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.

Prostitution, condom use, and invasive squamous cell cervical cancer in Thailand.

Cervical cancer is probably caused by a sexually transmitted agent. A case-control study was conducted in three hospitals in Thailand to investigate further the role of male sexual behavior, particularly regarding sexual contacts with prostitutes, in the development of this disease. Data were obtained from interviews with 225 married women with invasive squamous cell cervical carcinoma and 791 hospitalized controls, all of whom reported having only one sexual partner, and from interviews with their husbands. Risk of cervical cancer was strongly related to the women's husbands having visited prostitutes without using a condom when the husbands were less than 30 years old. A strong increasing trend in risk in relation to decreasing frequency of the husbands' condom use with prostitutes was observed, and a weaker increasing trend in risk with husbands' estimated lifetime total number of visits to prostitutes was found. The average latent period between the women's likely initial exposure to a sexually transmitted oncogenic agent and her diagnosis of invasive cervical cancer was about a quarter of a century. Regular use of condoms by customers of prostitutes could reduce the number of invasive cervical cancer cases in the general population of Thailand by at least one fourth.

PIP: Researchers compared data on 225 Thai married women with invasive squamous cell cervical cancer admitted to Siriraj and Chulalongkorn hospitals in Bangkok and at Maharaj Nakorn Chiang Mai Hospital during October 1979-September 1998 with data on 791 hospitalized Thai controls to examine the role of male sexual behavior and prostitution in the development of cervical cancer and the likely protective effect of condom use against cervical cancer. All the cases and controls claimed to have had only one sexual partner. Interviews were conducted with the husbands of all the cases and controls. There was a significant trend of increasing risk of cervical cancer as the frequency of husband's condom use with prostitutes declined (p = 0.004) (relative risk [RR] = 2.05 for rarely or never, 1.24 for sometimes, and 0.96 for always or frequently). The increasing risk of cervical cancer associated with little or no condom use with prostitutes was highest when the husbands were less than 30 years old (RR = 2.11 vs. 1.56-1.81 for age 20 or older). There was a weaker trend of increasing risk of cervical cancer with the husband's estimated lifetime total number of visits to prostitutes (p = 0.12). On average, the latent period between the wife's likely first exposure to a sexually transmitted oncogenic agent (i.e., date of their marriage) and her diagnosis of invasive cervical cancer was 24 years. These findings indicate the condom use with prostitutes would reduce the risk of cervical cancer.

Postexposure rabies vaccination during pregnancy: effect on 202 women and their infants.

This prospective study of 202 pregnant Thai women who received postexposure treatment for rabies with a tissue culture-derived rabies vaccine and human or equine rabies immune globulin revealed an adverse reaction rate similar to that seen among nonpregnant Thai patients who received the same treatment. Tissue culture-derived rabies vaccines as well as immune globulins are safe to use for postexposure prophylaxis during pregnancy. Such treatment should never be withheld or delayed if the patient possibly was exposed to rabies.

Rabies and its prevention.

The increase in world-wide travel means that physicians everywhere require an understanding of rabies and its prevention, to advise intending travellers, or to follow-up on treatment begun overseas. In this article, we discuss measures to prevent rabies.

A multicentre comparative study of serum lipids and apolipoproteins in long-term users of DMPA and a control group of IUD users. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation Special Programme of Research, Development and Research Training in Human Reproduction.

A clinical trial was conducted in three centres to assess the effects of long-term use of the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) on lipid metabolism. Fifty women who had used DMPA at a dose of 150 mg every three months for 3 to 9 years were recruited in Bangkok, Christchurch and Mexico City. They were compared to a control group of 120 IUD users. Total cholesterol, LDL-cholesterol, HDL-cholesterol, total triglycerides, apolipoproteins AI, AII and B were measured throughout one injection interval. Significant findings differed between centres. Compared to their own centre controls, DMPA users in Bangkok had higher LDL-cholesterol levels; those in Christchurch had lower HDL-cholesterol, apolipoprotein (apo) AI and apo AI/B ratio and higher apo B levels; those in Mexico City had a lower apo AI/B ratio. Further changes were observed during the injection interval, some of which were correlated to changes in serum MPA levels. It is concluded that long-term use of DMPA induces moderate changes in lipid metabolism which are unfavourable in terms of risk for atherosclerosis. This should be borne in mind when weighing the overall risks and benefits of this contraceptive method for a potential user.

Use of nonoxynol-9 and reduction in rate of gonococcal and chlamydial cervical infections.

The spermicide nonoxynol-9 (N-9) has been used as a contraceptive for over 30 years, but the use of a vaginal spermicide and condoms for the prevention of sexually transmitted infections has not been examined in randomised studies. We report a single-blind randomised field trial to assess the effect of N-9 film on the rate of gonococcal and chlamydial cervical infection in women at high risk of these diseases. 343 women were randomly assigned to use either condoms and N-9 (186 women) or condoms and a placebo (157). Compliance with condom use was much the same in the two groups. Overall, N-9 reduced the rate of cervical infection by 25% (rate ratio [RR] 0.75, 95% confidence interval [Cl] 0.5-1.1); in women who used N-9 for more than 75% of their coital acts the infection rate was reduced by 40% (RR 95% Cl 0.3-1.0). The rate of yeast vulvovaginitis or genital ulcers was not higher in N-9 users than in placebo users, but the rate of symptomatic irritation was increased by 70% (RR 95% Cl 1.1-2.6) among N-9 users. Condom use was more protective against cervical infection than N-9 use. The rate of infection was 50% (RR 95% Cl 0.3-0.7) lower with 75% than with 0-50% condom compliance. The use of a vaginal N-9 spermicide with condoms whenever possible seems to be a better strategy than the use of condoms only for prevention of gonococcal and chlamydial cervical infection.

Is injection of contaminated animal bite wounds with rabies immune globulin a safe practice?

In Asia, it is still controversial whether it is safe to inject a contaminated animal bite wound with a foreign protein such as equine or human rabies immune globulin, even though this is recommended by the World Health Organization. A prospective study of 114 severe animal bite wounds which were injected with equine or human rabies immune globulin revealed an overall incidence of gross infection of 11.4%. No matched control group of patients bitten by animals whose wounds were not injected with immune globulin could be studied in this environment with a high prevalence of canine rabies. The incidence of wound infection in lacerations inflicted by sharp objects and sutured under local anaesthesia was therefore studied prospectively in 100 Thai patients from a similar socio-economic milieu; it was found to be 13%. Wound infection was more common in animal bites and lacerations of the lower extremities. It is concluded that injecting a properly cleansed bite wound with equine or human rabies immune globulin is a safe practice and should be performed whenever there is a possibility that the biting animal might have rabies.

Immune response to rabies vaccine in Thai dogs: a preliminary report.

Serum neutralizing antibody to rabies virus was determined in previously unvaccinated Thai pet dogs after receiving one subcutaneous dose of inactivated tissue culture rabies vaccine (Rabdomun, Coopers Animal Health Company, Germany, 4.55 IU ml-1 potency). Geometric mean titres on days 14, 30, 60, 180 and 360 were 2.14, 2.30, 0.45, 0.14 and 0.05 IU ml-1, respectively, by the rapid immunofluorescent focus inhibition test. Titres of neutralizing antibody to rabies virus did not correlate with the age of the dog at the time of vaccination or with the presence or absence of anaemia or blood parasites. Six out of 50 (12%), 11 out of 43 (25.6%) and 13 out of 31 (42%) dogs had no detectable rabies antibody in serum 60, 180 and 360 days, respectively, after vaccination. Three of these antibody-negative dogs were given another dose of vaccine. Antibody reappeared on day 14 but rapidly declined within 60 days. These data suggest that one dose of tissue culture vaccine in dogs by the subcutaneous route of injection is not adequate to maintain rabies neutralizing antibody in serum for 1 year.

One-year study of the 2-1-1 intramuscular postexposure rabies vaccine regimen in 100 severely exposed Thai patients using rabies immune globulin and Vero cell rabies vaccine.

The 2-1-1 rabies postexposure treatment schedule is an abbreviated regimen in which a tissue culture rabies vaccine is administered intramuscularly at two sites on day 0, and at one site on days 7 and 21. Compared to the standard five-dose intramuscular regimen, the 2-1-1 schedule reduces the number of clinic visits from five to three and the amount of vaccine used by 20%. One hundred Thai patients, who were severely exposed to rabies, were treated with rabies immune globulin and the 2-1-1 regimen using purified Vero cell rabies vaccine. They were followed for 1 year. Rabies antibody titres were measured in 10% of this group. All patients survived and adverse reactions were mild. A satisfactory antibody response (a titre greater than 0.5 IU ml-1) occurred in all ten patients studied at day 14, but persisted for 90 days in 80% and for 360 days in only 50%. The authors therefore do not recommend use of the 2-1-1 schedule in severely exposed patients who also need to receive rabies immune globulin.

Rabies in Thailand: 1990.

Of the more than 100,000 courses of postexposure rabies treatment given in Thailand annually, 95% consist of brain tissue-derived vaccine without immune globulin. Rabies tissue culture vaccines and immune globulins are expensive by the standards of developing countries. When they are given according to either of two proven intradermal postexposure schedules, significant savings can be achieved without loss of efficacy. Purified equine rabies immune globulins account for approximately 10% of the cost of human products administered to exposed individuals and have been shown to be safe and effective. A canine preexposure immunogenicity study with a potent, inactivated tissue culture vaccine revealed that 12.5% of Thai dogs failed to develop protective antibody titers 2 months after one subcutaneous injection. Previous studies have shown significant antigenic differences between Thai street rabies virus and European and North African strains.

The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa.

The authors conducted a single-dose phase I local toxicity study of the effects of frequent insertion of nonoxynol-9 (N-9) on the lower genital tract to determine whether a phase II dose-ranging study is warranted. Fourteen women used 150 mg of N-9 cumulatively four times a day for 14 days. Epithelial disruption of the cervix and vagina, the main outcome of interest, occurred in 43% (95% CI, 18-71%) of women on this high-frequency use schedule. None of the women experienced symptoms that prompted them to discontinue the study. This preliminary study indicates that a phase II study to examine the local toxicity of different use schedules is needed to provide further safety information about the use of N-9.

PIP: A Phase I type clinical trial was conducted to study the local toxic effects of nonoxynol-9 (N-9) on the vaginal and cervical mucosa of women, to see whether a Phase II trial is needed, since women may use the spermicide frequently to prevent sexually transmitted diseases. 14 women inserted suppositories containing 150 mg N-9 every hour for 4 doses for 14 days. They were checked before the trail and for 2 or 3 weeks, with pelvic exam, smears for trichomonas and monilia, and colposcopy. 5 women inserted placebos to blind the trial. 43$ of the subjects had physical findings including sloughing of the cervical epithelium in 4, cervical erythema in 4, cervical bleeding in 1, vaginal erythema in 3, vaginal sloughing and bleeding in 1, vaginal dryness in 3, dryness in 2 and itching in 2. The cervical sloughing did not cross the transformation zone. 1 woman had edema and bleeding of the cervix resembling severe strawberry cervix. All symptoms resolved in 1 week. No effects were seen on the vulva, perineum or anus. The dose and frequency of use of N-9 in this trail are larger than women would normally be expected to use, but the data do justify a Phase II study.

Detection of Plasmodia in acridine orange stained capillary tubes (the QBC system).

The sensitivity, specificity and convenience of carrying out malaria diagnosis in acridine orange stained capillary tubes using a fluorescent microscope (the QBC system) was compared to screening for Plasmodia on conventional Giemsa stained thick smears. A dilution study revealed that the QBC is able to detect Plasmodia in as low a dilution as 5 organisms per ul. The QBC system was evaluated at a district hospital in Thailand. A preliminary study of 186 patients compared the QBC system to the routine malaria screening procedure (screening up to 30 microscopic fields on a thick smear). The sensitivity of the QBC was found to be 98.9% with a specificity of 94.4%. A second combined series of 465 febrile subjects were screened by thick smear and these results were compared to the QBC. 202 were positive for malaria on both QBC and thick smear. Sensitivity in this study was found to be 99.5% (202/203) and the specificity was 94.6% (248/262). When both series were combined, there were 14 QBC malaria positives that were not detected on thick smear, and 2 QBC malaria false negatives among the 651 patients studied. The parasite densities in these cases were between 10 and 320,000 organisms/microliters. The QBC system provided only a crude estimate of the level of parasitemia. The species of Plasmodia (P. falciparum and P. vivax) were correctly identified on QBC in 78% of cases.

Postexposure prophylaxis for rabies with antiserum and intradermal vaccination.

The Thai Red Cross intradermal postexposure rabies treatment schedule was prospectively assessed in 100 Thai patients severely bitten by proven rabid animals. It consists of 0.1 ml of purified Vero cell rabies vaccine containing more than 2.5 IU of rabies antigen per 0.5 ml of reconstituted vaccine given intradermally at two sites on days 0, 3, and 7, followed by one 0.1 ml injection on days 30 and 90. The commercial vaccine used had an antigen content of 3.17 IU per 0.5 ml ampoule. Purified equine or human rabies immuno-globulin was also given on day 0 to patients with severe exposures. As much of the immunoglobulin as possible was infiltrated around the wounds. All patients were followed for 1 year post exposure. There were no deaths; the efficacy of the regimen was 100%. Antibody titre determination in a randomly selected subgroup showed seroconversion in all 10 patients.

Equine rabies immune globulin: a product with an undeserved poor reputation.

Four hundred nineteen patients exposed to rabies in Thailand were treated with equine rabies immune globulin (ERIG) manufactured by Sclavo of Italy, a product also licensed in the United States of America. They were followed for a minimum of 1 month after ERIG injection and rabies vaccine administration. Adverse serum sickness-like reactions were noted in 15 patients (3.58%). These were clinically acceptable and only 1 of these patients required corticosteroid therapy and short term hospitalization for serum sickness. ERIG is approximately 1/10 of the cost of human rabies immune globulin (HRIG), which is not generally available in developing countries. ERIG is a safe and underutilized essential biological when HRIG is not affordable or available.

What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously?

Reported are the results of a study with the Thai Red Cross two-site intradermal purified Vero-cell rabies vaccine (PVRV) schedule that was deliberately injected into subcutaneous tissue. The 44 healthy nonimmune Thai adults who were enrolled in the study were randomly assigned to the following groups and given PVRV as shown: group A (two intradermal injections on days 0, 3, and 7); group B (one intradermal and one subcutaneous injection on days 0, 3, and 7); and group C (two subcutaneous injections on days 0, 3, and 7). Neutralizing antirabies antibody titres were determined on day 14 using the rapid fluorescent focus inhibition test. High rabies antibody titres were obtained for all three groups. These results suggest that the economical and safe Thai Red Cross intradermal PVRV regimen could be used in selected general health care facilities.

What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously?

Reported are the results of a study with the Thai Red Cross two-site intradermal purified Vero-cell rabies vaccine (PVRV) schedule that was deliverately injected into subcutaneous tissue. The 44 healthy nonimmune Thai adults who were enrolled in the study were randomly assigned to the following groups and given PVRV as shown: group A (two intradermal injections on days 0, 3, and 7); group B (one intradermal and one subcutaneous injection on days 0, 3, and 7); and group C (two subcutaneous injections on days 0, 3, and 7). Neutralizing antirabies antibody titres were determined on day 14 using the rapid fluorescent focus inhibition test. High rabies antibody titres were obtained for all three groups

These results suggest that the economical and safe Thai Red Cross intradermal PVRV regimen could be used in selected general health care facilties(AU)

Postexposure rabies vaccination during pregnancy: experience with 21 patients.

Twenty-one pregnant rabies exposed patients received postexposure vaccination using purified Vero cell rabies vaccine. Twelve of these with severe exposures were also given equine rabies immune globulin. Adverse reactions were mild, transient and required no treatment. Fifteen per cent of the patients reported side-effects such as myalgia, malaise, erythema and swelling at injection sites, urticarial rashes, and mild regional lymphadenopathy. The vaccine series was completed in all cases and none of the mothers or infants developed rabies after one year of follow-up. No congenital malformations were detected. All infants were well after one year. One patient experienced a spontaneous abortion.

Comparative immunogenicity study of four plasma-derived hepatitis B vaccines in Thai young adults.

Immunogenicity of four plasma-derived hepatitis B vaccines (Merck, Sharp and Dohme, Pasteur, Dutch CLB and Korean Cheil-Sugar) was compared in Thai young adults. After primoimmunization, only the Merck and Pasteur vaccines could achieve greater than 90% seroconversion (i.e. anti-HBs greater than or equal to 10 mIU ml-1) whereas both the CLB and Korean vaccines needed a fourth dose to achieve this level of seroconversion. The anti-HBs titres of both heat-inactivated vaccines (CLB and Korean) were also significantly lower than those of the other two vaccines. We propose that the HBsAg content in both heat-inactivated vaccines should be increased and a booster (fourth) dose should be given in order to enhance their immunogenicities.