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Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), for which there is an unmet therapeutic need. Altered calcium channel function and expression is known to lead to aberrant intracellular calcium (Cai2+) which promotes neoplastic transformation. There is growing evidence that expression of the voltage gated calcium channel (VGCC) family is increased in cancer, in particular the L-type channel CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in PCa patients with ongoing or post ADT compared to those with no treatment. This was corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. The expression of which was found to be a shortened 170kDA CaV1.3 isoform associated with intracellular membrane organelles. This isoform failed to mediate calcium influx through its canonical mechanism following membrane depolarisation. Instead, under ADT it mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE) through a non-canonical mechanism. This novel CaV1.3 mediated SOCE was linked to both proliferation and survival of long-term ADT CRPC cells. Overall, this study demonstrates for the first time in PCa that increased SOCE through CaV1.3 represents a novel oncogenic mechanism that contributes to ADT resistance and promotes CRPC biology. This highlights aberrant intracellular calcium in CRPC as a potential area for therapeutic development that could lead to improved patient outcomes.

The 11th Symposium on Polar Science/Ordinary sessions: [OA] Antarctic meteorites, Thu. 3 Dec.

Collagen is the most abundant component of the extracellular matrix (ECM), therefore it represents an ideal biomaterial for the culture of a variety of cell types. Recently, collagen-based scaffolds have shown promise as 3D culture platforms for breast cancer-based research. Two-dimensional (2D) in vitro culture models, while useful for gaining preliminary insights, are ultimately flawed as they do not adequately replicate the tumour microenvironment. As a result, they do not facilitate proper 3D cell-cell/cell-matrix interactions and often an exaggerated response to therapeutic agents occurs. The ECM plays a crucial role in the development and spread of cancer. Alterations within the ECM have a significant impact on the pathogenesis of cancer, the initiation of metastasis and ultimate progression of the disease. 3D in vitro culture models that aim to replicate the tumour microenvironment have the potential to offer a new frontier for cancer research with cell growth, morphology and genetic properties that more closely match in vivo cancers. While initial 3D in vitro culture models used in breast cancer research consisted of simple hydrogel platforms, recent advances in biofabrication techniques, including freeze-drying, electrospinning and 3D bioprinting, have enabled the fabrication of biomimetic collagen-based platforms that more closely replicate the breast cancer ECM. This review highlights the current application of collagen-based scaffolds as 3D in vitro culture models for breast cancer research, specifically for adherence-based scaffolds (i.e. matrix-assisted). Finally, the future perspectives of 3D in vitro breast cancer models and their potential to lead to an improved understanding of breast cancer diagnosis and treatment are discussed.

Objectives Lung cancer is the most common cause of cancer mortality worldwide and, while tobacco smoke remains the primary cause, there is increasing concern that vaping and E-cigarette use may also increase lung cancer risk. This review concentrates on the current data, scholarship and active foci of research regarding potential cancer risk and oncogenic mechanisms of vaping and lung cancer. Materials and methods We performed a literature review of current and historical publications on lung cancer oncogenesis, vaping device/e-liquid contents and daughter products, molecular oncogenic mechanisms and the fundamental, potentially oncogenic, effects of electronic cigarette smoke/e-liquid products. Results E-cigarette devices and vaping fluids demonstrably contain a series of both definite and probable oncogens including nicotine derivatives (e.g. nitrosnornicotine, nitrosamine ketone), polycyclic aromatic hydrocarbons, heavy metals (including organometal compounds) and aldehydes/other complex organic compounds. These arise both as constituents of the e-liquid (with many aldehydes and other complex organics used as flavourings) and as a result of pyrolysis/complex organic reactions in the electronic cigarette device (including unequivocal carcinogens such as formaldehyde – formed from pyrolysis of glycerol). Various studies demonstrate in vitro transforming and cytotoxic activity of these derivatives. E-cigarette device use has been significantly increasing – particularly amongst the younger cohort and non-smokers; thus, this is an area of significant concern for the future. Conclusion Although research remains somewhat equivocal, there is clear reason for concern regarding the potential oncogenicity of E-Cigarettes/E-Liquids with a strong basic and molecular science basis. Given lag times (extrapolating from tobacco smoke data) of perhaps 20 years, this may have significant future public health implications. Thus, the authors feel further study in this field is strongly warranted and consideration should be made for tighter control and regulation of these products.

Ran is a small ras-related GTPase and is highly expressed in aggressive breast carcinoma. Overexpression induces malignant transformation and drives metastatic growth. We have designed a novel series of anti-Ran-GTPase peptides, which prevents Ran hydrolysis and activation, and although they display effectiveness in silico, peptide activity is suboptimal in vitro due to reduced bioavailability and poor delivery. To overcome this drawback, we delivered an anti-Ran-GTPase peptide using encapsulation in PLGA-based nanoparticles (NP). Formulation variables within a double emulsion solvent evaporation technique were controlled to optimise physicochemical properties. NP were spherical and negatively charged with a mean diameter of 182–277 nm. Peptide integrity and stability were maintained after encapsulation and release kinetics followed a sustained profile. We were interested in the relationship between cellular uptake and poly(ethylene glycol) (PEG) in the NP matrix, with results showing enhanced in vitro uptake with increasing PEG content. Peptide-loaded, pegylated (10% PEG)-PLGA NP induced significant cytotoxic and apoptotic effects in MDA-MB-231 breast cancer cells, with no evidence of similar effects in cells pulsed with free peptide. Western blot analysis showed that encapsulated peptide interfered with the proposed signal transduction pathway of the Ran gene. Our novel blockade peptide prevented Ran activation by blockage of regulator of chromosome condensation 1 (RCC1) following peptide release directly in the cytoplasm once endocytosis of the peptide-loaded nanoparticle has occurred. RCC1 blockage was effective only when a nanoparticulate delivery approach was adopted.

Introduction National Cancer Organisations (NCO) provide web-based diet and nutrition information for patients with all types and stages of cancer. We examined diet and nutrition information provided by nine NCO in English-speaking countries. Methods Diet and nutrition information was examined under four headings: disease phases, treatment modalities, nutrition impact symptoms and cancer primary sites. We also examined the degree of concordance between NCO websites and appraised the readability of materials. Results Nine NCO websites from six English-speaking countries were included: Australia, Canada, Ireland, New Zealand, the United Kingdom and the United States. All provided general healthy eating advice. Information at diagnosis and pre-treatment was inadequate, but well-addressed for survivorship. Specific treatment modalities such as biological and hormone therapy were largely ignored. Symptom management was well-addressed, with some exceptions. Cancer site-specific advice was readily available. All recommended consultation with a dietitian/healthcare professional for personalised guidance. Only one met the universal health literacy standard. Conclusions NCO websites provided important general diet and nutrition information for cancer patients. The information was reliable and safe, but more in-depth, evidence-based and health-literate information is required. There is an urgent need for an international consensus for consistent cancer diet and nutrition advice.

Cancer stem cells (CSC's) have emerged as a key area of investigation due to associations with cancer development and treatment resistance, related to their ability to remain quiescent, self-renew and terminally differentiate. Targeting CSC's in addition to the tumour bulk could ensure complete removal of the cancer, lessening the risk of relapse and improving patient survival. Understanding the mechanisms supporting the functions of CSC's is essential to highlight targets for the development of therapeutic strategies. Changes in intracellular calcium through calcium channel activity is fundamental for integral cellular processes such as proliferation, migration, differentiation and survival in a range of cell types, under both normal and pathological conditions. Here in we highlight how calcium channels represent a key mechanism involved in CSC function. It is clear that expression and or function of a number of channels involved in calcium entry and intracellular store release are altered in CSC's. Correlating with aberrant proliferation, self-renewal and differentiation, which in turn promoted cancer progression and treatment resistance. Research outlined has demonstrated that targeting altered calcium channels in CSC populations can reduce their stem properties and induce terminal differentiation, sensitising them to existing cancer treatments. Overall this highlights calcium channels as emerging novel targets for CSC therapies.

Progression of cancer to advanced states is associated with treatment resistance and metastatic spread -- features that are linked to poor prognosis and patient mortality. Investigations into potential new treatments to reduce cancer spread are ongoing, with immunotherapy generating much interest. Natural killer (NK) cells are part of the body's innate immune system and are known for their ability to target and lyse cancer cells. Ion channels have previously been linked to the growth and development of tumors, but recent research suggests that these channels may also serve to alter immune cell functioning. This review examines the current understanding as to the role of ion channels in NK cells and how manipulation of these channels may increase NK effectiveness in targeting and removing cancer cells. With a large number of existing FDA-approved drugs targeting ion channels, potential exists for drug repurposing in order to improve immunotherapy and thus patient outcomes.

Androgen deprivation therapy (ADT) is the main treatment to prolong survival in advance stage prostate cancer (PCa) but associated resistance leads to the development of terminal castrate resistant PCa (CRPC). Current research demonstrates that prostate cancer stem cells (PCSC) play a critical role in the development of treatment resistance and subsequent disease progression. Despite uncertainty surrounding the origin of these cells, studies clearly show they are associated with poorer outcomes and that ADT significantly enhances their numbers. Here in we highlight how activation of HIF signalling, in response to hypoxic conditions within the tumour microenvironment, results in the expression of genes associated with stemness and EMT promoting PCSC emergence which ultimately drives tumour relapse to CRPC. Hypoxic conditions are not only enhanced by ADT but the associated decrease in AR activation also promotes PI3K/AKT signalling which actively enhances HIF and its effects on PCSC's. Furthermore, emerging evidence now indicates that HIF-2α, rather than the commonly considered HIF-1α, is the main family member that drives PCSC emergence. Taken together this clearly identifies HIF and associated pathways as key targets for new therapeutic strategies that could potentially prevent or slow PCSC promoted resistance to ADT, thus holding potential to prolong patient survival.

BACKGROUND: Increasing numbers of people with diabetes are adopting exercise programs. Fear of hypoglycemia, hypoglycemia itself, and injuries are major issues for many people with diabetes undertaking physical activity. The purpose of this study was to investigate the effects of type 1 diabetes mellitus on the risk of hypoglycemia, glycemic variability, exercise performance, changes in body composition, changes in insulin dosage, and psychosocial well-being during a multiday endurance exercise event. METHODS: Eleven participants (7 with type 1 diabetes, 4 with normal glucose tolerance) undertook a 15-day, 2300 km cycling tour from Barcelona to Vienna. Data were prospectively collected using bike computers, continuous glucose monitors, body composition analyzers, and mood questionnaires. RESULTS: Mean blood glucose in riders with and without diabetes significantly reduced as the event progressed. Glycemic variability and time spent in hypoglycemia did not change throughout the ride for either set of riders. Riders with diabetes in the lowest quartile of sensor glucose values had significantly reduced power output. Percentage body fat also significantly fell. Hypo- and hyperglycemia provoked feelings of anxiety and worry. CONCLUSIONS: This is the first study to describe a real-time endurance event in type 1 diabetes, and provides important new data that cannot be studied in laboratory conditions. Hypoglycemia continues to occurs in spite of peer support and large reductions in insulin dose. Glycemic variability is shown as a potential barrier to participation in physical activity through effects on mood and psychological well-being.

It is well accepted that influenza A virus predisposes individuals to often more severe superinfections with Streptococcus pneumonia. However, the mechanisms that lead to this synergy are not clearly understood. Recent data suggests that competent Th17 immunity is crucial to clearance and protection from invasive pneumococcal disease of the lung. We demonstrate that early influenza infection significantly reduced levels of pneumococcus driven IL-12p70, IL-23 and IL-27 in human monocytes with significant impairment of IL-17A and IFN-γ in HKSP-treated allogeneic mixed lymphocyte cultures. We also provide evidence to suggest that the hemagglutinin component of the virus is at least partially responsible for this downward pressure on IL-17 responses but surprisingly this suppression occurs despite robust IL-23 levels in hemagglutinin-treated monocyte cultures. This study demonstrates that influenza can directly affect the immunological pathways that promote appropriate responses to Streptococcus pneumonia in human immune cells. Importance Influenza virus is highly contagious and poses substantial public health problems due to its strong association with morbidity and mortality. Approximately 250,000–500,000 deaths are caused by seasonal influenza virus annually, and this figure increases during periods of pandemic infections. Most of these deaths are due to secondary bacterial pneumonia. Influenza-bacterial superinfection can result in hospitalisation and/or death of both patients with pre-existing lung disease or previously healthy individuals. The importance of our research is in determining that influenza and its component haemagglutinin has a direct effect on the classic pneumococcus induced pathways to IL-17A in our human ex vivo model. Our understanding of the mechanism which leaves people exposed to influenza infection during superinfection remain unresolved. This paper demonstrates that early infection of monocytes inhibits an arm of immunity crucial to bacterial clearance. Understanding this mechanism may provide alternative interventions in the case of superinfection with antimicrobial resistant strains of bacteria.

CF (cystic fibrosis) is a severe autosomal recessive disease most common in Northwest European populations. Underlying mutations in the CFTR (CF transmembrane conductance regulator) gene cause deregulation of ion transport and subsequent dehydration of the airway surface liquid, producing a viscous mucus layer on the airway surface of CF patients. This layer is readily colonized by bacteria such as Pseudomonas aeruginosa. Owing to the resulting environment and treatment strategies, the bacteria acquire genetic modifications such as antibiotic resistance, biofilm formation, antimicrobial peptide resistance and pro-inflammatory lipid A structures. Lipid A is a component of the lipopolysaccharide cell wall present on bacteria and is recognized by TLR4 (Toll-like receptor 4). Its detection elicits a pro-inflammatory response that is heightened over time due to the addition of fatty acids to the lipid A structure. Eradication of bacteria from the lungs of CF patients becomes increasingly difficult and eventually leads to mortality. In the present review, we describe the role of lipid A as a virulent factor of Ps. aeruginosa; however, it appears that further work is needed to investigate the role of CFTR in the innate immune response and in modifying the pathogen–host interaction.

Lipoxin A4has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl−channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.

It is encouraging that new hospital models are being developed that aim to improve what matters most—outcomes for patients. But the jury seems still to be out on several fronts about the reshaping of services and the delivery model being implemented at the Karolinska hospital. The new building at Solna is a …

A high level inquiry could detoxify the radical changes needed and command wide support, say Maurice Saatchi and Paul Buchanan ; but Nigel Crisp thinks that a less formal, more flexible and collaborative approach could be quicker Never has there been a better time or a more compelling reason, as Brexit is negotiated, for a considered and politically neutral review of our health services. The fiscal implications of dealing with the projected numbers of people with diabetes alone, for example, are enough to prompt a rethink of the whole system and of how society needs to change. ### Political football But the NHS has become a political football. People disagree even on whether it has a problem, let alone the possible solutions. We need an honest broker, a peacemaker: we need a royal commission on the NHS.1 Royal commissions are public inquiries at the highest level, called to look into matters of utmost importance, and few issues are more important to the future of our country than the health and wellbeing of our citizens. Their many advantages include the ability to secure the vital cross party support needed to embed lasting changes and to detoxify reforms that otherwise may be too politically dangerous to pursue. Royal commissions are independent—governments cannot interfere once they have started—and therefore sit outside politics. They are also powerful and can compel people to produce documents and other evidence in their inquiries. And we will need the power to ask difficult questions of experts from all sections of society. We must challenge what we think we know about the problems the NHS faces today. We must think beyond the structures and institutions of the previous century. Is the NHS no longer …

In cystic fibrosis (CF), the airway surface liquid (ASL) is depleted. We previously demonstrated that lipoxin A4 (LXA4) can modulate ASL height (ASLh) through actions on Cl− transport. Here, we report novel effects of lipoxin on the epithelial Na+ channel ENaC in this response. ASL dynamics and ion transport were studied using live‐cell confocal microscopy and short‐circuit current measurements in CF (CuFi‐1) and non‐CF (NuLi‐1) cell cultures. Low physiological concentrations of LXA4 in the picomolar range produced an increase in ASLh which was dependent on inhibition of an amiloride‐sensitive Na+ current and stimulation of a bumetanide‐sensitive Cl− current. These ion transport and ASLh responses to LXA4 were blocked by Boc‐2 an inhibitor of the specific LXA4 receptor ALX/FPR2. LXA4 affected the subcellular localization of its receptor and enhanced the localization of ALX/FPR2 at the apical membrane of CF cells. Our results provide evidence for a novel effect of low physiological concentrations of LXA4 to inhibit airway epithelial Na+ absorption that results in an ASL height increase in CF airway epithelia., LXA4 induced apical membrane ALX/FPR2 localization in CuFi‐1 monolayers. LXA4 induced an apical increase of ALX/FPR2 (green) expression (B). Primary rabbit anti‐ALX/FPR2 antibody and secondary Alexa‐Fluor 488 anti‐rabbit were used to label the ALX/FPR2 receptor. Localization of the receptor at the apical surface is shown in the merged fluorochrome images in yellow (A). Rhodamine‐phalloidin was used to stain f‐actin and DAPI used to stain the nuclei (C).

Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A4 (LXA4) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the "class switch" of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA4 to leukotriene B4 (LTB4) is depressed in CF BAL (p

In cystic fibrosis (CF), the airway surface liquid (ASL) height is reduced as a result of impaired ion transport, which favors bacterial colonization and inflammation of the airway and leads to progressive lung destruction. Lipoxin (LX)A4, which promotes resolution of inflammation, is inadequately produced in the airways of patients with CF. We previously demonstrated that LXA4 stimulates an ASL height increase and epithelial repair. Here we report the molecular mechanisms involved in these processes. We found that LXA4 (1 nM) induced an apical ATP release from non-CF (NuLi-1) and CF (CuFi-1) airway epithelial cell lines and CF primary cultures. The ATP release induced by LXA4 was completely inhibited by antagonists of the ALX/FPR2 receptor and Pannexin-1 channels. LXA4 induced an increase in intracellular cAMP and calcium, which were abolished by the selective inhibition of the P2RY11 purinoreceptor. Pannexin-1 and ATP hydrolysis inhibition and P2RY11 purinoreceptor knockdown all abolished the increase of ASL height induced by LXA4. Inhibition of the A2b adenosine receptor did not affect the ASL height increase induced by LXA4, whereas the PKA inhibitor partially inhibited this response. The stimulation of NuLi-1 and CuFi-1 cell proliferation, migration, and wound repair by LXA4 was inhibited by the antagonists of Pannexin-1 channel and P2RY11 purinoreceptor. Taken together, our results provide evidence for a novel role of LXA4 in stimulating apical ATP secretion via Pannexin-1 channels and P2RY11 purinoreceptors activation leading to an ASL height increase and epithelial repair.

In Cystic Fibrosis (CF), mutations of the CFTR gene result in defective Cl− secretion and Na+ hyperabsorption by epithelia which leads to airway lumen dehydration and mucus plugging and favours chronic bacterial colonization, persistent inflammation and progressive lung destruction. Beyond this general description, the pathogenesis of CF lung disease remains obscure due to an incomplete understanding of normal innate airway defense. This mini-review aims to highlight the role of the pro-resolution lipid mediator, Lipoxin A4, which is inadequately produced in CF, on several aspects of innate immunity that are altered in CF airway disease.

The innate immune response to bacterial infection is mediated through Toll-like receptors (TLRs), which trigger tightly regulated signaling cascades through transcription factors including NF-?B. LPS activation of TLR4 triggers internalization of the receptor-ligand complex which is directed toward lysosomal degradation or endocytic recycling. Cystic fibrosis (CF) patients display a robust and uncontrolled inflammatory response to bacterial infection, suggesting a defect in regulation. This study examined the intracellular trafficking of TLR4 in CF and non-CF airway epithelial cells following stimulation with LPS. We employed cells lines [16hBE14o-, CFBE41o- (CF), and CFTR-complemented CFBE41o-] and confirmed selected experiments in primary nasal epithelial cells from non-CF controls and CF patients (F508del homozygous). In control cells, TLR4 expression (surface and cytoplasmic) was reduced after LPS stimulation but remained unchanged in CF cells and was accompanied by a heightened inflammatory response 24 h after stimulation. All cells expressed markers of the early (EEA1) and late (Rab7b) endosomes at basal levels. However, only CF cells displayed persistent expression of Rab7b following LPS stimulation. Rab7 variants may directly internalize bacteria to the Golgi for recycling or to the lysosome for degradation. TLR4 colocalized with the lysosomal marker LAMP1 in 16 hBE14o- cells, suggesting that TLR4 is targeted for lysosomal degradation in these cells. However, this colocalization was not observed in CFBE41o- cells, where persistent expression of Rab7 and release of proinflammatory cytokines was detected. Consistent with the apparent inability of CF cells to target TLR4 toward the lysosome for degradation, we observed persistent surface and cytoplasmic expression of this pathogen recognition receptor. This defect may account for the prolonged cycle of chronic inflammation associated with CF. © 2013 the American Physiological Society.

BackgroundHuman cathelicidin LL-37 is a cationic antimicrobial peptide (AMP) which possesses a variety of activities including the ability to neutralise endotoxin. In this study, we investigated the role of LPS neutralisation in mediating LL-37's ability to inhibit Pseudomonas aeruginosa LPS signalling in human monocytic cells.Methodology/Principal FindingsPre-treatment of monocytes with LL-37 significantly inhibited LPS-induced IL-8 production and the signalling pathway of associated transcription factors such as NF-κB. However, upon removal of LL-37 from the media prior to LPS stimulation, these inhibitory effects were abolished. These findings suggest that the ability of LL-37 to inhibit LPS signalling is largely dependent on extracellular LPS neutralisation. In addition, LL-37 potently inhibited cytokine production induced by LPS extracted from P. aeruginosa isolated from the lungs of cystic fibrosis (CF) patients. In the CF lung, polyanionic molecules such as glycosaminoglycans (GAGs) and DNA bind LL-37 and impact negatively on its antibacterial activity. In order to determine whether such interactions interfere with the LPS neutralising ability of LL-37, the status of LL-37 and its ability to bind LPS in CF sputum were investigated. Overall our findings suggest that in the CF lung, the ability of LL-37 to bind LPS and inhibit LPS-induced IL-8 production is attenuated as a result of binding to DNA and GAGs. However, LL-37 levels and its concomitant LPS-binding activity can be increased with a combination of DNase and GAG lyase (heparinase II) treatment.Conclusions/SignificanceOverall, these findings suggest that a deficiency in available LL-37 in the CF lung may contribute to greater LPS-induced inflammation during CF lung disease.

This paper investigates the notion of digital poetry as a form of generative art and explores the creativity design process behind it and the interaction with the audience/reader digital poetry enforces.

Examines the wider issues of corporate governance based on the Korn‐Ferry annual survey of companies. Looks at: the composition of a board of directors; the things which concern boards of directors in the UK compared with the USA; and what are currently held to be the qualifications for non‐executive directors.

Three different training regimens were performed to study the influence of eccentric muscle actions on skeletal muscle adaptive responses to heavy resistance exercise. Middle-aged males performed the leg press and leg extension exercises two days each week. The resistance was selected to induce failure within six to twelve repetitions of each set. Group CON/ECC (n = 8) performed coupled concentric and eccentric actions while group CON (n = 8) used concentric actions only. They did four or five sets of each exercise. Group CON/CON (n = 10) performed twice as many sets with only concentric actions. Eight subjects did not train and served as controls. Tissue samples were obtained from m. vastus lateralis using the biopsy technique before and after 19 weeks of training, and after four weeks of detraining. Histochemical analyses were performed to assess fibre type composition, fibre area and capillarization. Training increased (P less than 0.05) Type IIA and decreased (P less than 0.05) Type IIB fibre percentage. Only group CON/ECC increased Type I area (14%, P less than 0.05). Type II area increased (P less than 0.05) 32 and 27%, respectively, in groups CON/ECC and CON/CON, but not in group CON. Mean fibre area increased (P less than 0.05) 25 and 20% in groups CON/ECC and CON/CON, respectively. Capillaries per fibre increased (P less than 0.05) equally for Type I and Type II fibres. Capillaries per fibre area for both fibre types, however, increased (P less than 0.05) only in groups CON and CON/CON. The changes in fibre type composition and capillary frequency were manifest after detraining.(ABSTRACT TRUNCATED AT 250 WORDS)

The speed-torque relationship of the right knee extensor muscle group was investigated in eight untrained subjects (28 +/- 2 yr old). Torque was measured at a specific knee angle during isokinetic concentric or eccentric actions at nine angular velocities (0.17-3.66 rad/s) and during isometric actions. Activation was by "maximal" voluntary effort or by transcutaneous tetanic electrical stimulation that induced an isometric torque equal to 60% (STIM 1) or 45% (STIM 2) of the voluntary isometric value. Torque increased (P less than 0.05) to 1.4 times isometric as the speed of eccentric actions increased to 1.57 rad/s for STIM 1 and STIM 2. Thereafter, increases in eccentric speed did not further increase torque. Torque did not increase (P greater than 0.05) above isometric for voluntary eccentric actions. As the speed of concentric actions increased from 0.00 to 3.66 rad/s, torque decreased (P less than 0.05) more (P less than 0.05) for both STIM 1 and STIM 2 (two-thirds) than for voluntary activation (one-half). As a result of these responses, torque changed three times as much (P less than 0.05) across speeds of concentric and eccentric actions with artificial (3.4-fold) than voluntary (1.1-fold) activation. The results indicate that with artificial activation the normalized speed-torque relationship of the knee extensors in situ is remarkably similar to that of isolated muscle. The relationship for voluntary activation, in contrast, suggests that the ability of the central nervous system to activate the knee extensors during maximal efforts depends on the speed and type of muscle action performed.

Leg compliance is "causally related with greater susceptibility" to orthostatic stress. Since peak O2 uptake (peak VO2) and muscle strength may be related to leg compliance, we examined the relationships between leg compliance and factors related to muscle size and physical fitness. Ten healthy men, 25-52 yr, underwent tests for determination of vascular compliance of the calf (Whitney mercury strain gauge), peak VO2 (Bruce treadmill), calf muscle strength (Cybex isokinetic dynamometer), body composition (densitometry), and anthropometric measurements of the calf. Cross-sectional areas (CSA) of muscle, fat, and bone in the calf were determined by computed tomography scans. Leg compliance was not significantly correlated with any variables associated with physical fitness per se (peak VO2, calf strength, age, body weight, or composition). Leg compliance correlated with calf CSA (r = -0.72, P less than 0.02) and calculated calf volume (r = -0.67, P less than 0.03). The most dominant contributing factor to the determination of leg compliance was CSA of calf muscle (r = -0.60, P less than 0.06), whereas fat and bone were poor predictors (r = -0.11 and 0.07, respectively). We suggest that leg compliance is less when there is a large muscle mass providing structural support to limit expansion of the veins. This relationship is independent of aerobic and/or strength fitness level of the individual.

The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (CaV) in cancer at the gene and protein level and discusses their potential functional roles. The ten members of the CaV channel family are classified according to expression of their pore-forming α-subunit; moreover, co-expression of accessory α2δ, β and γ confers a spectrum of biophysical characteristics including voltage dependence of activation and inactivation, current amplitude and activation/inactivation kinetics. CaV channels have traditionally been studied in excitable cells including neurones, smooth muscle, skeletal muscle and cardiac cells, and drugs targeting the channels are used in the treatment of hypertension and epilepsy. There is emerging evidence that several CaV channels are differentially expressed in cancer cells compared to their normal counterparts. Interestingly, a number of CaV channels also have non-canonical functions and are involved in transcriptional regulation of the expression of other proteins including potassium channels. Pharmacological studies show that CaV canonical function contributes to the fundamental biology of proliferation, cell-cycle progression and apoptosis. This raises the intriguing possibility that calcium channel blockers, approved for the treatment of other conditions, could be repurposed to treat particular cancers. Further research will reveal the full extent of both the canonical and non-canonical functions of CaV channels in cancer and whether calcium channel blockers are beneficial in cancer treatment.

Carbon monoxide and oxygen concentrations were measured in seventy-two structural fires using a personal air sampler carried by working firefighters. In a total sampling time of 1329 minutes the carbon monoxide concentration exceeded 500 ppm approximately 29 percent of the time. The maximum carbon monoxide concentration was 27,000 ppm and in 10 percent of the fires, the maximum concentration exceeded 5500 ppm. Only six runs indicated oxygen concentrations less than 18 percent. On the basis of these exposure data, a minimum protection factor of 100 is proposed for breathing apparatus for structural firefighting.

A free text decision support system (DSS) has been constructed for health care professionals that allows the analysis of complex medical cases and the creation of a diagnostic list of potential diseases for clinical evaluation. The system uses a PC-based text management system specifically designed for desktop operation. The texts employed in the decision support package include The Merck Manual (published by Merck Sharpe & Dohme) and Control of Communicable Diseases in Man (published by the American Public Health Association). The background and design of the database are discussed, along with a structured analysis procedure for handling free text DSS systems. A case study is presented to show the application of this technology and conclusions are drawn in the summary that point to expanded areas of professional interaction and new frontiers yet to be explored in this rapidly progressing field.

An electromyostimulation (EMS) unit that provides a range of stimulation variables was developed and used in a preliminary study of the current-torque relationship during percutaneous EMS. The knee extensors of one lower limb of ten subjects received stimulation on three different days, and the current-torque relationship was studied using an incremental protocol. A 2-s train of 500- mu s/sup 2/ monophasic pulses at 60 Hz was used to elicit one contraction every minute. Peak current and peak torque values among subjects ranged from 229 to 344 mA and from 61% to 106% of a given subject's maximum voluntary isometric torque. The EMS unit consistently elicits torque during stimulated contractions, providing a basis for evaluating the efficacy of a wide range of stimulation protocols. >