Delayed and persistent suppression of bronchoconstriction by trypsin in the airway lumen.

Mucosal trypsin, a protease-activated receptor (PAR) stimulant, may have an endogenous bronchoprotective role on airway smooth muscle. To test this possibility the effects of lumenal trypsin on airway tone in segments of pig bronchus were tested. Bronchial segments from pigs were mounted in an organ chamber containing Kreb's solution. Contractions were assessed from isovolumetric lumen pressure induced by acetylcholine (ACh) or carbachol added to the adventitia. Trypsin, added to the airway lumen (300 microg x mL(-1)), had no immediate effect on smooth muscle tone but suppressed ACh-induced contractions after 60 min, for at least 3 h. Synthetic activating peptides (AP) for PAR1, PAR2 or PAR3 were without effect, but PAR4 AP caused rapid, weak suppression of contractions. Lumenal thrombin was without effect and did not prevent the effects of trypsin. Effects of trypsin were reduced by N(omega)-nitro-L-arginine methyl ester but not indomethacin. Trypsin, thrombin and PAR4 AP released prostaglandin E2. Adventitially, trypsin, thrombin and PAR4 AP (but not PAR2 AP) relaxed carbachol-toned airways after <3 min. The findings of this study show that trypsin causes delayed and persistent bronchoprotection by interacting with airway cells accessible from the lumen. The signalling mechanism may involve nitric oxide synthase but not prostanoids or protease-activated receptors.     

Wound Botulism Associated with Black Tar Heroin

The incidence of wound botulism is increasing and the epidemiology of the disease is changing. The majority of new cases are associated with injection drug use, in particular, the use of Mexican black tar heroin. This case report and discussion of wound botulism illustrate the following important points: Dysphagia, dysphonia, diplopia, and descending paralysis, in association with injection drug use, should alert the treating physician to the possibility of wound botulism. In such patients, the onset of respiratory failure may be sudden and without clinically obvious signs of respiratory weakness. For the reported patient, maximum inspiratory force measurements were the only reliable indicator of respiratory muscle weakness. This is a measurement not routinely performed in the ED, but may prove essential for patients with suspected wound botulism. To minimize the effect of the botulinum toxin and to decrease length of hospital stay, antitoxin administration and surgical wound debridement should be performed early.     

Immunomodulatory Activity of A Novel Nucleoside, 7-thia-8-oxoguanosine: I. Activation of Natural Killer Cells in Mice

We reported recently that a novel immunomodulator, 7-thia-8-oxoguanosine (7T80G)² inhibited formation of pulmonary melanoma metastases (1), prevented against viral infection in mice (2) and potentiated the efficacy of a weakly immunogenic leukemia vaccine (3). Since certain tumor metastases and virus infected cells are targets to natural killer cells (NK cells), we now investigated whether 7T80G is capable of activating NK cells in mice using NK cell sensitive YAC-1 and B16 and NK cell insensitive P815 targets. CBA/CaJ spleen cells incubated in vitro with 7T80G at concentrations ranging from 0.005 to 0.5 mM responded with increased NK cell activity (32-62 %) compared to controls (4-8%) to YAC-1 targets. Similar levels of augmentation in NK cell activity were observed when 40-168 mg/kg of 7T80G was administered in vivo. In addition to the spleen, 7T80G activated NK cells in the bone marrow (BM), the lungs, the liver, and in peritoneal exudate cells (PE). Although 7T80G elicited activation of NK cells was observed as early as three hours after treatment, the maximal activity was observed after 24 h in the spleen; 12 h in the BM; 48 h in the lungs, and 72 h in PE. Administration of the drug by s.c, i.v., and i.p. routes all induced activition of NK cells in spleen, BM and PE. 7T80G was found to activate NK cells in seven inbred and an outbred mouse strain, suggesting that the induced cytotoxicity against allogeneic and syngeneic tumor cells is not strain specific as well as independent of MHC restriction. C3H/He, CBA/CaJ and BDF/1 displayed higher levels of increased NK cell activity, whereas AKR mice were low responders. Low concentrations of IL-2 (0.25-5 U/ml) that induce little or no NK cell activity, when used in combination with 7T80G, elicited significant enhancement of NK cell cytotoxicity. In contrast, IFN and 7T80G showed no such synergism.     

Circulating immune complexes in pre-eclampsia.

Serum samples from 20 non-pregnant women, 30 women with normal pregnancy and 50 women with pregnancy associated with pre-eclampsia were tested for circulating immune complexes using the polyethyleneglycol precipitation method. A highly significant positive correlation was found between circulating immune complexes and severe pre-eclampsia (BP greater than 140/90 mm Hg, albuminuria greater than 0.25 g/l). In contrast to this the difference in immune complex levels between non-pregnant subject, normal pregnancy cases and patients with mild pre-eclampsia was not statistically significant. A significant positive correlation was found between the level of circulating immune complexes and the severity of albuminuria. These findings suggest that circulating immune complexes, though not seeming to play an aetiological role in pre-eclampsia may very well be involved in its pathogenesis.     

De-coupling of cognitive performance and cerebral functional response during working memory in schizophrenia.

Working memory dysfunction is considered to be fundamental to the cognitive and clinical features evident in schizophrenia. Functional neuroimaging studies have begun to elucidate the neurobiological basis of such deficits, however, interpretation of these studies may be confounded by performance impairment, when the cognitive load exceeds the limited response capacity of patients with schizophrenia. In this study, patients were pre-selected on the basis of intact performance on a relatively low-load verbal working memory task, in order to mitigate against performance confounds. Subjects included 20 right-handed male subjects with chronic schizophrenia, and 20 right-handed, age-matched, male healthy controls, without personal or familial psychiatric history. All subjects underwent fMRI scanning whilst performing a verbal n-back task. There were no significant between-group differences in target identification; the patient group showed a significantly increased mean response latency. Both groups demonstrated robust fronto-parietal activation. In the control subjects, the power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex, however, this coupling of behavioural performance and cerebral response was not evident in the patients. This deficit, apparent within the performance capacity of the patients, may represent a fundamental abnormality in schizophrenia, and may compromise performance at higher cognitive loads.