Biochemical mechanisms of hydrogen peroxide- and hypochlorous acid-mediated inhibition of human mononuclear leukocyte functions in vitro: protection and reversal by anti-oxidants.

Both H2O2 (IC50 = 70 microM) and HOCl (IC50 = 8.5 microM) inhibited mitogen-induced MNL proliferation in a dose-dependent manner. This was found to be due to a depletion of intracellular ATP by at least two distinct mechanisms. HOCl and high concentrations (greater than 100 microM) of H2O2 inhibit ATP generation via sulfhydryl group oxidation on the active site of the glyceraldehyde-3-phosphate dehydrogenase (G3PDH) enzyme of the glycolytic pathway. On the other hand, low H2O2 concentrations cause ATP depletion by an activation of the DNA repair enzyme, poly(ADP-ribose)polymerase (pADPRP), leading to consumption of NAD+, an essential cofactor for G3PDH. The anti-oxidants ascorbate and cysteine protected MNL against the anti-proliferative effects of HOCl. Similar results were achieved with the HOCl-mediated inhibition of ATP production and G3PDH activity. However, ascorbate was unable to protect against H2O2-mediated inhibition of MNL functions, while cysteine protected against the inhibitory effects on ATP production and G3PDH activity, induced by this oxidant.     

Characteristics of wheeze during histamine-induced airways obstruction in children with asthma.

BACKGROUND--An automated system has been developed for the detection of sound patterns suggestive of airways obstruction in long term recordings. The first step, presented here, was tracheal sound recording during histamine-induced airways obstruction. METHODS--The tracheal sounds of 29 children aged 8-19 years with asthma were recorded during airways obstruction caused by histamine inhalation using a system for continuous respiratory telemetry and computer analysis. Sound patterns were analysed, classified, and related to airways obstruction measured by lung function tests based on the forced expiratory volume in one second (FEV1). RESULTS--Five sound patterns were identified, one dominant sensitive and four specific to a fall in FEV1 of > 20%. The presence of at least one of three specific sound patterns during unforced respiration predicted a fall in FEV1 of > 20% in 87.5% of the subjects. The inspiratory and expiratory sound patterns were almost equally informative of airways obstruction. CONCLUSIONS--Wheezes can be differentiated with more precision than is currently accepted. Tracheal sound patterns are sensitive and specific predictors of histamine-induced airways obstruction. These patterns are neither invariably nor proportionally related to the results of lung function testing. However, they can be used for detection of airways obstruction on the basis of their presence or absence.     

Infection of broiler chicks (Gallus domesticus) with human intestinal spirochaetes

One-day-old broiler chicks were infected orally with spirochaetes isolated from cases of intestinal disorder in humans. Three different isolates were studied in an experiment of 22 days duration. No signs of clinical disease were observed; the infection did not cause changes in the concentration of carotenoids or in the activity of alkaline phosphatase in the serum. Spirochaetes were shed in the caecal faeces. At autopsy, no lesions were seen in the intestinal tracts of the birds. Large numbers of spirochaetes were present in the caecum of 30 to 100% of the infected birds; in a few birds small numbers of spirochaetes were observed in scrapings from the mucosa of the small intestine. On histological examination massive colonisation of the caecal mucosa was observed. Spirochaetes of two isolates had invaded the caecal mucosa and for one of these, they were found between enterocytes, but not below the basement membrane. The other isolate had produced gap-like lesions, subepithelial accumulations of spirochaetes and focal erosion. No signs of an inflammatory reaction were observed.     

Leukoencephalopathy with swelling in children and adolescents: MRI patterns and differential diagnosis

In children, several neurological disorders are characterised by spongiform leukoencephalopathy. MRI of the brain typically shows white matter swelling, but does not enable differentiation of the various underlying disorders. The aim of this article is optimisation of the diagnostic value of MRI in leukoencephalopathy accompanied by swelling. MRI-based inclusion criteria were met by 20 patients in our database. The images were analysed using a detailed scoring list. In 13 of the 20 patients the clinical diagnosis was known (11 definite and 2 probable diagnoses). Characteristic MRI abnormalities could be defined in these patients. Of the 7 patients without a diagnosis, 5 had identical MRI abnormalities: difuse hemisphere swelling and typical cysts in frontoparietal subcortical white matter and the tips of the temporal lobes. The clinical picture was also similar in these patients, suggesting a similar disease.     

Static footprint analysis: a time-saving functional evaluation of nerve repair in rats.

Walking track analysis is a widely accepted technique for functional evaluation after sciatic nerve repair in rats, but it is labour-intensive. In 2000, Bervar described a time-saving digitised static footprint analysis. In that study there were good correlations between the traditional sciatic function index (SFI) and the newly-developed static sciatic index (SSI) and static toe spread factor (TSF), respectively. Despite promising results, static footprint analysis is still not widely used. The present study was designed to validate it. After transection of the sciatic nerve, end-to-end repair was assessed using video recorded dynamic and static footprints in 45 Wistar rats. We found an even better correlation between the SFI and both the SSI and the static TSF. In conclusion, static footprint analysis is a time-saving and easy technique for accurate functional assessment of peripheral nerve regeneration in rats.     

Serum concentrations of oestradiol-17beta, progesterone, relaxin and chorionic gonadotrophin during blastocyst implantation in natural pregnancy cycle and in embryo transfer cycle in the rhesus monkey

The present study was undertaken to assess the temporal association between the profiles of serum concentrations of oestradiol-17beta, progesterone, chorionic gonadotrophin (CG) and relaxin in pregnancies established naturally, and after embryo transfer, as well as in failed pregnancies in rhesus monkeys. In naturally mated cycles (group 1) a conception rate of 75% was obtained. In group 1, the mean day of CG detection in serum was 11.5 +/- 1.9 day post-ovulation, and for relaxin, 9.0 +/- 2.5 day post-ovulation. In group 2, embryo transfer to synchronous, non-mated surrogate recipients was performed; seven embryo transfer cycles yielded three pregnancies which were allowed to continue to term and normal infants were delivered. In embryo transfer cycles the mean day of CG detection was 14.8 +/- 1.8 day post- ovulation, and for relaxin, 11.4 +/- 2.6 day post-ovulation. A delay of about 3 days was observed in the appearance in circulation of CG (P < 0.05) and also of relaxin (P < 0.05) between natural mated and embryo transfer conception cycles. Significant differences (P < 0.05 for progesterone and P < 0.03 for oestradiol) were obtained for the areas under the curves for progesterone and oestradiol between days 12 and 16 in conception cycles compared with failed pregnancies. These data provide the first observation of the normal hormonal signals associated with maternal recognition of transferred embryos during the peri- implantation period, and suggest that the use of such an experimental primate embryo transfer model may help to elucidate components of maternal and embryonic signal-response mechanisms during embryo implantation.      

Efficacy and tolerability of a new estradiol delivering matrix patch (Estraderm MX) in postmenopausal women

OBJECTIVE: To examine the efficacy and tolerability of a new matrix patch delivering estradiol (E2 Matrix) at doses of 0.05 and 0.10 mg per day (Estraderm MX 50, 100) in the treatment of moderate to severe postmenopausal symptoms. METHODS: A total of 254 postmenopausal women were randomized to receive treatment with E2 Matrix 0.10 mg (N = 86), E2 Matrix 0.05 mg (N = 82), or placebo (N = 86) in a double-blind, double-dummy fashion for a period of 12 weeks continuously. Patches were applied twice weekly to the buttocks with each patient wearing two patches at all times. The primary efficacy criterion was the difference from baseline of the mean number of moderate to severe hot flushes per 24 h during the last 2 weeks of treatment. Other efficacy variables included reduction in hot flushes at 4 and 8 weeks, reduction in daytime flushing and night sweats, and Kupperman Index at 4, 8, and 12 weeks. RESULTS: E2 Matrix 0.10 and 0.05 mg were both significantly superior to placebo in reducing hot flushes per 24 h after 4, 8, and 12 weeks of treatment (P < 0.001). Also, for all other efficacy parameters studied, both dosage strengths of E2 Matrix were statistically significantly superior to placebo at all time points (P < 0.001). Local tolerability was good in both groups. A slight increase in estrogen related adverse effects (breast tenderness, leukorrhoea) was seen with the 0.10 mg patch. Adhesion of patches and compliance were good. Overall systemic tolerability was good in both treated groups. However, a 4.8% overall incidence of endometrial hyperplasia was observed in patients with an intact uterus. CONCLUSIONS: This new matrix patch offers an effective and well tolerated dosage form for delivery of 0.05 and 0.1 mg estradiol per day. It may be particularly suitable for those women who experience local sensitivity to alcohol-containing systems. In light of the observed hyperplasia after treatment in five patients, estrogen therapy should as yet be supplemented monthly with a progestogen in women with an intact uterus.