Randomised controlled single-blind study of conventional versus depot mydriatic drug delivery prior to cataract surgery

BACKGROUND: A prerequisite for safe cataract surgery is an adequately dilated pupil. The authors conducted a trial to assess the efficacy (in terms of pupil diameter) of a depot method of pre-operative pupil dilatation, as compared with repeated instillations of drops (which is time-consuming for the nursing staff and uncomfortable for the patient). METHODS: A prospective randomised masked trial was conducted comprising 130 patients with no significant ocular history undergoing elective clear corneal phacoemulsification. 65 patients had mydriatic drops (Tropicamide 1%, Phenylephrine 2.5%, Diclofenac sodium 0.1%) instilled prior to surgery, 65 had a wick soaked in the same drop mixture placed in the inferior fornix. Horizontal pupil diameters were recorded on a millimetre scale immediately prior to surgery. RESULTS: There was no significant difference in pupil size between the two groups (p = 0.255, Student's t-test). CONCLUSION: There was no significant difference between the mydriasis obtained with the depot system compared with conventional drop application. Use of a depot mydriatic delivery system appears to be a safe and efficient method of drug delivery. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register ISRCTN7804776

Constitutively Active Canonical NF-κB Pathway Induces Severe Bone Loss in Mice

Physiologic osteoclastogenesis entails activation of multiple signal transduction pathways distal to the cell membrane receptor RANK. However, atypical osteoclastogenesis driven by pro-inflammatory stimuli has been described. We have reported recently a novel mechanism whereby endogenous mutational activation of the classical NF-κB pathway is sufficient to induce RANKL/RANK-independent osteoclastogenesis. Here we investigate the physiologic relevance of this phenomenon in vivo. Using a knock-in approach, the active form of IKK2, namely IKK2SSEE, was introduced into the myeloid lineage with the aid of CD11b-cre mice. Phenotypic assessment revealed that expression of IKK2SSEE in the myeloid compartment induced significant bone loss in vivo. This observation was supported by a dramatic increase in the number and size of osteoclasts in trabecular regions, elevated levels of circulating TRACP-5b, and reduced bone volume. Mechanistically, we observed that IKK2SSEE induced high expression of not only p65 but also p52 and RelB; the latter two molecules are considered exclusive members of the alternative NF-κB pathway. Intriguingly, RelB and P52 were both required to mediate the osteoclastogenic effect of IKK2SSEE and co-expression of these two proteins was sufficient to recapitulate osteoclastogenesis in the absence of RANKL or IKK2SSEE. Furthermore, we found that NF-κB2/p100 is a potent inhibitor of IKK2SSEE-induced osteoclastogenesis. Deletion of p52 enabled more robust osteoclast formation by the active kinase. In summary, molecular activation of IKK2 may play a role in conditions of pathologic bone destruction, which may be refractory to therapeutic interventions targeting the proximal RANKL/RANK signal

Health-related Quality of Life among hospitalized older people awaiting residential aged care

BACKGROUND: Health related quality of life (HRQoL) in very late life is not well understood. The aim of the present study was to assess HRQoL and health outcomes at four months follow-up in a group of older people awaiting transfer to residential aged care. METHODS: Secondary analysis of data from a randomized controlled trial conducted in three public hospitals in Adelaide. A total of 320 patients in hospital beds awaiting a residential aged care bed participated. Outcome measurements included HRQoL (Assessment of Quality of Life; AQoL), functional level (Modified Barthel Index), hospital readmission rates, survival, and place of residence at four months follow-up. RESULTS: In this frail group the median AQoL was poor at baseline (median 0.02; 95%CI -0.01 - 0.04) and at follow-up (0.05; 95%CI 0.03 - 0.06). On leaving hospital, more than one third of participants who were moving for the first time into nursing home care rated themselves in a state worse than death (AQoL < or = 0.0). Poor HRQoL at discharge from hospital (AQoL < or = 0.0) was a significant predictor of mortality (HR 1.7; 95%CI 1.2 - 2.7), but not hospital readmission nor place of residence at four months follow-up. Improved function was a predictor of improved HRQoL among the surviving cohort. CONCLUSION: People making the transition to residential aged care from hospital have very poor HRQoL, but small gains in function seem to be related to improvement. While functional gains are unlikely to change discharge destination in this frail group, they can contribute to improvements in HRQoL. These gains may be of great significance for individuals nearing the end of life and should be taken into account in resource allocation.Lynne C. Giles, Graeme Hawthorne and Maria Crott

Determinants of access to experimental antiretroviral drugs in an Italian cohort of patients with HIV: a multilevel analysis

<p>Abstract</p> <p>Background</p> <p>Identification of the determinants of access to investigational drugs is important to promote equity and scientific validity in clinical research. We aimed to analyze factors associated with the use of experimental antiretrovirals in Italy.</p> <p>Methods</p> <p>We studied participants in the Italian Cohort of Antiretroviral-Naive Patients (ICoNA). All patients 18 years or older who had started cART (≥ 3 drugs including at least two NRTI) after their enrolment and during 1997-2007 were included in this analysis. We performed a random effect logistic regression analysis to take into account clustering observations within clinical units. The outcome variable was the use of an experimental antiretroviral, defined as an antiretroviral started before commercial availability, in any episode of therapy initiation/change. Use of an experimental antiretroviral obtained through a clinical trial or an expanded access program (EAP) was also analyzed separately.</p> <p>Results</p> <p>A total of 9,441 episodes of therapy initiation/change were analyzed in 3,752 patients. 392 episodes (360 patients) involved an experimental antiretroviral. In multivariable analysis, factors associated with the overall use of experimental antiretrovirals were: number of experienced drugs (≥ 8 drugs versus "naive": adjusted odds ratio [AOR] = 3.71) or failed antiretrovirals(3-4 drugs and ≥ 5 drugs versus 0-2 drugs: AOR = 1.42 and 2.38 respectively); calendar year (AOR = 0.80 per year) and plasma HIV-RNA copies/ml at therapy change (≥ 4 log versus < 2 log: AOR = 1.55). The probability of taking an experimental antiretroviral through a trial was significantly lower for patients suffering from liver co-morbidity(AOR = 0.65) and for those who experienced 3-4 drugs (vs naive) (AOR = 0.55), while it increased for multi-treated patients(AOR = 2.60). The probability to start an experimental antiretroviral trough an EAP progressively increased with the increasing number of experienced and of failed drugs and also increased for patients with liver co-morbidity (AOR = 1.44; p = 0.053). and for male homosexuals (vs heterosexuals: AOR = 1.67). Variability of the random effect associated to clinical units was statistically significant (p < 0.001) although no association was found with specific characteristics of clinical unit examined.</p> <p>Conclusions</p> <p>Among patients with HIV infection in Italy, access to experimental antiretrovirals seems to be influenced mainly by exhaustion of treatment options and not by socio-demographic factors.</p

New synthesis of KT5823 indolocarbazole aglycone

The indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycone of the selective protein kinase G inhibitor KT5823 has been synthesised in four steps and 36% overall yield from 2,3-dichloro-N-methylmaleimide by utilising an efficient new two step reduction sequence for the key imide to amide transformation

Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase.

Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure-activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases

Performing Cyborgian Identity: Enacting Agential Cuts in Second Life

Part 4: Considering Communication and PerformanceInternational audienceAs people live their lives online more and more, they increasingly rely on digital bodies to extend their senses and to perform identities. With this hybridization of physical and digital embodiments, they become cyborgs and are compelled to negotiate the dualistic space defined by the binary opposition of actual and virtual reality. Whereas actuality typically connotes concrete existence, virtuality signifies phenomena that are ideal, essential and unrealized but that have actual effects.This paper seeks to understand how individuals negotiate the liminal space that combines virtual and actual reality, especially as it relates to their sense of self, in their performance of cyborgian identities. Drawing on Boland’s [1] Engine of Inquiry and Barad’s [2] agential cuts as a conceptual infrastructure, this paper analyzes one identity performance of a single Second Life user in order to answer the following research question: How are cyborgian identities enacted in virtual worlds