Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones

The neuropeptide substance-P (SP) is expressed from the TAC1 gene in sensory neurones where it acts as a key modulator of neurogenic inflammation. The promoter of TAC1 (TAC1prom) plays a central role in the regulation of the TAC1 gene but requires the presence of a second regulatory element; ECR2, to support TAC1 expression in sensory neurones and to respond appropriately to signalling pathways such as MAPkinases and noxious induction by capsaicin. We examined whether the effect of capsaicin on ECR2-TAC1prom activity in larger diameter neurones was cell autonomous or non- cell autonomous. We demonstrate that TRPV1 is not expressed in all the same cells as SP following capsaicin induction suggesting the presence of a non-cell autonomous mechanism for TAC1 up-regulation following capsaicin induction. In addition, we demonstrate that induction of SP and ECR1-TAC1prom activity in these larger diameter neurones can be induced by potassium depolarisation suggesting that, in addition to capsaicin induction, transgene activity may be modulated by voltage gated calcium channels. Furthermore, we show that NK1 is expressed in all SP- expressing cells after capsaicin induction and that an agonist of NK1 can activate both SP and the transgene in larger diameter neurones. These observations suggest the presence of an autocrine loop that controls the expression of the TAC1 promoter in sensory neurones. In contrast, induction of the TAC1 promoter by LPS was not dependent on ECR2 and did not occur in large diameter neurones. These studies demonstrate the diversity of mechanisms modulating the activity of the TAC1 promoter and provide novel directions for the development of new anti-inflammatory therapies.     

Walking speed and peak plantar pressure distribution during barefoot walking in persons with diabetes

Background. The impact of walking speed has not been evaluated as a feasible outcome measure associated with peak plantar pressure (PPP) distribution, which may result in tissue damage in persons with diabetic foot complications. The objective of this pilot study was to determine the walking speed and PPP distribution during barefoot walking in persons with diabetes. Methods. Nine individuals with diabetes and nine age–gender matched individuals without diabetes participated in this study. Each individual was marked at 10 anatomical landmarks for vibration and tactile pressure sensation tests to determine the severity of sensory deficits on the plantar surface of the dominant limb foot. A steady state walking speed, PPP, the fore and rear foot (F/R) PPP ratio and gait variables were measured during barefoot walking. Results. Persons with diabetes had a significantly slower walking speed than the age–gender matched group resulting in a significant reduction of PPP at the F/R foot during barefoot walking (p < 0.05). There was no significant difference in F/R foot PPP ratio in the diabetic group compared with the age–gender matched group during barefoot walking (p > 0.05). There was a significant difference between the diabetic and non‐diabetic groups for cadence, step time, toe out angle and the anterior–posterior excursion (APE) for centre of force (p < 0.05). Conclusion. Walking speed may be a potential indicator for persons with diabetes to identify PPP distribution during barefoot walking in a diabetic foot. However, the diabetic group demonstrated a more cautious walking pattern than the age–gender matched group by decreasing cadence, step length and APE, and increasing step time and toe in/out angle. People with diabetes may reduce the risk of foot ulcerations as long as they are able to prevent severe foot deformities such as callus, hammer toe or charcot foot. Copyright © 2011 John Wiley & Sons, Ltd.     

Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild-to-moderate renal impairment

BackgroundMany antibiotics require dosage adjustments in patients with renal impairment. In Phase III studies, omadacycline was non-inferior to moxifloxacin and linezolid in adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), respectively. This analysis evaluated efficacy and safety measures from three omadacycline studies by patient renal function.MethodsPatients were stratified as having normal renal function (creatinine clearance >89 mL/min), mild renal impairment (creatinine clearance 60–89 mL/min) or moderate renal impairment (creatinine clearance <60 mL/min); creatine clearance ≤30 mL/min (severe renal impairment) was an exclusion criterion. Efficacy endpoints were clinical success at the early clinical response (ECR) and post-treatment evaluation (PTE) time-points. Safety was evaluated as treatment-emergent adverse events (TEAEs) and laboratory measures.ResultsThis subgroup analysis included 773 patients with CABP and 1339 patients with ABSSSI in intent-to-treat (ITT) and modified ITT populations, respectively. Clinical success rates were high at ECR and PTE across the studies (CABP 75–90%; ABSSSI 74–95%), and broadly similar between treatments, irrespective of renal function. Rates of TEAEs in patients with ABSSSI ranged from 33% to 52%, and were similar across renal function groups. In patients with CABP, higher rates were observed in patients with moderate renal impairment (56–61%) compared with patients with normal renal function or mild renal impairment (35–49%). The most common TEAEs were nausea and vomiting.ConclusionsClinical success was similar across renal function groups, indicating no notable difference in the efficacy of omadacycline in patients with mild or moderate renal impairment. Omadacycline and comparators displayed similar safety profiles.ClinicalTrials.gov registryOPTIC (NCT02531438); OASIS-1 (NCT02378480); OASIS-2 (NCT02877927).     

Community-Based Collaboration in Prevention and Mental Health Promotion: Benefiting from and Building the Resources of Partnership

Successful primary prevention and promotion initiatives in mental health recognize and include the perspectives of multiple stakeholders. Community-based collaboration is an important strategy for achieving this balance and for facilitating the achievement of other key characteristics that are consistently associated with effective programs. We examine the powerful benefits of collaboration – described in terms of the resources contributed by each partner as well as the environment and processes created by diverse partners working together – within the context of ten characteristics of successful prevention and promotion programs. We also review some of the most common challenges to collaboration and offer recommendations for overcoming them in order to facilitate success in mental health promotion.     

Investigation of Biases in the General Public in Evaluating Mild Head Injury Using Neuropsychological and CT Scan Results: Forensic Implications

The purpose of this study was to determine how the general public considers neuropsychological (NP) vs. CT scan data in assessing the effects of a possible mild traumatic brain injury (MTBI). Ten scenarios depicting an MTBI from a motor vehicle accident were presented to community volunteer participants. Case scenarios differed with regard to diagnostic information presented (i.e., all combinations of normal, abnormal, or absent NP and CT results were provided). The number of participants ranged from 31 to 42 across the 10 cases and there were no age or educational differences among the groups. Participants rated the likelihood of symptoms being attributable to brain damage from the accident on a 7-point Likert-type scale. Scenarios with positive NP or CT results were rated as more likely to have sustained brain damage than when NP/CT results were negative. However, when NP and CT data were contradictory (i.e., one positive and the other negative), there were no differences in the ratings of the participants. Thus, members of the general public did not demonstrate any preconceived bias about the validity of NP vs. CT results in MTBI. Women were more likely than men to attribute symptoms to brain damage from the motor vehicle accident, as did participants with a history of TBI. Forensic implications are discussed.     

Preprocedural computed tomography before cardiac implanted electronic device lead extraction: Indication,technique, and approach to interpretation

Cardiac implantable electronic devices (CIEDs) frequently need to be extracted due to infection, hardware failure, and other causes. The extraction of the CIED is typically performed using percutaneous methods. While these procedures are mostly performed without incident there is a small risk of significant complications. Dedicated imaging pre‐CEID removal to include the central veins and heart with multidetector computed tomography (MDCT) can be utilized to evaluate the lead course and termination, the integrity of the central veins and cardiac chambers, and identify potential complications that may alter the lead extraction procedure as well as reimplantation of subsequent leads. Indications for preprocedural imaging, the technique of dedicated preprocedural lead extraction MDCT, and the approach to the interpretation of the images is discussed in this review.