In order to test the hypothesis that glycogen sparing observed early during exercise following caffeine ingestion was a consequence of tighter metabolic control reflected in faster VO2 kinetics, we examined the effect of caffeine ingestion on oxygen uptake (VO2), carbon dioxide production (VCO2) and expiratory ventilation (VE) kinetics at the onset of both moderate (MOD) and heavy (HVY) intensity exercise. Male subjects (n = 10) were assigned to either a MOD (50 % VO2,max, n = 5) or HVY (80 % VO2,max, n = 5) exercise condition. Constant-load cycle ergometer exercise was performed as a step function from loadless cycling 1 h after ingestion of either dextrose (placebo, PLAC) or caffeine (CAFF; 6 mg (kg body mass)-1). Alveolar gas exchange was measured breath-by-breath. A 2- or 3-component exponential model, fitted through the entire exercise transient, was used to analyse gas exchange and ventilatory data for the determination of total lag time (TLT: the time taken to attain 63 % of the total exponential increase). Caffeine had no effect on TLT for VO2 kinetics at either exercise intensity (MOD: 36 ± 14 s (PLAC) and 41 ± 10 s (CAFF); HVY: 99 ± 30 s (PLAC) and 103 ± 26 (CAFF) (mean ± S.D.)). TLT for VE was increased with caffeine at both exercise intensities (MOD: 50 ± 20 s (PLAC) and 59 ± 21 s (CAFF); HVY: 168 ± 35 s (PLAC) and 203 ± 48 s (CAFF)) and for VCO2 during MOD only (MOD: 47 ± 14 s (PLAC) and 53 ± 17 s (CAFF); HVY: 65 ± 13 s (PLAC) and 69 ± 17 s (CAFF)). Contrary to our hypothesis, the metabolic effects of caffeine did not alter the on-transient VO2 kinetics in moderate or heavy exercise. VCO2 kinetics were slowed by a reduction in CO2 stores reflected in pre-exercise and exercise end-tidal CO2 pressure (PET,CO2) and plasma PCO2 which, we propose, contributed to slowed VE kinetics.

The urinary bladder has only two functions, to store urine and to eliminate it from the body at socially convenient times. These functions depend on total integrity of the nervous system from brain to bladder. Many different neurotransmitter pathways are involved, modulating proper voluntary control over the reciprocal relationship between the storage function of the bladder and the outlet sphincters of the urethra. When voluntary control is lost or disrupted through neurological disease or damage then aberrant reflexes can take over resulting in incontinence. Such reflexes often involve the loss of those inhibitory mechanisms which normally suppress bladder contractions during the filling phase or sphincter contractions during the emptying phase. Treatment of incontinence by applied neuromodulation probably utilizes residual reflex pathways by which electrical stimulation can inhibit unwanted detrusor contractions or suppress the overactive urethral sphincter. With improvements in our understanding of the pathophysiology of voiding dysfunction, better diagnosis and the latest technical advances, for example, combining neuromodulation for detrusor hyper-reflexia with sacral anterior root stimulation for emptying the paralysed bladder (Brindley, 1988), we might hope to develop a new generation of implantable devices for treating people with incontinence (Craggs, 1997).There are still many gaps in our knowledge of neuromodulation of the lower urinary tract, for example we know little about the cerebral control of micturition in man. Such knowledge may be important for a better understanding of the many conditions we currently label 'idiopathic'. Future opportunities offered by functional magnetic resonance imaging and spectroscopy may help us to identify pathways and neurotransmitters in the brain of humans to complement the latest animal studies using transneuronal virus tracing to identify central micturition pathways.

Oedema is caused by impaired lymphatic drainage and/or increased microvascular filtration. To assess a postulated role for the latter in postmastectomy oedema, filtration was studied in the forearms of 14 healthy subjects and 22 patients with chronic, unilateral arm oedema caused by surgical and radiological treatment for breast cancer. A new non-contact optical device (the Perometer) and a conventional mercury strain gauge were used simultaneously to record forearm swelling rates caused by microvascular filtration during applied venous congestion. Filtration rate (FR) per 100 ml tissue was measured over 10-15 min at a venous pressure of 30 cmH2O, a pressure reached in the dependent forearm (FR30), and then at 60 cmH2O (FR60). Apparent filtration capacity of 100 ml soft tissue (CFCa) was calculated from FR60 - FR30/30, after adjustment for bone volume. The Perometer and strain gauge gave similar results in normal and oedematous arms. Mean CFCa in healthy subjects was (3·8 ± 0·4) × 10-3 ml (100 ml)-1 cmH2O-1 min-1, close to literature values. In the patients, FR30 was 47 % lower in the oedematous forearm than in the opposite, unaffected forearm (P = 0·04). FR60 showed a similar trend but did not reach significance (P = 0·15). The values of CFCa of (2.2 ± 0.5) × 10-3 ml (100 ml)-1 cmH2O-1 min-1 in the oedematous arm and (2.8 ± 0.5) × 10-3 ml (100 ml)-1 cmH2O-1 min-1 in the unaffected arm were not significantly different (P = 0.47). When differences in arm volume on the two sides were taken into account, the total fluid load on the lymphatic system of the oedematous forearm was (411.0 ± 82.2) × 10-3 ml min-1 at 30 cmH2O and (1168 ± 235.6) × 10-3 ml min-1 at 60 cmH2O, similar to the normal side, namely (503.7 ± 109.3) × 10-3 ml min-1 and (1063 ± 152.0) × 10-3 ml min-1, respectively (P >= 0·50). The filtration capacity of the entire oedematous forearm (CFCa scaled up by total soft tissue volume), (25.4 ± 6.2) × 10-3 ml cmH2O-1 min-1, was not significantly greater than that of the normal forearm, (18.3 ± 2.6) × 10-3 ml cmH2O-1 min-1 (P = 0.40). The results indicate that no major change occurs in the microvascular hydraulic permeability-area product of the forearm, or in the total filtration load on the lymph drainage system during dependency, in the arm with postmastectomy oedema compared with the normal arm. This argues against a significant haemodynamic contribution to postmastectomy oedema.

Breast volume and morphology of eight subjects were measured before conception and at intervals throughout pregnancy until 1 month of lactation. Breast volume before conception ranged from 293 to 964 ml. At the end of pregnancy the volume of breast tissue had increased by 145 ± 19 ml (mean ± S.E.M., n = 13 breasts, range 12-227 ml) with a further increase to 211 ± 16 ml (n = 12 breasts, range 129-320 ml) by 1 month of lactation. Urinary excretion of lactose increased at 22 weeks of pregnancy, signalling the capacity of the breast to synthesize lactose at this time. During pregnancy, both the change in breast volume and the change in cross-sectional area of the areola were related to the concentration of human placental lactogen in the plasma. The growth of the nipple and the rate of excretion of lactose were related to the concentration of prolactin in the plasma. During the first 3 days after birth, the rate of excretion of lactose was related to the rate of excretion of progesterone. There was no relationship between the growth of the breast during pregnancy and the amount of milk produced at 1 month of lactation.

The kinetics and the isozyme composition of lactate dehydrogenase (LDH) were measured in rat plantaris muscle during a 26 week endurance-training program. Alterations in the LDH isozyme pattern were detectable after 6 weeks as the percentage of the M4 isozyme was reduced from 89 to 76 % and the total percentage of M subunits compared with H subunits declined by 8 %. At 16 weeks, M4 accounted for only 62 % of the total. The replacement of M with H subunits continued when training was prolonged as M4 represented only 52 % of the total isozymes at 26 weeks. Conversely, training for 6 and 16 weeks produced no changes in either Vmax or Km. At 26 weeks, these values declined for both the forward (pyruvate to lactate) and backward reactions. The rate constants for both reactions were also reduced. These data suggest that changes in LDH isozyme pattern do not contribute significantly to the enhancement of lactate oxidation that may occur after training. They also suggest that the functional significance of alterations in LDH structure and/or function are best determined from analysis of the overall reaction kinetics as opposed to individual characteristics such as the isozyme pattern, Km or Vmax.

This book is designed to meet the needs of advanced undergraduates and graduate students from a range of disciplines including neurobiology, psychology and speech sciences. The description of the book as a new analysis and synthesis is inappropriate as the book covers established areas. Basic physiological mechanisms of sound representation and psychological aspects of hearing are discussed with the emphasis on the latter. The book is therefore in a niche that includes physiological texts such as those by Pickles, and the well-established psychoacoustic texts by Moore.

Bladder, or detrusor, instability is a symptomatic condition which is characterized by uncontrollable rises in pressure within the bladder lumen leading to a feeling of urgency of micturition and, if severe enough, urinary incontinence. The rises in pressure are brought about by contraction of the detrusor smooth muscle which forms the major tissue component of the urinary bladder wall. This abnormality can be associated with a number of clinical conditions and when there is evidence of associated neurological deficits it is termed detrusor hyper-reflexia. An increase in bladder outflow resistance is also associated with detrusor instability and this is especially prevalent in men due to the age-related hypertrophy of the prostate gland which surrounds the urethra. However, in the majority of cases the cause is idiopathic and probably multifactorial. No matter what the cause, detrusor instability is one the largest causes of morbidity in the community; in the UK its prevalence increases from about 2 % in men and 9 % in women aged 15-64 years to 7 % and 12 %, respectively, in the over 65 years age group (Thomas et al. 1980; Brocklehurst, 1993).

To study the effect of temperature on muscle metabolism during submaximal exercise, six endurance-trained men had one thigh warmed and the other cooled for 40 min prior to exercise using water-perfused cuffs. One cuff was perfused with water at 50-55¡C (HL) with the other being perfused with water at 0¡C (CL). With the cuffs still in position, subjects performed cycling exercise for 20 min at a work load corresponding to 70 % VO2,peak (where VO2,peak is peak pulmonary oxygen uptake) in comfortable ambient conditions (20-22¡C). Muscle biopsies were obtained prior to and following exercise and forearm venous blood was collected prior to and throughout the exercise period. Muscle temperature (Tmus) was not different prior to treatment, but treatment resulted in a large difference in pre-exercise Tmus (difference = 6á9 ± 0á9¡C; P < 0á01). Although this difference was reduced following exercise, it was nonetheless significant (difference = 0á4 ± 0á1¡C; P < 0á05). Intramuscular [ATP] was not affected by either exercise or muscle temperature. [Phosphocreatine] decreased (P < 0á01) and [creatine] increased (P < 0á01) with exercise but were not different when comparing HL with CL. Muscle lactate concentration was not different prior to treatment nor following exercise when comparing HL with CL. Muscle glycogen concentration was not different when comparing the trials before treatment, but the post-exercise value was lower (P < 0á05) in HL compared with CL. Thus, net muscle glycogen use was greater during exercise with heating (208 ± 23 vs. 118 ± 22 mmol kg-1 for HL and CL, respectively; P < 0á05). These data demonstrate that muscle glycogen use is augmented by increases in intramuscular temperature despite no differences in high energy phosphagen metabolism being observed when comparing treatments. This suggests that the increase in carbohydrate utilization occurred as a direct effect of an elevated muscle temperature and was not secondary to allosteric activation of enzymes mediated by a reduced ATP content.

The lactate threshold is a widely used and, at times, controversial construct in exercise physiology and pathophysiology. Its non-invasive estimation during incremental exercise depends upon CO2 output increasing as a function of O2 uptake, i.e. 'V-slope', as a result of bicarbonate buffering during the lactic acidosis. However, we hypothesised that the V-slope deflection could also occur as a consequence of metabolic CO2 being diverted proportionally more into the CO2 stores in the early phase of exercise. Eight healthy males performed two incremental exercise tests on a cycle ergometer, with and without controlled prior hyperventilation; the hyperventilation caused end-tidal PCO2 to decline by [sim]10 mmHg, with the clearance of a CO2 volume averaging 2547 ml. This corresponded to an 'effective' CO2 capacitance of some 3·12 ml mmHg-1 kg-1. Gas exchange was determined breath-by-breath, and blood was sampled from the dorsum of the heated hand. Our results demonstrate that the early dynamics of CO2 wash-in to the previously depleted body stores can result in a 'pseudo-threshold', i.e. significantly before the onset of the actual lactic acidosis. Precautions should therefore be taken to avoid hyperventilation prior to non-invasive estimation of the lactate threshold.

One of the earliest events in the formation of an atherosclerotic lesion is the adherence of circulating monocytes to the vascular endothelium, through which they then gain entry to the sub-intimal tissue. This early lesion subsequently evolves over a number of years to form an atherosclerotic plaque, through the migration and proliferation of cells, the accumulation of lipid in the vessel wall and through the extensive deposition and modification of a connective tissue matrix. Pathological studies have described a wide spectrum of structural architecture in atherosclerotic plaques which suggests that, with time, the vascular connective tissue matrix is extensively modified during atherogenesis. This process of vascular connective tissue remodelling, where matrix macromolecules are both deposited and degraded, is controlled by a complex network of cell-cell and cell-matrix interactions, involving the secretion of a wide variety of growth factors and cytokines and chemokines.

The urinary bladder is a smooth muscle organ the function of which is to collect and store urine at low intravesical pressures, and then periodically to expel urine via a highly co-ordinated sustained contraction (Levin et al. 1990a; Anderson, 1993; Steers, 1994; Zderic et al. 1996a). The urethra functions to maintain continence during bladder filling, and then to provide a low-resistance pathway during micturition. The control of lower urinary tract function is through the autonomic nervous system. During bladder filling, the sympathetic nervous system is active and this produces an increase in tension of the bladder base and urethra via activation of a-adrenergic receptors, and relaxation of the bladder body via activation of ß-adrenergic receptors. In addition, sympathetic activity inhibits parasympathetic ganglionic transmission via postsynaptic sympathetic fibres which act upon a2-type receptors located in the ganglia. Micturition is mediated via the co-ordinated parasympathetic activation of cholinergic muscarinic receptors of the bladder body with the simultaneous inhibition of [alpha]-adrenergic tone of the bladder neck and urethra (Steers, 1994; Zderic et al. 1996a). Active urethral relaxation mediated by nitric oxide may also play a role during micturition (Anderson, 1993; Steers, 1994; Zderic et al. 1996a).

Quantitative measurements were made of relative breast volume and milk production from 1 month of lactation until 3 months after weaning, and the storage capacity of the breasts was calculated. The increase in breast tissue volume from before conception until 1 month of lactation was maintained for the first 6 months of lactation (means ± S.E.M.) (190.3 ± 13.1 ml, number of breasts, nb = 46). During this period of exclusive breast-feeding, 24 h milk production from each breast remained relatively constant (453.6 ± 20.1 g, nb = 48), and storage capacity was 209.9 ± 11.0 ml (nb = 46). After 6 months, breast volume, milk production and storage capacity all decreased. There was a relationship between 24 h milk production and the storage capacity of the breasts, and these both appeared to be responding to infant demand for milk. At 15 months of lactation, the 24 h milk production of each breast was substantial (208.0 ± 56.7 g, nb = 6), even though the breasts had returned to preconception size. This was associated with an apparent increased efficiency of the breast (milk production per unit breast tissue) after 6 months, which may have been due to redistribution of tissues within the breast. The possible causes of the decrease in breast volume are discussed.

We discovered in 1987 that the shorter form of apolipoprotein B (B48) synthesized in the intestine is due to the action, previously unrecognized in mammalian cells, of an mRNA-editing process, and more recently we demonstrated that this was due to a specific enzyme (APOBEC-1) with cytidine deaminase activity. We show here, by sequence alignment, molecular modelling and mutagenesis, that APOBEC-1 is a cytidine deaminase, responsible for editing apoB mRNA, and that is related in crystal structure to the cytidine deaminase of Escherichia coli (ECCDA). The two enzymes are both homodimers with composite active sites formed with loops from each monomer. In the sequence of APOBEC-1, three gaps compared with ECCDA match the size and contour of the minimal RNA substrate. We propose a model in which the asymmetric binding of one active site to the substrate cytidine which is positioned by the downstream binding of the product uridine and that this helps to target the other active site for deamination.

To effectively control bladder activity, and to treat urinary incontinence caused by bladder overactivity, identification of suitable targets for pharmacological intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. The causes of bladder overactivity are not known, but theoretically increased afferent activity, decreased inhibitory control in the CNS and/or peripheral ganglia, and increased sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Potentially, drugs affecting GABA, opioid, 5-HT, noradrenaline, dopamine, or glutamatergic receptors and mechanisms can be developed, but a selective action on the lower urinary tract may be difficult to obtain. Traditionally, drugs used for treatment of bladder overactivity have had a peripheral site of action, mainly the efferent neurotransmission or the detrusor muscle itself. Antimuscarinic drugs, β-adrenoceptor agonists, α-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents have been used. However, none of them has been developed specifically for treatment of bladder disorders, and their efficacy, as judged from controlled clinical trials (where performed), is often limited. Recent information on the α-adrenoceptor, β-adrenoceptor (β3), and muscarinic receptor subtypes of the human detrusor and outflow region can be the basis for the development of compounds with effect on bladder overactivity and with improved tolerance. New ways of decreasing acetylcholine release may represent a promising way of controlling bladder contraction. Potassium channel (KATP) openers are theoretically attractive, but the drugs available so far have targeted vascular rather than bladder smooth muscle, which has limited their clinical use. However, new drugs belonging to these groups with an interesting profile of action have been developed. Drugs decreasing afferent activity represent an attractive therapeutic approach and transmitters of afferent nerves and their receptors are possible targets for pharmacological interventions. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and have been shown to influence bladder function. Agents affecting these nerves by causing release of tachykinins, such as capsaicin and resiniferatoxin, given intravesically can be effective in some cases of bladder overactivity, and agents antagonizing tachykinin receptors may also be of therapeutic interest.New drugs specifically directed for control of bladder activity are under development and will hopefully lead to improved treatment of urinary incontinence.This study was supported by the Swedish Medical Research Council (grant no. 6837).

Urinary outflow from the mammalian bladder occurs through the urethra. This outflow tract is a complicated structure composed of striated and smooth muscle and vascular urothelium. It is controlled by somatic and autonomic nerves and has several functions: it generates sustained tone to prevent urinary leakage during bladder filling; it generates transient reflex increases in pressure to prevent opening of the lumen when abdominal pressure rises; it undergoes relaxation preceding micturition and can generate urethral opening and shortening during micturition. A urethral pressure profile shows a peak pressure of [greater than or equal to] 100 cmH2O. The outermost coat is striated muscle, the striated or external sphincter. The fibres are predominantly circularly oriented. The extent varies in different species and between sexes. In the human female it extends the length of the urethra, and is composed mainly of slow twitch fibres. In the male, the sphincter extends from the membranous urethra over the base of the prostate and has nearly equal numbers of slow and fast twitch fibres. In both sexes, the posterior border may be deficient in striated muscle, and filled by circularly oriented smooth muscle. Activity in the slow twitch fibres through somatic nerves may be continuous during bladder filling. Outer circular and inner longitudinal smooth muscle is present Strips from either layer will generate sustained tone particularly if dissected from the high pressure zone. This tone is myogenic, and may be achieved in the absence of action potentials, but relies on influx of calcium through L-type calcium channels. Both layers receive sympathetic and parasympathetic excitatory innervation and nitrergic inhibitory innervation. Normal urethral pressure requires blood flow to the urothelium (lamina propria). Striated and smooth muscles are both thought to contribute to the resting urethral pressure in the human. The precise role of the smooth muscles during micturition is as yet unresolved.

Presented at the Cambridge Meeting of the Society in December 1997 This symposium paper has already been published as a Review Article in Experimental Physiology, volume 83, pp. 573-584.

Lateral ventricular volumes were monitored and quantified using accurately registered magnetic resonance images (MRIs) in six healthy individuals 30 min before and up to 4 h after ingestion of a glucose drink. The volume of the lateral ventricles increased by an average (± S.E.M.) of 2Σ4 ± 0Σ4 % as blood glucose levels rose from 4Σ8 ± 0Σ2 mmol l-1 to 8Σ4 ± 0Σ4 mmol l-1. This was followed by a peak decrease of 5Σ99 ± 3Σ3 % below initial fasting volumes as blood glucose levels fell to 5Σ0 ± 0Σ3 mmol l-1. We suggest that the secondary volume decrease demonstrates a homeostatic process of brain volume regulation for which the mechanism remains uncertain.

As skeletal muscle fibres mostly express a single myosin isoform, they are a potential source of pure myosin isoforms. A technique is described that allows extraction and identification of pure myosin isoforms from single fibres, and testing of such myosins in an in vitro motility assay (IVMA). The results show that the extraction procedure does not alter myosin function and support the view that single fibres are reliable sources of purified myosin isoforms for IVMA.

The thresholds for detection of a tremor-like movement are described. Detection is poorest at frequencies which correspond to natural tremor. The results are in accord with the failure of persons often to notice that their hands are tremulous.

Glandular Mechanisms of Salivary Secretion. Edited by J. R. Garrett, J. Ekström and L. C. Anderson. Pp. 226. Karger, Basle, 1998. $167.00 hardback. ISBN 3 8055 6630 1.