Efficiency and cross-bridge work output of skeletal muscle is decreased at low levels of activation

The purpose of this study was to determine how the mechanical efficiency of skeletal muscle is affected by level of activation. Experiments were performed in vitro (35 °C) using bundles of fibres from fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles of mice. Measurements were made of the total work and heat produced in response to 10 brief contractions. Mechanical efficiency was the ratio of total work performed to (total heat produced + work performed). Level of activation was varied by altering stimulation frequency between 40 and 160 Hz. Efficiency did not differ significantly between the two muscle types but was significantly lower using 40 Hz stimulation (mean efficiency ± SEM, 0.092?±?0.012, n?=?12, averaged across EDL and soleus) than at any of the other frequencies (160 Hz: 0.147?±?0.007, n?=?12). Measurements of the partitioning of energy output between force-dependent and force-independent components enabled calculation of the amount of Ca²⁺ released and number of cross-bridge cycles performed during the contractions. At 40 Hz stimulation frequency, less Ca²⁺ was released than at higher frequencies and fewer cross-bridge cycles were performed. Furthermore, less work was performed in each cross-bridge cycle. It is concluded that skeletal muscles are less efficient at low levels of activation than when fully activated and this indicates that level of activation affects not only the number of cycling cross-bridges but also the ability of individual cross-bridges to perform work.     

EXPLORING THE VALIDITY AND PREDICTIVE POWER OF AN EXTENDED VOLUNTEER FUNCTIONS INVENTORY WITHIN THE CONTEXT OF EPISODIC SKILLED VOLUNTEERING BY RETIREES

The current study examined the structure of the volunteer functions inventory within a sample of older individuals (N = 187). The career items were replaced with items examining the concept of continuity of work, a potentially more useful and relevant concept for this population. Factor analysis supported a four factor solution, with values, social and continuity emerging as single factors and enhancement and protective items loading together on a single factor. Understanding items did not load highly on any factor. The values and continuity functions were the only dimensions to emerge as predictors of intention to volunteer. This research has important implications for understanding the motivation of older adults to engage in contemporary volunteering settings.     

Evidence-Based,Pharmacological Treatment Guideline for Depression in Korea,Revised Edition

This paper aims to introduce, summarize, and emphasize the importance of the ''Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition''. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.     

Offering prenatal diagnostic tests: European guidelines for clinical practice

For over four decades, it has been possible to offer prenatal diagnostic testing for fetal abnormalities. Prenatal testing is now available for a wide range of monogenic disorders as well as chromosomal abnormalities and should be provided within the ethical framework of informed consent and autonomous choice. However, there are no published guidelines for health professionals from varied disciplines who offer prenatal diagnosis (PND) in a range of possible settings including departments of maternity, obstetrics and clinical genetics. We used an Expert Group technique to develop a set of guidelines for provision of prenatal diagnostic services. Thirteen European health professionals, all experts in PND, participated in a workshop to develop the guidelines, which were then subjected to a wide consultation process. The objective of PND was defined as providing prenatal diagnostic testing services (for genetic conditions) that enable families to make informed choices consistent with their individual needs and values and which support them in dealing with the outcome of such testing. General principles, logistical considerations, clinical care and counselling topics are all described and are equally applicable to invasive and non-invasive testing. These guidelines provide a framework for ethical clinical care; however, they are flexible enough to enable practitioners to adapt them to their particular setting. Ideally, an individualised approach to each family is required to ensure autonomous choice and informed consent regarding prenatal diagnostic testing within the local ethical and legal framework.     

Upregulation of the ATR‐CHEK1 pathway in oral squamous cell carcinomas

The ATR‐CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR‐CHEK1 pathway overactivation compensates, leads to prolonged G₂ arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR–CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA‐mediated ATR or CHEK1 knockdown led to loss of G₂ cell cycle accumulation and an increased sub‐G₀ apoptotic cell population by flow cytometric analysis. In conclusion, the ATR‐CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G₁ phase cell cycle checkpoint. The upregulated ATR‐CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G₂ checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR–CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC. © 2013 Wiley Periodicals, Inc.     

Fluoroquinolones and Tendinopathy: A Guide for Athletes and Sports Clinicians and a Systematic Review of the Literature

Context:

Fluoroquinolone antibiotics have been used for several decades and are effective antimicrobials. Despite their usefulness as antibiotics, a growing body of evidence has accumulated in the peer-reviewed literature that shows fluoroquinolones can cause pathologic lesions in tendon tissue (tendinopathy). These adverse effects can occur within hours of commencing treatment and months after discontinuing the use of these drugs. In some cases, fluoroquinolone usage can lead to complete rupture of the tendon and substantial subsequent disability.

Objective:

To discuss the cause, pharmacology, symptoms, and epidemiology of fluoroquinolone-associated tendinopathy and to discuss the clinical implications with respect to athletes and their subsequent physiotherapy.

Data Sources:

We searched MEDLINE, Cumulative Index to Nursing and Allied Health (CINAHL), Allied and Complementary Medicine Database (AMED), and SPORTDiscus databases for available reports of fluoroquinolone-related tendinopathy (tendinitis, tendon pain, or rupture) published from 1966 to 2012. Search terms were fluoroquinolones or quinolones and tendinopathy, adverse effects, and tendon rupture. Included studies were written in or translated into English. Non—English–language and non-English translations of abstracts from reports were not included (n = 1).

Study Selection:

Eligible studies were any available reports of fluoroquinolone-related tendinopathy (tendinitis, tendon pain, or rupture). Both animal and human histologic studies were included. Any papers not focusing on the tendon-related side effects of fluoroquinolones were excluded (n = 71).

Data Extraction:

Data collected included any cases of fluoroquinolone-related tendinopathy, the particular tendon affected, type of fluoroquinolone, dosage, and concomitant risk factors. Any data outlining the adverse histologic effects of fluoroquinolones also were collected.

Data Synthesis:

A total of 175 papers, including 89 case reports and 8 literature reviews, were identified.

Conclusions:

Fluoroquinolone tendinopathy may not respond well to the current popular eccentric training regimes and may require an alternative, staged treatment approach. Clinicians, athletes, athletic trainers, and their medical support teams should be aware of the need to discuss and possibly discontinue these antibiotics if adverse effects arise.Key Words: adverse effects, tendinitis, tendon rupture

Key Points:

• Tendinopathy can be a complication of treatment with fluoroquinolone antibiotics and usually is linked with 1 or more synergistic factors.
• Symptoms of fluoroquinolone-related tendinopathy can present within hours of starting treatment or up to 6 months after ceasing treatment, and recovery can be slower and require a less aggressive approach early in rehabilitation than for other types of tendinopathy.
• Treatment with fluoroquinolones should be discontinued and treatment with a nonquinolone antibiotic should be considered in patients who present with tendinopathy.
• Clinicians, athletes, athletic trainers, and medical support teams should be aware of and alert to the potential adverse effects of fluoroquinolones.

The ability of fluoroquinolone antibiotics to adversely affect tendons has been the subject of many articles and case reports in the medical literature for nearly 3 decades. Clinicians, patients, athletes, and athletic trainers should be aware of the potential risks that fluoroquinolones pose with respect to both cause and potentiation of tendinopathy, which is described as the clinical presentation of pain associated with tendon loading.¹ These drugs also can cause tendon rupture. Therefore, the purpose of this systematic review is to discuss the cause, pharmacology, symptoms, and epidemiology of fluoroquinolone-related tendinopathy. We also discuss the clinical implications of fluoroquinolone-related tendinopathy with respect to athletes and their subsequent physiotherapy, because this type of tendinopathy requires a different rehabilitation approach to tendinopathy that is not associated with fluoroquinolones.     

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA,and their analogs

5F‐PY‐PICA and 5F‐PY‐PINACA are pyrrolidinyl 1‐(5‐fluoropentyl)ind (az)ole‐3‐carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F‐PY‐PICA, 5F‐PY‐PINACA, and analogs featuring variation of the 1‐alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (LC–QTOF–MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB₁) or type 2 (hCB₂), all analogs showed minimal affinity for CB₁ (pK_i < 5), although several demonstrated moderate CB₂ binding (pK_i 5.45–6.99). In fluorescence‐based membrane potential assays using AtT20‐hCB₁ or ‐hCB₂ cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB₁, although several showed slightly higher relative efficacy at hCB₂. Expansion of the pyrrolidine ring of 5F‐PY‐PICA to an azepane ( 8 ) conferred the greatest hCB₂ affinity (pK_i 6.99) and activity (pEC₅₀ 7.54, E_max 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F‐PY‐PICA and 5F‐PY‐PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.