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SETTING: Mandalay Division, Myanmar. AIM: To assess the effect of an initiative to involve private general practitioners (GPs) in the National Tuberculosis Programme (NTP) and to identify lessons learnt for public-private mix scale-up. METHODS: Source of referral/diagnosis and place of treatment were included in the routine recording and reporting systems to enable disaggregated analysis of the contribution of GPs to case notification and treatment outcomes. Case notification trends were compared between the intervention and control areas over a 4-year period. RESULTS: Private GPs contributed 44% of new smear-positive cases registered during the study period (July 2002-December 2004). The notification of new sputum smear-positive TB in the study area increased by 85% between the year prior to the GP involvement and 2 years after (from 46 to 85/100,000). Case notification increased by 57% in the control townships and by 42% in all of Mandalay Division. The treatment success rate for new smear-positive cases treated by GPs was 90%. CONCLUSIONS: The involvement of private GPs substantially increased TB case notification, while a high treatment success rate was maintained. Success factors include a well-developed local medical association branch, strong managerial support, training and supervision by the public sector and provision of drugs and consumables free of charge by the NTP.

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Cystitis cystica, a common urothelial pathology whose aetiology, morphology and clinical significance are poorly understood, affects the human urinary bladder and trigone in both sexes. We have studied the fine structure of urothelial cysts in 11 patients diagnosed cystoscopically as suffering from cystitis cystica. Several abnormal features were observed in the adjacent urothelium, including large intracellular vacuoles (4 patients), Brunn's nest (5), lymphocyte infiltration (10) and generally disorganised urothelial architecture (10). Squamous metaplasia was observed in one case. The wall of each cyst consisted of a 2-3 layered epithelium with either tall columnar or flattened cells lining the fluid-filled lumen. Both types of lining cell possessed short microvilli, while the columnar type also contained numerous membrane-bound, electron dense secretory granules in the apical cytoplasm. Rough endoplasmic reticulum, mitochondria and Golgi membranes were plentiful in the surface cells. Junctional complexes joined adjacent lining cells. The deeper cells contained relatively fewer organelles, while a basal lamina separated the cyst wall from the underlying connective tissue.

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The aetiology, morphology and clinical significance of Brunn's nests in human bladder urothelium are poorly understood. In the present study, 9% of a population of 100 consenting patients undergoing diagnostic or review cystoscopies were histologically found to have Brunn's nests, although their presence was not detected endoscopically. Of the nine cases, four were diagnosed with cystitis cystica, two with bladder papillomata, one with transitional cell carcinoma and cystitis cystica, and two were considered to be macroscopically normal. Mucosal biopsies were removed from areas unaffected by macroscopic abnormalities. Brunn's nests consisted of rounded collections of cells, whose nuclei contained prominent nucleoli and occasional nuclear bodies. The cytoplasm frequently contained clusters of mitochondria, together with Golgi membranes and cisternae of granular endoplasmic reticulum while small membrane bound vesicles containing electron dense material were present in some cells. Presumptive lysosomes were rarely observed. Thus Brunn's nest cells generally resembled normal urothelial cells in both their nuclear and cytoplasmic fine structure. Brunn's nests were surrounded by a basal lamina and loose connective tissue containing fenestrated capillaries.

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A comprehensive study of human bladder urothelium was undertaken to define the normal histological and fine structural features of this tissue. Urothelial biopsies from consenting male and female patients undergoing diagnostic or review cystoscopies were analysed. In 31 patients there was an apparently normal urothelium lining the bladder, and in 3 patients the trigone appeared normal. Normal urothelium was not observed to contain lymphocytes, lymphoid follicles, mast cells, Brunn's nests or cysts. No mitoses were seen despite examining about 50,000 urothelial cells. Trigonal and bladder urothelium normally consisted of 3 and 3-6 cell layers, respectively, but they shared the same basic architecture of basal, intermediate and superficial (or surface) cell types. The urothelium possessed a regular, polarised architecture of increasing morphological complexity and differentiation from base to surface. Occasional, slender, cytoplasmic projections were observed to reach the basal lamina from the intermediate cell layer, but not from the surface cell layer. Human urothelium should therefore be considered a stratified, not a pseudostratified, epithelium. The nuclear shape in cross-section was indented in the basal layer, and rounded in the superficial layer. Correspondingly, chromatin configurations of urothelial nuclei were evenly and finely granular in the superficial layer and condensed in the basal layer, suggesting a greater degree of transcriptional activity in the former. Intermediate cell nuclei assumed intermediate degrees of shape and chromatin configuration. Prominent nucleoli were found in the nuclei of all cell layers. Both basal and intermediate cell nuclei and superficial cell nuclei contained characteristic nuclear bodies. Urothelial cells of all layers were connected by interdigitations of cytoplasmic processes and by desmosomes. Clusters of mitochondria were seen throughout the urothelium. Elaborate Golgi membranes and rough endoplasmic reticulum, although rare in the basal layer, were observed in the remainder of the urothelium. Large, prominent lysosomes were identified with the electron microscope and histochemically in the surface layer. The superficial aspect of the urothelium was lined, at least in some regions, by an asymmetric luminal membrane. Tight junctions linked adjacent urothelial surface cells. Such junctions were not observed anywhere else in the urothelium. Fine cytoplasmic filaments, probably of the intermediate type, were most conspicuous in the surface layer. Overall, normal human bladder urothelium is arranged in increasing complexity from base to surface.

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The present investigation provides a histological and fine structural description of pseudomembranous trigonitis, an ill-understood metaplastic condition affecting particularly the female trigone. Normal trigonal urothelium consists of 3 cell layers (basal, intermediate and superficial), whereas pseudomembranous trigonitis constitutes many layers of stratified squamous epithelium. The basal cells contain prominent nuclei with condensed chromatin, nucleoli and nuclear bodies. The cytoplasm of these cells is rich in mitochondria. The profiles of the urothelial cells become progressively elongated, their nuclei increasingly smaller and their content of cell organelles gradually reduced as the luminal surface is approached. The squamous surface cells, linked by desmosomes, retain many longitudinally arranged fine filaments, together with an occasional degenerate nucleus. The mitotic index of pseudomembranous trigonitis is 0.17% (SD 0.09%), i.e. significantly higher than normal (0%).

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The present research has employed a novel, nonradioactive technique to quantitatively study normal urothelial proliferation in foetal, neonatal, juvenile and adult mouse bladder. Using whole mount histological preparations, the total number of urothelial nuclei per mouse bladder, and per given urothelial cell layer, have been assessed to provide data of the (unstimulated) kinetic behaviour of basal urothelial cells (the proliferative population), to analyse characteristics of the normal urothelial cell cycle. The urothelial cell cycle time increases from 30.6 h (foetal) to 40 weeks (adult), the duration of mitosis from 0.23 h (foetal) to 2.71 h (adult) and the duration of DNA synthesis from 2.52 h (neonatal) to 10.83 h (adult). These are average values for the urothelial cell cycle, which do not preclude the possible existence of proliferative units. The ratio of superficial nuclei to basal and intermediate nuclei, possibly indicative of a urothelial proliferative unit, declines to reach a plateau (1:40) in adult mice. These findings indicate that rapid urothelial proliferation during early murine development was likely to be a) biologically useful, since intrauterine foetal metabolic activity may require a functional bladder urothelium at an early stage, b) kinetically similar to acutely regenerating adult urothelial cells after cytotoxic insult. During murine life, the range of durations of mitosis and DNA synthesis is much less than the range of cell cycle times. Normal unstimulated urothelium of adult mice was confirmed to proliferate slowly.

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Developing murine urothelium undergoes pronounced proliferation until at least 10 days after birth. Thereafter, both mitotic and [3H]TdR-labelling indices fall sharply with age. The ratio of labelling to mitotic indices also alters dramatically during development, which is probably due to both endoreduplication and changes in the relative durations of the DNA synthesis and mitotic phases. This ratio reaches stability at 5 weeks of age. The adult labelling and mitotic indices were 0.11 and 0.019% respectively, indicating a very slow turnover.

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Normal unstimulated urothelium of adult mice appears to be essentially quiescent, as demonstrated by an 3HTdR-pulse labelling index of 0.11%. There is no evidence that this labelling index may be artificially low. Results from continuous labelling experiments, where 3HTdR was supplied in the drinking water of mice for varying periods, render it possible that the urothelium satisfies its small renewal requirements via a low growth fraction of cycling cells. The remainder may consist of quiescent cells, which may be capable of resuming cell cycle progression when required, and of post-mitotic cells, which are incapable of further proliferation. There are three possible levels of adult urothelial proliferation with cell cycle times of about a) one year (if the urothelium is homogeneous and the growth fraction unity), b) three weeks (if the growth fraction is about 5%), and c) 15 h (when the urothelial cells are rapidly regenerating).

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Data are presented on the postnatal growth of the mouse bladder. Both bladder size (measured as surface area) and bladder wet weight increase steadily with age, respectively reaching 2.5 times and 4 times their newborn values by the age of ten weeks. Despite this growth, which may be due principally to non-urothelial components of the bladder, the body weight rises 10-15 fold above the newborn levels. The ratio of bladder weight to the total body weight steadily declines from a peak value in newborn mice to a stable plateau reached at about five weeks of age. The results indicate that a fairly mature bladder exists at birth.

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Three growth rate experiments involving several sampling points were performed to investigate the previous finding that very low concentrations of HgCl2 inhibit the growth of murine lymphoblasts in vitro. However, results presented here do not confirm this, there being no significant differences between the three independent growth rate experiments.

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