Integration of human papillomavirus type-16 and type-18 is a very early event in cervical carcinogenesis.

AIM: Human papillomavirus (HPV) integration is a critical event in cervical carcinogenesis. The aim of this study was to explore the physical status of HPV-16 and HPV-18 during the progression of cervical precancerous lesions. METHODS: A series of 101 HPV-16 or HPV-18 positive cervical neoplasms (32 cervical intraepithelial neoplasia (CIN) cases and 69 cervical carcinoma (CC) cases) were evaluated. The physical status of both types of HPV was assessed from paraffin-embedded formaldehyde-fixed surgical specimens by real-time PCR. RESULTS: For HPV-16, integrated DNA was observed in 5 (83.3%) of 6 CIN I cases, 10 (90.9%) of 11 CIN II/III cases, 29 (82.9%) of 35 FIGO (International Federation of Gynecology and Obstetrics) stage I CC cases and 16 (94.1%) of 17 FIGO stages II approximately IV CC cases. For HPV-18, integrated DNA was observed in 3 (50%) of 6 CIN I cases, 5 (55.6%) of 9 CIN II/III cases, 9 (64.3%) of 14 FIGO stage I CC cases, and 1 (33.3%) of 3 FIGO stages II approximately IV CC cases. The mixed form of HPV DNA was the most prevalent physical state in HPV-16. There was no significant difference between the physical state of HPV-16 and HPV-18 DNA with regard to the various grades of cervical lesions. CONCLUSIONS: These data imply that integration of HPV-16 and HPV-18 DNA into the host genome occurs in the very early stage of cervical neoplastic progression. These early events may play an initiating role in the malignant transformation of HPV-16- and HPV-18-related low-grade lesions into high-grade dysplasia and invasive carcinoma.

p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome.

OBJECTIVES: Abnormal expression of the p53 and p21(waf1/cip1) tumor suppressor genes has been observed in a variety of human tumors, but little is known about its expression during cervical tumorigenesis. To identify the potential implications of both genes in the development of cervical carcinoma and explore the clinical importance of changes in gene expression, we assessed the levels of both proteins in precancerous lesions and carcinomas of the cervix. METHODS: In our study, 10 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of p53 and p21 was studied by immunohistochemistry using monoclonal antibodies specific for these proteins. RESULTS: p21 was expressed in all samples of normal epithelium, LSIL, and HSIL, and the mean values of expression were 50.3, 42.5, and 44.5%, respectively. Conversely, the expression of p21 was significantly reduced in microinvasive (30.7%) and invasive carcinomas (9.9%). p53 nuclear staining was not detected in normal epithelium samples or LSILs, while 4 (11.4%) of 35 HSILs, 1 (8.3%) of 12 microinvasive carcinomas, and 38 (36.9%) of 103 invasive carcinomas were positive for p53. Compared with the results of the control group, precancerous lesions, and microinvasive carcinoma, the mean value of p53 expression (4.8%) in invasive carcinoma was significantly higher. Furthermore, p53 overexpression was significantly associated with advanced stage of the tumor (P < 0.001) [16/67 (23.9%) stage I, 15/28 (53.6%) stage II, and 7/8 (87.5%) stage III/IV]. In univariate analysis, p53 overexpression was a significant predictor of poor survival, whereas it had no independent influence on overall survival using the Cox regression method. Our data also revealed that no association between p53 immunostaining and p21 expression was found. CONCLUSIONS: The trend of reduced p21 expression in microinvasive and invasive carcinomas suggests that p21 may play a tumor-suppressor function in neoplastic transformation in cervical epithelium and inactivation of p21 may be an early event in cervical carcinogenesis. Our results indicated that p53 overexpression was a significant predictor of poor disease outcome in univariate analysis. Moreover, significantly increased expression of p53 in advanced-stage cervical carcinoma implies that inactivation of p53 is associated with tumor progression. Finally, this study further supports the notion that induction of p21 expression can be regulated in a p53-independent manner.

Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain.

The present studies were undertaken to characterize the regional and temporal patterns of neurotrophin messenger RNA and protein levels for beta-nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the developing CNS. We have examined the levels of these neurotrophin messenger RNAs with ribonuclease protection assays and corresponding protein levels with enzyme-linked immunosorbent assays in the developing Long-Evans rat hippocampus, neocortex and cerebellum on postnatal days 1, 7, 14, 21, and 92. In addition, immunohistochemistry was used to localize the neurotrophins in these developing brain regions. Results indicated that in neocortex and hippocampus, messenger RNA for both nerve growth factor and brain-derived neurotrophic factor increased in an age-dependent manner, reaching a plateau by postnatal day 14. In the neocortex, nerve growth factor and brain-derived neurotrophic factor protein levels both peaked at postnatal day 14. In hippocampus, nerve growth factor protein peaked at postnatal day 7 while brain-derived neurotrophic factor peaked at postnatal day 14. In cerebellum, nerve growth factor messenger RNA levels were flat, while nerve growth factor protein peaked at postnatal day 7. Brain-derived neurotrophic factor messenger RNA increased in an age-dependent manner while the pattern for its protein levels was mixed. Neurotrophin-3 messeger RNA levels increased in an age-dependent manner in hippocampus, peaked at postnatal day14 in cerebellum, and no changes occurred in neocortex. Neurotrophin-3 protein was at its peak at postnatal day 1 and thereafter decreased at other postnatal days in all three brain regions. Results of neurotrophin immunohistochemistry often paralleled and complemented enzyme-linked immunosorbent assay data, demonstrating specific cell groups containing neurotrophin proteins in these regions. Within each region, patterns with regard to messenger RNA and respective protein levels for each neurotrophin were unique. No consistent relationship between patterns of neurotrophin messenger RNAs and their cognate proteins was observed between regions. The different regional patterns for neurotrophin messengerRNA and protein levels in each brain region indicate that messenger RNA studies of neurotrophin messenger RNA must be augmented by protein determination to fully characterize spatial and temporal neurotrophin distribution.

Reducing lead exposure by surveillance system: the Taiwan experience.

To evaluate the performance of a lead-surveillance program in reducing blood lead levels of workers in Taiwan, the authors conducted prospective and cross-sectional studies. A total of 6 905 workers, whose job titles indicated a direct exposure to lead in 1995, were included in this surveillance system. In this study, the authors compared the mean blood lead levels in 1994 (i.e., year of onset of surveillance) with that in 1995 in workers of major industries. Lead-exposed workers had a statistically significant decrease (i.e., average of 1.8 microg/dl) in blood lead levels during this 1-y period. The decrease was particularly obvious in individuals who worked in chemical products manufacturing, ship building/repairing, and plastic products manufacturing. The significant decreases in blood lead levels in these workers indicated that this surveillance system was effective. Surveillance, combined with control measures, might be an important means by which occupational lead exposure can be reduced.

Surveillance of noise-induced hearing loss in Taiwan, ROC: a report of the PRESS-NHL results.

BACKGROUND: To understand the extent of noise-induced hearing loss (NIHL) among noise-exposed workers, an ongoing public health surveillance system (Program to Reduce Exposure by Surveillance System or PRESS-NIHL) was established in Taiwan in 1995 to monitor the prevalence of NIHL. METHODS: A total of 9,535 noise-exposed (> 85 dBA) workers were recruited into PRESS-NIHL from January to June 1995. Each received a periodic annual audiometric examination at 1 of 73 well-qualified audiometric examination rooms in accredited hospitals. Among those examined, 9,463 audiograms were acceptable for evaluation to determine the severity of NIHL at 4K Hz. RESULTS: The mean hearing threshold at 4K Hz was 36.8 dB among male workers and 29.7 dB among female workers. The mean hearing loss at 4K Hz of male workers was higher than that of female workers. Among both men and women, hearing ability was found to decrease with increasing age. A total of 3,216 (34.0%) workers were found to have NIHL, with a hearing threshold higher than 40 dB (NIHL) in either one or both ears. Among these workers, 1,886 (19.9%) had mild NIHL (hearing threshold between 40 and 55 dB) and 1,330 (14.1%) had severe NIHL (hearing threshold above 55 dB) in either one or both ears. The proportion of severe NIHL was higher in certain industries, including construction (38.6%), ship building/repairing (19.2%), and weapon manufacturing (13.6%). CONCLUSION: This surveillance system for NIHL is on of the first surveillance systems in the world established to monitor and control NIHL in the setting of industrial hygiene and occupational disease prevention. Our finding of a high prevalence of NIHL in certain industries will trigger immediate actions to control noise hazard, which in turn will provide better protection for noise-exposed workers.

Whitefly (Hemiptera: Aleyrodidae) binding site for imidacloprid and related insecticides: a putative nicotinic acetylcholine receptor.

Imidacloprid is used extensively to control sweetpotato whiteflies, Bemisia argentifolii Bellows & Perring [also known as B. tabaci (Gennadius) biotype B]. As a radioligand, [3H]imidacloprid binds rapidly to a single class of high-affinity sites in membrane preparations from whole adult whiteflies with an apparent dissociation constant of 2 nM and maximal binding capacity of 101 fmol/mg protein. Three related compounds (the nitromethylene analog of imidacloprid, acetamiprid, and nitenpyram) inhibit [3H]imidacloprid binding by 50% at 0.40, 2.9, and 57 nM, respectively. The pharmacological profile of the binding site (examined with imidacloprid and the analogs listed above, and nicotine, alpha-bungarotoxin, carbachol, acetylcholine [with paraoxon], and atropine) is consistent with that anticipated for a nicotinic acetylcholine receptor and correlates well with binding results for house fly, Musca domestica L., head membranes under the same conditions. Thus, [3H]imidacloprid is a suitable radioligand to investigate the putative nicotinic acetylcholine receptor of Bemisia and the possible modifications of this target site associated with selection of resistant strains.

Epidemiologic study of occupational injuries among foreign and native workers in Taiwan.

This study was designed to compare the risk of occupational injuries in foreign workers compared to native workers in Taiwan. The cohort of foreign workers under study was constructed by records of legally registered workers migrated from foreign countries to Taiwan from July 1, 1991 to December 31, 1993. The native Taiwanese workers for comparison were labor-insured workers working in the same industries as foreign workers in 1992. The number of occupational injuries in the first year of employment were obtained by matching the cohort of foreign workers with the labor insurance payment records by name, birth date and passport number. The 1-year incidence rate of occupational injuries in the first year of employment was calculated and a standardized morbidity ratio (SMR) was used for comparison with adjustment for age distribution and to accommodate the small sample size of foreign workers. The risk to occupational injuries among total (SMR = 0.86) and male (SMR = 0.58) foreign workers was not higher; indeed, it was even lower, than that among native workers in Taiwan. However, the risk to female migrant workers, especially in the construction industry, was significantly higher than that of female Taiwanese workers (SMR = 1.60). Stratified by industry, the incidence was high in the fabricated metal products manufacturing industry and in machinery and equipment manufacturing industry for male foreign workers, while a high incidence for the female foreign workers occurred in construction industry and rubber products manufacturing industry. The risk of occupational injuries was greater for foreign workers who had been in Taiwan for only a short time. Most of the injuries occurred within the first 6 months of employment. Eighty-four out of the 394 occupational injuries among foreign workers resulted in disabilities. None of the accidents was fatal, but most of the disabilities were severe. The most common disabling injuries were cut or crushed fingers. The finding of a similar distribution of occupational injuries among foreign and native workers indicates that control measures are needed to reduce occupational injuries for all foreign and native workers in Taiwan.

The epidemiology and surveillance of blood lead in Taiwan (ROC): a report on the PRESS-BLL project.

To monitor the lead hazards in industries and to investigate the prevalence of elevated blood lead levels (BLLs) in lead-exposed workers, a lead surveillance system (PRESS-BLLs) has been established and operated in Taiwan, Republic of China, since July 1993. A cohort of lead-exposed workers who received a periodic annual health examination at 55 accredited hospital laboratories was constructed. A total of 9807 separate BLL measurements were reported to the system in 1994. The mean BLL was 15.8 micrograms/dl in male workers and 11.6 micrograms/dl in female workers. The mean BLL of lead-exposed workers was significantly (P < 0.05, z-test) higher than that of the general Taiwanese population (8.6 micrograms/dl for males and 6.7 micrograms/dl for females). In addition, the BLLs of 983 (10.0%) workers exceeded the regulatory action level (40 micrograms/dl for males; 30 micrograms/dl for females). The workplaces and homes of 57% of the workers with elevated BLLs were thoroughly investigated to determine the sources of lead contamination. These actions identified the causes of elevated BLLs and set up strategies to reduce workers' lead exposure. The establishment of this occupational lead surveillance system represents a method for monitoring of lead hazards from occupational and environmental settings to prevent lead poisoning. The information acquired from the system can help in the setting up of a priority of prevention and the development of control measures. It is also useful for further monitoring of changes in the BLLs of the lead-exposed cohort. The Health Department of Taiwan can use this information to evaluate the effectiveness of current industrial hygiene practice. Subjects with elevated BLLs have been medically treated and placed on long-term follow-up for sequelae.

Establishment of a work-related diseases surveillance system in Taiwan, Republic of China.

BACKGROUND: The occurrence of occupational illness and injury has been seriously underestimated in Taiwan, which subsequently contributes to difficulties in performing effective control of occupational hazards and implementing intervention programs for protecting workers. METHODS: Based on the successful experience of the nationwide blood lead level surveillance program, the Department of Health, the Executive Yuan, Taiwan, Republic of China, has established a work-related diseases surveillance system. This government-administered system requests practicing physicians to report the suspected cases suffering from six categories of work-related disorders. RESULTS: An occupational illness and injury surveillance program in Taiwan has been in operation since June of 1995. CONCLUSION: Background information of work-related diseases obtained from this surveillance system will be useful for providing better management of available resources for occupational medicine, for preventing hazards, and for enforcing occupational diseases prevention programs. Our experience in establishing this surveillance system will be used in other countries and settings.

[The clinical significance of nuclear DNA content measurements in pancreatic neoplasms and their Kaplan-Meier survival analysis].

Between 1979 and 1991, 48 cases of pancreatic paraffin-embedded specimens, ie 32 carcinomas and 16 islet cell tumors, confirmed by operative and pathological examination, were studied by flow cytometric nuclear DNA content measurements. 10 specimens taken from the normal pancreatic tissue nearby the tumor transection margin and another 8 specimens in pancreatitis were compared as controls. The results demonstrated that the aneuploid rate and DNA index in pancreatic carcinoma was obviously higher than that of non-pancreatic tumor (P < 0.01). In the field of pancreatic carcinoma, the S-phase fraction was much higher in aneuploid specimens (P < 0.05). Then the nuclear DNA content was a relatively independent factor to evaluate the cancerous biological behavior. The surgical resectability of pancreatic tumors with diploid DNA was significantly higher than aneuploid ones (P < 0.05), and the later carried a shorter survival time proved by Kaplan-Meier survival analysis (P < 0.05). Finally, the clinical significance of DNA content measurements in islet cell tumor was also discussed.

Metabolic changes in the rat brain after acute and chronic ethanol intoxication: a 31P NMR spectroscopy study.

In this work, 31P phosphorus NMR (31P NMR) studies of the brain have been conducted in rats acutely and chronically intoxicated with ethanol. In both groups, changes in levels of high-energy phosphates were observed: increase of phosphocreatinine (PCr)/beta AaTP and PCr/inorganic phosphate (Pi) in acute and long-term ethanol exposure, and decrease of Pi/beta ATP after acute ethanol administration. These changes in high-energy phosphates, indicative of a reduction of adenosine triphosphate (ATP) and PCr consumption (PCr+ ADP+ H+ ATP+ Cr; ATP ADP+ Pi), suggest a reduction of cerebral metabolism both in acute and chronic ethanol exposure. In addition, in the group of rats chronically intoxicated with ethanol, there were variations in phosphodiester peak intensities (decrease of phosphomonoester (PME)/phosphodiester (PDE), increase of PDE/beta ATP), suggesting increased breakdown of membrane phospholipids. These changes could provide a metabolic explanation for the development of cerebral atrophy in chronic alcoholism.

Gestational and congenital syphilis in Hualien.

From September 1987 to April 1991, 19 pregnant women (0.97%) with syphilis were detected out of 1,955 pregnant women who received prenatal serologic screening at the Buddhist Tz'u-Chi General Hospital. The ages ranged from 17 to 34 years (average, 26). Three cases had recurrent gestational syphilis. The time of diagnosis was: the third trimester, 11 cases; the second trimester, six cases; and the first trimester, two cases. The reasons for late (third trimester) diagnosis were: delay of prenatal care, four cases; failure to screen syphilis in the pregnancy, four cases; and negative first test and late infection, three cases. Late diagnosis and treatment often resulted in poor fetal outcome: syphilitic stillbirth, two cases; probable and possible congenital syphilis, seven cases; and normal infant, two cases. Patients (delivered, five; undelivered, two; abortion, one) who had been diagnosed before the third trimester had a better fetal outcome: possible congenital syphilis, one case; and normal infant, four cases. The perinatal mortality and morbidity were significantly higher in the late diagnosis group (9/11) than in the early diagnosis group (1/5). Pregnant women should be screened in early pregnancy by a serologic test for syphilis. In areas of high prevalence, or in patients at high risk, screening should be repeated in the third trimester and again at delivery.