Changes in tuberculosis prevalence in a south Indian rural community following a tuberculosis control programme over a seven years period (A preliminary report)

A tuberculosis programme based upon detection of bacillary cases of pulmonary tuberculosis, isolation and treatment in hospital as well as on BCG vaccination of non-infected persons was introduced in Madanapalle in 1948 and in the surrounding villages in 1950. The total study population was about 50,000, later increasing to about 60,000. The present report deals with the results obtained after a period of seven years in a population of about 40,000 living in nearly 200 villages within a radius of about ten miles of Madanapalle but excludes the town population. In 1950-51 an X-ray survey by a mobile unit was carried out and about 21,000 persons were photographed. Between 1951 and 1954 another three rounds of X-ray examinations were done bringing the total of persons X-rayed up to nearly 32,000 and many of these had repeat X-rays. At the same time an intensive examination by tuberculin tests was done, about 25,000 persons being tested at least once. Details of these activities have been given in a previous report (Frimodt-Moller, 1960). In 1957-58 the same population was again X-rayed. This time about 32,000 were X-rayed, the coverage being better than during the first survey. Tuberculin examinations were not done. At all surveys, cases showing significant pulmonary pathology on X-ray were selected for further examination by large X-ray and bacteriology. The present report, however, deals only with the prevalence of tuberculosis based upon the radiological findings

Post-vaccination allergy eleven years after BCG vaccination

The risk of being infected with tubercle bacilli is greatest at the age of 10 to 19 years. If BCG vaccination is given in the preschool or during the first school years, the postvaccination allergy should be maintained at a fairly high level for a period of up to 10 to 15 years. Is it possible that BCG-induced allergy can last that long? In Danish children BCG allergy has been maintained at a high level for 5 years (WHO Tub. Res. Office 1956). The two BCG assessment teams which carried out retests in India in 1954 and 1955 respectively found also BCG induced allergy at a moderate level in children vaccinated 4 years earlier (WHO Tub. Res. Office, 1955 and 1957). At Madanapalle, presence of BCG allergy could be demonstrated after an interval of 4 years (Frimodt-Moller, 1960). Kul Bushan (1960) examined between August 1955 and October 1958 the post-vaccination allergy in school children in 129 different localities throughout India. The interval between vaccination and retests ranged from 1J months to 3J years, the average being 13 months. The mean size of indurations during the first 6 months was 13.0mm., during the second half year 11.5mm., during the third half year 11.2 mm., during the fourth half year 12.8 mm., and after 2-3 J years 12.1 mm. Our experience with BCG vaccination at Madanapalle dates back to 1948 when a high proportion of the town population was tuberculin tested and nearly all tuberculin negative persons vaccinated (Frimodt-Moller, 1949). In 1950 the village population of 37,000 within 10 miles of Madanapalle was submitted to a community-wide survey by tuberculin tests and X-ray. The first place to be surveyed was Vayalpad, a small town of 5,500 inhabitants. During the summer of 1950 all persons reacting with less than 6 mm., to 1 and 10 TU were offered BCG vaccination. In 1961, i.e., 11 years later, a series of tuberculin tests was carried out in the Board High School at Vayalpad. Fifty-five per cent of the school children were found to have been vaccinated earlier, and many of these as far back as 1950. The present report describes the results of these retests

A controlled study of the effect of domiciliary tuberculosis chemotherapy programme in a rural community in South India

To study thc ellicttq of a domiciliary drug-therapy programme in the control of tuberculosis in a rural community, an investigation was set lip in 1958 under the auspices of the Indian Council of Medlenl I{C!IClln:h ill 12 towns with populations ranging from 6000 to 25000, all within 160 km of Madanapallc (Andhra Pradt'Sh). The prevalences of bacillary and radioloj.(ic~ll cases of pulmonary tuberculosis in adults (llgcd 15 )T or more) were estimated in .. ch town by carrying out a hase-Iine random sample survey iu 1959; also, the prevalences of tuberculous infcl'tion in all schoolchildrt,n aged 5 to 9yr wen' estimated. These thn.'t' in.dices of prevalence were used to rank the 12 towns and tben ndomlyallocate them into two l'omparable groups of 6 towns each, designated as 'Ireatment' and '~:ontmJ' tOWIlS. In treatment tOWIIS, intensi"e case finding ,,-as undertaken hy means of 2 X-ray surveys (suney I during 1960-61 and survey II during 1962-64) l'ovcring alllldults, sputum examinations by microSl'op' Hnd culture when indicated, and eriodic follow lip of all 'suspect' cases with X-ray and SPlltuDl examinations. All bacillary cases were offered domiciliary treatment for onc ~'ear with isoniazid and PAS in the J treatment IOWll~ (selected at random) a.nd with isoniazid alone in the other 3 town.·,. Of 148 2easc~ eligible for trcat-at ment in tJlC 6 treatment towns, 15 per l'en.t refused treatment nd 29 per cent discontin.ued chemotherapy prematurely. In lhe rontrol towns, 0.0 spcdal faeililies for di~gn()sis 01' calment ,vere introduced, and patients w~'re left to the routine treatment facilities aV:lilahk' locally. A tuberculosis prcntlcm:e survey (~ul'l'ey Ill) t'O\'cri~ all adults was 1.1lrried out iD 9.1112 towns during 1965-68, am! lhi:; ~:l." followed hy a random tuberculin sample survey during 1966-69. The overall results of treatment at the end of one year ,,'eJ'e.' (i) among cases initially positive hy micro~opy, 10 per' nt died, 33 per locnt rcmllincd sputum-positive IUld 51 per cent became sputum-negative in INH-PAS towns, the mrl'lsponding percentages fur INH lowns being 15, 48 and 37 per cent respectivel~'; (ii): moug cases initially positive by culture ()nJy, 6 per ent died, 26 J1er cent remained sputum-posithc and 68 per cent became sputum negative in lNH-PAS towns, tbe correspondi percentages for tile INH town~ being 1, 38 an. 55 IJer cent respectively. All the bacillary cases (treated or untrcatt'lf) were followed up and their status at the end of 5 yr was 40.4 per cent dead, 18.2 per cent sputum-positive and 41.4 pCT cent sputum-ne'~ative. Spntum status at one year had considerable prognostic value. Of 532 sputum-negative ea .. at one year, 18 per l'ent were dead, 16 per CCDt sputuDl-posithe and 66 per cent sputum-ncgath'e 5 yr aftenvards, where'd!! the corresponding percentagt'S for (JIC 319 sputum-positive cases at one year were 56, 20 llnd 24 respectively. There was an intennl of about 2l ~'r between sunc)' [ and survey [[ and ahout 4 yr between survey [J and survey 111 in the 6 treatmellt towns. The prevalence of badllary cases in these sUr\'eys was age-standardised, cousidering separately l'UseS found hy microscopy and cases found by culture only. The lJlean prevalence of cases (Wsitive hy microscopy in the 6 treatment towns was 6.81 per thousand in survey I and it decre~sed significanUy (P < 0,01) to 5.01 in survey nand 4.83 in survey Ill. Change of culture technique during the course of the investi~ation complicated the interpretation of prcva· lenl'C:l of culture-positive cases. BetwCCR the 1959 base-line survey and tbe resurvey in 1965·68, the prevalence ()f smear-positive tuberculosis decreas~d from 5.92 per thousand adults to 4.78 in the 6 treatment towns, and similarly from 5.72 to 4.21 in the 6 control towns. The prcvalenl-e of 'culture only-positive' cases was 3.85 and 2.44 per thousand adults in the treatment and control towns respectively at the base-line survey and (with the more sesnsitive culture technique) 4.92 and 4.82 per thousand adults at the resurvey in 1965·68. Lastly, tho tuberculin survey in 1966·69 did not I" .,'ell! any' significant differences between the tr t· ment and the control towns. The inability ofthe domiciliary treatment programme to make an impact on the prevalefl:lc of tuberculosis in the rural community around Madanapalle is a finding that has cOllsidera lie siJ,(nilicance in the context of the tubercUlosis control programme in fndia; the rl'asons for the failure aud its implications are discussed

Effect of a reduction in glomerular filtration rate after nephrectomy on arterial stiffness and central hemodynamics: rationale and design of the EARNEST study

Background: There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group.&lt;p&gt;&lt;/p&gt; Hypotheses: The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure.&lt;p&gt;&lt;/p&gt; Methods: This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease.&lt;p&gt;&lt;/p&gt; Conclusions: These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program.&lt;p&gt;&lt;/p&gt

Intradialytic versus home based exercise training in hemodialysis patients: a randomised controlled trial

Background: Exercise training in hemodialysis patients improves fitness, physical function, quality of life and markers of cardiovascular disease such as arterial stiffness. The majority of trials investigating this area have used supervised exercise training during dialysis (intradialytic), which may not be feasible for some renal units. The aim of this trial is to compare the effects of supervised intradialytic with unsupervised home-based exercise training on physical function and arterial stiffness

Genomic epidemiology of the Escherichia coli O104:H4 outbreaks in Europe, 2011

The degree to which molecular epidemiology reveals information about the sources and transmission patterns of an outbreak depends on the resolution of the technology used and the samples studied. Isolates of Escherichia coli O104:H4 from the outbreak centered in Germany in May–July 2011, and the much smaller outbreak in southwest France in June 2011, were indistinguishable by standard tests. We report a molecular epidemiological analysis using multiplatform whole-genome sequencing and analysis of multiple isolates from the German and French outbreaks. Isolates from the German outbreak showed remarkably little diversity, with only two single nucleotide polymorphisms (SNPs) found in isolates from four individuals. Surprisingly, we found much greater diversity (19 SNPs) in isolates from seven individuals infected in the French outbreak. The German isolates form a clade within the more diverse French outbreak strains. Moreover, five isolates derived from a single infected individual from the French outbreak had extremely limited diversity. The striking difference in diversity between the German and French outbreak samples is consistent with several hypotheses, including a bottleneck that purged diversity in the German isolates, variation in mutation rates in the two E. coli outbreak populations, or uneven distribution of diversity in the seed populations that led to each outbreak

Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG

BACKGROUND:In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB. During decades of in vitro cultivation BCG not only lost some genes due to deletions of regions of the chromosome but also underwent gene duplication and other mutations resulting in increased antioxidant production. METHODOLOGY/PRINCIPAL FINDINGS:To determine whether microbial antioxidants influence vaccine immunogenicity, we eliminated duplicated alleles encoding the oxidative stress sigma factor SigH in BCG Tice and reduced the activity and secretion of iron co-factored superoxide dismutase. We then used assays of gene expression and flow cytometry with intracellular cytokine staining to compare BCG-specific immune responses in mice after vaccination with BCG Tice or the modified BCG vaccine. Compared to BCG, the modified vaccine induced greater IL-12p40, RANTES, and IL-21 mRNA in the spleens of mice at three days post-immunization, more cytokine-producing CD8+ lymphocytes at the peak of the primary immune response, and more IL-2-producing CD4+ lymphocytes during the memory phase. The modified vaccine also induced stronger secondary CD4+ lymphocyte responses and greater clearance of challenge bacilli. CONCLUSIONS/SIGNIFICANCE:We conclude that antioxidants produced by BCG suppress host immune responses. These findings challenge the hypothesis that the failure of extensively cultivated BCG vaccines to prevent pulmonary tuberculosis is due to over-attenuation and suggest instead a new model in which BCG evolved to produce more immunity-suppressing antioxidants. By targeting these antioxidants it may be possible to restore BCG's ability to protect against pulmonary TB