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.     

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.     

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.     

Patent information: an historical perspective

An historical survey of one specific technical field, as illustrated in patent disclosures, is presented. The field is umbrellas, parasols and walking sticks, from the first British patent of 1780 up to the present day, using classified abridgements in bound volumes of hard copy until the mid 1970s and online databases thereafter. More detailed analyses of the last 20 years are provided. Unlike many recent rapidly developing fields, this field has changed relatively little over two centuries; annual inputs are comparable since the middle 1800s, while many similar solutions to recurrent problems resurface periodically. Nevertheless, discernible commercially and technically significant improvements occur throughout this period, as well as many short-lived tangential developments. Some reasons for this pattern are suggested.     

A survey of hospital diet. Connection between the nutritive value found by analysis and by calculation

The primary aim of this study is to determine the nutritional quality of the food prepared in a selected Danish hospital. Samples consisted of four double portions of the hospital's standard daily ration from two randomly chosen weeks. The amounts of fatty acid, protein, ash, total dry material, and vitamin C were measured. The amount of carbohydrate, energy, and percentage of available energy were calculated. The total energy level was measured to eight MJ per day. The measured percentage of available energy given as protein (17%) and the vitamin C levels (14 mg/MJ) have fulfilled the recommendations. The percentage of energy given as carbohydrates (38%) is below and the percentage of energy given as fat (45%) is above the recommended levels (50% and 32%). There is a direct correlation between the average calculated and the average measured values when all of the meals are analysed as an entity, but the correlation is weak for individual meals.     

Production and determination of specificity of monoclonal IgG anti-mouse-blastocyst antibodies

Five monoclonal anti-mouse-blastocyst IgG antibodies were raised by intrasplenic immunization of three mice with adhesive-stage mouse blastocysts. Each mouse received a total of 60-70 blastocysts which were either nitrocellulose-immobilized or living but irradiated. Tests for pre-implantation stage-specificity showed that the antibodies differed in specificity. None were specific for surface epitopes. One antibody recognized epitopes only on blastocysts. Other antibodies were able to discriminate between unfertilized and fertilized oocytes, uncompacted and compacted morulae, or delayed and adhesive blastocysts. By applying reduced SDS-PAGE and Western blotting to blastocysts the blastocyst-specific antibody was seen to be bound to a peptide of M(r) 34.     

Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus

OBJECTIVE: To study the comparative importance of environment and genes in the development of islet cell autoimmunity associated with insulin dependent diabetes mellitus. DESIGN: Population based study of diabetic twins. SETTING: Danish population. SUBJECTS: 18 monozygotic and 36 dizygotic twin pairs with one or both partners having insulin dependent diabetes. MAIN OUTCOME MEASURES: Presence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase (GAD65) in serum samples from twin pairs 10 years (range 0-30 years) and 9.5 years (2-30 years) after onset of disease. RESULTS: In those with diabetes the prevalence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase in the 26 monozygotic twins was 38%, 85%, and 92%, respectively, and in the dizygotic twins was 57%, 70%, and 57%, respectively. In those without diabetes the proportions were 20%, 50%, and 40% in the 10 monozygotic twins and 26%, 49%, and 40% in the 35 dizygotic twins. CONCLUSION: There is no difference between the prevalence of islet cell autoantibodies in dizygotic and monozygotic twins without diabetes, suggesting that islet cell autoimmunity is environmentally rather than genetically determined. Furthermore, the prevalence of islet cell antibodies was higher in the non-diabetic twins than in other first degree relatives of patients with insulin dependent diabetes. This implies that the prenatal or early postnatal period during which twins are exposed to the same environment, in contrast with that experienced by first degree relatives, is of aetiological importance.