Nitric oxide signaling in pain and nociceptor sensitization in the rat

We investigated the role of nitric oxide (NO) in inflammatory hyperalgesia. Coinjection of prostaglandin E2 (PGE2) with the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (L-NMA) inhibited PGE2-induced hyperalgesia. L-NMA was also able to reverse that hyperalgesia. This suggests that NO contributes to the maintenance of, as well as to the induction of, PGE2-induced hyperalgesia. Consistent with the hypothesis that the NO that contributes to PGE2-induced sensitization of primary afferents is generated in the dorsal root ganglion (DRG) neurons themselves, L-NMA also inhibited the PGE2-induced increase in tetrodotoxin-resistant sodium current in patch-clamp electrophysiological studies of small diameter DRG neurons in vitro. Although NO, the product of NOS, often activates guanylyl cyclase, we found that PGE2-induced hyperalgesia was not inhibited by coinjection of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a guanylyl cyclase inhibitor. We then tested whether the effect of NO depended on interaction with the adenylyl cyclase-protein kinase A (PKA) pathway, which is known to mediate PGE2-induced hyperalgesia. L-NMA inhibited hyperalgesia produced by 8-bromo-cAMP (a stable membrane permeable analog of cAMP) or by forskolin (an adenylyl cyclase activator). However, L-NMA did not inhibit hyperalgesia produced by injection of the catalytic subunit of PKA. Therefore, the contribution of NO to PGE2-induced hyperalgesia may occur in the cAMP second messenger pathway at a point before the action of PKA. We next performed experiments to test whether administration of exogenous NO precursor or donor could mimic the hyperalgesic effect of endogenous NO. Intradermal injection of either the NOS substrate L-arginine or the NO donor 3-(4-morphinolinyl)-sydnonimine hydrochloride (SIN-1) produced hyperalgesia. However, this hyperalgesia differed from PGE2-induced hyperalgesia, because it was independent of the cAMP second messenger system and blocked by the guanylyl cyclase inhibitor ODQ. Therefore, although exogenous NO induces hyperalgesia, it acts by a mechanism different from that by which endogenous NO facilitates PGE2-induced hyperalgesia. Consistent with the hypothesis that these mechanisms are distinct, we found that inhibition of PGE2-induced hyperalgesia caused by L-NMA could be reversed by a low dose of the NO donor SIN-1. The following facts suggest that this dose of SIN-1 mimics a permissive effect of basal levels of NO with regard to PGE2-induced hyperalgesia: (1) this dose of SIN-1 does not produce hyperalgesia when administered alone, and (2) the effect was not blocked by ODQ. In conclusion, we have shown that low levels of NO facilitate cAMP-dependent PGE2-induced hyperalgesia, whereas higher levels of NO produce a cGMP-dependent hyperalgesia.     

Nonlinear energy stability and convection near the density maximum

Summary A nonlinear energy stability analysis is developed for penetrative convection with the cubic and fifth order equations of state proposed by Merker et al. [1]. A conditional stability limit is obtained by using the method of coupling parameters and an unconditional limit is also obtained by constructing a suitable weighted energy.     

Local side-effects during 4-year treatment with inhaled corticosteroids--a comparison between pressurized metered-dose inhalers and Turbuhaler

Local side-effects, such as hoarseness and oropharyngeal candidiasis, are often seen during treatment of patients with inhaled corticosteroids (ICS). We investigated whether changing from pressurized metered-dose inhalers (pMDI) to Turbuhaler influenced the type and frequency of local side-effects. Local side-effects were recorded for a 2-year period in which 154 patients used ICS pMDI with a spacer device. They were followed for an equally long period of time (26.2 +/- 5.7 months) while using Turbuhaler, as were 90 patients who received Turbuhaler as their first ICS preparation. After inhalation, all patients rinsed out their mouths with water. In experienced pMDI-users, the frequency of local side-effects decreased from 21% to 6%. The reduction was due to a lower incidence of hoarseness. Candidiasis or hoarseness was not seen in patients given Turbuhaler as their first ICS device. Our fear of an increased incidence of local side-effects when giving ICS in Turbuhaler was unwarranted.     

Electron microscopy study of martensite in Cu–11.2 wt% Al–3 wt% Ni

The structures of martensites in a Cu–11.2 wt% Al–3 wt% Ni specimen, which was quenched from 1173 K, have been studied by high resolution electron microscopy (HREM) and diffraction techniques. Two kinds of martensites, i.e. β′1 and γ′1, coexisting adjacent to each other in the specimen were observed. The γ′1 matensite consists of microtwins with monoclinic structure. Three variants of the twin structure, i.e. {1 2 1}, {2 1 0} and {1 0 1} twins, are arranged within a single plate. The β′1 martensite possesses basically ordered N9R structure, but mixed with thin 2H domains. Some diffraction spots of this martensite shift along the [0 0 1] direction. In addition, extra weak reflections appear in the diffraction pattern due to heterogeneous atomic displacements. The microstructural features of the martensites are examined and discussed. This revised version was published online in November 2006 with corrections to the Cover Date.     

Structural replacement of active site monovalent cations by the epsilon-amino group of lysine in the ATPase fragment of bovine Hsc70

We have assessed the ability of the epsilon-amino group of a non-native lysine chain to substitute for a monovalent cation in an enzyme active site. In the bovine Hsc70 ATPase fragment, mutation of cysteine 17 or aspartic acid 206 to lysine potentially allows the replacement of an active site potassium ion with the epsilon-amino nitrogen. We examined the ATP hydrolysis kinetics and crystal structures of isolated mutant ATPase domains. The introduced epsilon-amino nitrogen in the C17K mutant occupies a significantly different position than the potassium ion. The introduced epsilon-amino nitrogen in the D206K mutant occupies a position indistinguishable from that of the potassium in the wild-type structure. Each mutant retains <5% ATPase activity when compared to the wild type under physiological conditions (potassium buffer) although substrate binding is tighter, probably as a consequence of slower release. It is possible to construct a very good structural mimic of bound cation which suffices for substrate binding but not for catalytic activity.     

Vesicovaginal and vesicocutaneous fistulas: transurethral suture cystorrhaphy as a new closure technique

PURPOSE: We assessed the usefulness of endoscopic treatment of vesical fistulas. MATERIALS AND METHODS: Two bladder fistula patients underwent transurethral surgery in an attempt to close the fistula. RESULTS: Both patients were cured of the fistula, without undergoing an open procedure. CONCLUSIONS: Cystoscopically assisted suture closure of vesical fistulas can be a successful procedure in selected patients. Nontraditional instrumentation and technique allowed for transurethral closure of these fistulas.     

Calcium and magnesium balance in 9-14-y-old children

Few data are available regarding calcium and magnesium absorption and endogenous fecal excretion in children. We used a multitracer stable isotope technique to assess calcium and magnesium balance in 12 boys and 13 girls aged 9-14 y (mean weight: 42 kg) maintained on relatively high calcium intakes (mean: 1310 +/- 82 mg/d). There were no significant differences in absorption of calcium or magnesium from milk between boys and girls. Calcium retention (balance) correlated positively with calcidiol (25-hydroxyvitamin D) concentration (r = 0.48, P = 0.02) and serum alkaline phosphatase activity (r = 0.44, P = 0.03). There was no significant relation between magnesium balance and concentration. When data from this study were combined with our previously reported data, an increase in total calcium absorption was seen for pubertal (Tanner stages 2-4) but not prepubertal (Tanner stage 1) white children over the range of intakes from approximately 750 to 1350 mg/d. Despite intakes similar to the 1989 recommended dietary allowance for magnesium (mean intake: 6.4 +/- 1.2 mg.kg-1.d-1), 11 of the 25 subjects (6 girls and 5 boys) were in negative magnesium balance. We conclude that benefits from higher calcium intakes, < or = 1350 mg/d, were most apparent in pubertal children. In addiction, higher magnesium intakes should be considered for children.     

Redefining the purpose of patient classification

One hospital's nursing staff used a structured process to challenge the purpose and function of the patient classification system. The result was internal development of a more effective system with significant cost savings.