FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway

Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair. This pathway is inactivated in FA, a devastating genetic disease, which leads to hematologic defects and cancer in patients. Here we report the isolation and characterization of a novel 20-kDa FANCA-associated protein (FAAP20). We show that FAAP20 is an integral component of the FA nuclear core complex. We identify a region on FANCA that physically interacts with FAAP20, and show that FANCA regulates stability of this protein. FAAP20 contains a conserved ubiquitin-binding zinc-finger domain (UBZ), and binds K-63-linked ubiquitin chains in vitro. The FAAP20-UBZ domain is not required for interaction with FANCA, but is required for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the FA pathway. These findings reveal critical roles for FAAP20 in the FA-BRCA pathway of DNA damage repair and genome maintenance.     

Study of "spontaneous" abortion in Thailand.

This analysis includes data on 3 530 patients with septic or incomplete, inevitable or threatened abortions who were treated at the Siriraj Hospital in Bangkok between January 1972 and December 1973. Data on the patients' socio-demographic characteristics; their reproductive, abortion, and medical histories; their pre- and postabortion contraceptive acceptance; and a clinical profile of their abortion treatment, including procedure time, length of hospitalization, and immediate and delayed postoperative complications are analyzed.     

Laparoscopic electrocoagulation and tubal ring techniques for sterilization: a comparative study.

From August 1975 through May 1976, a comparative study was made of the effects of sterilization by standard electrocoagulation and tubal ring application techniques. The two techniques were randomly assigned to 300 patients. Results show that standard electrocoagulation and tubal ring procedures can easily and safely be performed on an outpatient basis, using local anesthetics and analgesics. Rates of surgical complications for both techniques were clinically acceptable, although tubal risk patients had a higher rate. Pain during the procedure and during the immediate recovery period was more severe for tubal ring patients. Despite the higher incidence of surgical complications and pain associated with the ring, many physicians prefer this method of sterilization because it eliminates the possibility, inherent in electrocoagulation, of inadvertent serious electrical burns.     

Human papillomaviruses and cervical cancer in Bangkok. II. Risk factors for in situ and invasive squamous cell cervical carcinomas

To identify risk factors for progression of intraepithelial cervical lesions, 190 women with invasive cervical cancer were compared with 75 women with in situ disease diagnosed in Bangkok, Thailand, between September 1991 and September 1993. Polymerase chain reaction-based assays for type-specific human papillomavirus (HPV) DNA in cervical scrapings revealed oncogenic types in 79% of invasive and 57% of intraepithelial tumors. Types 16 and 18, but not types 31/33/35/39, were more common in invasive than intraepithelial tumors, and untyped HPV DNA was found more commonly in the in situ lesions, suggesting that in situ disease is four times more likely to become invasive if due to type 16 or 18 than to other causes, and that tumors with only untyped HPV are not at increased risk of progression. After controlling for HPV type, the risk of developing invasive diseases, compared with the risk of developing intraepithelial lesions, was not related to any of a large number of sexual and hormonal factors considered or to smoking, suggesting that any cofactors these variables represent act before the development of in situ carcinoma. Two indices of socioeconomic status were associated with a reduced risk of only invasive disease, suggesting the existence of unknown protective factors that operate after intraepithelial lesions develop.     

Alcohol,tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies,including 58,515 women with breast cancer and 95,067 women without the disease

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P<0.00001) for an intake of 35-44 g per day alcohol, and 1.46 (1.33-1.61, P<0.00001) for >/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98-1.07, and for current smokers=0.99, 0.92-1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.     

Dietary risk factors for invasive and in-situ cervical carcinomas in Bangkok,Thailand

OBJECTIVE: Although human papillomavirus (HPV) may be a necessary cause of cervical cancer, most women with HPV infections do not develop this disease. This study was conducted to evaluate the possible effects of specific dietary factors on cervical carcinogenesis.METHODS: Fifty hospitalized in-situ cases and 125 controls were identified from family planning or gynecologic clinics associated with Siriraj hospital in Bangkok, Thailand, and 134 hospitalized invasive cases and 384 hospitalized controls from the public wards of Siriraj Hospital were administered a food-frequency questionnaire and tested for HPV DNA in exfoliated cervical cells. Odds ratios in relation to intake of foods high in vitamin C, folate, vitamin E, vitamin A, -carotene, retinol, and cruciferous vegetables were estimated using logistic regression in case–control comparisons and in case–case comparisons adjusted for HPV status.RESULTS: High intake of foods rich in vitamin A, and particularly high-retinol foods, were associated with a reduced risk of in-situ disease and less strongly also with a reduced risk of invasive as compared to in-situ disease. No association was found between intake of cruciferous vegetables, foods high in vitamin C, folate, vitamin E, and -carotene and risk of either in-situ or invasive cervical cancer.CONCLUSIONS: Increasing intake of foods rich in total vitamin A, and particularly high-retinol foods, may reduce risk of in-situ cervical cancer, and at the highest level of intake may inhibit progression to invasion. If others confirm these results they suggest means of reducing the risk of cervical cancer that are amenable to public health action.     

A comparison of laparoscopy and culdoscopy for internal sterilization.

In recent years, the increased demand for sterilization by women who have achieved their desired family size has emphasized the need to improve both existing methods of tubal occlusion and the means of access to the Fallopian tubes. Utilization of diagnostic instruments such as the laparoscope and culdoscope to perform sterilization minimizes the trauma associated with standard laparotomy and colpotomy and promises to reduce morbidity occurring as a result of sterilization. In order to evaluate and compare the improved techniques of laparoscopy and culdoscopy for elective interval sterilization, 722 women were studied between January and August of 1973 at the Siriraj Hospital in Bangkok. For 279 patients (Group I), sterilization was performed by culdoscopic tubal ligation using a modified Pomeroy technique; for 443 patients (Group II), the procedure used was laparoscopic tubal cauterization and cutting. All procedures were performed using local anesthesia on an outpatient basis. Complication rates and required surgical time were similar for both procedures and compared favorably with rates reported by other investigators. Because of a low incidence of complications and the elimination of the need for general anesthesia and hospitalization, both endoscopic procedures appear to be of particular value in developing countries where hospital facilities and physician time are in short supply.     

Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: Norethisterone oenanthate and medroxyprogesterone acetate: 2. Bleeding patterns and side effects

The present paper reports the bleeding patterns and side effects experienced by women using norethisterone oenanthate (NET-OEN) and depot-medroxyprogesterone acetate (DMPA) in a WHO-sponsored comparative trial.Only a small minority of women had consistently normal cycles: the vast majority experienced some menstrual abnormality, with 47% of NET-OEN and 70.6% of DMPA users not having any normal cycles.Amenorrhoea was significantly more frequent with DMPA than with NET-OEN and its incidence increased with time. At the end of one year 35% of DMPA and 8.6% of NET-OEN users had total amenorrhoea.There were only minor differences between the two drugs with respect to the frequency or duration of bleeding episodes, but DMPA caused significantly more spotting than NET-OEN. With both treatments there were large individual variations and the bleeding pattern was totally unpredictable.Headache, the most important nonmenstrual side effect, was reported by 6.9% of the NET-OEN and 10.7% of the DMPA users. In the case of DMPA its incidence increased with time. Other complaints such as abdominal discomfort and nervousness were reported with similar frequency on both drugs. There was, with both treatments, a slight increase in body weight and a decrease in blood pressure.     

Pharmacokinetic study of different doses of Depo Provera

Doses of DepoProvera of 25, 50, 100 and 150 mg were administered to four groups of women. The mean time for the return of follicular and luteal activity increased with increasing dose of DepoProvera. Luteal activity was suppressed for a longer period than follicular activity. None of the women receiving the two higher doses of DepoProvera showed a return of luteal function within 100 days of injection. The period for which medroxyprogesterone acetate (MPA) was detectable in serum increased with increasing dose but the values for the 100 and 150 mg doses were not significantly different. There was a significant correlation between the concentration of MPA in blood and the return of follicular and luteal function. It is suggested that in the population studied, 100 mg DepoProvera would be as effective as the usual 150 mg dose and that injection of 50 mg DepoProvera would provide a contraceptive effect for two months. The dose of MPA in the monthly injectable CycloProvera could be substantially reduced without loss of effectiveness.     

Effects of hormonal contraceptives on milk volume and infant growth: WHO Special Programme of Research and Development and Research Training in Human Reproduction

WHO conducted a three-centre study in Hungary and Thailand to evaluate the effects of hormonal contraception on lactation and infant growth. Women choosing oral contraceptives were randomly assigned to a combined oral contraceptive containing 30ug ethinyl estradiol and 150ug levonorgestrel (N=86) or a progestin-only preparation containing 75ug dl-norgestrel (N=85). Identical packaging and treatment schedules allowed double-blind observation. One-hundred-and-eleven women using no contraception or non-hormonal methods acted as controls. In the two Thai centres 59 women using depot-medroxyprogesterone acetate formed an additional comparison group. All subjects were healthy women with normal deliveries, whose infants had normal birth weights and satisfactory growth in the neonatal period.Breast milk volume was determined by pump expression using standardized procedures. Information was obtained on nursing frequency and supplementation, infant growth and morbidity. Pretreatment observations at 6 weeks post-partum were used as a baseline, and subjects were followed-up at 9, 12, 16, 20 and 24 weeks post-partum.Women using combined oral contraceptives had a decline in milk volume within 6 weeks of initiating treatment, whereas no significant decrease was observed in the other treatment groups. After 18 weeks of treatment, combined oral contraceptive users experienced a 41.9% decline in milk volume, compared to 12.0% with progestin-only minipills and 6.1% in the non-hormonal controls. The prevalence of complementary feeding and withdrawals due to inadequate milk supply were comparable in the four treatment groups. However, data were not available on the daily amounts of complementary feeds. There were no significant differences in growth of infants between treatment groups. Thus, women may have compensated for declines in milk volume by more supplementary feeding or by more prolonged and intense suckling episodes.We conclude that 30 ug estrogen-containing combined oral contraceptives impair milk secretion, but in the selected healthy group of mothers and children studied with the prevailing level of supplementary feeding, this did not adversely affect infant growth.