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Notes: A series of eleven comparative wart treatment trials undertaken between 1969 and 1975 and involving 1802 patients is described. A method of coding provided groups of patients matched for age, type, number and duration of warts, within which treatments could be randomized. The variation in response to treatment was shown to be influenced significantly by these factors and the level of cure to depend on the proportions of the various response groups within the population under consideration. These proportions were found to vary geographically and at different periods. In all the trials the results were assessed at 12 weeks.In the treatment of hand warts, the percentage cure of patients treated with liquid nitrogen fell significantly from 75 to 40% when the interval between freezings was increased from 3 to 4 weeks. The average number of freezings required for a cure was 3 I amongst all patients cured by 6 or less freezings at intervals of 2 or 3 weeks.In a two–centre trial there was no significant difference between the percentage cure of patients with hand warts treated with liquid nitrogen (69%) and of those applying a paint containing salicylic and lactic acids (SAL) (67%). Patients receiving both treatments concurrently did better (78%) but the difference was not found to be statistically significant.In the treatment of simple plantar warts the percentage cure for the SAL paint (84%) was found to compare favourably with that for a podophyllin treatment (81%). Only one of the patients cured by the paint in that trial was found to have had a recurrence after 6 months. The paint was found to be satisfactory for use under general practice conditions. Additions to the formula did not alter its effectiveness.In the treatment of mosaic plantar warts the overall percentage cure for the SAL paint in a series of comparative trials (1969–75) was 45%. In these trials it was compared directly with one or more other preparations. No differences were found between its efficacy and that of 10% buffered gluteraldehyde (47%), 40% benzalkonium chloride dibromide (Callusolve 40) (30%) and 5% 5-fluorouracil in dimethyl sulphoxide (53%). Only 25% of thirty-six patients treated with 5% idoxuridine in dimethyl sulphoxide were cured.Throughout the trials approximately 30% of patients with hand warts, 2o% of those with simple plantar warts and 50% of those with mosaic plantar warts were found to be resistant to treatment.The adoption of treatment with SAL paint for hand warts and simple plantar warts by the general practitioners in the Edinburgh area has proved satisfactory. Only resistant cases are now referred to hospital and these can be treated within a few weeks instead of 4-5 months as was the case in 1969.

Notes: Drugs are hitting at the roots of our productivity and competitiveness, as their usage escalates amongst current employees and those entering full-time work for the first time. Main symptoms are rising absenteeism, injuries, damage and stealing. But employers are having difficulty in recognising their cause, mainly through ignorance, lack of trained knowledge and fear of what is still a relatively new phenomenon. The realistic answer is the development and implementation of effective substance misuse policies in full consultation with staff representatives. But this is a precise and skilled activity requiring proper training of personnel management and staff supervisors. The article exposes the breadth of the problem, discusses how to train British staff and examines how our training industry can gear up to learn this newest and most vital of training subjects.

Notes: 1. Cultured renomedullary interstitial cells (RMIC) isolated from 4-week-old Sprague-Dawley rat kidneys possess ETA receptors, as identified by reverse transcription–polymerase chain reaction (RT-PCR).2. Treatment with endothelin (ET)-1 (10−6 mol/L) increases the intracellular inositol 1,4,5-trisphosphate concentrations within 10 s and intracellular calcium concentrations after 7 s.3. Endothelin-1 (10−7 and 10−10 mol/L) induced increases in intracellular cAMP concentrations, but only in the presence of Nω-nitro-L-arginine, a nitric oxide synthase (NOS) inhibitor. Addition of ET-1 (10−10 mol/L) to the RMIC culture led to increases in intracellular cGMP concentrations through activation of NOS.4. In the presence of ET-1 (10−7 and 10−10 mol/L) and during NOS inhibition, RMIC responded with increased cell proliferation and extracellular matrix (ECM) synthesis. These responses were abolished by BQ-123 (10−6 mol/L), suggesting mediation via the ETA receptor subtype. The proliferative effect of ET-1 was also abolished by atrial natriuretic peptide (10−6 mol/L).5. The present study provides evidence that binding of ET-1 to ETA receptors on RMIC activates several intracellular second messenger systems that mediate cell proliferation and ECM synthesis.6. These results also highlight an important interaction between ET-1 and nitric oxide in the control of RMIC function.

Notes: 1. Understanding the regulation of calcium (Ca2+), the most common of the mineral ions within the human body, has always been of extreme interest to physiologists. While the importance of Ca2+ in contributing to physiological events through regulation of levels has been significantly established, seldom is consideration given to the intricacies of this ion and its mechanics in producing such diverse physiological responses in different regions of the cell.2. The present review will summarize new methodologies used in our laboratories for the study of two major intracellular organelles, mitochondria and the nucleus. These techniques are based predominantly on the use of molecular biological approaches to both create and then target protein-based sensor molecules to specific intracellular locations.3. The regulation of Ca2+ in the mitochondria and nucleus is of particular interest to us because of the central involvement of these organelles in: (i) cardiac cell responses during ischaemia/reperfusion; and (ii) the control of gene expression, respectively.

Notes: 1. Considerable debate exists as to whether the properties of diaphragm muscles can be modified by training. As the diaphragm is chronically activated during normal respiration, it is of interest to determine whether this muscle is resistant to further modification by exercise. The aim of this study was to investigate the contractile activation characteristics of single skinned muscle fibres from the diaphragm of both CONTROL and TRAINED rats.2. Male rats were subjected to a 20 week high-intensity endurance exercise training programme that consisted of running on a motorized treadmill, 5 days/week, 90–120 min/day, 27–30 m/min, up a 20° incline. At the conclusion of training, rats were killed with an overdose of ether and costal regions of the diaphragm were removed and stored in a glycerol-based skinning solution at—20° C.3. Single skinned (membrane-permeabilized) diaphragm muscle fibres were attached to a sensitive force transducer and activated in Ca2+- and Sr2+-buffered solutions in order to determine relative force-pCa and force-pSr characteristics. Fibres were allocated into discrete groups (population I, population II, intermediate, mixed) on the basis of their physiological (contractile) properties.4. Population I (slow-twitch) fibres from the diaphragm of TRAINED rats exhibited a reduced sensitivity to Ca2+ (indicating a rightward shift of the force-pCa relationship) compared to those diaphragm fibres from CONTROL animals. An increased number of population II (fast-twitch) fibres were sampled from TRAINED rats, however, training did not affect the activation properties of these fibres.5. The fact that training-induced alterations in the contractile characteristics did occur in one group of fibres indicates that the intensity of training was sufficient to induce some modifications to the costal fibres of the diaphragm muscle. However, the lack of alterations to the contractile characteristics of the population II (fast-twitch) fibres may also suggest that the overall properties of the diaphragm are relatively resistant to modification despite high-intensity training.

Notes: 1. This study was designed to establish whether long-term treatment with the powerful anabolic agent clenbuterol has beneficial effects on dystrophin-deficient skeletal muscle function.2. Normal (C57BL/10) and dystrophic (mdx) mice were administered clenbuterol (2 mg/kg per day) for 15 weeks. At 20 weeks of age, the extensor digitorum longus (EDL) and soleus muscles were removed, and their contractile and histochemical properties analysed.3. Absolute and relative muscle masses were larger (P〈0.001) in mdx compared to C57BL/10 mice. These larger muscles produced larger absolute forces (P〈0.01) in the soleus of mdx mice compared to normal mice. Relative tetanic force was also larger (P〈0.05) in the soleus of mdx mice. In contrast, the absolute tetanic tension of the EDL was reduced (P〈0.01) in mdx mice compared to C57BL/10 mice, and both relative twitch and tetanic tensions were also lower (P〈0.001) in mdx mice.4. Clenbuterol increased the lean muscle mass in both normal (10%, P〈0.05 and 20%, P〈0.01 for the EDL and soleus, respectively) and dystrophic (7%, P〈0.05 and 11%, P〈0.01) groups. Twitch contraction times were significantly faster in both the EDL (P〈0.001) and soleus (P〈0.01) muscles following clenbuterol administration, supported by fibre-type transitions towards fast-twitch fibres. Relative force levels of the soleus muscle of both C57BL/10 (40%, P〈0.01) and rndx (20%, P〈0.01) mice were increased significantly following clenbuterol treatment. No changes in the absolute or relative forces of the EDL muscles were observed in response to clenbuterol administration.5. Clenbuterol was thus able to increase the force output of a slow-twitch, mixed (hence humanlike) muscle but not fast-twitch muscle from mdx mice. The results lend tentative support to the potential role of clenbuterol as an anabolic agent in the treatment of muscle wasting diseases.

Notes: 1. Studies have shown that, in isolated skeletal muscles, maximum isometric force production (Po) is dependent on muscle redox state. Endurance training increases the anti-oxidant capacity of skeletal muscles, a factor that could impact on the force-producing capacity following exogenous exposure to an oxidant. We tested the hypothesis that 12 weeks treadmill training would increase anti-oxidant capacity in rat skeletal muscles and alter their response to exogenous oxidant exposure.2. At the conclusion of the 12 week endurance-training programme, soleus (slow-twitch) muscles from trained rats had greater citrate synthase (CS) and catalase (CAT) activity compared with soleus muscles from untrained rats (P 〈 0.05). In contrast, CAT activity of extensor digitorum longus (EDL; fast-twitch) muscles from trained rats was not different to EDL muscles of untrained rats. The CS activity was lower in EDL muscles from trained compared with untrained rats (P 〈 0.05).3. Equilibration with exogenous hydrogen peroxide (H2O2, 5 mmol/L) increased the Po of soleus muscles from untrained rats for the duration of treatment (30 min), whereas the Po of EDL muscles was affected biphasically, with a small increase initially (after 5 min), followed by a more marked decrease in Po (after 30 min). The H2O2-induced increase in Po of soleus muscles from trained rats was less than that in untrained rats (P 〈 0.05), but no differences were observed in the Po of EDL muscles following training.4. The results indicate that 12 weeks endurance running training conferred adaptations in soleus but not EDL muscles. These adaptations were associated with an attenuation of the oxidant-induced increase in Po of soleus muscles from trained compared with untrained rats. We conclude that endurance training-adapted soleus muscles have a slightly altered redox–force relationship.

Notes: 1. The ectopic expression of genes has proven to be an extremely valuable tool for biologists. The most widely used systems involve electrically or chemically mediated transfer of genes to immortalized cell lines and, at the other end of the spectrum, transgenic animal models. As would be expected, there are compromises to be made when using either of these broad approaches. Immortalized cell lines have limited ‘physiological relevance’ and transgenic approaches are costly and out of the reach of many laboratories. There is also significant time required for the de novo generation of a transgenic animal.2. As a viable alternative to these approaches, we describe the use of recombinant adenovirus and Sindbis virus to deliver genes to cells and tissues.3. We exemplify this approach with studies from our laboratories: (i) an investigation of Ca2+ handling deficits in cardiac myocytes of hypertrophied hearts using infection with recombinant adenovirus encoding either green fluorescent protein (GFP) or the sarcoplasmic/endoplasmic reticulum calcium-ATPase (Serca2a); (ii) a study of the mechanism of macrophage/microglial migration by infection of embryonic phagocytes with a GFP-encoding virus and coculture with brain slices to then track the movement of labelled cells; and (iii) we are also exploiting the natural tropism of the Sindbis virus to label neurons in hippocampal brain slices in culture to resolve high-resolution structure and to map neuronal connectivity.4. Further development of these approaches should open new avenues of investigation for the study of physiology in a range of cells and tissues.