Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by cognitive decline, presence of amyloid-beta peptide (Aß) aggregates and neurofibrillary tangles. Kinins act through B1 and B2 G-protein coupled receptors (B1R and B2R). Chronic infusion of Aß peptide leads to memory impairment and increases in densities of both kinin receptors in memory processing areas. Similar memory impairment was observed in C57BL/6 mice (WTAß) but occurred earlier in mice lacking B2R (KOB2Aß) and was absent in mice lacking B1R (KOB1Aß). Thus, the aim of this study was to evaluate the participation of B1R and B2R in Aß peptide induced cognitive deficits through the evaluation of densitiesof kinin receptors, synapses, cell bodies and number of Aß deposits in brain ofWTAß, KOB1Aß and KOB2Aß mice. An increase in B2R density was observed in both WTAß and KOB1Aß in memory processing related areas. KOB1Aß showed a decrease in neuronal density and an increase in synaptic density and, in addition, an increase in Aß deposits in KOB2Aß was observed. In conclusion, memory preservation in KOB1Aß, could be due to the increase in densities of B2R, suggesting a neuroprotective role for B2R, reinforced by the increased number of Aß plaques in KOB2Aß. Our data point to B2R as a potential therapeutic target in AD.

Kallikrein-kinin system mediated inflammation in Alzheimer's disease in vivo.

The Kallikrein-Kinin System (KKS) has been associated to inflammatory and immunogenic responses in the peripheral and central nervous system by the activation of two receptors, namely B1 receptor and B2 receptor. The B1 receptor is absent or under-expressed in physiological conditions, being up-regulated during tissue injury or in the presence of cytokines. The B2 receptor is constitutive and mediates most of the biological effects of kinins. Some authors suggest a link between the KKS and the neuroinflammation in Alzheimer's disease (AD). We have recently described an increase in bradykinin (BK) in the cerebrospinal fluid and in densities of B1 and B2 receptors in brain areas related to memory, after chronic infusion of amyloid-beta (Aß) peptide in rats, which was accompanied by memory disruption and neuronal loss. Mice lacking B1 or B2 receptors presented reduced cognitive deficits related to the learning process, after acute intracerebroventricular (i.c.v). administration of Aß. Nevertheless, our group showed an early disruption of cognitive function by i.c.v. chronic infusion of Aß after a learned task, in the knock-out B2 mice. This suggests a neuroprotective role for B2 receptors. In knock-out B1 mice the memory disruption was absent, implying the participation of this receptor in neurodegenerative processes. The acute or chronic infusion of Aß can lead to different responses of the brain tissue. In this way, the proper involvement of KKS on neuroinflammation in AD probably depends on the amount of Aß injected. Though, BK applied to neurons can exert inflammatory effects, whereas in glial cells, BK can have a potential protective role for neurons, by inhibiting proinflammatory cytokines. This review discusses this duality concerning the KKS and neuroinflammation in AD in vivo.

Phosphate shielding under different conditions results in an enhanced DNA duplex stability.

Neutralization of charge of the phosphodiester groups in DNA and the significance for transfer of genetic information will be demonstrated. Theoretical models based on proton shielding are elaborated with ab initio level calculations for a Watson-Crick-type dimer. These results are compared with molecular mechanics studies for duplexes of a hexamer with Rp and Sp phosphate-methylated backbones.

The role of the carboxamide group in nicotinamide adenine dinucleotide in relation to hydride transfer: the reduced form of the dinucleotide as remedy in the modulation of neurotransmission.

The stereochemical significance of the carboxamide group in combination with the ring nitrogen in NADH-NAD+ conversions has been demonstrated. This has been shown in model systems as well as under enzymatic conditions. The role of the carboxamide group in selective regiospecific interactions has been discussed for neurodegenerative diseases.

Biocompatibility of an electrochemical sensor for continuous glucose monitoring in subcutaneous tissue.

BACKGROUND: The continuous monitoring of glucose allows for tighter control of the glucose concentration and thus may prevent hyper- and hypoglycemia as well as long-term complications of diabetes. While most current systems depend on the transport of fluid to a glucose sensor outside the body, we investigate the possibility of implanting a reagent-based sensor directly into the skin. In this manuscript, the biocompatibility of an electrochemical sensor for continuous glucose monitoring was assessed in vitro and in vivo. METHODS: Cytotoxicity was investigated in vitro using agar diffusion testing. In vivo biocompatibility was assessed by means of histomorphological examination of the surrounding tissue 10 days after sensor implantation in rats. RESULTS: The grade of cytotoxicity of the individual sensor components in vitro was between none and mild based on agar diffusion testing. The complete sensor also showed no cytotoxic effects when coated with the co-polymer MPC (2-methacryloyloxyethyl phosphorylcholine, Lipidure CM 5206, NOF Corp., Tokyo, Japan) and when assessed under working conditions, i.e., when a bias voltage was applied to the sensor. Additionally, the hydrogen peroxide-which is inherently generated by the enzymatic glucose detection process using glucose oxidase (GOD)-is likely to have been sufficiently decomposed under these working conditions. Finally, no toxic leachable substances were found during the cytotoxicity testing of sensors and its extracts in vitro. In the in vivo experiments, the strongest foreign body reaction (FBR) was found near the GOD-electrode using a sensor without MPC coating and without a porous membrane. Covering the sensor with MPC, a porous membrane, or both led to a gradual decrease of the FBR down to the level of the negative control. CONCLUSIONS: The electrochemical, reagent-based sensor with MPC coating and/or a porous membrane is suitable for continuous monitoring of glucose from a biocompatibility standpoint.

Acute radiation toxicity assessment of a 3-D conformal head and neck radiation treatment technique.

Patients undergoing radiation treatment for head and neck cancer have many critical structures within or adjacent to the treatment area. Avoiding these critical structures is more efficient and easier using 3-D conformal planning. At Sir Charles Gairdner Hospital an investigation into the acute radiation toxicity was undertaken when the head and neck treatment technique was changed from the conventional 2-D plan to the conformal 3-D plan. Although the primary target volume (PTV), fraction size and overall dose remain the same for the two techniques, differing beam configurations mean that treatment fields enter and exit through different parts of the head and neck. Ten patients were initially assessed to gain a baseline appearance of their head and neck region, and then graded weekly according to the toxicity criteria during treatment and at 4, 8 and 12 weeks after treatment. The results of the assessment indicate that there is no increase in toxicity as a result of treating using the conformal head and neck technique.

The biochemical significance of parallel DNA duplexes.

Structural and synthetic model are given for (modified) parallel DNAs with non-Watson and Crick duplex formation.

Nicotinamide adenine dinucleotide a unique compound for theoretical and synthetic model studies: chirality as source for high stereospecificity.

A dynamic model is given for the hydride transfer of the redox couple NAD+-NADH with model systems and quantum chemical calculations.

Assessment of adrenal suppression from two new dry powder inhaler formulations of budesonide delivered by Clickhaler compared with the Pulmicort Turbuhaler.

Assessment of adrenal suppression via systemic cortisol levels provides an indirect measure of the lung delivery of inhaled corticosteroids. This randomized, placebo-controlled, double-blind, double-dummy crossover study compared urinary and plasma cortisol levels in healthy adult volunteers following single 1,000-microg doses of budesonide from two multiple dose dry powder inhalers (DPIs). Two new formulations of budesonide (lactose and PassCal) delivered from the Clickhaler were compared with Pulmicort from the Turbuhaler. An open dose (2,000 microg) of Pulmicort Turbuhaler was included to validate the experimental model. Overnight (22:00-07:00 h) and early morning (07:00-08:00 h) urine and 08:00 h plasma samples were collected after each treatment and cortisol levels analyzed by radioimmunoassay. Combined overnight and early morning urinary cortisol values for PassCal Clickhaler and Pulmicort Turbuhaler (1,000 microg) were statistically significantly lower than placebo (p < 0.05). The lactose budesonide Clickhaler showed a non-significant urinary cortisol reduction compared with placebo. Differences between the three 1,000-microg budesonide treatments were not significant. The Pulmicort Turbuhaler 2,000 microg showed significant urinary cortisol suppression compared with placebo. Plasma cortisol showed similar effects, with significance between the two Pulmicort doses. These results suggest that adrenal suppression can be used to assess the pulmonary bioavailability of different formulation.

Imiquimod 5% cream in the treatment of anogenital warts in female patients.

OBJECTIVE: To investigate the efficacy and safety of imiquimod 5% cream in the treatment of anogenital warts in a female population. METHODS: In two open-label studies, female patients with anogenital warts applied imiquimod 5% cream three times a week for up to 16 weeks. Patients who cleared their warts were monitored for a 6-month follow-up period. Patients could be re-treated with imiquimod 5% cream for up to an additional 16 weeks if their warts recurred or new warts developed during the follow-up period. The treatment period could also be extended for up to an additional 16 weeks if patients only experienced partial clearance during the initial 16-week treatment period. RESULTS: Of the female patients who applied imiquimod 5% cream, 75% (449/600) experienced complete clearance of their warts (treatment failure analysis). This includes 46 patients who experienced total clearance when they applied imiquimod for longer than 16 weeks as their warts had only partially cleared in the initial 16 weeks of therapy. During the 6 months of follow-up after the initial treatment period, 15% of patients had recurrent warts. Thirty-nine (75%) of those patients experienced total clearance again after they re-applied imiquimod for up to an additional 16 weeks. The most frequently observed local skin reaction was erythema. CONCLUSION: In these studies, imiquimod 5% cream was an effective and well-tolerated treatment for anogenital warts in females and continued to be safe and effective in the small proportion of patients who needed to re-apply imiquimod after wart recurrence.

Bioavailability of budesonide delivered by the clickhaler® and turbuhaler® dry powder inhalers in healthy volunteers : a pilot study.

OBJECTIVE: To compare the pharmacokinetic profile and bioavailability of budesonide after inhalation from the Clickhaler® dry powder inhaler with the Turbuhaler® as standard. DESIGN: Randomised, placebo-controlled, double-blind, double-dummy, crossover pilot study. SUBJECTS: Six healthy adult males aged 19 to 44 years (mean age 28 ± 9 years). METHODS: Each subject received budesonide 1000µg from the Clickhaler® or Turbuhaler® inhaler devices, and oral charcoal was administered to block gastrointestinal absorption. Plasma levels of budesonide and cortisol were determined at timepoints up to 8 hours postdose. Cortisol was also determined 24 hours postdose. RESULTS: The ratio of the plasma budesonide area under the concentration-time curve (AUC) calculated to 8 hours for the Clickhaler® to Turbuhaler® was 1.17 [90% confidence interval (CI) 0.90 to 1.54], indicating that pulmonary bioavailability was similar following inhalation from the two devices. Likewise, the time to the highest plasma concentration and maximum plasma concentration of budesonide following delivery from the Clickhaler® were similar to those following delivery of budesonide from the Turbuhaler®, with ratios of 0.95 (90% CI 0.51 to 1.77) and 1.14 (90% CI 0.76 to 1.72), respectively. The corresponding ratio for plasma cortisol AUC was 1.03 (90% CI 0.77 to 1.39). CONCLUSION: Budesonide Clickhaler® and budesonide Turbuhaler® dry powder inhalers demonstrated similar pharmacokinetic profiles, pulmonary bioavailability and systemic activity. As this was a small pilot study, it was not possible to determine the clinical implications of these results, but they suggest that the Clickhaler® and the Turbuhaler® achieve similar drug delivery.

Projections of the paratrigeminal nucleus to the ambiguus, rostroventrolateral and lateral reticular nuclei, and the solitary tract.

The paratrigerminal nucleus (Pa5), a constituent of the spinal interstitial system, was linked to the pressor effect caused by bradykinin injected in the dorsal lateral medulla of the rat. The nucleus receives primary afferent sensory fibers contained in branches of the trigeminal, glossopharyngeal and vagus nerves. In this investigation connections of the paratrigeminal nucleus to other medullary structures were studied with the use of retrograde and anterograde neuronal tracers. Fluorescent light microscopy analyses of medullary sections of rats injected with the retrograde transport tracer Fluoro-gold in the nucleus of the solitary tract (NTS) or in the pressor area of the rostral ventrolateral medulla (RVLM) revealed labeled neuronal cell bodies in the ipsi- and contralateral Pa5. FluoroGold microinjections in the caudal ventrolateral medulla (CVLM) did not produce fluorescent labeling of Pa5 neurons. Microinjection of the anterograde transport neuronal tracer biocytin in the Pa5 produced bilateral labeling of the solitary tract (sol). rostroventrolateral reticular nucleus (RVL), ambiguus nucleus (Amb), lateral reticular nucleus (LRt) and ipsilateral parabrachial nuclei, but not the contralateral Pa5. Confocal laser microscopy showed fluorescence labeling of fibers and presumptive terminal varicosities in the NTS, RVL, Amb and LRt. The present findings showing the paratrigeminal nucleus interposed between sensory afferent and stuctures associated to cardiovascular and respiratory functions, suggest that the structure may act as a medullary relay nucleus for sensory stimuli directly connecting primary afferents to structures mediating cardiovascular and respiratory reflexes.

Combinatorial discovery of alloy electrocatalysts for amperometric glucose sensors.

Combinatorial methods were used to search for active alloy electrocatalysts for use in enzyme-free amperometric glucose sensors. Electrode arrays (715-member) containing combinations of Pt, Pb, Au, Pd, and Rh were prepared and screened by converting anodic current to visible fluorescence. The most active compositions contained both Pt and Pb. Bulk quantities of catalysts with compositions corresponding to those identified in the screening experiments were prepared and characterized. The best alloy electrocatalysts catalyzed glucose oxidation at substantially more negative potentials than pure platinum in enzyme-free voltammetric measurements. They were also insensitive to potential interfering agents (ascorbic and uric acids, and 4-acetamidophenol), which are oxidized at slightly more positive potentials. Rotating disk electrode (RDE) experiments were carried out to study the catalytic mechanism. The improvement in catalytic performance was attributed to the inhibition of adsorption of oxidation products, which poison Pt electrodes.

Neuronal connections of the paratrigeminal nucleus: a topographic analysis of neurons projecting to bulbar, pontine and thalamic nuclei related to cardiovascular, respiratory and sensory functions.

The paratrigeminal nucleus, which receives sensory input from trigeminal, glossopharyngeal and vagus nerves, has efferent projections to bulbar, pontine and possibly to thalamic structures associated with nociception, thermoregulation and cardiovascular control. Anterograde neuronal tracers were used to study paratrigeminal efferent connections. Labeled terminal fibers, evidencing bilateral efferent paratrigeminal projections were observed in the medial and caudal solitary tract (sol), lateral reticular nucleus (LRt), ambiguus nucleus (Amb), rostroventrolateral reticular nucleus (RVL), while ipsilateral projections were found in the parabrachial (PB) nuclei and ventral portion of the ventral posteromedial thalamic nucleus (VPM). This extends other findings that describe paratrigeminal projections. Retrograde neuronal transport tracers, microinjected in the defined projection areas were used to map distribution of the paratrigeminal neurons originating different efferent connections. Microinjection of latex microspheres containing fluorescein or rhodamine and Fluoro-gold in the ventral VPM, PB, RVL, Amb, LRt and NTS revealed sets of labeled paratrigeminal nucleus neurons respectively organised in a rostral-caudal sequence. The largest extent of the paratrigeminal nucleus (medial portion) contained neurons projecting to the RVL/Amb, structures associated with cardiovascular regulation. The data show a segmented topographical organization of the nucleus, with different sets of neurons within delimited segments, projecting to neuronal structures associated with different functions. This points to a complex and extensive role for the paratrigeminal nucleus in the integration of somatosensory reflexes related to cardiovascular, respiratory and pain mechanisms. The nucleus may act as a medullary relay interposed between sensory afferents and different structures related to homoeostatic functions.

The ideal inhaler for asthma therapy.

Innovations in multidose nebulisers and dry-powder inhalation devices have been stimulated by the development of new chemical entities and the availability of generic drugs. In addition, conventional pressurised inhalers are being replaced because of the phasing-out of chlorofluorocarbon gases. This article highlights the key features that constitute the ideal inhaler.

College health needs to participate in the national STD debate.

We have a window of opportunity in which events are coming together, and we in ACHA can make a significant impact on STDs/STIs. College health professionals can choose to become actively involved or we can be bystanders. Our population, our tradition, and our moral imperatives all urge us to become engaged at all levels. We work with one of the most highly educated of all groups--a group that also shows some of the highest rates of risky behaviour--and we should be able to demonstrate the highest levels of successful intervention.