (MCH) Service approach that provides crucial factors missing in the present on-going programs. The specific objectives were: 1) To test the effectiveness of trained nurse/midwives (MW) assigned as change agents in the Health Sub-Center (HSC) to bring about the changes in the eight FP/MCH indicators, namely; (i)FP/MCH contacts between field workers and their clients (ii) the use of effective FP methods, (iii) the inter-birth interval and/or open interval, (iv) prenatal care by medically qualified personnel, (v) medically supervised deliveries, (vi) the rate of induced abortion, (vii) maternal and infant morbidity, and (viii) preinatal & infant mortality. 2) To measure the integrative linkage (contacts) between MW & HSC workers and between HSC and clients. 3) To examine the organizational or administrative factors influencing integrative linkage between health workers. Study design; The above objectives called for quasi-experimental design setting up a study and control area with and without a midwife. An active intervention program (FP/MCH minimum 'package' program) was conducted for a 2 year period from June 1982-July 1984 in Seosan County and 'before and after' surveys were conducted to measure the change. Service input; This study was undertaken by the Soonchunhyang University in collaboration with WHO. After a baseline survery in 1981, trained nurses/midwives were introduced into two health sub-centers in a rural setting (Seosan county) for a 2 year period from 1982 to 1984. A major service input was the establishment of midwifery services in the existing health delivery system with emphasis on nurse/midwife's role as the link between health workers (nurse aids) and village health workers, and the referral of risk patients to the private physician (OBGY specialist). An evaluation survey was made in August 1984 to assess the effectiveness of this alternative integrated approach in the study areas in comparison with the control area which had normal government services. Method of evaluation; a. In this study, the primary objective was first to examine to what extent the FP/MCH package program brought about changes in the pre-determined eight indicators (outcome and impact measures) and the following relationship was first analyzed; b. Nevertheless, this project did not automatically accept the assumption that if two or more activities were integrated, the results would automatically be better than a non-integrated or categorical program. There is a need to assess the 'integration process' itself within the package program. The process of integration was measured in terms of interactive linkages, or the quantity & quality of contacts between workers & clients and among workers. Intergrative linkages were hypothesized to be influenced by organizational factors at the HSC clinic level including HSC goals, sltrurture, authority, leadership style, resources, and personal characteristics of HSC staff. The extent or degree of integration, as measured by the intensity of integrative linkages, was in turn presumed to influence programme performance. Thus as indicated diagrammatically below, organizational factors constituted the independent variables, integration as the intervening variable and programme performance with respect to family planning and health services as the dependent variable: Concerning organizational factors, however, due to the limited number of HSCs (2 in the study area and 3 in the control area), they were studied by participatory observation of an anthropologist who was independent of the project. In this observation, we examined whether the assumed integration process actually occurred or not. If not, what were the constraints in producing an effective integration process. Summary of Findings; A) Program effects and impact 1. Effects on FP use: During this 2 year action period, FP acceptance increased from 58% in 1981 to 78% in 1984 in both the study and control areas. This increase in both areas was mainly due to the new family planning campaign driven by the Government for the same study period. Therefore, there was no increment of FP acceptance rate due to additional input of MW to the on-going FP program. But in the study area, quality aspects of FP were somewhat improved, having a better continuation rate of IUDs & pills and more use of effective Contraceptive methods in comparison with the control area. 2. Effects of use of MCH services: Between the study and control areas, however, there was a significant difference in maternal and child health care. For example, the coverage of prenatal care was increased from 53% for 1981 birth cohort to 75% for 1984 birth cohort in the study area. In the control area, the same increased from 41% (1981) to 65% (1984). It is noteworthy that almost two thirds of the recent birth cohort received prenatal care even in the control area, indicating that there is a growing demand of MCH care as the size of family norm becomes smaller 3. There has been a substantive increase in delivery care by medical professions in the study area, with an annual increase rate of 10% due to midwives input in the study areas. The project had about two times greater effect on postnatal care (68% vs. 33%) at delivery care(45.2% vs. 26.1%). 4. The study area had better reproductive efficiency (wanted pregancies with FP practice & healthy live births survived by one year old) than the control area, especially among women under 30 (14.1% vs. 9.6%). The proportion of women who preferred the 1st trimester for their first prenatal care rose significantly in the study area as compared to the control area (24% vs 13%). B) Effects on Interactive Linkage 1. This project made a contribution in making several useful steps in the direction of service integration, namely; i) The health workers have become familiar with procedures on how to work together with each other (especially with a midwife) in carrying out their work in FP/MCH and, ii) The health workers have gotten a feeling of the usefulness of family health records (statistical integration) in identifying targets in their own work and their usefulness in caring for family health. 2. On the other hand, because of a lack of required organizational factors, complete linkage was not obtained as the project intended. i) In regards to the government health worker's activities in terms of home visiting there was not much difference between the study & control areas though the MW did more home visiting than Government health workers. ii) In assessing the service performance of MW & health workers, the midwives balanced their workload between 40% FP, 40% MCH & 20% other activities (mainly immunization). However, $85{\sim}90%$ of the services provided by the health workers were other than FP/MCH, mainly for immunizations such as the encephalitis campaign. In the control area, a similar pattern was observed. Over 75% of their service was other than FP/MCH. Therefore, the pattern shows the health workers are a long way from becoming multipurpose workers even though the government is pushing in this direction. 3. Villagers were much more likely to visit the health sub-center clinic in the study area than in the control area (58% vs.31%) and for more combined care (45% vs.23%). C) Organization factors (admistrative integrative issues) 1. When MW (new workers with higher qualification) were introduced to HSC, it was noted that there were conflicts between the existing HSC workers (Nurse aids with less qualification than MW) and the MW for the beginning period of the project. The cause of the conflict was studied by an anthropologist and it was pointed out that these functional integration problems stemmed from the structural inadequacies of the health subcenter organization as indicated below; i) There is still no general consensus about the objectives and goals of the project between the project staff and the existing health workers. ii) There is no formal linkage between the responsibility of each member's job in the health sub-center. iii) There is still little chance for midwives to play a catalytic role or to establish communicative networks between workers in order to link various knowledge and skills to provide better FP/MCH services in the health sub-center. 2. Based on the above findings the project recommended to the County Chief (who has power to control the administrative staff and the technical staff in his county) the following ; i) In order to solve the conflicts between the individual roles and functions in performing health care activities, there must be goals agreed upon by both. ii) The health sub·center must function as an autonomous organization to undertake the integration health project. In order to do that, it is necessary to support administrative considerations, and to establish a communication system for supervision and to control of the health sub-centers. iii) The administrative organization, tentatively, must be organized to bind the health worker's midwive's and director's jobs by an organic relationship in order to achieve the integrative system under the leadership of health sub-center director. After submitting this observation report, there has been better understanding from frequent meetings & communication between HW/MW in FP/MCH work as the program developed. Lessons learned from the Seosan Project (on issues of FP/MCH integration in Korea); 1) A majority or about 80% of the couples are now practicing FP. As indicated by the study, there is a growing demand from clients for the health system to provide more MCH services than FP in order to maintain the achieved small size of family through FP practice. It is fortunate to see that the government is now formulating a MCH policy for the year 2,000 and revising MCH laws and regulations to emphasize more MCH care for achieving a small size family through family planning practice. 2) Goal consensus in FP/MCH shouBd be made among the health workers It administrators, especially to emphasize the need of care of 'wanted' child. But there is a long way to go to realize the 'real' integration of FP into MCH in Korea, unless there is a structural integration FP/MCH because a categorical FP is still first priority to reduce the rate of population growth for economic reasons but not yet for health/welfare reasons in practice. 3) There should be more financial allocation: (i) a midwife should be made available to help to promote the MCH program and coordinate services, (in) there should be a health sub·center director who can provide leadership training for managing the integrated program. There is a need for 'organizational support', if the decision of integration is made to obtain benefit from both FP & MCH. In other words, costs should be paid equally to both FP/MCH. The integration slogan itself, without the commitment of paying such costs, is powerless to advocate it. 4) Need of management training for middle level health personnel is more acute as the Government has already constructed 90 MCH centers attached to the County Health Center but without adequate manpower, facilities, and guidelines for integrating the work of both FP and MCH. 5) The local government still considers these MCH centers only as delivery centers to take care only of those visiting maternity cases. The MCH center should be a center for the managment of all pregnancies occurring in the community and the promotion of FP with a systematic and effective linkage of resources available in the county such as i.e. Village Health Worker, Community Health Practitioner, Health Sub-center Physicians & Health workers, Doctors and Midwives in MCH center, OBGY Specialists in clinics & hospitals as practiced by the Seosan project at primary health care level.