Inhibition of Mitochondrial Permeability Transition Pores by Cyclosporine A Improves Cytochrome c Oxidase Function and Increases Rate of ATP Synthesis in Failing Cardiomyocytes

Background: We previously showed that mitochondrial respiratory function is abnormal in dogs with chronic heart failure (HF). Mitochondrial permeability transition pores (MPTP) can affect mitochondrial inner membrane potential (Δ < eqid1 > _m) and mitochondrial function in normal cardiomyocytes. The potential impact of MPTP on Δ < eqid2 > _m and mitochondrial respiratory function in HF has not yet been determined. We tested the hypothesis that cyclosporine A, a potent blocker of the MPTP, can improve mitochondrial function in HF. Methods: Cardiomyocytes were isolated from the left ventricular myocardium of 7 dogs with HF produced by intracoronary microembolizations and from 7 normal dogs. Cardiomyocytes were treated for 24 hours with cyclosporine A. Δ < eqid3 > _m, cytochrome c oxidase protein expression, mitochondrial cytochrome c oxidase-dependent respiration (CDOR) and ATP synthesis were measured. Results: Δ < eqid4 > _m, protein expression of cytochrome c oxidase, CDOR and the rate of ATP synthesis were decreased in HF compared to normal controls. Inhibition of MPTP in failing cardiomyocytes with low dose of cyclosporine A (0.2 μM) increased Δ < eqid5 > _m, preserved expression of cytochrome c oxidase, improved CDOR and the rate of ATP synthesis. Conclusion: MPTP opening contributes to the loss of mitochondrial function observed in the failing heart. Inhibition of MPTP opening represents a potential therapeutic target for the treatment of HF. This study was supported by a grant from the National Heart, Lung, and Blood Institute PO1 HL074237-01.     

Variation in the masseteric silent period in older dentate humans and in denture wearers

The masseteric silent period was elicited by chin taps at 40% clenching in the masseter muscle of the preferred chewing side in 22 younger dentate individuals, in 22 older dentate individuals, in 22 older experienced denture wearers and in 7 older inexperienced denture wearers. One simple and three combined types of silent period (combination of early and late phases of depression) were recorded in all groups. An early silent period was always elicited, the only exception being in some inexperienced denture wearers. Both the age and the extent of rehabilitation with dentures in the trained denture wearers affected reflex latencies (p < 0.05), while the variation in duration was not significant (p>0.05). The duration of the silent period was, however, affected by the type of silent period, thus by the measuring technique (p < 0.05). Increased variation was observed in the inexperienced denture wearers, who were in a period of adaptation.     

Surface EMG activity of the masseter muscle in denture wearers during chewing of hard and soft food

Previous studies mainly on dentate subjects, have clearly shown that food texture affects the various chewing parameters. The purpose of this investigation was to study the influence of food texture on the surface electromyographic (EMG) activity of the masseter muscle in a sample of denture wearers. Nine experienced denture wearers (mean age of 68·7 years) with clinically satisfactory dentures consented to participate in this study. Carrots and peeled apples cut into equally sized pieces were choosen as representing a hard and a soft food respectively. The parameters studied from the raw and integrated EMG recordings were: chewing rate, mean peak RMS activity, chewing cycle and chewing burst duration and relative contraction period. The findings were in line with those earlier reported on dentate subjects, in that harder foods require higher chewing rates, higher electrical activity of the masseter muscle and higher relative contraction periods, accompanied by shorter cycle durations. Most of these differences were statistically significant ( P < 0·05) as tested by paired t ‐test. Moreover a strong inverse correlation was found between chewing rate and cycle duration ( r = –0.92, P < 0·05). We concluded that the texture of food has an obvious effect on all the studied parameters of EMG activity, and that those adjustments to food consistency are probably due to a combined powerfull peripheral input mediated through receptors, other than the periodontal ones.     

Activation of membrane androgen receptors potentiates the antiproliferative effects of paclitaxel on human prostate cancer cells

Genomic signaling mechanisms require a relatively long time to get into action and represent the main way through which steroid hormones affect target cells. In addition, steroids may rapidly activate cellular functions by non-genomic signaling mechanisms involving membrane sites. Understanding in depth the molecular mechanisms of the non-genomic action represents an important frontier for developing new and more selective pharmacologic tools for endocrine therapies. In the present study, we report that membrane-impermeable testosterone-bovine serum albumin (BSA) acts synergistically with paclitaxel in modifying actin and tubulin cytoskeleton dynamics in LNCaP (androgen sensitive) and DU-145 (androgen insensitive) human prostate cancer cell lines. In addition, coincubation of either cell line with testosterone-BSA and paclitaxel induced inhibition of cell proliferation and apoptosis. Finally, in vivo experiments in LNCaP and DU-145 tumor xenografts in nude mice showed that both agents decrease tumor mass, whereas testosterone-BSA enhances the effect of paclitaxel. Our findings suggest that chronic activation of membrane androgen receptors in vitro and in vivo facilitates and sustains for a longer time the antitumoral action of cytoskeletal acting agents.     

Patent disclosure requirements for therapeutic antibody patents

Introduction: Therapeutic antibodies have grown to become an important product class within the biopharmaceutical market. A prerequisite to their commercialization is adequate patent protection. Disclosure requirements and the types of claims available in different jurisdictions can impact the scope of protection available for antibodies.

Areas covered: A comparative review of statutory bases, patent office practices and selected decisions in Canada, the United States and the United Kingdom related to disclosure requirements is provided.

Expert opinion: Differences in disclosure requirements exist in different jurisdictions which can impact the type of claims obtained and their survival when attacked in litigation. Including a wide variety of claim types is a key strategy to ensuring therapeutic antibodies are adequately protected. Method of use claims may provide advantages and broader protection in some circumstances and should also be considered.     

An Expert Opinion from the European College of Gerodontology and the European Geriatric Medicine Society: European Policy Recommendations on Oral Health in Older Adults

This is an expert opinion paper on oral health policy recommendations for older adults in Europe, with particular focus on frail and care‐dependent persons, that the European College of Gerodontology (ECG) and the European Geriatric Medicine Society (EUGMS) Task and Finish Group on Gerodontology has developed. Oral health in older adults is often poor. Common oral diseases such as caries, periodontal disease, denture‐related conditions, hyposalivation, and oral pre‐ and cancerous conditions may lead to tooth loss, pain, local and systemic infection, impaired oral function, and poor quality of life. Although the majority of oral diseases can be prevented or treated, oral problems in older adults remain prevalent and largely underdiagnosed, because frail persons often do not receive routine dental care, due to a number of barriers and misconceptions. These hindrances include person‐related issues, lack of professional support, and lack of effective oral health policies. Three major areas for action are identified: education for healthcare providers, health policy action plans, and citizen empowerment and involvement. A list of defined competencies in geriatric oral health for non‐dental healthcare providers is suggested, as well as an oral health promotion and disease prevention protocol for residents in institutional settings. Oral health assessment should be incorporated into general health assessments, oral health care should be integrated into public healthcare coverage, and access to dental care should be ensured.     

Growth kinetic analysis of bi-recombinant poliovirus vaccine strains

Attenuated strains of Sabin poliovirus vaccine replicate in the human gut and in rare cases may cause vaccine-associated paralytic poliomyelitis (VAPP). Mutations at specific sites of the genome and recombination between Sabin strains may result in the loss of the attenuated phenotype of OPV (Oral Poliovirus Vaccine) strains and the acquisition of traits characteristic of wild polioviruses, such as increased neurovirulence and loss of temperature sensitivity. In this study, we determined the phenotypic traits such as temperature sensitivity and growth kinetics of eight OPV isolates (six bi-recombinant and two non-recombinant). The growth phenotype of each isolate as well as of Sabin vaccine strains in Hep2 cell line at two different temperatures (37 and 40°C) was evaluated using two different assays, RCT test (Reproductive Capacity at different Temperatures) and one-step growth curve analysis. Moreover, the nucleotide and amino acid positions in the genomes of the isolates that have been identified as being involved in the attenuated and thermo sensitive phenotype of Sabin vaccine strains were investigated. Mutations that result in loss of the attenuated and thermo sensitive phenotype of Sabin vaccine strains were identified in the genomes of all isolates. Both mutations and recombination events correlated well with the reverted phenotypic traits of OPV-derivatives. In the post-eradication era of wild polioviruses, the identification and the characterization (genomic and phenotypic) of vaccine-derived polioviruses become increasingly important in order to prevent cases or even outbreaks of paralytic poliomyelitis caused by neurovirulent strains.     

Bilateral variation of the masseteric myotatic reflex and the silent period in young humans

Increased bilateral differences in jaw reflexes have been considered as pathological findings. The aim of this study was to investigate the normal variation between sides in the jaw jerk and the silent period and determine the range of its boundaries, using the present experimental set-up. Electromyographic data were simultaneously recorded from the right and left masseter muscles by surface electrodes, using a computerized recording and analysis system. The reflexes were elicited by chin taps during mandibular rest and at moderate intercuspal clenching in 20 healthy dentate adults (10 males and 10 females) with a mean age of 26 years. The reflexes were always elicited bilaterally and no overall significant differences were observed between sides for occurrence, latency, duration and amplitude of the jaw jerk and for the latency and duration of the silent period (P > 0.05). However, in the individual analysis significant bilateral variation was occasionally recorded, particularly for the jaw jerk at rest and mainly in the amplitude measurements. On the other hand, in the silent period duration measurements individual variation was very limited. Bilateral individual latency differences for the jaw jerk did not exceed 1 ms at rest (x = 0.3 +/- 0.3 ms) and 0.7 ms at clench (x = 0.3 +/- 0.2 ms), while latency differences for the silent period did not exceed 0.8 ms for the early type (x = 0.4 +/- 0.2 ms) and 4.8 ms for the late phase of depression (x= 1.9 +/- 1.7 ms). Bilateral differences for the silent period duration did not exceed 7.1 ms (x = 2.2 +/- 2.3 ms) in the early type (simple + early phase of combined types) and 3.3 ms (x = 1.5 +/- 0.9 ms) in the total duration of the combined types.