Effect of aerosol challenge with sensitising antigen on the permeability of the surface of the rat trachea in life.

A rat model of immediate pulmonary hypersensitivity was used to investigate the permeability changes in the tracheal epithelium produced by aerosol challenge with antigen. The rats were sensitised by the intraperitoneal injection of antigen (dinitrophenyl (DNP19) ovalbumin). Sensitised and control animals were then challenged for 60 minutes with an aerosol of the same antigen, which also contained the electron dense pore marker lanthanum. Histological examination and x ray probe microanalysis showed a greater intercellular concentration of lanthanum in the tracheal epithelium in sensitised than in control animals. The results show that in sensitised rats increased intercellular penetrance of antigen can occur after antigen challenge.     

Stimulus-secretion coupling: role of cyclic AMP, cyclic GMP and calcium in mediating enzyme (kallikrein) secretion in the submandibular gland.

1. The role of adenosine 3':5'-phosphate (cyclic AMP) and guanosine 3':5'-phosphate (cyclic GMP) as second messengers for the enzyme secretory response evoked by the autonomic neurotransmitters, noradrenaline and acetylcholine, is examined in this in vitro study on the guinea-pig submandibular gland. 2. Noradrenaline increased enzyme (kallikrein) secretion. The initial stimulation of enzyme release appeared to be dose-dependent. The time course of cumulative kallikrein secretion revealed a complex pattern. Isoprenaline and phenylephrine were almost as potent as noradrenaline in releasing kallikrein. Both propranolol and phentolamine were required to fully inhibit the noradrenaline-stimulated enzyme secretion. 3. The cumulative secretion of kallikrein evoked by acetylcholine was dose-dependent. The onset of secretion showed a significantly greater time-lag than that observed with noradrenaline. Atropine effectively blocked the release of kallikrein by acetylcholine. 4. Dibutyryl cyclic AMP stimulated enzyme secretion. Dibutyryl cyclic GMP caused an initial increase which was not maintained. 5. The cyclic nucleotide phosphodiesterase inhibitors, theophylline and papaverine, increased basal kallikrein secretion. The action of the cyclic phosphodiesterase inhibitors on the secretory response to noradrenaline, acetylcholine, dibutyryl cyclic AMP and dibutyryl cyclic GMP was complex. In general, the increase in enzyme release produced by the secretagogues was additively enhanced by both inhibitors. 6. Omission of calcium inhibited both acetylcholine and dibutyryl cyclic GMP stimulated kallikrein release, but to a lesser degree than that of noradrenaline and dibutyryl cyclic AMP. High concentrations of extracellular calcium (10 mM) appeared to enhance the action of acetylcholine. 7. Noradrenaline produced a rise in the intracellular level of cyclic AMP. The increase preceded the stimulated secretion of kallikrein. Of the various adrenergic agonists, noradrenaline and isoprenaline were the most potent, whereas phenylephrine was significantly less effective in raising basal cyclic AMP values. Acetylcholine was without effect, even in the presence of a cyclic phosphodiesterase inhibitor. 8. Acetylcholine and noradrenaline raised intracellular levels of cyclic GMP only when the tissue incubations were performed in the presence of a cyclic phosphodiesterase inhibitor. The increase in cyclic GMP produced by acetylcholine preceded enzyme secretion. 9. Morphological data substantiated the finding that the in vitro release of kallikrein evoked by the secretagogues was associated with the depletion of secretory granules and vacuolations in acinar cells of the gland slices. 10. The molecular mechanisms which control enzyme secretion in the exocrine submandibular gland are discussed. Models are presented for the role of transmitter-specific cyclic nucleotides and calcium in stimulus-secretion coupling.     

The quest for wholeness: health care strategies among the residents of council-built hostels in Cape Town

The 1980s in South Africa have witnessed an extraordinary interest by health care professionals in the relevance of health care and healing systems outside the dominant biomedical system. The debate centres around the most effective way of incorporating "these other forms" of healing into the dominant system in the best interest of the patient. It is essentially a debate amongst professionals based on their perceptions of "the best interest" without any significant input from the "patients" who are the object of their concern. This paper attempts to bring into focus "patients" perceptions of different health care systems, their access to them and the rationale behind their choice of therapy. The experience of acute symptoms, especially pain, identifies an illness episode and initiates therapeutic action. Biomedical services are, most often, the first choice of the hostel dwellers. Hostel dwellers, although poor, are often prepared to pay for the services of the private biomedical practitioner. In some cases they have no other biomedical option, the lengthy delays encountered at the local government hospitals and clinics are costly for poorly paid unskilled labourers. The local government services, unlike the private practitioner, are not available at times convenient to working people.     

Spores of Clostridium engineered for clinical efficacy and safety cause regression and cure of tumors in vivo

Spores of some species of the strictly anaerobic bacteria Clostridium naturally target and partially lyse the hypoxic cores of tumors, which tend to be refractory to conventional therapies. The anti-tumor effect can be augmented by engineering strains to convert a non-toxic prodrug into a cytotoxic drug specifically at the tumor site by expressing a prodrug-converting enzyme (PCE). Safe doses of the favored prodrug CB1954 lead to peak concentrations of 6.3 μM in patient sera, but at these concentration(s) known nitroreductase (NTR) PCEs for this prodrug show low activity. Furthermore, efficacious and safe Clostridium strains that stably express a PCE have not been reported. Here we identify a novel nitroreductase from Neisseria meningitidis, NmeNTR, which is able to activate CB1954 at clinically-achievable serum concentrations. An NmeNTR expression cassette, which does not contain an antibiotic resistance marker, was stably localized to the chromosome of Clostridium sporogenes using a new integration method, and the strain was disabled for safety and containment by making it a uracil auxotroph. The efficacy of Clostridium-Directed Enzyme Prodrug Therapy (CDEPT) using this system was demonstrated in a mouse xenograft model of human colon carcinoma. Substantial tumor suppression was achieved, and several animals were cured. These encouraging data suggest that the novel enzyme and strain engineering approach represent a promising platform for the clinical development of CDEPT.     

Cimetidine Reduces the Risk of Rebleeding from Duodenal Ulcers Displaying Signs of Recent Haemorrhage

The presence of endoscopic signs of recent haemorrhage (SRH) greatly increases the risk of rebleeding from peptic ulcers. Fifty-five patients with acute bleeding from chronic duodenal ulcers with SRH completed a randomized double-blind trial to assess the effect of administration of Cimetidine (800 mg daily intravenously for 2 days, then 1000 mg daily orally for 10 days in divided doses) versus placebo on rebleeding and need for emergency surgery. In the Cimetidine group (n = 29), 5 rebled, compared with 11 receiving placebo (n = 26) (p > 0.05; relative risk, 0.28, 95% confidence interval, 0.08-0.97). This reduction in rebleeding rate in the cimetidine-treated patients was observed only in subjects over 60 years of age. Fifteen patients receiving Cimetidine required blood transfusion (mean. 2.3 ± 0.6 (SEM) units per patient) compared with 19 receiving placebo (3.5 ± 0.5) (p > 0.1). Emergency surgery to arrest bleeding was required in three patients receiving Cimetidine and four receiving placebo (p > 0.5). Cimetidine therapy should be considered in patients more than 60 years old who present with haemorrhage from a chronic duodenal ulcer with SRH and who arc at high risk of rebleeding.     

The use of immediate postoperative instillations of intravesical chemotherapy after TURBT of NMIBC among European countries

Purpose

The aim of this study was to assess the use of immediate postoperative instillation of intravesical chemotherapy (IPOIC) after transurethral resection of bladder tumour (TURBT) of nonmuscle invasive bladder cancer (NMIBC) in Europe.

Methods

Urologists based in five European Union nations were asked to extract information from the records of patients with NMIBC–urothelial carcinoma who received at least one TURBT. Multivariate logistic regression models were developed to determine the significant predictors of IPOIC usage. Data were weighted to control for country-to-country and other differences.

Results

Overall, 324 urologists (58 France, 72 Germany, 62 Italy, 65 Spain, 67 United Kingdom) were involved; the participation rate was 55 %. Overall, 771 patients received 954 TURBTs (mean—1.2/patient), of which 413 of the TURBTs (43.3 %) were administered IPOIC . Sixty-six of the 413 IPOICs (16.0 %) were for a recurrent tumour. Five of the tested variables were significantly associated with a patient’s likelihood of receiving IPOIC after TURBT. Variables in the order of significance are as follows: (1) country (United Kingdom, patients most likely to receive IPOIC; France, least likely); (2) progression risk (physician assessed) [lower-risk conditions (no CIS, tumour < 3 cm) or intermediate risk—more likely]; (3) whether urologist completed a uro-oncology fellowship (completed—more likely); (4) recurrence risk (physician assessed) [higher-risk conditions (≥T2, ≥3 cm, CIS)—more likely]; and (5) physician’s NMIBC patients volume (higher volume—more likely).

Conclusions

This study revealed wide practice variation and substantial noncompliance with European Association of Urology Guidelines on the use of IPOIC after TURBT for NMIBC.