A Point Mutation at F1737 of the Human Nav1.7 Sodium Channel Decreases Inhibition by Local Anesthetics

Abstract: Voltage-gated sodium channels (VGSC) contribute to the initiation and propagation of action potentials within the nervous system. These channels are important targets for inhibition by several classes of drugs, including antiarrhythmics and local anesthetics. Structural and pharmacological studies have localized the binding of these drugs to a common site near the channel's intracellular pore region. Point mutations within this region disrupt local anesthetic inhibition of cardiac, CNS, and skeletal muscle VGSC subtypes. This study was designed to test whether a similar structural requirement for drug binding exists on the peripheral neuronal VGSC subtype; Na_v1.7. In support of this hypothesis, an alanine substitution for phenylalanine at position 1737 (F1737A) in the pore lining S6 segment of domain IV in human Na_v1.7 reduced both use- and state- dependent inhibition of the local anesthetics, lidocaine and tetracaine, by 8–21-fold. We also saw a 2–3-fold reduction in tonic inhibition with the F1737A mutant. The voltage dependence of both activation and inactivation were unaffected by the F1737A mutation, however, fast inactivation kinetics were impaired, such that a significant portion of inward current remained at the end of a 20-ms depolarization. These data suggest that F1737 forms a part of the high affinity binding of local anesthetics as well as mediating inactivation processes of neuronal Na_v1.7 channels.     

Metastatic disease of the breast and local recurrence

Multimodality primary therapies for breast cancer combined with earlier detection have led to a sharp decline in the death rate from breast cancer in the UK over the last 40 years in the face of a rising incidence. The latest UK statistics from Cancer Research UK report 50,285 new cases of breast cancer in 2011 with 11,716 deaths from breast cancer recorded in 2012. Crudely, this equates to a cure rate in excess of 75% for all comers. Despite this good news, there are still significant numbers of women (and men) who suffer from either a local recurrence or metastatic disease following apparently successful treatment for early breast cancer (Stage I–III). Only a minority of individuals, 6.6% with the stage recorded at diagnosis, present with stage IV disease. This review considers the treatment options available to individuals with locally recurrent and advanced breast cancer (ABC).     

Noninvasive measurement of local arterial pulse wave velocity in humans by ultrasound

An improved method for noninvasive measurement of the local velocity of arterial pulse wave propagation by an echo-tracking-based ultrasound system is described. A data acquisition image interface was programmed in the ultrasound machine simultaneously to record M-mode ultrasound signals at two locations of a given distance apart along an artery. The selections of measurement sites, separation, and time resolution were performed on the control interface. The temporal sampling frequency could be as high as 10?kHz. The displacements of the blood vessel wall along the time axis were calculated from the M-mode signals by cross-correlation of the radio-frequency data and the distension waveforms were obtained. The temporal separation of the feet of the distension curves from the two measurement locations was derived to give the travel time of the pulse wave. Measurements were made in vivo on human carotid arteries. The pulse wave velocities measured from four volunteers were from 4.1 to 7.2 m/s with coefficients of variation from 5.9 to 29.5%. Some of the factors contributing to the variation in measured values of the velocity are discussed. The method is simple to implement and should be suitable for clinical research into local pulse wave velocity.     

平阳霉素局部注射治疗小儿皮肤血管瘤疗效评价

目的:评价平阳霉素局部注射治疗小儿皮肤血管瘤的临床疗效。方法:根据患儿年龄、病变部位、皮损大小等,使用不同剂量的平阳霉素治疗草莓状血管瘤、海绵状血管瘤和混合性血管瘤126例。结果:经过3年的随访,总有效率75.6%。结论:平阳霉素局部注射治疗小儿皮肤草莓状血管瘤、海绵状血管瘤和混合性血管瘤有效。     

Cognitive performance among cohorts of children exposed to a waste disposal site containing heavy metals in Chile

Between 1984 and 1998, people living in Arica were involuntarily exposed to metal-containing waste stored in the urban area. The study aims to determine whether children who lived near the waste disposal site during early childhood experienced negative effects on their cognitive development. The cognitive performance was assessed using the Wechsler Intelligence Scale for Children. The exposure variable was defined by the year of birth in three categories: (1) Pre-remediation (born before 1999); (2) During-remediation (born between 1999 and 2003); and (3) Post-remediation (born after 2003). In the crude analysis, a difference of 10 points in the IQ average was observed between the group born in the pre- (81.9 points) and post-remediation period (91.1 points). The difference between both groups was five times higher as compared to children of similar age and socioeconomic status in other cities of Chile. This result could be related with a period of high potential for exposure to this contaminated site.     

Efficacy of epinephrine‐free articaine compared to articaine with epinephrine (1:100 000) for maxillary infiltration,a randomised clinical trial

The selection of local anaesthetic in dental practice is essential to the patient′s comfort and the success of the treatment. Many patients prefer anaesthesia even for short treatments. Articaine is a local anaesthetic commonly used for dental practice. The duration of the effect of articaine on the nerve fibres is not yet precisely reported. This study was aimed to evaluate the clinical efficacy of 4% articaine with and without epinephrine in treatment of occlusal caries. Thirty healthy patients were included in this randomised double‐blind study. Each subject received 4% articaine with and without epinephrine (1:100 000). Maxillary infiltration was used for occlusal caries of the maxillary premolars on right and left sides. Quantitative sensory testing (QST) was performed in the innervation area of the infraorbital nerve, and pulp vitality test was performed on restoration‐free canines. Duration of anaesthesia was longer when articaine with epinephrine was used. Articaine without epinephrine showed faster recovery of sensory blockade compared to articaine with epinephrine. The epinephrine‐containing agent, when compared to the plain articaine solution, showed significantly stronger and longer anaesthetic efficacy on the soft tissue by all parameters of QST. Articaine with epinephrine caused a more reliable pulpal analgesia. A pain‐free treatment of the soft tissue up to 15 minutes can be performed under the vasoconstrictor‐free anaesthetic without causing long‐lasting numbness. Epinephrine‐containing articaine delivers a longer, more effective anaesthesia and is preferable for caries treatments and longer invasive treatments of the soft tissue.     

Thyroid Hormones and Cardiovascular Function and Diseases

Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction, and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease.