In the many descriptive studies on prescribed psychotropic drug use by community-dwelling older persons, several sociodemographic and other factors associated with drug use receive inconsistent support.Empirical reports with data on at least benzodiazepine or antidepressant drug use in samples of older persons published between 1990 and 2001 (n = 32) were identified from major databases and analyzed to determine which factors are most frequently associated with psychotropic drug use in multivariate analyses. Methodological aspects were also examined.Most reports used probability samples of users and non-users and employed cross-sectional designs. Among variables considered in 5 or more reports, race, proximity to health centers, medical consultations, sleep complaints, and health perception were virtually always associated to drug use. Gender, mental health, and physical health status were associated in about two-thirds of reports. Associations with age, marital status, medication coverage, socioeconomic status, and social support were usually not observed.The large variety of methods to operationalize drug use, mental health status, and social support probably affected the magnitude of observed relationships. Employing longitudinal designs and distinguishing short-term from long-term use, focusing on samples of drug users exclusively, defining drug use and drug classes more uniformly, and utilizing measures of psychological well-being rather than only of distress, might clarify the nature of observed associations and the direction of causality. Few studies tested specific hypotheses. Most studies focused on individual characteristics of respondents, neglecting the potential contribution of health care professionals to the phenomenon of psychotropic drug use among seniors. The use of prescribed psychotropic drugs by older persons has been a subject of interest for several decades ,2. PsychThe prevalence of psychotropic drug use among community-dwelling older persons  varies from about 20% to 48% -5. More Since aging increases the likelihood of drug accumulation and intoxication, older persons are particularly vulnerable to adverse effects from psychotropic drugs . NotableAlthough more psychotropic drug users are found among older persons than any other age group, the prevalence of mental disorders appears to be lower among older than younger adults. This has been shown for major depression, anxiety disorders and sleep disorders ,22-30. OThe inappropriate prescription of psychotropic drugs may account partially for the discrepancy between low levels of distress and high levels of drug use among older persons. Inappropriate prescriptions include questionable drug combinations (such as two benzodiazepines), excessive treatment duration, and drugs contraindicated for use by older people . Authors estimate that one-fifth to one-half of psychotropic drug prescriptions to the elderly are "inappropriate" ,16,31,32These findings suggest that older persons' psychological well-being is not the principal determinant of their psychotropic drug use. In the present article, we review recent empirical studies in order to identify other factors that may account for psychotropic drug use among older persons. A large body of work bears on this age group and their use of psychotropic and other drugs ,34. EarlMedLine, Cumulative Index to Nursing & Allied Health Literature, Psychlit, Eric and Sociological Abstracts for the years 1990 to 2001. Various keywords were used. Selected reports had to: (1)constitute either a peer-reviewed journal article or a government publication published in English or French; (2) present specific retrievable empirical results concerning older persons, regardless of other age groups studied (some reports [Reports were selected on April 20, 2001, from the following bibliographic databases:  reports ,39,45 we reports ,46,47 weThe 32 publications report on 30 different studies conducted in ten different countries. Unless indicated otherwise, each report is treated as a separate study. Most reports originated from the United States (31%) and Canada (28%), followed by France (12.5%), Sweden (9.5%), and 3% each (one report) from Australia, Austria, Ireland, the Netherlands, Spain, and the United Kingdom (Table 1 see ). Of 26 Most reports (24, 75%) presented multivariate data analyses, usually multivariate logistic regression, where the independent contribution of various variables to the variance in psychotropic drug use could be ascertained while controlling for the contribution of other variables. Although variables with statistically significant associations (p < .05) to drug use that remained in the regression equation were often considered "predictors," strictly speaking only an association is demonstrated in this fashion, and the direction of causality can rarely be established. This is especially so when a theoretical model is not specified prior to the data analysis, as was the case in the vast majority of reports. The eight remaining studies conducted bivariate analyses solely, and most examined three or less variables.In the following review, associations of sociodemographic factors and life conditions with psychotropic drug use are examined first. A factor was deemed well supported by the review studies when 70% of the results from all studies that considered this factor were statistically significant and pointed in the same direction. Second, methodological and conceptual issues relevant to the study of psychotropic drug use among the elderly, and salient in the reviewed studies, are discussed.Weighted average prevalence rates of psychotropic drug use were estimated from all reports having collected data from probability samples or entire populations (n = 22). In longitudinal studies, data from the last year of the study were used. Average prevalence of any psychotropic drug use from 9 studies was 29.0% (range 11.8% – 42.5%). For drugs identified in the reports as benzodiazepines, minor tranquilizers, anxiolytics, or sedative-hypnotics, the average prevalence in 13 studies was 21.5% (range 6% – 43.8%). In 11 studies with data on antidepressants, the average prevalence was 6.9% (range 2.3% – 14%). Finally, for neuroleptics, it was 3.1% (6 studies, range 1% to 6%).Older people are more likely than any other age group to use any type of medication . HoweverOver the past three decades, numerous hypotheses have been proposed to explain the higher prevalence of psychotropic drug use among women than men: women are more inclined to reveal their emotional problems to their doctor,36,52-55In this review, 73% of the relevant studies support the established finding that women are more likely to use psychotropic drugs than men. In two studies, the relationship with gender holds only among those aged between 65 and 74 years, and in a third, the results are opposite. However, the studies shed little light on reasons for this disparity.Only two studies identified as a secondary objective to look at the gender issue in relation to psychotropic drug use ,49. A feThe role of culture, ethnicity, and race has received little attention so far in the literature on older persons' psychotropic drug use. Explaining cultural, ethnic, or racial disparities in use of health services is a complex endeavor, requiring analysis of predisposing, structural, access, and other variables in interaction -78. In tInterpretations of the race-specific findings from these six studies focused mostly on professional-and individual-level determinants. Brown et al.  suggesteIt has been suggested that older widows would be more likely to use psychotropic drugs because of the distress of bereavement . Eleven Living in deprived environments and having an unskilled occupation, low income and little formal education are variables associated with psychological distress among adults, and it might be assumed that the same would hold among older people. However, the studies reviewed fail to support this association. Socioeconomic status (SES) is typically operationalized by education, income, and occupation. As Table 2 see  shows, While the importance of SES as a predisposing or mediating influence on drug use might be more established in general population studies, it may be less relevant in the older age group because of a lower rate of psychological distress and greater access to income security plans and retirement pensions that prevent extreme poverty.In the United States and until recently in Canada, older persons benefited from Medicare or provincial health insurance plans without medication coverage. Insurance coverage has been shown to influence psychotropic drug use by the elderly . Five stNo study examined meso-level variables related to SES, such as census-tract or neighborhood poverty, except proximity to health centers. The use of health services, including medications, may be increased by proximity to such services . Close oStressful events may increase people's likelihood of using psychotropic drugs. Only three studies examined this relationship, each reporting a different result: a positive association , a negatA recent qualitative synthesis of the literature concludes that the pathway to psychotropic drug use among older people typically includes the presence of organic disease  (and lonIn this review, nine of 16 studies (56%) found a significant association between the presence or the number of physical illnesses and psychotropic drug use. In their conceptual model, Gustaffson et al.  suggest Four of six studies (60%) examining the relationship between psychotropic drug use and use of other medications found a significantly positive association, but the direction of causality remains unclear.Health perception–the self-evaluation of one own's health–has been shown to be more strongly associated with psychotropic drug use than actual diagnosis of disease . Some reIn this review, seven of eight studies (87.5%) examining the association between health perception and drug use found a positive relationship. However, two thirds of the reviewed studies were cross-sectional, preventing conclusions about cause-effect relationship, and typically more than 80% of the psychotropic drugs used by their subjects were benzodiazepines. This raises the possibility that some subjects had poor health perception as a result of benzodiazepine consumption. Iatrogenic effects of long term benzodiazepine use may worsen health and functional capacity, hence health perception ,91. The It has previously been proposed that low social support is associated with psychotropic drug use among older people ,93. In 1Either social support is a minor strand in the tapestry of psychotropic drug use, or the concept of social support may be inadequately operationalized by standard scales. These may need to measure, beyond frequency of social contacts and residential status, subjective judgments of loneliness and of opportunities for social intimacy. Whereas a summed scale score indicating "social isolation" was not associated with benzodiazepine use in one study , in bothThe association between a diagnosis or rating of mental disorder or psychological distress and the use of psychotropic drugs is evidently anticipated. In 18 studies, 22 tests of this association were carried out, and it was significant in 17 (77%). An intriguing observation is that two of the four studies that failed to support the association included only the antidepressant drug class ,71. WhilDSM-III-R criteria [In the general population, Ohayon and Caulet  have clecriteria , is assoThe number of annual visits to a doctor's office has an obvious influence on the number of prescriptions since it has been shown that up to 75% of visits by older people end up with a prescription ,97. All Among the 16 factors identified in this review of 32 empirical reports, only the variables of language and stressful events were examined in less than five different studies. Gender, age, and mental health status were most frequently examined. The variables of race, medical consultations, proximity to health centers, sleep complaints and health perception are significantly associated with drug use in all or almost all studies incorporating them. Gender and mental health status are associated with drug use in over 70% of studies, while physical illness and number of medications are associated in slightly over half of relevant studies. However, significant associations with age, marital status, socioeconomic status, and social support are observed in only 27% to 36% of studies in which these factors are examined.Conflicting results could be explained partially by methodological and conceptual characteristics of many of the studies reviewed. The following discussion focuses on study design, sample, concept definitions and measurements , as well as distinction between short-and long-term psychotropic drug use. Table 1 see  lists tDescriptive methods (100%) using cross-sectional data (62%) predominate in this body of recent reports of psychotropic drug use in the elderly. Cross-sectional data are vulnerable to sample bias, especially when respondents are not randomly selected, as was the case in 9 of 30 (30%) studies. Given the greater costs involved, the proportion of longitudinal research (38%) seems respectable. Possibly because of cost factors, these studies examined fewer variables in relation to psychotropic drug use. However, besides highlighting the phenomenon of long-term use of psychotropic drugs by the elderly , they prVirtually all samples (29 in the 30 distinct studies) were composed of older consumers and non-consumers of psychotropic drugs. Comparisons between these two groups allow researchers to identify what differentiates users from non-users of psychotropic drugs. However, one notices from this review that researchers do not always succeed. One possible reason may be that short-and long-term users are combined in one group. Indeed, in almost every study it appears that investigators are comparing long-term users with non users. About 20% to 30% of community-dwelling older persons use psychotropic drugs , with ovThus, if most psychotropic drug use among the elderly transforms into long-term use, the process of transformation itself requires more observation and explanation, again by means of longitudinal research. Immediate problems leading to the first prescription of a psychotropic drug, such as psychological distress or insomnia, might have little relevance among long-term users. Possibly, drug dependence has developed among some long-term users and sustains long-term consumption . The sixIt also appears that over the past decade, the use of mixed samples of users and non-users of psychotropic drugs has provided little information about older consumers themselves. Although comparison is essential for understanding, perhaps more studies should target older drug users exclusively. For instance, we know of no study examining mental health outcomes of older psychotropic drugs users over time. One might deem it illogical if no studies had been conducted on the long-term effects of antihypertensive medication on blood pressure. Grad  made theThe concepts of mental health, psychological distress, depression, and social support are often studied in relation to psychotropic drug use, but operationalized differently across studies. For instance, in the body of studies here reviewed, mental or emotional state is generally measured by standardized, self-rated scales that focus on the manifestation or experience of various symptoms of psychological or bodily distress, or by structured diagnostic interviews aiming to identify mental disorders according to official diagnostic criteria. In all, at least 12 different instruments or scales, 4 different systems of diagnostic criteria (ICD-9 and ICD-10, DSM-III-R and DSM-IV), and 3 unstructured open questions were used in 18 studies to measure concepts identified as depression (12 studies), anxiety (6 studies), psychological distress, mental disorders, life events (3 studies each), psychiatric syndromes (2 studies each), and morale, nervous or emotional disorders, melancholy, nerves, emotional condition, dementia, and sleep problems (1 study each). This variability in concepts and instruments surely impacts the variability of observed relationships between drug use and mental health status , few investigators test specific hypotheses to account for the associations. For example, sparse work focuses on cultural factors that might explain drug use disparities between Whites and African-Americans. Similarly, with most drug users being long-term and most drug treatments for insomnia losing their effectiveness with long-term use, the strong association between sleep complaints and drug use needs thorough examination.One of the least studied aspects of the phenomena in the reviewed studies concerns the role of health care professionals. Physicians, nurses, and pharmacists all interact significantly with community-dwelling older persons, especially with those who take psychotropic medications. Only through a health care professional such as a physician and a pharmacist would the vast majority of older people obtain a psychotropic drug to relieve a sleep problem. Recently, the Internet and mail-order pharmacies without face-to-face interaction have facilitated individuals' access to prescription drugs. Each professional's role, as mentioned, is also likely to alter as the individual's phase of consumption transforms from short-to long-term. Researchers must face the challenge to incorporate variables related to health care professionals' attitudes and behaviors, as well as to new modes of distribution of psychotropic drugs to consumers, in their study of the phenomenon.Approximately one third of community-dwelling older persons use psychotropic medications. If the rate of psychiatric disorders among a population serves as a guideline, then obviously older persons' use of psychiatric drugs far outpaces these drugs' standard indications and has extended into areas where drugs have little documented effectiveness. Viewed in this light, the ubiquitous phenomenon of long-term psychotropic drug use should evoke concern and caution. The discipline of nursing can definitely contribute to the rational use of these agents among older people. As suggested in this review, researchers do not still fully grasp the dynamics of psychotropic drug use among this population and creative and rigorous research from several disciplines, and from interdisciplinary perspectives, is needed. However, nurses concerned by the problem of the overuse of medication and its adverse consequences can already implement and evaluate programs to educate older people and allied health care and social service professionals about the risks of psychotropic drugs and alternatives to drugs for the management of everyday anxiety, loneliness, depression, and especially insomnia. Nurses can also actively implement and evaluate drug withdrawal programs aimed at long-term users who have had difficulty in withdrawing, and especially at short-term users who might soon be trapped into dependency and thus long-term use. Conversely, diverse patterns of psychotropic drug use undoubtedly exist among older persons, and positive patterns of use, emanating from users' own experiences and discoveries, need to be documented and disseminated.None declared.PV and DC conducted the literature review and drafted the manuscript. SL and JC revised the literature review and subsequent drafts. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Characteristics of 32 empirical reports on psychotropic drug use among community-dwelling older persons, 1990–2001. Reports on psychotropic drug use among community-dwelling older persons.Click here for fileFactors associated with psychotropic drug use among community-dwelling older persons in 32 empirical reports, 1990–2001. Factors associated with psychotropic drug use among community-dwelling older persons.Click here for file


There is a dearth of standardized studies examining exposure to environmental tobacco smoke (ETS) and its relationship to respiratory health among adults in developing countries.1 and FVC). Logistic and linear regression analyses were conducted to study the relation between ETS score and studied outcomes, whereby categorical (tertiles) and continuous scores were used respectively, to evaluate the association between ETS exposure and respiratory health, and explore the dose-response relationship of the association.In 2004, the Syrian Center for Tobacco Studies (SCTS) conducted a population-based survey using stratified cluster sampling to look at issues related to environmental health of adults aged 18–65 years in Aleppo (2,500,000 inhabitants). Exposure to ETS was assessed from multiple self-reported indices combined into a composite score (maximum 22), while outcomes included both self-report (symptoms/diagnosis of asthma, bronchitis, and hay fever), and objective indices (spirometric assessment of FEVOf 2038 participants, 1118 were current non-smokers with breath CO levels ≤ 10 ppm (27.1% men, mean age 34.7 years) and were included in the current analysis. The vast majority of study participants were exposed to ETS, whereby only 3.6% had ETS score levels ≤ 2. In general, there was a significant dose-response pattern in the relationship of ETS score with symptoms of asthma, hay fever, and bronchitis, but not with diagnoses of these outcomes. The magnitude of the effect was in the range of twofold increases in the frequency of symptoms reported in the high exposure group compared to the low exposure group. Severity of specific respiratory problems, as indicated by frequency of symptoms and health care utilization for respiratory problems, was not associated with ETS exposure. Exposure to ETS was associated with impaired lung function, indicative of airflow limitation, among women only.This study provides evidence for the alarming extent of exposure to ETS among adult non-smokers in Syria, and its dose-response relationship with respiratory symptoms of infectious and non-infectious nature. It calls for concerted efforts to increase awareness of this public health problem and to enforce regulations aimed at protecting non-smokers. The deleterious effects of exposure to ETS on the respiratory system of adults and children is well documented -4. ExposThe situation with exposure to ETS in developing countries is likely to be aggravated by the widespread of smoking, lack of restrictions regarding indoor smoking, overcrowded housing conditions, and failure of health services -15. CigaDespite these troubling facts, there is a dearth of research examining the relationship between ETS exposure and respiratory health in developing countries, with the few available studies limited by poor outcome definition, lack of systematic exposure assessment, and inadequate control of confounding ,22. A reThe target population consisted of adults 18–65 years of age residing in the greater city of Aleppo (around 2,500,000 inhabitants). Detailed description of the sampling design and procedures of the AHS is reported elsewhere and illustrated in Figure The survey was conducted between May-August 2004, and the protocol and the informed consent documents were approved by the Institutional Review Boards at the University of Memphis and SCTS.This interviewer-administered survey involved six, 2-person, mixed gender teams of surveyors equipped with notebook computers programmed to record questionnaire responses and measurements using a custom data entry program (Delphi programming language and SQL server DBMS). The questionnaire included 8 main sections; socio-demographics, general health and disability, chronic disease, respiratory health, household members' health, environmental health, smoking, and ETS exposure. For the assessment of respiratory health and risks, the questionnaire was developed based on relevant instruments , as well surveys done in Syria -35. NextData from self-reported non-smokers (both cigarettes and waterpipe), validated by breath CO levels ≤ 10 ppm Table  29-35].-35.29-35Past year recurrent cough and recurrent shortness of breath were defined as having 3 or more recognizable episodes of these symptoms. Those reporting recurrent cough or shortness of breath were asked to select, from a provided list, one or more options that best described their symptoms Table . Medicatst second (FEV1) and Forced Vital Capacity (FVC) were measured for all participants according to standard guidelines [Forced Expiratory Volume in the 1idelines . We usedidelines . We usedidelines  (Table 51, FVC, FEV1/FVC and ETS score. Logistic regression was used to estimate the odds ratio (OR) and the 95% confidence interval for the relation between ETS score and respiratory symptoms adjusting for age, sex, SES score, parental allergy, occupational exposure to other respiratory pollutants, and pack years (for ex-daily smokers). Linear regression analysis was used to assess the relationship between ETS score and lung function (FEV1, FVC, and FEV1/FVC) adjusting for age, BMI, SES score, and occupational exposure to other respiratory irritants, as well as interaction terms of age with height and weight. This analysis was performed separately for men and women, since lung development and response to ETS has been shown to differ by gender [p for dose-response relationship. Because of the concern that ex-smokers may avoid ETS exposure and have respiratory problems , we repeated the analysis including only never smokers, but this did not affect the results considerably . All analyses were done by SPSS 11.Descriptive statistics were calculated for the overall study population and for measures of ETS exposure among non-smokers Tables ,2. Compoy gender ,28. In bFrom a total of 2038 valid survey responses (45.2% men, mean age 35.3 ± 12.1, response rate 86%), 1118 (27.1% men) satisfied the inclusion criteria for the exposure-symptoms analysis (Table p for dose response 0.004), past year recurrent shortness of breath (ORs 1.6 and 1.7, p = 0.001), past year recurrent exertional shortness of breath that disappears after rest (ORs 1.8 and 2, p < 0.001), past year recurrent shortness of breath almost all of the time (ORs 3 and 2.6, p = 0.02). Additionally, several symptoms suggestive of asthma/allergy were related to ETS exposure, including past year recurrent wheezing/whistling in the chest (ORs 1.4 and 1.7, p = 0.05), past year recurrent episodic dry cough accompanied by wheezing (ORs 1.9 and 1.9, p = 0.05), past year recurrent episodic shortness of breath accompanied by wheezing (ORs 2.2 and 1.6, p = 0.06), past year recurrent nocturnal cough not related to cold that wakes the subject up (ORs 1.2 and 1.9, p = 0.02), and past year hay fever symptoms (ORs 0.9 and 1.5, p = 0.01). Among symptoms suggestive of chronic bronchitis, ETS exposure was associated with recurrent shortness of breath accompanied by cough and phlegm (ORs 2.2 and 2.5, p = 0.02). And finally, past year episodes of acute lower respiratory infection (bronchitis, pneumonia) were associated with exposure to ETS (OR 1.3 and 1.9, p = 0.03) . General respiratory symptoms associated with exposure to ETS were past year recurrent cough (ORs for comparison between middle, high, with the low exposure group were 1.3 and 1.9, respectively, with In contrast, exposure to ETS was not related to severity of respiratory complaints judged by the number of episodes (wheezing, sinusitis, acute bronchitis, pneumonia), medical care utilization for respiratory problems in general Table , as well1 (coefficient -0.1, p < 0.001), FVC (-0.1, p = 0.002), and %FEV1/FVC (-0.6, p = 0.1). Linear regression analysis between ETS exposure score and lung functions showed significant inverse associations with indices of airflow limitation (FEV1 and FEV1/FVC) only in women. Women in the middle category of ETS exposure had on average 88 ml deficit in FEV1 and 2% in FEV1/FVC in comparison to those in the low exposure category. This association did not show a dose-response relationship  among women only.This study shows that exposure to ETS is universal among non-smoking adults in Aleppo-Syria. This exposure is associated with respiratory complaints of both infectious and non-infectious etiology in a dose-response fashion, suggesting a causal relationship. Unlike data from developed countries, however, exposure to ETS was not related to increased severity of asthma or other respiratory conditions judged by symptoms frequency and medical care utilization because of respiratory problems. ETS exposure was associated with decrements in lung functions suggestive of airflow limitation  irritation for a quarter of nonsmokers. In comparison, less than a quarter of non-smokers in a national sample of 43,732 adults in the US report exposure to ETS . InteresIn general, this study shows stronger and dose-dependent relationships of ETS exposure with general respiratory symptoms (i.e. recurrent cough or shortness of breath) than with symptoms characteristic of specific respiratory problems (asthma, bronchitis). Arguably, general symptoms are more easily identifiable as well as shared among many respiratory problems. The magnitude of difference in self-reported asthma symptoms according to exposure level is generally in the range of a twofold increase. This effect magnitude is similar to that reported in adults from 16 European countries , but lower than that reported from the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) ,50. SimiLevel of exposure to ETS in our population was not associated with severity of asthma, sinusitis, or lower respiratory tract infection. In contrast, in a study of 349 adults with asthma in the US, Eisner and colleagues found that exposure to ETS at baseline was associated with more symptom severity and emergency/hospital admissions because of asthma at 18 month followup . Medical1, FVC, FEV1/FVC) in women but not men [1, and FEV1/FVC) in female but not male non-smokers. The reduction for the middle compared to low exposure category was in the magnitude of 88 ml for FEV1 and 2% for FEV1/FVC. Although other studies have reported similar gender-specific vulnerability of women [1 in the univariate analysis. It is possible that we are dealing in our setting with levels of exposure that exceed those occurring in western societies. Indeed, because of the low magnitude of the effect of ETS exposure on lung function, studies have relied on comparisons of exposed vs. non-exposed individuals to assess this relationship [Studies of the relation between exposure to ETS and lung function have generally shown a detrimental effect of such exposure. This effect, however, was not consistent and of low magnitude generally (50–100 ml) . For exa not men . Data fr not men . The eff not men . Our stuof women , it is itionship ,53-55. IThis study shows that exposure to ETS is rampant among adult non-smokers in Syria, where it is hard to escape it due to a high prevalence of smoking, household over-crowding, and lack of smoking restrictions. This exposure is leading to increased respiratory symptoms/disease of both infectious and non infectious etiologies, and is likely to have deleterious effects on respiratory function among women. In addition, the dose-response association found between exposure to ETS and respiratory symptoms point towards causal relationship. These results send a clear message to health advocates and policy makers about the spread and harmful effects of exposure to ETS in Syria and on the importance of collective efforts to educate both the public and authorities about this major health hazard and ways to effectively protect non-smokers from it. In addition to giving further support to the health hazards of ETS exposure, this study can provide guidance for future research on this issue in other developing countries.• AC- air condition• AHS- Aleppo Household Survey• ECRHS- European Community Respiratory Health Survey• ETS- environmental tobacco smoke1- forced expiratory volume in the 1st second• FEV• FVC- forced vital capacity• NHANES III- third National Health and Nutrition Examination Survey• OR- odds ratio• PC- personal computer.• ppm- part per million• PPS- probability proportionate to size• SAPALDIA Swiss Study on Air Pollution and Lung Diseases in Adults• SD-standard deviation• TV- televisionst draft of the manuscript. KD Ward, T Eissenberg, participated in the study design and co-authored the manuscript. S Rastam and F Mzayek participated in the data management, analysis, and co-authored the manuscript.W Maziak, designed the study, conducted the analysis and wrote the 1Appendix 1 : Composite scores for SES and ETS used in the study with the total score categorized around tertile cut off points.Click here for file


Viral promoters are used in mammalian expression vectors because they generally have strong activity in a wide variety of cells of differing tissues and species.The utility of the BLV LTR/promoter (BLVp) for use in mammalian expression vectors was investigated through direct comparison to the CMV promoter (CMVp). Promoter activity was measured using luciferase assays of cell lines from different tissues and species stably transduced with BLVp or CMVp driven luciferase vectors including D17, FLK, BL3.1 and primary bovine B cells. Cells were also modified through the addition of BLV Tax expression vectors and/or BLV infection as well as treatment with trichostatin A (TSA).Results indicate the BLV promoter, while having low basal activity compared to the CMV promoter, can be induced to high-levels of activity similar to the CMV promoter in all cells tested. Tax or BLV infection specifically enhanced BLVp activity with no effect on CMVp activity. In contrast, the non-specific activator, TSA, enhanced both BLVp and CMVp activity.Based on these data, we conclude the BLV promoter could be very useful for transgene expression in mammalian expression vectors. Viral promoters are commonly used as regulatory elements in gene therapy vectors due to their strong activity in various cell lines in vitro. Probably the most widely used promoter in mammalian expression systems is the human cytomegalovirus immediate-early gene (CMV) promoter. The CMV promoter induces high-level constitutive expression in a variety of mammalian cell lines . In manycis-acting elements in addition to the CAAT box, TATA box, and transcription start site [cis-elements contain motifs resembling the cyclic AMP-responsive element (CRE) as well as an E box sequence [The U3 region of the BLV promoter, located in the 5' long terminal repeat (LTR), contains several important art site . The majsequence . Tax doesequence -9. The tsequence . There isequence . A nuclesequence . Finallysequence . This PUWe hypothesized that the BLV promoter could be used in mammalian expression vectors for regulated high-level gene expression. Our approach was to compare reporter gene expression driven by either the BLV promoter or CMV promoter in different cell types with or without BLV infection or Tax induction. Our results demonstrate that the BLV promoter can be induced to express the reporter gene to levels as great as the constitutive CMV promoter.All cells used in these studies were maintained in RPMI 1640 medium (Invitrogen) supplemented with 10% fetal calf serum (FCS), 4.5% dextrose, 1 mM sodium pyruvate, and antibiotic-antimycotic solution (100 μg/ml penicillin G sodium, 100 μg/ml streptomycin sulfate, 0.25 μg/ml amphotericin B). In addition, the following concentrations of drugs were added for each selective media: Blasticidin-S (Invivogen) 10 μg/ml; G418-sulfate  400 μg/ml. The following cell lines were used: D17 [dog osteosarcoma; ATCC CCL-183; ], FLK s], BL3.1 7 cells were stained for 15 min at 6° – 12°C with 10 μg/100 μl total volume anti-IgM . After washing, 20 μl/100 μl total volume of MACS rat anti-mouse IgG2a+b microbeads were mixed with the cells and incubated for 15 min at 6° – 12°C. Cells were thoroughly washed, and magnetically separated. These IgM+ cells were considered primary B cells. Microfluorimetry using anti-IgM  indicated 90% purity. Stably transduced cell lines were generated after one week in selective media. Primary B cells were analyzed after one week in selective media since they began to die out after two weeks in culture.Primary bovine B cells were purified as follows. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized cow blood through a ficoll density gradient as previously described . B cellsBam HI-Hind III fragment) to create the vector pLNBlv. The pLNBlv and pLNCX retrovector plasmids were modified to place the Gateway Rfa cassette  downstream of the internal promoters (BLV or CMV) in order to simplify further cloning, to create retrovector plasmids pLNBlv-G or pLNC-G. For enhanced protein expression, the WPRE element (from plasmid BluescriptII SK+ WPRE-B11 (a gift from Tom Hope–the same as bp 2717–3309 of Genbank Locus OHVHEPBA ACCESSION J04514) was cloned downstream of the Gateway Rfa cassette with standard cloning methods to create vectors pLNC-GW and pLNBlv-GW. The source for firefly luciferase encoding sequence was pGEM-luc (Promega). The luciferase coding sequence was subcloned into pENTR1A (Invitrogen) to engineer the Gateway entry vector pENTR1A/luc. The Luciferase gene was recombined into pLNC-GW or pLNBlv-GW using LR Clonase (Invitrogen) per manufacturer's instructions. The promoter-less luciferase expression control vector pLN[]W/luc was engineered by removing the BLV promoter (Bam HI digest) from pLNBlv/luc. BLV Tax (Genbank Locus AAF97920) was isolated by reverse transcription PCR from FLK cells and subcloned into pENTR1A (Invitrogen) to engineer the Gateway entry vector pENTR1A/Tax. The Tax gene was recombined into pLBC-GW where the neomycin resistance gene of pLNC-GW was replaced with the blasticidin resistance gene.The plasmid pBLV913 (a gift from David Derse), coding for an infectious molecular clone of BLV  was usedThroughout these studies we assayed expression vectors with and without the WPRE. WPRE enhanced transgene expression in all cell lines used, and in a promoter-independent fashion (about 2-fold greater for BLVp and CMVp in D17 cells). Subsequently, all data shown in this report are only with vectors containing WPRE.Retrovirus-mediated gene transfer was accomplished using the BD Retro-X System (BD Biosciences Clontech) following the manufacturer's suggested protocol. Briefly, 100 mm × 20 mm tissue culture dishes  were seeded with the packaging cell line GP2-293 at 70–90% confluency. Each dish of GP2-293 cells was co-transfected with 5 μg each of retroviral vector and the envelope glycoprotein expression vector pVSV-G using 15 μl/transfection of Lipofectamine 2000 (Invitrogen) cationic lipid reagent for 3 h in a total volume of 5 ml medium/dish. Subsequently, transfection medium was replaced with 10 ml growth medium, and the cells were incubated for 72 h. Retrovirus-containing supernatant was then harvested and passed through a 0.45 μm cellulose acetate filter, then concentrated by ultracentrifugation at 50,000 × g for 30 min at 4°C. Supernatant was carefully poured off and virus was resuspended in the residue (~200 μl) and frozen (-70°C) for future use. Cells for transduction were plated on 6-well tissue culture plates  at 50% confluency. Concentrated retrovirus (titer unknown) along with polybrene (8 μg/ml) were added to one ml/well cells (in a 6-well plate) and incubated overnight. Transduction medium was replaced with fresh growth medium, and the following day cells were split into appropriate selective medium. BLV was harvested from supernatant of FLK cells, concentrated, and used to transduce cells in a similar fashion.6 cells were aliquoted to 1.5 ml microcentrifuge tubes. Then, cells were pelleted at 300 × g for 10 min, washed once with PBS, and lysed with 200 μl reporter lysis buffer (Promega). Lysate was stored at -20°C until assayed. Lysate was thawed and pelleted (300 × g for 10 min), and luciferase was measured with the luminometer using 10 μl lysate/50 μl reagent for 10 s. Linear range was under 1 × 107 RLU.Luciferase assays (Promega) were performed using a single-tube luminometer (Pharmingen) to measure relative light units (RLU) on a linear scale. Cells to be assayed were counted using a hemacytometer, and 1 × 10Student's t-test was performed for statistical evaluation of the results. Results are expressed as the arithmetic mean with the variance of the mean (mean ± SE).Our studies utilized a commercially available retroviral system with its standard CMV promoter (CMVp) or replaced with the BLV promoter (BLVp). Figure cis elements that are dependent on BLV Tax for transgene expression [cis element that is B cell specific (PU.1/Spi-B). We therefore compared the strengths of BLV and CMV promoters in primary B cells and a BLV infected B cell line hypothesizing that BLVp expression would be comparable to CMVp activity. BLVp activity was still less than CMVp activity in primary B cells but by only about a 5-fold difference . Luciferase assays demonstrated that BLV promoter activity in infected D17 cells was about 10-fold greater than BLV promoter activity in non-infected D17 cells  has been shown to be the most efficient activator of BLV expression known to date . To detecis-acting elements and the dependence upon Tax using reporter vectors in mammalian cell lines has been published [Viral promoters are used in mammalian expression vectors because they can have strong activity in a wide variety of cells of differing tissues and species. Probably the most employed is the CMV promoter because of its proven high-level constitutive expression in a variety of mammalian cell lines ,25. Whilublished ,27,28. HSeveral attributes are important in developing a mammalian expression vector. Probably the most important attribute of a mammalian expression vector promoter is its ability to accomplish high-level transcriptional activity in a large variety of cell types of different tissues and species. Our studies showed that the BLV promoter could achieve similar high-level activity to the CMV promoter in cells expressing BLV Tax or infected with BLV. This comparatively high BLV promoter activity was demonstrated in D17 cells which we have found to be the highest expresser of CMV promoter driven transgenes of all cell lines tested in our laboratory. The CMV promoter activity was still about 5-fold greater than BLV promoter activity in the BLV infected D17 cells compared to the relatively equal activity of the CMV promoter versus BLV promoter in BLV infected FLK cells. However, FLK cells contain four copies of the BLV provirus  whereas cis-elements have demonstrated significant decreases in basal level activity, as with the mutation of the GRE site [A second important attribute of an inducible promoter apart from high-induced expression is low basal expression. Researchers have reported barely detectable BLV promoter Tax-independent activity through luciferase assays of COS-1, C8, and KU-1 cell transient transfections . Our resGRE site , signifiGRE site , or eithGRE site . Still, A third important attribute for an inducible promoter would be a sensitive modulated response to a specific inducer. Enhancement of the BLV promoter can occur independent of Tax by the addition of activating agents. Phorbol esters, phytohemaglutinin, and lipopolysaccharides have all been shown to enhance BLV promoter expression . Howeverfos. Clearly, there is great potential to magnify the desirable traits of the BLV promoter/Tax system for mammalian expression vectors and minimize undesirable traits.Nevertheless, the transactivating properties of BLV Tax are not limited to activation of the BLV promoter. Tax has been shown to upregulate Bcl-2 and increase nuclear NFkB activity . Tax expTo determine whether the BLV promoter could be a useful mammalian expression vector element, we compared its activity with the CMV immediate early promoter in dog osteosarcoma (D17), BLV-infected fetal lamb kidney (FLK), BLV-infected bovine B-lymphosarcoma (BL3.1), and primary bovine B-cells. Without concomitant Tax expression from a transgene or BLV infection, the BLV promoter activity was low compared to CMV promoter activity. In the presence of Tax or BLV expression, the BLV promoter activity became equally as active as the CMV promoter. The CMV promoter was not influenced by Tax or BLV. Tax overexpressed as a transgene in BLV infected cells resulted in BLV promoter expression greater than CMV promoter expression. The deacetylase inhibitor, trichostatin A was a potent upregulator of both BLV and CMV promoters. Our results indicate the BLV promoter has great potential use as an inducible promoter for mammalian expression vectors.None declared.JSH carried out cell culture work including transfection/transduction and luciferase assays, data preparation and analyses, and drafted the manuscript. KAE performed genetic engineering of vectors. LSK did preliminary work to establish study concepts. RDB and GAS participated in the design and coordination of the study. All authors read and approved the final manuscript.


This study was designed to examine the knowledge, attitude and beliefs about causes, manifestations and treatment of mental illness among adults in a rural community in northern Nigeria.A cross sectional study design was used. A pre-tested, semi-structured questionnaire was administered to 250 adults residing in Karfi village, northern Nigeria.The most common symptoms proffered by respondents as manifestations of mental illness included aggression/destructiveness (22.0%), loquaciousness (21.2%), eccentric behavior (16.1%) and wandering (13.3%). Drug misuse including alcohol, cannabis, and other street drugs was identified in 34.3% of the responses as a major cause of mental illness, followed by divine wrath/ God's will (19%), and magic/spirit possession (18.0%). About 46% of respondents preferred orthodox medical care for the mentally sick while 34% were more inclined to spiritual healing. Almost half of the respondents harbored negative feelings towards the mentally ill. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects .Our study demonstrates the need for community educational programs in Nigeria aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons. Throughout the world, there is an increasing awareness of mental illness as a significant cause of morbidity . This awMental and behavioral disorders are common, affecting more than 25% of all people at some time during their lives . They arThe role of the community in the prevention and care of the mentally handicapped has now been widely acknowledged and is regarded as the most appropriate basis for the development of mental health programs. Several studies have shown that knowledge of public attitude to mental illness and its treatment is a vitally important prerequisite to the realization of successful community-based programs -6. The rPeople tend to have strong beliefs about the mentally ill, and many of these concepts are based on prevailing local systems of belief . In deveThe 1995 Nigeria National Mental Health Policy advocates the integration of mental health promotion, treatment and rehabilitation into primary health care services (PHC). However, this goal cannot be successfully achieved without an understanding of community attitudes towards mental illness. We therefore set out to ascertain the perceptions, attitudes and beliefs of adults regarding the causes, manifestations and treatment options of mental illness in a traditional Hausa community near Kano, Nigeria.The study population included 250 adults residing at Karfi village, about 15 kilometers from Kano city. This typical Hausa community has 11,314 inhabitants . MajoritA cross sectional descriptive studyA multistage sampling technique was adopted. In the first stage, four wards out of the seven in the village were randomly selected. After house numbering, 250 houses were selected from the four wards using a table of random numbers. Where more than one household was found in a house, one household was selected by balloting. Finally, one adult was selected at random from each household for the interview. A final sample size of 250 adults was therefore obtained.We adopted and modified a pre-existing semi-structured questionnaire  to evaluThe study instrument was validated using a pilot study of 10 randomly selected households in a nearby village with similar demographic characteristics (Kumbotso). Results of the pilot study were used to modify content and wording of the questionnaire. Previously trained medical undergraduates fluent in Hausa language administered the questionnaires to the sample population.® 6.0 statistical software package (CDC Atlanta, Georgia, USA). Descriptive statistics were depicted using absolute numbers, simple percentages, range, and measures of central tendency (mean, median) as appropriate. The Chi-square test was used to test the significance of associations between categorical groups. All tests of hypothesis were two-tailed with a type 1 error rate fixed at 5%.The data was analyzed using the Epi-InfoIn all, 250 respondents were interviewed with 167 males and 83 females giving a sex ratio of 2:1 in favor of males. Their ages ranged from 18 to 74 years. Majority (78.0%) of the respondents were aged between 25 and 60 years. The median age (± SD) for the respondents was 34.5 ± 4.6 years; 36.0 ± 2.3 years for males and 28.5 ± 1.6 years for females. The Hausa-Fulani ethnic group constituted 89% of respondents, and the rest were Yoruba 2.0%, Igbo 5.0% and other minority Nigerian tribes 4.0%. About 16.0% of respondents had primary education, 12.0% had secondary education, and 4.0% had tertiary (post-secondary school) education. Approximately 27.0% of the population sampled had no formal education. Nevertheless, 41.0% of all respondents had Quranic education. The majority of respondents (90.0%) were Muslims and the remaining 10.0% were Christians. About 10.0% were single, 80.0% were married, 6.0% were divorced and the remaining 4.0% were widowed. Forty eight per cent of the respondents were engaged in farming, 25.0% were full-time housewives, 20.0% were engaged in petty trading, 7.0% were students and the remaining 4.0% were civil servants. About 13 persons interviewed (5.2%) had a relative with mental illness, but because of the small sample size we did not separately analyze findings from this group of participants.The most common symptoms proffered by respondents as manifestations of mental illness Table  includedThe majority of respondents (46.0%) opted for orthodox medical care when asked about preferred source of treatment for the mentally ill. This was followed by spiritual healing (exorcism) 34.0%) and the use of traditional herbal medicines (18.0%)  . Our finding is also in contrast to Adebowale and Ogunlesi [Belief in demons as the cause of mental health problems is a well-known phenomenon in many cultures of the world  but in oOnly 1.0% of respondents admitted that financial distress or poverty was a possible cause of mental disorder. Such a low score in the face of the present adverse socio-economic conditions prevailing in Nigeria may be explained by the Hausa cultural cum religious belief in providence and patience in the face of adversity. Other factors have also been reported by investigators as being associated with perceived causes of mental illness among patients and their relatives. Srinivasan and Thara  found thThere was a higher score on the preference for modern medical care in treating psychiatric illness. Similar changes in attitude towards the modern scientific approach regarding mental disorders was documented by Alem et al  in theirFear and avoidance of the mentally sick was frequent among female respondents. Traditionally, men are expected to be outwardly brave and less submissive towards aggression. The high frequency of negative attitudes among our respondents may be due to the fact that the concept of the mentally sick has an unfavourable public image. It has been shown that people may evaluate mental illness negatively, reject and discriminate against mental patients, and base their views on traditional stereotypes ,10,16.et al. [et al. [et al. [Literacy was found to be significantly associated with positive attitude towards the mentally sick. Similar findings were reported by Madianos et al.  in Greec [et al.  in Ethio [et al. . Interes [et al. . Our res [et al.  that negThis study demonstrates the need for educational programs aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons. Our findings may be of utility to health policy makers in the design of community mental health education programs and community mental health services in existing primary health centers in Nigeria.None declared.KM and IZ initiated the study, and participated in the field work. IZ and AIS did the preliminary analysis and wrote the draft manuscript. KM, AIS and IZ participated in the design of the study and performed the statistical analysis. KM, IZ, and AIS participated in its design and coordination. AMH, KM and IZ wrote the final version of the draft manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Pneumocystis pneumonia (PCP) is an increasing problem amongst patients on immunosuppression with autoimmune inflammatory disorders (AID). The disease presents acutely and its diagnosis requires bronchoalveolar lavage in most cases. Despite treatment with intravenous antibiotics, PCP carries a worse prognosis in AID patients than HIV positive patients. The overall incidence of PCP in patients with AID remains low, although patients with Wegener's granulomatosis are at particular risk.In adults with AID, the risk of PCP is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis.Corticosteroids, lymphopenia and a low CD4+ count in particular, have been identified as risk factors for the development of PCP in adults with AID. Trimethoprim-sulfamethoxazole (co-trimoxazole) is an effective prophylactic agent, but indications for its use remain ill-defined. Further prospective trials are required to validate our proposed prevention strategy. Pneumocystis carinii was identified a hundred years ago by Chagas  and recoPneumocystis pneumonia is caused in humans by the recently renamed Pneumocystis jiroveci Frenkel 1999), previously known as Pneumocystis carinii and now thought to be related to fungi on the basis of DNA analysis, despite morphological similarities to protozoa . The org99, previPneumocystis pneumonia is almost always exclusive to immunocompromised hosts. Two thirds of cases occur in HIV positive patients and constitutes the initial manifestation of AIDS in 46% of these patients . A thirdP. jiroveci trophozoites proliferate and attach to type I alveolar pneumocytes causing desquamation, leading to a foamy eosinophilic exudate visible on hematoxylin-eosin staining and a "honey comb" appearance of lung tissue. Both antibody and cell mediated immunity have been postulated as being involved in host protection .HIV-negative patients with PCP are older (48–61 years) than HIV positive patients. Males are affected more often than females . The clinical course is typically more acute, with an average duration of 6–13 days. The most frequent clinical symptoms are dyspnoea (63–100%), cough (55–74%), weakness (47%), loss of appetite (38%) expectoration 22–25%), sweating (19%), weight loss (13%), haemoptysis (9%) and thoracic pain (9%). Physical findings include fever >38°C (63–85%), râles (55–66%), tachycardia (25%) and tachypnoea (22%). Chest radiography may show bilateral abnormalities (68–88%), interstitial opacities (64–80%) and alveolar opacities (31–47%), but may be normal (5–7%) -16,18,21–25%, sweP. jiroveci infection is diagnosed in most cases by bronchoalveolar lavage, which, depending on the staining method used, has been reported to have a sensitivity of 81 to 90% and a specificity of 90 to 100% . Other mTwo antibiotic regimes have been shown to work, co-trimoxazole and parenteral pentamidine isethionate. Efficacies are comparable, although side-effects are particularly common with co-trimoxazole in HIV associated PCP and affect up to 60% of such patients . These iThe prognosis of HIV negative PCP is worse than for those HIV positive, with intensive care admission in 31–60%; mechanical ventilation in 14–64%; overall mortality 19–47%, rising to 50–71% on intensive care, although some series suggest an improved mortality in recent years ,27. PoorWhile PCP in HIV positive patients has been associated with a high incidence of relapse after successful therapy, this has not been seen in patients with AID, even without secondary prophylaxis and despite ongoing immunosuppressive treatment. This is thought to be related to better clearance of organism, confirmed by repeat bronchoalveolar lavage .There is no specific surveillance system in the United Kingdom (UK) for PCP, other than in HIV infection. Although laboratories are invited to report isolates of P. jiroveci to the Communicable Disease Surveillance Centre, it is estimated that only a fifth of clinically diagnosed cases of PCP are reported . As the The overall incidence of PCP from 1990 to 1999 has declined in the UK , as a reAttempts have been made to characterise the incidence of PCP amongst patients with AID, usually by retrospective analysis of case records. Ward & Donald's review of 223 cases of PCP in AID is the largest series and covered 2.6 million hospitalisations over the period 1983 to 1994 . They foPneumocystis pneumonia in AID is unusual in the absence of steroid treatment. Corticosteroids have been recently administered in over 90% of cases in most series ,17,18,22A number of cytotoxic and other immunosuppressive agents commonly used in the treatment of AID are frequently associated with PCP, including cyclophosphamide, azathioprine, methotrexate and ciclosporin . Cycloph3) is almost a prerequisite, with 91% of patients exhibiting a low lymphocyte count. Fifty percent of such PCP patients have total lymphocyte counts of <400 cells/mm3 [3 was recorded in ten (83%) of 12 patients with PCP, but such a low lymphocyte count was recorded in 11 (34%) of 32 with Wegener's unaffected by PCP [3 which captured 4 out of 6 cases with PCP and SLE, but only 1 of 20 patients with SLE unaffected by PCP.Data on PCP associated with AID indicates lymphocytopenia  and have a particularly poor prognosis, as discussed earlier.Any method used to select patients for prophylactic treatment needs to be assessed against set standards and have a high sensitivity and specificity. The standards should address the percentage of PCP cases captured by the selection criteria  and the risk of the condition in the selected group (which should be significant). In HIV patients who meet the criteria for PCP prophylaxis as set out by the US Public Health Service , the ann3 would capture 91% of cases of PCP in all HIV negative patients, but would also include 39–46% of patients on systemic steroids, most of whom would be unaffected by PCP. Administering prophylaxis to such large numbers of patients would unnecessarily expose patients to drug side-effects and potentially encourage drug resistance. However, analysis of their data reveals that the subgroup of patients with AID who developed PCP had CD4+ counts of <250 cells/mm3 and six out of eight had counts <200 cells/mm3 [In the study by Mansharamani et al, their proposed cut off of <300 CD4+ cells/mmells/mm3 .Given the laboratory costs, we would argue in favour of performing CD4+ counts after one month's immunosuppression only on patients who satisfy the following three screening criteria:• Steroid dosage >15 mg prednisolone or equivalent/day• >three months corticosteroid treatment proposed3• total lymphocyte count <600 cells/mm3 might then warrant the use of prophylactic co-trimoxazole, if the annual risk of PCP in these patients is greater than 9%. Most cases of PCP in patients with AID would be captured by these criteria, according to published series.A CD4+ count <200 cells/mm3, information which is currently unavailable.Clearly, further prospective investigation is required to gather sufficient data to validate any selection method. To justify our proposed threshold for prophylaxis we would need to know the risk of PCP for patients on steroid-based immunosuppression for AID with CD4+ counts of <200 cells/mmP. jiroveci infection in HIV negative patients presents more acutely and has a worse prognosis. The incidence of PCP in patients with AID is low, although these patients still represent a considerable proportion of all HIV negative cases. It is important to have a high index of suspicion of PCP when treating AID with steroid based immunosuppressive regimes, as early treatment could improve prognosis. The risk of infection is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Effective and relatively safe prophylaxis is available. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis. Further prospective trials are required to validate our proposed prevention strategy.The authors declare that they have no competing interests.AJ Carmichael initiated the discussion, appraised results, lead departmental debates and helped revise the manuscript. ES carried out the literature search, presented at meetings and wrote the original manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Molecular oxygen may be necessary for life but with its beneficial properties comes formation of potentially toxic reactive oxygen species. One of the ways in which bacteria protect themselves is explained Nevertheless, with the beneficial properties of O2 comes the inadvertent formation of reactive oxygen species, including superoxide (O−2), hydrogen peroxide (H2O2), and hydroxyl radical (•OH); these differ from O2 in having one, two, and three additional electrons, respectively  groups of cysteinyl amino acid residues in proteins. Elevated levels of H2O2 also are associated with the oxidation of other amino acids, leading to the formation of methionine sulfoxide and a variety of carbonyls. Lastly, because of its extreme reactivity, •OH targets all of the major macromolecules of cells: RNA, DNA, protein, and lipids. The extent to which membrane lipids are targets appears to depend on the presence of polyunsaturated fatty acids in lipids, which are not as prevalent in bacteria as they are in mammals.The major target of Oubstrate . Since sth media . H2O2 foE. coli  in the presence of NADPH and glutathione reductase. There are two thioredoxins in E. coli that also function to reduce disulfide bonds. Reduced thioredoxin is regenerated by thioredoxin reductase and NADPH. The fact that NADPH is required to maintain the reduced state of glutathione and thioredoxin indicates that the response to oxidative stress is coupled to the physiological status of core pathways that generate NADPH.Another component to the oxidative stress response is the reduction of oxidized thiols that arises through one of the mechanisms described below. The tripeptide glutathione and the thiol reductants glutaredoxin and thioredoxin are key to the restoration of thiols to their reduced state (SH) . E. coli2O2. The reaction of cysteinyl thiolates with H2O2 can lead to the formation of different modifications, such as sulfenic acid (–SOH), sulfinic acid (–SO2H), and sulfonic acid (–SO3H), as well as disulfide bond formation (–S–S–) and glutathione conjugation (–S–GSH)  (As mentioned above, proteins—in particular, the thiols of cysteines—are the major targets of H(–S–GSH)   .Given the reversible nature of most forms of thiol oxidation, it has been suggested that thiol modifications can play roles in signal transduction that are similar to protein phosphorylation/dephosphorylation . In suppE. coli and a variety of other bacteria. OxyR contains two critical cysteines that are oxidized to form an intramolecular disulfide bond when cells encounter peroxide stress , and zinc is released upon oxidation of the thiols. For both proteins, oxidation and zinc release are associated with an opening of the protein structure. For Hsp33, this structural change allows for dimerization and activates its chaperone activity (Two other examples of redox-regulated proteins are the in Hsp33  and the or, RsrA . For theactivity . RsrA, oactivity . Among tXanthomonas campestris pv. phaseoli (Bacillus subtilus (2O2 or by organic peroxides (ROOH) formed by the oxidation of a variety of organic molecules in the cell or in the environment. The B. subtilis OhrR transcription regulator contains only a single cysteine that forms a relatively stable sulfenic acid upon its reaction with H2O2 or organic peroxides (The peroxide-sensing repressor OhrR from phaseoli  and Bacisubtilus  can be ieroxides . OxidatiIn this issue, 2O2. We do not currently understand all of the features that determine the reactivity of a particular thiol to H2O2 (As illustrated by the examples above, an array of chemical modifications obtained by oxidizing cysteinyl residues has been exploited in combating oxidative stress. Yet it is important to note that not all cysteinyl residues of proteins are readily oxidized by oxidants such as H to H2O2 . The pKaE. coli has also been shown to contain a H2O2-labile zinc site, although the loss of zinc does not change its reductase activity (The added complexity of the cysteine targets that compose part of a Zn binding site found for Hsp33 and RsrA raises questions about the function of the zinc. Perhaps Zn binding provides some additional control over the reactivity of the cysteine thiols, or perhaps the loss of the zinc facilitates conformational changes. Recently, the oxidative, stress-induced thioredoxin-2 from activity . Thus, t2O2 and the experimental challenges associated with their detection has made it difficult to catalog all the proteins that are modified and all the types of modifications that exist. In this issue, The extent of thiol oxidation within the cell remains another open question. The variety of modifications that arise from treatment with HSaccharomyces cerevisiae requires a peroxidase denoted Gpx3 or Orp1 (2O2 reacts with a cysteine in Orp1, forming an unstable sulfenic acid intermediate that then reacts with a cysteinyl residue of Yap1 to form an intermolecular disulfide. The disulfide undergoes an exchange with a second cysteine within Yap1 to form an intramolecular disulfide that locks Yap1 in a confirmation that masks the nuclear export signal (The importance of monitoring transient changes in cysteines is highlighted by the recent finding that oxidation of the Yap1 activator of antioxidant genes in the yeast  or Orp1 . In thist signal . Thus, mThe examples mentioned here illustrate the versatile potential of thiol modifications. Given the reversibility of thiol oxidations and the wide range of structural constraints that can be imposed by the formation of a sulfenic or sulfinic acid or a disulfide bond, we predict there will be many more examples of regulation by thiol modification.


Helicobacter pylori causes chronic gastritis, peptic ulcer disease, gastric carcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. It infects over 50% of the worlds' population, however, only a small subset of infected people experience H. pylori-associated illnesses. Associations with disease-specific factors remain enigmatic years after the genome sequences were deciphered. Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma. Recent studies revealed mechanisms through which the cagA protein triggers oncopathogenic activities. Other candidate genes such as some members of the so-called plasticity region cluster are also implicated to be associated with carcinoma of stomach. Study of the evolution of polymorphisms and sequence variation in H. pylori populations on a global basis has provided a window into the history of human population migration and co-evolution of this pathogen with its host. Possible symbiotic relationships were debated since the discovery of this pathogen. The debate has been further intensified as some studies have posed the possibility that H. pylori infection may be beneficial in some humans. This assumption is based on increased incidence of gastro-oesophageal reflux disease (GERD), Barrett's oesophagus and adenocarcinoma of the oesophagus following H. pylori eradication in some countries. The contribution of comparative genomics to our understanding of the genome organisation and diversity of H. pylori and its pathophysiological importance to human healthcare is exemplified in this review.The human gastric pathogen  Helicobacter pylori is a bacterium that colonizes the harshly acidic milieu of the human stomach. More than half of the world's population carries this infection. Infection rates vary among the developed and developing countries of the world. H. pylori infection is on a steep decline in most of the western countries mainly due to the success of combination therapies and improved personal hygiene and community sanitation to prevent re-infection. However, the situation is not improving in many of the developing countries due to failure of treatment regimes and emergence of drug resistance. The infection in some cases leads to chronic superficial gastritis, chronic active gastritis, peptic ulcer disease and gastric adenocarcinoma [H. pylori is the genetic diversity between clinical isolates obtained from different patient populations. Most H. pylori isolates can be discriminated from others by DNA profiling [H. pylori has a panmictic or freely recombining population structure [H. pylori chromosome. However, such genetic recombinations in the H. pylori genome might not be deleterious because they occur in the plasticity zone, a special cluster of DNA rearrangements that protects the essential complement of genes by acting as a bed for foreign DNA insertion or abrogation. DNA loss and rearrangement are therefore a norm for H. pylori, and flexibility and diversity in gene content may contribute to bacterial fitness in different members of the diverse human host population. Post genomic analyses have revealed interesting attributes of H. pylori pathogenicity and novel mechanisms of causation of ulcer disease and cancer have been envisaged. Efforts to know the cause and potential benefits of the genetic diversity of this bacterium has led to some interesting discoveries relating to its co-evolution with the human host, microevolution while during infection and quasi-species development, virulence determinants and eradication strategies. Recent studies reviewed herein collectively aim at testing the speculation about whether H. pylori may be beneficial to human health in certain circumstances and whether eradication of this organism is always necessary? Epidemiological studies are needed in the context of such intriguing hypotheses. Results obtained from such studies might enable the development of a high-throughput screening system for high-risk groups within the huge population of H. pylori-infected individuals. Recent studies have shown that H. pylori infection protects against gastro-oesophageal reflux and oesophageal carcinoma. So it will be important to selectively eradicate H. pylori in people that are at the highest risk of developing gastric carcinoma. Eradication of highly pathogenic H. pylori specifically from high-risk groups would markedly reduce the worldwide incidence of ulcer and gastric cancer.arcinoma -4. One orofiling -8 or seqrofiling ,10. Alsotructure  and is ntructure . These cH. pylori infection is usually acquired during childhood, where transmission occurs predominantly within families [H. pylori populations that are evolving in each individual separately from one another [H. pylori strains, there are distinct sets of H. pylori genotypes colonising different human populations. With different strains evolving separately of one another and the fact that H. pylori is a genetically diverse (panmictic) organism, distinct genotypes have been found to be associated with particular geographic regions [vacA gene (a gene encoding a vacuolating cytotoxin) within a local H. pylori population has led to predominant vacA genotypes being characteristic of isolates from different geographic regions. In addition, worldwide studies encompassing H. pylori isolates from many geographic regions have demonstrated weak clonal groupings and geographic partitioning of H. pylori isolates [H. pylori population, exchange of genetic sequences can genetically homogenise this population. As H. pylori is naturally competent and recombination occurs frequently [families . A coupl another ,10. It i regions ,16. For isolates ,17. If requently , specifiH. pylori population from a particular geographic region to another H. pylori population from another geographic region via human migration makes the association of particular genotypes with specific geographic locations more difficult. Although the introduction of new polymorphisms into a particular H. pylori population poses a problem with identifying specific genotypes within certain geographic locales, it may, however, provide information on the ancestry of the hosts in whose stomachs the strains were carried. Studies have been aimed at demonstrating the path of human migration to Latin America with conflicting results regarding whether European or Asian populations brought H. pylori to South America [et al. [H. pylori isolates recovered from twenty-seven countries displayed geographic partitioning. Thus, polymorphisms within the H. pylori genome can serve as useful markers for studying ancient human migrations. However, a mix up of H. pylori strains between migrated and native populations can sometimes complicate analysis. Accordingly, the study of migrated populations that have remained isolated from the native populations is essential.Introduction of polymorphisms and sequence variants from one  America ,11. Howe [et al.  demonstrH. pylori has been linked to various pathologies and a strong association with gastric carcinoma and mucosa-associated lymphoid tissue lymphoma [H. pylori is definitely responsible for these diseases, only less than 10% of people colonized with H. pylori portray disease symptoms. This suggests that specific H. pylori strains may be responsible for virulence in different hosts. Many studies have shown that certain allotypes of the vacA gene and the presence a functional cagA gene are associated with an increased risk of peptic ulceration and gastric cancer, respectively [H. pylori alleles with clinical diseases have failed.Since its successful isolation in 1983 by Warren and Marshall, ectively -22. HoweH. pylori strains trigger higher virulence as compared to other strains? Current approaches in functional genomics based on protein- protein interaction and microarray based transcription profiling are helping to decode this mystery. Functional genomics often uses the gene chip based expression profiling to provide a condition-dependent and time-specific genome wide profile of an organism's transcriptome [in silico modelling to summarise gene encoded (or putative) functions. H. pylori has been the first prokaryote wherein full genome sequence of two different patient isolates [J99 and 26995] were characterized and compared [H. pylori is a freely recombining or panmictic organism [H. pylori genomes [H. pylori chromosome. Recombinational events including the presence of insertion elements, pathogenicity islands, horizontally acquired genes (restriction recombination genes), mosaics and chromosomal rearrangements were frequently annotated in subsequent bioinformatics based attempts. It has been argued that such diversity is a result of a lack of direct competition between strains, even when resident within different individuals within the same community [H. pylori genome [H. pylori has extensive, non-randomly distributed repetitive chromosomal sequences, and that recombination between identical repeats contributes to the variation within individual hosts [H. pylori is representative of prokaryotes, especially those with smaller (<2 megabases) genomes, that have similarly extensive direct repeats, suggests that recombination between such direct DNA repeats is a widely conserved mechanism to promote genome diversification [H. pylori has been termed as a panmictic organism [H. pylori populations exist [H. pylori in some populations shows a clonal descent and suggest that a large array of H. pylori clonal lineages co-exist, which evolve in isolation from on another [H. pylori isolates have been shown to exhibit little genetic heterogeneity, based on fingerprint profiles [H. pylori isolates undergo 'microevolution' and give rise to sub-species during prolonged colonisation of a single host [H. pylori population to specific host niches, facilitated by unknown advantages conferred to them by select plasticity region genes. Bjorkholm et al. [cag pathogenicity island (cag PAI) in one isolate and not the other. As the cagA gene and cag PAI are principle virulence factors within the strains, the excision or abrogation of the cag PAI within a strain may indicate that attenuating the virulence of a strain could be a favourable adaptation.So how do a few criptome ,24. Whercriptome ,26. Bothcompared ,28. As Horganism  the quesorganism ,28. Straorganism ,30, in w genomes  and reclommunity . Howeveri genome . It has al hosts . That H.fication . In addiorganism ,35, it ins exist -39. Rece another . Moreoveprofiles ,40. Funcprofiles , the traprofiles , the ideprofiles ,30 and tprofiles . One of gle host -46. The m et al.  demonstrH. pylori is a model for studying genome plasticity in the colonization of individual hosts. For H. pylori, neither point mutation, nor intergenic recombination requiring the presence of multiple colonizing strains, is sufficient to fully explain the observed diversity.Within the bacterial populations, genome content may not be fixed, as changing selective forces favour particular phenotypes; however, organisms well adapted to particular niches may have evolved mechanisms to facilitate such plasticity. The highly diverse H. pylori genomes sequenced to date are each from ethnic Europeans, and genomic comparisons modelled on these data are sufficient to identify novel loci from new strains, especially from understudied Asian populations. However, these genome sequences may not be fully representative of the entire diversity of the gene pool. Identification and characterization of such loci which are more abundant in the Asian gene pool may lead to newer insights into the mechanisms of H. pylori colonization, carriage and virulence in the countries of Asia which are more seriously under threat from H. pylori. Therefore, future high throughput efforts involving a large number of strains are clearly needed. Taking the Indian example for instance, according to the Ethnologue database , there are about 1683 languages and dialects ('mother tongues') in this country and H. pylori diversity therefore can be assumed to coincide with this figure. So one has to roughly look at the inter-strain genomic diversity contributed by approximately 1683 different strains representing each dialect and or a community.The two Nonetheless, genotypic data from each geographic area or a community is extremely vital and might constitute a missing piece of a large, biologic jigsaw puzzle.H. pylori harbours a dedicated type IV apparatus, the comB gene cluster [comB gene cluster is essential for the bacterium to take up plasmid and chromosomal DNA during natural transformation. To identify the genes essential for natural transformation competence in H. pylori, genetic approach of transposon shuttle mutagenesis has been used and the comB locus was located, consisting of orf2 and comB1-comB3 [Agrobacterium tumifaciens type IV secretory apparatus) as comB7, comB8, comB9 and comB10 respectively . One of the principal virulence factors of H. pylori, the cagA antigen is contained in the 40 kb cag-PAI. The tyrosine-phosphorylated cagA protein is translocated to the epithelial cells by the type IV secretion system (forming a sort of syringe like structure) [cag-PAI interfere with tyrosine phosphorylation and induction of interleukin-8 secretion [cag-PAI are essential for cagA translocation and/or interleukin 8 induction, a complete mutagenesis of the cag-PAI was performed [H. pylori [Molecular analysis of bacterial transport has been attempted in several bacterial pathogens. Among such transport systems, Type IV secretion systems have been described in greater detail in diverse bacteria. In ructure) -53. Uponecretion . In receerformed . In gene. pylori . All the. pylori . However. pylori .H. pylori 26695 has revealed a sheathed, surface organelle, coded by the cag-PAI genes, HP0527 (forms sheath around the pilus needle) and HP0532/ cagT (forms the base of the pilus) [H. pylori to the host niches and this might mediate biological as well as transport functions of the cag-PAI encoded proteins. Computational analyses to predict the macromolecular assemblies of such apparatuses are needed to have a more simplified understanding of the entire model of the H. pylori type IV secretion mechanismVery recently, and for the first time, ultrastructure analysis of the surface of e pilus) . This stH. pylori-infected population than in the H. pylori-uninfected population [cagA gene of H. pylori is assumed as partially responsible for eliciting signaling mechanisms that lead to the development of gastric adenocarcinoma. Based on the carriage of a functional cagA as a marker for the cag PAI, the H. pylori species is divided into cagA-positive and cagA-negative strains. The cagA-positive strains are associated with higher grades of gastric or duodenal ulceration and are more virulent than the cagA-negative strains [cagA positive H. pylori in the development of atrophic gastritis, peptic-ulcer disease and gastric carcinoma [cagA gene product, cagA, is translocated to the gastric epithelial cells to undergo tyrosine phosphorylation by SRC family kinases [cagA-positive H. pylori promotes gastric carcinogenesis. Cag A is noted for its variation at the SHP2 binding site and, based on the sequence variation, it is sub- classified into two main types – East-Asian cagA and Western cagA. East-Asian cagA shows stronger SHP2 binding and greater biological activity than Western cagA. In East-Asian countries, endemic circulation of H. pylori strains that carry biologically active forms of cagA might underlie the high incidence of gastric carcinoma. One puzzling attribute of H. pylori infection is why some populations with high incidences of H. pylori infection, such as those in Japan and Korea, have high incidences of gastric carcinoma, whereas other highly infected populations, such as populations in central Africa, do not. Possible reasons could be the differences in genetic susceptibility among populations, environmental factors such as dietary habits, and strain differences of H. pylori. Among these, diversity of cagA in H. pylori strains might be involved in determination of the type and severity of disease. As discussed above, East-Asian and Western forms of cagA possess the distinctly structured tyrosine phosphorylation/ SHP2-binding sites – EPIYA-D and EPIYA-C, respectively [cagA-positive strain is associated with the mortality rate of gastric cancer in Asia. Therefore, populations infected with East-Asian cagA positive H. pylori are at greater risk for gastric cancer than those infected with Western cagA-positive strains.A large-scale prospective study revealed that the risk for development of gastric carcinoma was much greater in the pulation . The cag strains . Some eparcinoma ,62. The  kinases . Tyrosinectively . Notablyectively . FurtherH. pylori [Among Western CagA species, the number of EPIYA-C sites directly correlates with levels of tyrosine phosphorylation, SHP2-binding activity and morphological transformation . Further. pylori .H. pylori has a single copy of the vacA gene. Screening of H. pylori chromosomal fragments permitted the identification of a 3864-base pair open reading frame (vacA) that encoded the vacuolating cytotoxin [vacA gene includes a 33 amino acid signal sequence. With the exception of a hydrophobic region at the N terminus, the mature 90-kDa protein (amino acids 34 to 842) is mainly hydrophilic [H. pylori strains. The different combinations of s and m regions determine the production of cytotoxic activity. Strains with the genotype s1 m1 produce high levels of vacuolating cytotoxin in vitro. Strains with the genotype s2 produce an inactive toxin. Whereas, strains with the genotype m2 produce toxic activity with a different target cell specificity from those of m1 genotype. Genotypic variations in the vacA gene structure specific to a geographic locale have been recognised. While the vacA m1a allele is specific for the European strains [ytotoxin . The seqrophilic . The cyt strains , the vac strains . Yet ano strains . Among ovir B operon of A. tumifaciens carried in a 16.3 kb genomic fragment called tfs3  of the mucosa-associated lymphoid tissue (MALT)-type and strains from age matched patients with gastritis only [v 49%) and JHP1462 (26% v 3%). JHP950 proved specific for gastric MZBL when tested against a group of strains from patients with duodenal ulcer and patients with adenocarcinoma, with significant prevalence (49% and 39%, respectively), and is therefore the candidate marker for gastric MZBL. Interestingly, the candidate ORF JHP950 is located in the plasticity region of the J99 genome [The plasticity region as a whole displays certain characteristics of pathogenicity islands  with relormation . Interesormation . Many geormation . Researctis only . Two ORF9 genome ,76. In vH. pylori is still controversial. However, it is accepted that this organism has colonized humans possibly for many thousands of years, and the successful persistence of H. pylori in human stomach for such a long period may be because this organism offers some advantages to the host. Unfortunately, the H. pylori infection is on steep decline in the western world. This is mainly due to the success rate of combination therapies and subsequent prevention of re-infection due to improvement in sanitation and personal hygiene. This may seem good news to many gastro-enterologists around the world, but having a H. pylori infection may be advantageous. A study has shown that H. pylori produces a cecropin-like peptide  with high antimicrobial properties [H. pylori were less likely to have diarrhoea than children without an infection [H. pylori may have beneficial properties to human hosts. Interestingly, there has been a marked decline in the instances of peptic ulcer disease and gastric cancer in the 20th century. Concurrent with this is a dramatic increase in the incidences of gastro-oesophageal reflux disease (GERD), Barrett's oesophagus and adenocarcinoma of the oesophagus in Western countries [H. pylori may in some way be associated with these diseases and perhaps capable of preventing their onset. Studies have also shown that cagA+ H. pylori strains have a more protective effect than cagA- strains [cagA+ H. pylori strains can reduce the acidity of the stomach, and it is believed that the raising of the pH by H. pylori prevents GERD, Barrett's oesophagus and adenocarcinoma of the oesophagus . Conversely, arguments have been made that, although H. pylori may prevent these reflux-associated diseases, the risks of acquiring gastric cancer via H. pylori infection far outweigh any possible benefits it may provide [H. pylori does provide protection from GERD, the notion of restriction of anti-H. pylori treatment to only a few cases (peptic ulcer disease and MALT lymphoma) could be justified [H. pylori in erosive reflux oesophagitis [How long humans carried operties . A Germanfection , implyinountries . This ob strains . The pre provide . Howeverustified . In spitphagitis -85. Howephagitis  it seemsH. pylori in non-users of non-steroidal anti-inflammatory drug (NSAID). In addition, the incidence of H. pylori-negative, non-NSAID peptic ulcer disease (PUD) (idiopathic PUD) is reported to increase with time. Moreover, it appears that H. pylori-positive ulcers are not always H. pylori-induced ulcers because there are two paradoxes of the H. pylori myth, first the existence of H. pylori-positive non-recurring ulcer and secondly, recurring ulcer after cure of H. pylori infection. To summarise, H. pylori is not the only cause of peptic ulcer disease. Therefore, it is still necessary to seriously consider the need for eradication in all cases of PUD, which may exist even after the elimination of H. pylori.On the other hand, eradication also is not an ultimate choice. Some ulcers recur even after successful eradication of H. pylori in health and disease may be fully ascertained only if we analyze genetic diversity of the pathogen as juxtaposed to the host diversity and the environment (food and dietary habits). A possible working hypothesis (that we are currently nurturing) may be that among the ocean of molecular host-pathogen interactions that could potentially occur with micro-evolution of this bacterium during long term colonization, some could prove advantageous where the bacterium and the host negotiate nearly a 'symbiotic' and balanced relationship. Such a 'friendship' might have taken thousands of years to develop. If so, why has this bacterium survived for such a long time? Microbes that have long been persisted in humans may be less harmful than recently emerged microbes, such as the human immunodeficiency viruses (HIV). This suggests that the colonization may either be beneficial or of low biological cost to the host. In addition to characterization of bacterial virulence apparatuses that are for sure linked to disease outcome, host responses to such factors must also be examined hand in hand, to completely ascertain mechanisms that lead to gastroduodenal disease. For instance polymorphisms linked to the host immune apparatus, such as IL-1β, TNF-α, and IL-10, which are responsible for elevated proinflammatory potential of the strains. These polymorphisms increase the risk for atrophic gastritis and distal gastric adenocarcinoma among H. pylori-infected persons. Cancer of stomach is a highly lethal disease and establishment of H. pylori as a risk factor for this malignancy deserves an approach to identify persons at increased risk; however, infection with this organism is extremely common and most colonized persons never develop cancer. Thus, screens to identify high-risk subpopulations must use high-resolution biological markers. Fortunately, this task appears to be highly simplified due to the availability of biological tools, which were never thought in the past. Genome sequences (H. pylori, human, C. elegans), quantitative phenotypes , and practical animal models (Mongolian gerbils) can be harnessed to decipher the molecular basis of H. pylori-associated malignancies, which should have direct clinical applications. It is important to gain more insight into the pathogenesis of H. pylori-induced gastric adenocarcinoma, not only to develop more effective diagnostics and treatment for this common cancer, but also to validate the role of chronic inflammation in the genesis of other tumours of the alimentary tract.In our opinion, the intricacies of the role of