The past, present, and future of the prevention of lung cancer

The article relates details of the history of research into the causal association of cigarette smoking and lung cancer on the basis of multidisciplinary studies that have explored the epidemiology, biology, chemistry, and biochemistry of tobacco carcinogenesis and research in behavioral sciences and health education that has sought to address one of our nation's foremost public health problems. Recalling past and present challenges and achievements in all of these areas, the author then outlines his vision for addressing this health problem in the future. This is laid out for various segments of the research community and for society as a whole, i.e., Cancer Centers and hospitals, epidemiologists, laboratory scientists, legislators, educators and behavioral scientists, and the media. It is proposed that for the current policy initiatives in tobacco-related cancer control to succeed, there needs to be a focus on preventing the initiation of tobacco use among children and adolescents. All segments of society can help to achieve this goal. In the nation's research planning, there needs to be a proper balance between basic and applied research, including research on and application of preventive principles, because cancer need not be an inevitable consequence of aging but is largely preventable.     

Cancer prevention: past, present, future

There are many examples of different types of cancers that have been prevented by appropriate measures in the past. Most of them were related to occupational, iatrogenic or accidental factors, often as the outcome of heavy exposure of humans to specific carcinogenic agents. Cancer is a disease of DNA, and is generally associated with multiple genetic alterations, these being produced in the typical case by exposure to various carcinogens, each of which exists at minute concentrations. Thus, the impact of carcinogenic factors, xenobiotics and autobiotics, is due to their actions in concert. However, a single mutation yielding genomic instability exerts a disproportionately large influence by resulting in a large number of secondary mutational events. Epigenetic changes can also not be disregarded especially from the view point of prevention of neoplasia. The occurrence of multiple primary cancers among survivors of initial primaries, and the presence of hereditary groups with a high risk of cancer development provide a strong stimulus for establishment of effective approach for cancer prevention, which should be, in principle, multi-faceted. Therefore, a holistic approach is essential with improvement in life style including choosing a balanced diet and avoidance of cigarette smoking and other sources of carcinogens, as integral elements.     

Nosocomial tuberculosis: new progress in control and prevention

Nosocomial cases of tuberculosis have affected both health care workers and hospitalized patients, and each group has transmitted the infection to the other. This situation has been exacerbated by increases in the number of patients concurrently infected with human immunodeficiency virus and organisms resistant to multiple drugs; by inadequate implementation of procedures for the recognition, isolation, and treatment of patients with tuberculosis in health care and correctional facilities; and by a lack of practical engineering interventions for the control of airborne transmission. Epidemics at several hospitals have been controlled by the implementation of multiple measures listed in recent federal guidelines. Rapid recognition of cases and their effective isolation should be a priority at public hospitals, which can least afford the expensive engineering changes and personal respirators that are now mandated. Lacking are data on engineering controls (especially for retrofitting of existing facilities) and requirements for mask use that are both effective and financially practical. If relevant programs are to be developed, new methods are needed for the direct measurement of airborne transmission of tuberculosis. Fortunately, new federal guidelines allow individual hospitals and health care systems the flexibility to assess likely risk and to act in accordance with their findings to develop system-wide control programs.     

Laboratory diagnosis of tuberculosis: past, present, and future

Resurgence of tuberculosis justifies extraordinary efforts to expedite TB diagnosis and susceptibility testing. This demands that laboratory support expand to a "second generation" of methods and procedures, including rapid availability of fluorochrome smears of concentrated specimens, faster techniques for detection (e.g., the BACTEC radiometric broth system and microcolony detection), quicker identification (e.g., high-pressure liquid chromatography, nonisotopic genetic probes), more rapid susceptibility testing methods (e.g., BACTEC), and reporting of these results as critical values. Guidelines have been established for turnaround time for results of smears, TB organism identification, and susceptibility testing to usual first-line drugs. A "third generation" of laboratory techniques soon will make testing not only more effective but also more efficient. These methods include direct testing of respiratory specimens through nonisotopic genetic probes as well as nucleic acid amplification techniques utilizing polymerase chain reaction (PCR) and other molecular procedures. These new procedures and protocols place heavy demands on laboratory test volume, technologist time and costs. For the healthcare system or clinical laboratory without the resources to deal with these new demands, referral of TB specimens represents a reasonable alternative, as long as transport is adequate to meet current CDC and other guidelines for turnaround time.     

Pulmonary tuberculosis and primary-infection tuberculosis. Epidemiology, diagnosis, course, treatment, prevention

The herpes simplex virus type 1 (HSV-1) helicase-primase, an essential component of the viral DNA replication machinery, is a trimeric complex of the virus-coded UL5, UL8, and UL52 proteins. An assembly of the UL5 and UL52 subunits retains both enzymic activities, and the UL8 protein has been implicated in modulating these functions, facilitating efficient nuclear uptake of the complex and interacting with other viral DNA replication proteins. To further our understanding of UL8, we have constructed plasmids expressing mutant proteins, truncated at their N- or C-termini or lacking amino acids internally, under the control of the human cytomegalovirus major immediate-early promoter. Deletion of 23 amino acids from the N-terminus or 33 from the C-terminus abolished the ability of UL8 to support DNA replication in transient transfection assays. None of the UL8 mutants tested exhibited a strong dominant negative phenotype in the presence of the wild-type product, although some inhibition of replication was observed with mutants lacking 165 N-terminal or 497 C-terminal amino acids. The ability of the UL8 mutants to facilitate efficient nuclear localization of UL52 in the presence of coexpressed UL5 was examined by immunofluorescence. Selected mutants were also expressed by recombinant baculoviruses and tested for interaction with UL5 and UL52 in immunoprecipitation assays. The replicative ability of the mutants was found to correlate with their ability to localize UL52 to the nucleus, but not their interaction with UL5 and UL52. This property precluded the identification of any region of UL8 important for its presumed nuclear functions.     

HIV prevention case management: current practice and future directions

The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.     

Current therapy and prevention of malaria and perspectives for the future

At present the basic antimalarial drugs are still the 4-aminoquinolines chloroquine and amodiaquine, the combinations of antifol compounds (such as pyrimethamine and sulfadoxine = Fansidar), and quinine. In South East Asia and parts of Latin America Plasmodium falciparum has become highly resistant to chloroquine, and increasingly so to the antifol combinations. By selecting the antimalarials bearing the lowest risk of resistance, or combinations of them, an attempt can be made to avoid failures of treatment and chemoprophylaxis. The other areas endemic for malaria tropica may still be generally considered "chloroquine sensitive", although sporadic low-grade resistance to chloroquine is reported. It would be a mistake to replace chloroquine systematically by antifol combinations in those parts of the world now as well. The questions when drug resistance is to be suspected, and how individual treatment can be adjusted to it, are likewise discussed. Mefloquine is the best known new compound, with excellent activity against multiresistant Plasmodium falciparum. A combination with Fansidar is now being developed to prevent the former from inducing resistant strains. Despite considerable experimental advances a malaria vaccine is unlikely to be generally available before the end of this decade.     

BCG vaccines for the prevention of tuberculosis in the world]

The BCG vaccines will celebrate the 100th anniversary of their discovery in a decade at the beginning of the next century since Albert Calmette and Camille Guerin had presented it before the Academie des Sciences in 1908. At present tuberculosis kills more people than any other infectious disease about 3 million people a year, including almost 300,000 children under 15, and is producing over 7,000 deaths and over 24,000 new cases every day. Therefore, WHO declared a global health emergency in 1993. More worse, recently multi-drug resistant tubercle bacilli are emerging rapidly making TB patients incurable. Under these situations we need a potent anti-tuberculosis vaccine. So first of all, we must check the century-old BCG before proceeding further. At moment, the BCG vaccines are being used worldwide in the largest quantities in the world, but still most controversial vaccines anywhere. I would like to describe here their success and failure in the combat against the white plague. 1. The Expanded Programme on Immunization (EPI). In 1974, when the EPI was launched by WHO, less than 5% of the world children were immunized against six infectious diseases including tuberculosis. In 1995 statistics, BCG gave the highest vaccination coverage, 87% higher than any other 5 vaccines of EPI for children. The BCG in EPI must have saved a lot of infants as the vaccine, has been proved to be most effective against the blood-born tuberculosis of child type. 2. The efficacy of BCG vaccination against tuberculosis. Results of each 10 of randomized controlled trials (RCT) and Case-control studies (CCS) showed the protective efficacy against tuberculosis as uncertain, unpredictable, as protective efficacy varied from 80% to 0%. More recently, a Meta-analysis of selected papers on BCG field trials which were so far collected. They recalculated vaccine protective effect separately for pulmonary TB and for meningeal/miliary TB in the trials. As the result, it was found that protective effect against pulmonary TB could not be calculated, but protective effect against meningeal and miliary TB was calculated as 86%, 75% respectively, in RCT and CCS, being higher than against pulmonary TB. 3. The duration of BCG efficacy against tuberculosis was confirmed to continue for 15 years after vaccination. The incidence of every form of tuberculosis decreased steeply during the 15 years following vaccination. 4. BCG revaccination. A WHO statement was issued in 1995 mentioning that there is no definitive evidence that repeated BCG vaccination confers additional protection against tuberculosis. Therefore WHO has not recommended to repeat BCG vaccination because of no scientific evidence to support this practice. Multiple BCG revaccinations are not indicated in any persons. 5. Complications with BCG Second IUATLD study (1988) on complications induced by BCG was reviewed, especially following two points: 1-2) Regional suppurative lymphadenitis 3) Generalized lesions: fatal cases 1-2 Several African regions had experienced that the risk of outbreak of suppurative BCG lymphadenitis was low for vaccines with Glaxo and Japanese strains, but much higher for vaccines with Pasteur. This experience in nineteen eighties has led EPI to replace the Pasteur BCG vaccine with less reactogenic BCG, Japanese or Glaxo BCG to solve the outbreak of suppurative adenitis complication. 3 At moment, the only contra-indication of EPI BCG vaccination is symptomatic HIV infection (AIDS), but in the future asymptomatic HIV infection should be placed on alert, because fatal BCG generalized disseminations have already been experienced by HIV positive vaccinees although in a few cases in USA. 6. BCG seed lots for use of vaccination in the world. Nearly 10 seed lots (BCG) are being used in the world at present. However, they are more or less different each other in various characteristics: morphological, biochemical, biophysical, immunological, vaccinological and so on. None of them is the same