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The Styblo model is the result of international collaboration aimed at the expansion of national tuberculosis (TB) programs in partner countries. This model is the foundation of the DOTS strategy launched in the 1990s and which was subsequently expanded as a global strategy. This paper discusses the impact and relevance of this body of work. The basic principles supporting the model still hold. There is a tendency to be all-inclusive when global strategies are devised, which increases the complexity of such strategies. Whereas it is relatively easy to standardize diagnosis and surveillance, this is not the case with patient care and treatment where, as recent experiences in TB programs show, universal recommendations can be controversial. It may be unwise to put forward global strategies when the terrain is as variable as it is in different parts of the world. Since the conception of the model, the human immunodeficiency virus (HIV) pandemic has been gaining force in Africa. As a result, TB control efforts on the continent have been severely undermined. The relevance of the model in this setting is questioned. Although HIV infection has contributed to outbreaks of drug-resistant TB, it has also facilitated the control of outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Where MDR-TB has reached critical proportions in the absence of HIV, it has proven difficult to control. Technological development has not kept up with the need for new tools. Whereas many policy analysts agree that a revised strategy is required, a convincing breakthrough has yet to appear.

Background: Respiratory syncytial virus (RSV) infections during infancy are considered to be a risk factor for developing asthma and possibly allergic sensitization., Objective: The aim of this study was to investigate the cytokines, chemokines, and eosinophil cationic protein in the nasopharyngeal secretions of infants < or = 7 months of age with RSV infections or other respiratory viral infections and healthy infants as controls. Groups were also analyzed according to age, < or = 3 months and >3 months, and the levels were compared within and between groups., Results: Thirty-nine infants with RSV, 9 with influenza or parainfluenza virus infections and 50 controls with no history of infections, were enrolled in the study. The RSV-infected infants had significantly higher levels of IL-4; macrophage inflammatory protein 1beta, a chemoattractant for T cells; and eosinophil cationic protein in nasopharyngeal secretions compared with the control group. The levels of the TH2 cytokine IL-4 were significantly higher in RSV-infected infants < or = months of age compared with RSV-infected infants >3 months of age. In infants < or = 3 months of age, infections with influenza or parainfluenza virus caused TH2-like responses similar to those produced by RSV., Conclusion: Infections with RSV as well as with influenza and parainfluenza virus during early infancy preferentially promote a TH2-like response in the nose with local production of IL-4, IL-5, and macrophage inflammatory protein 1beta and infiltration and activation of eosinophils.

Objective: To evaluate practices in initial drug susceptibility testing (DST) in Moldova, anti-tuberculosis drug resistance and the implications for tuberculosis control., Methods: Retrospective record review in the national reference laboratory., Results: Of 3463 cases, 57.1% were recorded as 'new' and 24.6% as 'retreatment' cases; previous treatment status was not recorded for 18.3%. Of the 'new' cases, 1655 were correctly classified according to international recommendations and 322 were misclassified. The number of cases increased from 443 in 1995 to 939 in 1999; the proportion of 'retreatment' increased from 17.4% to 35.5%, 'any drug resistance' from 20.3% to 41.6%, and 'multidrug resistance' from 2.7% to 11.2%. In 1998-1999, 'any drug resistance' and 'multidrug resistance' in 800 previously untreated cases were respectively 29.1% and 5.3%, and respectively 61.0% and 21.9% in 521 'retreatment' cases. Of a total of 216 'multidrug-resistant' cases in 1998-1999, 21.8% were reported resistant to ethambutol and 81.5% to streptomycin., Conclusions: Initial specimens for culture are frequently taken late, after the start of treatment, compromising their usefulness for case management or surveillance. Inadequate treatment has led to an increase in the number of cases, the proportion of previously treated cases and the prevalence of drug resistance. In 1998-1999, a high proportion of cases with 'multidrug resistance' were susceptible to ethambutol.

Objective: Cervical cancer is a disease caused in part by an infection with an oncogenic subtype of human papillomavirus (HPV). In this study we analysed all cervical cancer samples diagnosed in Iceland during two periods, 1958-1960 and 1995-1996, and asked whether significant changes in viral or immunological parameters had occurred over a period that spanned both significant changes in sexual attitude and the implementation of organized screening for cervical cancer., Methods: Samples from 47 patients (46 squamous cell carcinomas (SCC) and 1 adenosquamous carcinoma (ASC)) in the first period and 30 patients (20 SCC, 4 ASC, and 6 adenocarcinomas (AC)) in the later period were analysed for viral subtype and expression of Fas, FasL, MHC class I, p53 and apoptosis., Results: AC and ASC are proportionately much more common today than 40 years ago (30% vs 2%). The distribution of HPV in cervical cancer is similar in both periods, with HPV16 found in 75% and HPV18 in 13% of cases. Other HPV types found were 31,33,45, and 59. No significant differences were found in the immunological profiles of tumors from the two periods except that a higher fraction of SCC in the later period stained positive for FasL. When SCC are compared with AC/ASC, the latter have less expression of MHC class I, less expression of Fas, and stronger FasL expression., Conclusions: AC/ASC tumors show some immunological features that suggest that they are more resistant to immune attack than SCC.

Setting: Vientiane municipality, Laos., Objective: To describe and evaluate the implementation of standardized registration and reporting procedures within the municipality in a period of decentralization. The purpose of the standardization was to obtain complete and reliable information on case-finding and treatment results., Design: Evaluation by review of quarterly reports on case-finding and treatment results, and comparison of information from the records of individual patients on site with the records of the supervisors., Results: Case-finding increased in 1994-1998. Treatment success improved from 26.8% (95% CI 21.5-44.0) to 74.6% (95% CI 69.9-79.3). Given an option for autoadministered long-course treatment versus directly observed short-course treatment, 97% of the patients registered in 1998 received the latter. Following decentralization, evaluation of results of treatment was incomplete due to a high ratio of 'transfer out' patients (16.4%, 95% CI 11.5-21.3). After intervention this proportion was reduced to 2.3% (95 %CI 0.7-3.9). In 1998, approximately 40% of smear-positive patients diagnosed at the National Tuberculosis Center and residing in the districts evaluated were 'transferred' or 'referred' to the districts. All but three of the 68 patients presented at the district hospitals, mostly without delay. Registration and reporting was reasonably accurate. At the end of the period evaluated, decentralization was only partial and problems in case-holding were still evident., Conclusions: When decentralizing services it is important to establish procedures for management of information flow in order to allow the activities to be evaluated and problems amenable for correction to

Setting: Laos, where the implementation of a national tuberculosis program started in 1995., Objective: To estimate the prevalence (P) and annual risk of tuberculosis infection (ARTI) and relate this to case rates in the tuberculosis program., Methods: Tuberculin survey in schools in Vientiane municipality and three provinces. Sampling was not representative, but included schools in accessible districts in provinces with different characteristics. A group of 150 tuberculosis patients were tested for comparison., Results: An intra-dermal tuberculin test (PPD RT23/ Tween80) was applied to 11237 children; 9968 reactions were read, 4035 among first and second grade children with no BCG scar: 818 in Vientiane (mean age 8.4), 803 in Savannakhet (8.9), 1563 in Xiengkhuang (8.4), and 851 in Luangprabang (7.9). If reactions of > or =10 mm are counted, ARTI is estimated as 1.1% for the areas included in the survey with a strong variation by province (Vientiane 1.3%; Savannakhet 1.4%; Luangprabang 0.6%; Xiengkhuang 0.1%). The difference in ARTI is in accordance with differences in reported case rates in the provinces. The ARTI varied from 0.5% to 1.2%, depending on the method used for calculating P (Vientiane 0.6%-1.4%; Savannakhet 0.5-1.5%; Xiengkhuang 0.1%-0.2%; Luangprabang 0.4%-0.9%)., Conclusions: The ARTI is unequally distributed geographically and/or by ethnic group. It is generally higher in south and lower in central and north Laos. Improved methods are needed for estimating the prevalence of infection.

Setting: IUATLD collaborative programme, Nicaragua., Objective: To analyse reported trends in the retreatment failure rate (2SRHZE/1RHZE/5R3H3E3), and assess demographic characteristics, drug resistance and survival in patients who fail retreatment., Design: A retrospective, descriptive study. Reports from 1988-1996 were analysed and records of 69 patients who failed retreatment were reviewed., Results: The treatment success rate in new cases improved from 71% in 1988-1991 to 79% in 1992-1996, the default rate decreased from 16% to 10%, and the failure rate remained stable at 2-3%. The proportion of previously treated patients among all smear-positives decreased from 20% to 15%. In retreatment patients the failure rate declined from 6.6% to 4.3% and the average annual number of failures from 24 to 13. In 1992-1996, 64 patients, 0.8% of new smear-positive cases treated during this period, failed retreatment; the corresponding figures for 1988-1991 are 95 and 1.6%. Among 69 retreatment failure cases reviewed, there was male predominance and increasing age during the study period. Drug susceptibility results were available for 38, of whom 89% were resistant to isoniazid and rifampicin. The median survival of patients after failure was 3.9 years., Conclusion: Treatment results improved over the study period. The proportion of patients on retreatment out of all smear positives treated decreased, as did the absolute number of failures and the retreatment failure rate. Development of multidrug resistance has been largely prevented in Nicaragua; the low failure rate justifies the continued use of the standardised retreatment regimen.

The global burden of tuberculosis is enormous, even if estimates are somewhat uncertain. The forces counteracting control measures, namely demographic factors, drug resistance, HIV, migration, poverty and marginalization, are enormous as well. With accelerated reforms in tuberculosis programs important progress can be made towards the control of tuberculosis early in the 21st century. This is confirmed by studying reports from countries where control measures have been implemented and sustained. Well-functioning programs can make good use of technological progress, such as improved tools for diagnosis and treatment, when these become available at an affordable cost. It is important now to use the opportunity of increased resources in order to reform tuberculosis programs. The biggest impact on global tuberculosis control in the 21st century can be made in Asia. Success in this part of the world depends on political commitment. Elsewhere, the main forces counteracting control measures are HIV in Africa and multidrug resistance in parts of Europe and the former Soviet Union. Here solutions are still on the drawing board. The long time-frame for tuberculosis control when using the currently recommended strategy, the uncertain impact of "improved" tools on this time-frame and the constant threat that political commitment will not be sustained are reasons why field workers look towards new technology in hope of progress in vaccine research. Here, the prospects are uncertain and the forecasted time-frame is long. Skeptics even doubt that an effective vaccine can be developed. However, when predicting progress it is important to realize that it is for the most part unpredictable.

Setting: Laboratories performing sputum smear microscopy for tuberculosis in Benin, Malawi, Nicaragua and Senegal., Methods: Analysis of computerized laboratory registers to ascertain workload, yield from serial smear examination, and demographic characteristics of examinees., Results: Data from more than 60,000 examinees in 42 laboratories showed that the average number of smears examined per day ranged from 4 to 19 (mean 6) per country. To find one case of tuberculosis, on average 21 smears of suspects were examined (range 8 to 50). Of all cases with ultimately at least one positive result, 87% were already positive on the first examination. Demographic characteristics of cases differed considerably by country and gender. In 35 of 42 laboratories, males were more frequently found to be cases than females, and with increasing age an increasingly larger number of female than male suspects had to be examined to identify one case., Conclusions: This study demonstrates the usefulness of a standardized recording system for results of acid-fast microscopy in obtaining essential information for program management and on demographic characteristics of persons presenting for examination.

Objective: To compare treatment results before and after introduction of short course tuberculosis chemotherapy and to identify factors affecting the results., Design/setting: An eight-month chemotherapy regimen for smear-positive pulmonary tuberculosis was introduced in Nicaragua in 1984 with external financial assistance. We performed a retrospective record review to compare treatment results before and after introduction of short-course chemotherapy. Information on support services and programme administration, availability of hospital beds for tuberculosis patients, access to health services and the economic and war situation in the two periods was assessed., Results: The overall success ratio improved by 39% between the two periods reviewed, in spite of evidence of a deteriorating economy and escalation in civil war. A success ratio of 71% was achieved and we estimate that between 80 and 90% of registered cases stopped transmitting tuberculosis. The best results were obtained in the treatment of previously untreated patients with eight-month chemotherapy and in retreatment of relapses. The worst results were obtained in retreatment of defaulters. Analysis of the findings by region suggests that short-course chemotherapy was important, but not enough by itself to guarantee success. Factors likely to have influenced treatment results are: commitment by health authorities in guaranteeing personnel and hospital beds, training of personnel, and supervision of service delivery. Possibilities for further improvement are discussed., Conclusions: Good results were achieved in tuberculosis control with the introduction of short-course chemotherapy in spite of poverty and war. Government commitment and simultaneous improvement in supportive services and programme management is important when introducing short-course chemotherapy in low income countries.

Background: Primary cytomegalovirus (CMV) infections in healthy adults are considered extremely rare. To study the extent of this problem in Iceland we undertook a two year (1989-1990) retrospective study of all new CMV infections in adults., Methods: All positive tests for CMV antibodies in clinical samples (194) were identified in the sole virology laboratory in Iceland. Patients younger than 16 years and all patients with underlying diseases that could cause immunosuppression were excluded (154). The 40 remaining patients were contacted, their case histories reviewed and their serology for CMV, Epstein-Barr and HIV antibodies remeasured. Primary CMV infection was not confirmed in 14 patients leaving 26 immune competent patients who fullfilled our criteria for primary sym-tomatic CMV infection by the presence of IgM anti-CMV antibodies., Results: Duration of illness in the 26 study patients varied from 1 to 25 weeks, usually 7-10 weeks. Fifteen patients were hospitalized. Diagnostic delay was considerable. Immunological tests (DTH skin test, serum immunoglobulines and lymphocyte differential counts) done 172-2 years after the illness did nor reveal any persistent immune abnormalities except for an absolute increase in the number of CD8+ T lymphocytes Conclusions: We conclude that primary CMV infections in adults are not uncommon and probably underdiagnosed. When adult patients present with non-specific symptoms such as low grade fever, malaise and unexplained fatigue, CMV should be considered or excluded with appropriate serological tests.

Serum and cerebrospinal fluid samples from multiple sclerosis (MS) patients containing various levels of Clq-reactive immune complexes (IC) and samples from age- and sex-matched controls were tested by an antigen-specific IC radioimmunoassay which detects IC containing myelin membrane-related antigens. Positive reactivity in the assay was significantly associated with IC-containing MS sera (P less than 0.005) but such an association was not observed with MS cerebrospinal fluid. Analysis of longitudinal specimens revealed that the levels of the antigen-specific serum IC fluctuated with time. Significant correlation between serum levels of Clq-reactive IC and serum levels of IC containing myelin membrane-related antigens was observed (r = 0.62; P less than 0.001). Sucrose gradient centrifugation of sera from 1 patient showed that the IC had a peak density of 1.075 g/ml, indicating the presence of lipid material. The results suggest that serum IC of MS patients frequently contain myelin membrane-related antigens and that these antigens may be lipids or lipid-associated.