Age-related changes to lumbosacral spinal cord motoneurons that modulate bladder and bowel functions in male C57BL/6 mice

Incontinence and sexual dysfunction are often increased in the aged human population. In rats and mice the pattern of micturition and faecal clearance also changes with ageing and is suggestive of bladder and bowel dysfunction

Changes in murine anorectum signaling across the life course

Background: Increasing age is associated with an increase in the incidence of chronic constipation and fecal impaction. The contribution of the natural aging process to these conditions is not fully understood. This study examined the effects of increasing age on the function of the murine anorectum.Methods: The effects of increasing age on cholinergic, nitrergic, and purinergic signaling pathways in the murine anorectum were examined using classical organ bath assays to examine tissue function and electrochemical sensing to determine age‐related changes in nitric oxide and acetylcholine release.Key Results: Nitrergic relaxation increased between 3 and 6 months, peaked at 12 months and declined in the 18 and 24 months groups. These changes were in part explained by an age‐related decrease in nitric oxide (NO) release. Cholinergic signaling was maintained with age by an increase in acetylcholine (ACh) release and a compensatory decrease in cholinesterase activity. Age‐related changes in purinergic relaxation were qualitatively similar to nitrergic relaxation although the relaxations were much smaller. Increasing age did not alter the response of the anorectum smooth muscle to exogenously applied ACh, ATP, sodium nitroprusside or KCl. Similarly, there was no change in basal tension developed by the anorectum.Conclusions and Inferences: The decrease in nitrergic signaling with increasing age may contribute to the age‐related fecal impaction and constipation previously described in this model by partially obstructing defecation

Schools and civil society : corporate or community governance

School improvement depends upon mediating the cultural conditions of learning as young people journey between their parochial worlds and the public world of cosmopolitan society. Governing bodies have a crucial role in including or diminishing the representation of different cultural traditions and in enabling or frustrating the expression of voice and deliberation of differences whose resolution is central to the mediation of and responsiveness to learning needs. A recent study of governing bodies in England and Wales argues that the trend to corporatising school governance will diminish the capacity of schools to learn how they can understand cultural traditions and accommodate them in their curricula and teaching strategies. A democratic, stakeholder model remains crucial to the effective practice of governing schools. By deliberating and reconciling social and cultural differences, governance constitutes the practices for mediating particular and cosmopolitan worlds and thus the conditions for engaging young people in their learning, as well as in the preparation for citizenship in civil society

Enhanced electrical and optical properties of room temperature deposited Aluminium doped Zinc Oxide (AZO) thin films by excimer laser annealing

High quality transparent conductive oxides (TCOs) often require a high thermal budget fabrication process. In this study, Excimer Laser Annealing (ELA) at a wavelength of 248 nm has been explored as a processing mechanism to facilitate low thermal budget fabrication of high quality aluminium doped zinc oxide (AZO) thin films. 180 nm thick AZO films were prepared by radio frequency magnetron sputtering at room temperature on fused silica substrates. The effects of the applied RF power and the sputtering pressure on the outcome of ELA at different laser energy densities and number of pulses have been investigated. AZO films deposited with no intentional heating at 180 W, and at 2 mTorr of 0.2% oxygen in argon were selected as the optimum as-deposited films in this work, with a resistivity of 1×10−3 Ω.cm, and an average visible transmission of 85%. ELA was found to result in noticeably reduced resistivity of 5×10−4 Ω.cm, and enhancing the average visible transmission to 90% when AZO is processed with 5 pulses at 125 mJ/cm2. Therefore, the combination of RF magnetron sputtering and ELA, both low thermal budget and scalable techniques, can provide a viable fabrication route of high quality AZO films for use as transparent electrodes

A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma

Lomeguatrib, an O6-methylguanine-DNA methyltransferase inactivator, was evaluated in an extended dosing regimen with temozolomide, designed according to pharmacodynamic data from previous studies. Patients with unresectable stage 3 or 4 cutaneous or unknown primary melanoma metastases were treated with lomeguatrib 40 mg, b.i.d. for 10 or 14 days and temozolomide 75–100 mg m−2 on days 1–5. Drugs were administered orally with cycles repeated every 28 days, for up to six cycles. A total of 32 patients were recruited to the study. Lomeguatrib for 10 days with temozolomide 75 mg m−2 was established as the optimal extended lomeguatrib dosing schedule, with haematological toxicity being dose limiting. There were two partial responses to treatment giving an overall response rate of 6.25%. Extending lomeguatrib administration beyond that of temozolomide requires a reduced dose of the latter agent. Only limited clinical activity was seen, suggesting no advantage for this regimen over conventional temozolomide administration in the treatment of melanoma

Insecticide resistance and the future of malaria control in Zambia.

BACKGROUND: In line with the Global trend to improve malaria control efforts a major campaign of insecticide treated net distribution was initiated in 1999 and indoor residual spraying with DDT or pyrethroids was reintroduced in 2000 in Zambia. In 2006, these efforts were strengthened by the President's Malaria Initiative. This manuscript reports on the monitoring and evaluation of these activities and the potential impact of emerging insecticide resistance on disease transmission. METHODS: Mosquitoes were captured daily through a series of 108 window exit traps located at 18 sentinel sites. Specimens were identified to species and analyzed for sporozoites. Adult Anopheles mosquitoes were collected resting indoors and larva collected in breeding sites were reared to F1 and F0 generations in the lab and tested for insecticide resistance following the standard WHO susceptibility assay protocol. Annual cross sectional household parasite surveys were carried out to monitor the impact of the control programme on prevalence of Plasmodium falciparum in children aged 1 to 14 years. RESULTS: A total of 619 Anopheles gambiae s.l. and 228 Anopheles funestus s.l. were captured from window exit traps throughout the period, of which 203 were An. gambiae malaria vectors and 14 An. funestus s.s.. In 2010 resistance to DDT and the pyrethroids deltamethrin, lambda-cyhalothrin and permethrin was detected in both An. gambiae s.s. and An. funestus s.s.. No sporozoites were detected in either species. Prevalence of P. falciparum in the sentinel sites remained below 10% throughout the study period. CONCLUSION: Both An. gambiae s.s. and An. funestus s.s. were controlled effectively with the ITN and IRS programme in Zambia, maintaining a reduced disease transmission and burden. However, the discovery of DDT and pyrethroid resistance in the country threatens the sustainability of the vector control programme

Perfect weddings abroad

Approximately 16% of UK couples are currently married abroad. However, academic or practitioner focused research that explores the complex nature of a couple’s buying preferences or the development of innovative marketing strategies by businesses operating within the weddings abroad niche sector, is almost non-existent. This exploratory paper examines the role and relevance of marketing within the weddings abroad sector. The complex nature of customer needs in this high emotional and involvement experience, are identified and explored. A case study of Perfect Weddings Abroad Ltd highlights distinctive features and characteristics. Social networking and the use of home-workers, with a focus on reassurance and handholding are important tools used to develop relationships with customers. These tools and techniques help increase the tangibility of a weddings abroad package. Clusters of complementary services that are synergistic and provide sources of competitive advantage are identified and an agenda for future research is developed

A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer

To evaluate the tumour response to lomeguatrib and temozolomide (TMZ) administered for 5 consecutive days every 4 weeks in patients with metastatic colorectal carcinoma. Patients with stage IV metastatic colorectal carcinoma received lomeguatrib (40 mg) and TMZ (50–200 mg m−2) orally for 5 consecutive days every 4 weeks. Response was determined every two cycles. Pharmacokinetics of lomeguatrib and TMZ as well as their pharmacodynamic effects in peripheral blood mononuclear cells (PBMC) were determined. Nineteen patients received 49 cycles of treatments. Despite consistent depletion of O6-methylguanine-DNA methyltransferase in PBMC, none of the patients responded to treatment. Three patients had stable disease, one for the duration of the study, and no fall in carcinoembryonic antigen was observed in any patient. Median time to progression was 50 days. The commonest adverse effects were gastrointestinal and haematological and these were comparable to those of TMZ when given alone. This combination of lomeguatrib and TMZ is not efficacious in metastatic colorectal cancer. If further studies are to be performed, emerging data suggest that higher daily doses of lomeguatrib and a dosing period beyond that of TMZ should be evaluated

Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin