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1 Diazoxide 300 mg and labetalol 150 mg were each injected intravenously on separate occasions into five patients with essentail hypertension. The reduction in BP caused by labetalol was slightly greater than that produced by diazoxide. 2 In contrast the reduction in cerebral blood flow (CBF) by labetalol was not statistically significant, whereas diazoxide gave a greater and statistically significant reduction in CBF. 3 These observations suggest that labetalol may have an advantage over diazoxide for the rapid reduction in BP.

Mary Warner, as she was mainly known in the mathematical world, died in April 1998. At a time when few women mathematicians reached the top in their profession, she succeeded in doing so through her ability and determination. Her research contributions were commemorated at a recent international conference on fuzzy topology, the field in which she was one of the pioneers and recognized as one of the leading figures for the past thirty years. She was also an outstanding teacher. But to understand her achievements properly it is necessary to know something of her life.

Aims Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other β-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between β-adrenoceptor blockers and rizatriptan. Methods Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various β-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. Results Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0,∞) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the β-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other β-adrenoceptor blockers significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. Conclusions These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other β-adrenoceptor blockers does not require consideration of a dose adjustment.

Among British mathematicians of the Victorian age there may be others who are comparable with Sylvester in terms of scientific achievement, but surely none whose life story makes such fascinating reading. Any modern biographical memoir of this extraordinary man must obviously depend a great deal on the obituaries published following his death, just a century ago. Of these the two most important are that by Baker, for the London Mathematical Society, and that by MacMahon, for the Royal Society. The former, which was reprinted in the fourth volume of Sylvester's Mathematical Papers, is the longer and more detailed, but the latter is the primary source for most of the biographical material. As the centenary approached there has been a rekindling of interest in Sylvester's life and work. Notably Professor Parshall, of the University of Virginia, is preparing a full–scale biography. Sylvester's contributions to mathematical research are undergoing something of a reevaluation at present, and what is said about them here is therefore kept to a minimum. The account of his life that follows is drawn from various sources both old and new.

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.

This paper is the third in a series of four. The constructions which were developed in Reduced product spaces [5],' and On the suspension triad [6], are applied to the suspension triad of a sphere, with the help of the method of spectral sequences. There are many applications of the theorems which we shall prove to the theory of homotopy groups of spheres, and these will be the subject of a concluding article, On the suspension sequence. The definitions and notations of [6] are carried over to the present work. In particular, Sn denotes the euclidean n-sphere

The first part of this article concerns the general relation between blood pressure lowering and cerebral blood flow. Factors known to affect cerebral blood flow are reviewed, and recent advances in the field of innervation of cerebral blood vessels are outlined. Special emphasis is placed on the importance of the phenomenon of autoregulation and how this is disturbed in patients with hypertension. Not all antihypertensive drugs exert the same action on the cerebral circulation to produce the same blood pressure-lowering effect. In addition, the actions exerted by common antihypertensive drugs on the cerebral circulation are described. The second part of the article provides a comparison between the effect of carvedilol and that of propranolol on blood pressure reduction and cerebral blood flow. In a double-blind, crossover study involving 14 patients with mild-to-moderate hypertension, carvedilol was shown to have no effect on cerebral blood flow, whereas there was a slight tendency for lower flows to occur with the use of propranolol. Because of the small sample size, statistical significance was not reached. These results are consistent with other recently published findings.

This study was designed to test the benefit of acetyl-l-carnitine in patients with dementia. Seventy-one patients of 65 years and over, living in their own homes or in residential care, took part in a 24-week randomized, double-blind, placebo-controlled, parallel-group clinical trial. The outcome was measured by comparing psychometric tests at 24 weeks to baseline measures. The active treatment group improved in mean scores in seven out of eight psychometric tests, the placebo treatment group in only two out of eight tests. The improvements were statistically significant in one test, recognition memory (p < 0.01). Linear discriminant function analysis indicated that active and placebo therapy could be distinguished according to the pattern of responses to the eight psychological tests (p < 0.01). In this small trial, acetyl-l-carnitine was shown to be non-toxic and possibly beneficial. Further large-scale trials are needed over long periods of time.

SynopsisThe purpose of this paper is to introduce a fibrewise generalisation of category, in the sense of Lusternik–Schnirelmann. This reduces to the classical concept when the space is a point. Fibrewise category may be compared with equivariant category, which has been the subject of some recent research [1,7,8]. Many variations on the basic idea of category have been discussed in the literature, for example the concept of category of a map, but since the generalisations to the fibrewise case are fairly routine they are not considered here.

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Point-set topology seems to have become separated from the rest of topology around the middle of the twentieth century. For most of the period we shall be considering in this article the term combinatorial topology meantl “practically everything which could not better be described as point-set topology”. Most of the pioneers were equally at home in both disciplines, but more recently that has become rather unusual. One of the purposes of this article is to try and throw some light on this situation. It is easier to describe what happened than to explain why, but some insight may be gained if we try to understand what it must have been like to be a topologist in the first half of the century, especially in the second quarter. At the end of this article I will attempt an explanation.

Objective To determine whether muscle blood flow before and after exercise is abnormal in patients with diabetes mellitus. Research Design and Methods Muscle blood flow (MBF) was measured with the 133Xe clearance technique in 15 nondiabetic subjects, 10 patients with insulin-dependent diabetes mellitus (IDDM), and 11 patients with non-insulin-dependent diabetes (NIDDM) at rest and after exercise. None of the patients had neuropathy. Results The median resting MBF was similar in all three groups. The median postexercise MBF was significantly greater in nondiabetic subjects (40.1 ml· min−1·100 g−1 of tissue) than in patients with IDDM (25.7 ml· min−1·100 g−1 of tissue; P Conclusions Diabetic patients have abnormalities of MBF in response to exercise. This abnormality occurs in the absence of clinical diabetic neuropathy.

A fibrewise coHopf space X over a base B is a sectioned space for which the diagonal map X —> X x BX may be compressed into X VBX up to fibrewise pointed homotopy. Such spaces have been investigated by I. M. James in the case where X is a sphere bundle over a sphere. The purpose of this thesis is to demonstrate some of the properties of fibrewise coHopf spaces over more general bases. Particular attention is given to sphere bundles and fibrations with spherical fibre. The fibrewise reduced suspension of a sectioned fibrewise space with closed sec- tion is fibrewise coHopf with associative comultiplication (up to fibrewise pointed homotopy) and a fibrewise inversion. Examples of fibrewise coHopf spaces not of this form are exhibited, and sufficient conditions are given to ensure that a fibrewise coHopf space has the primitive fibrewise pointed homotopy type of a fibrewise re- duced suspension, in terms of the dimension and connectivity of the space, its base and the fibres. It is shown that these conditions may be relaxed if the fibrewise coHopf structure on the space is assumed to be homotopy-associative. An example of a non-associative fibrewise coHopf sphere bundle is given. It is shown that, if q > 1 is odd, a sectioned orientable q-sphere bundle over a finite connected complex is fibrewise coHopf if and only if its fibrewise localisation at the prime 2 is fibrewise coHopf. Moreover, the fibrewise rationalisation of an odd-dimensional sphere bundle over a finite polyhedron whose fibrewise unreduced suspension is fibrewise coHopf is shown to be a trivial fibration. As an application, it is shown that new fibrewise coHopf spherical fibrations may be constructed by mixing. The Thorn space is used to determine the cohomology ring of the total space of a fibrewise coHopf sphere bundle in terms of that of its base, and a generalised Hopf invariant is constructed which vanishes on fibrewise coHopf sphere bundles.

After an experimental study in dogs, authors report a new therapeutic device for peritoneal seedings (Intra-Peritoneal Chemo-Hyperthermia) and their preliminary results in five patients. They observed no mortality and no morbidity with this protocol using Mitomycin as antimitotic and hyperthermia as sensibilisation agent. This new technique means important technological and time investment but preliminary results appear to be encouraging and authors intend to standardize the present apparatus in order to go on using this device and obtain more experience.

1. The role of histamine in PAF-induced acute inflammatory responses (flare and weal) in the skin has been evaluated in a series of three separate studies. 2. Terfenadine, a potent H1-selective histamine antagonist virtually abolished the flare response and significantly inhibited the weal response. 3. Histamine depletion in the skin using compound 48/80 resulted in similar effects on the flare and weal response. Two consecutive daily injections of compound 48/80 were found to deplete comprehensively skin sites of histamine and the ability of skin to respond to PAF was completely restored within 2 weeks of compound 48/80 treatment. 4. Intradermally injected PAF was associated with acute rises in plasma histamine in blood drawn from a draining vein with peak concentrations occurring within 5 min of injection. 5. No difference in PAF-induced flare and weal response was found between atopic and non-atopic subjects and this was reflected in the peak plasma histamine results. A significantly higher baseline plasma histamine was found in the atopic group, however, when compared with the non atopic group. 6. It is concluded that histamine has an important role in the acute inflammatory responses to intradermally injected PAF, although there does appear to be a significant direct vascular component in the PAF-induced weal response.

The influence of hepatic disease on the pharmacokinetics of the new ACE inhibitor, benazepril hydrochloride, was evaluated in 12 male patients suffering from liver cirrhosis. The patients received a single oral 20 mg dose. The plasma concentrations and urinary excretion of unchanged benazepril and its active metabolite benazeprilat were determined. Compared with a historical control group of healthy volunteers treated with the same benazepril. HC1 dose, the plasma concentrations of benazepril were doubled in the cirrhotic patients. However, the time to reach maximum concentration (0.5 h) was not affected. The plasma kinetics and the urinary excretion of the metabolite benazeprilat were not significantly altered: Area under the curve and maximum concentration as well as time to maximum concentration (1.5 h) were comparable with those in the healthy subjects. There was also no significant difference between the two populations for the total urinary excretion and the renal clearance of benazeprilat. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 94 per cent, respectively). In conclusion, the rate and the amount of bioactivation of the inactive prodrug benazepril to the active benazeprilat were virtually unaffected by hepatic cirrhosis. Thus, there seems to be no need for dosage adjustment of benazepril hydrochloride in patients suffering from cirrhosis of the liver.

I assume the reader to be familiar with the classical theory of covering spaces in the topological sense, as in Godbillon [5] or (with some technical differences) in Massey [16], An important branch of the theory concerns the case where the base space is a topological group, which is dealt with more fully in Chevalley [3] but see also Taylor [22], This suggests that it ought to be possible to develop a uniform version of the notion of covering space and in the final section I give an outline of the form which such a theory might take. In the topological theory there is an essential difference between the notion of local topological equivalence and that of covering map. In the uniform theory we can expect to find we need to strengthen the definition of local uniform equivalence in a similar fashion. To start with, let R be an equivalence relation on the uniform space X. In Section 2 we have defined the terms weakly compatible and compatible. What we now need is a stronger condition still.

This book is based on a course taught to an audience of undergraduate and graduate students at Oxford, and can be viewed as a bridge between the study of metric spaces and general topological spaces. About half the book is devoted to relatively little-known results, much of which is published here for the first time. The author sketches a theory of uniform transformation groups, leading to the theory of uniform spaces over a base and hence to the theory of uniform covering spaces. Readers interested in general topology will find much to interest them here.

Intra-peritoneal chemo-hyperthermia with mitomycin C was used to treat 9 patients with very advanced gastrointestinal cancers with peritoneal seedings. Resection of the primary tumor was possible in 3 cases. After temporary of closure of the abdominal wall, 90 to 120 minutes of intra-peritoneal chemo-hyperthermia was performed under general anaesthesia with 32 degrees C of systemic hypothermia, via 3 intra-peritoneal drains forming a closed circuit, using 10 mg/l of mitomycin C in 61 of peritoneal dialysate warmed at the inflow temperature of 46 to 49 degrees C. We observed no mortality or morbidity. There were only minor and temporary laboratory side effects and for 6 patients, no malignant cells could be found in the ascitic fluid after intra-peritoneal chemo-hyperthermia. In six patients, we conserved an improvement in the Karnofsky index 3 to 7 months after intra-peritoneal chemo-hyperthermia. These results show that intraperitoneal chemo-hyperthermia with mitomycin C is a safe and reliable treatment for peritoneal seedings in severely advanced gastrointestinal cancers and encourage us to proceed with this new therapeutic modality.

EDITOR, - Peter Brooks's editorial on the recent decision in a British court that repetitive strain injury does not exist as a separate medical condition is important.1 Musicians are prone to aches and pains that are specific to their profession; they may also suffer from the health problems to which everyone is prone. If these problems are not recognised and tackled quickly the resultant inability to work for even quite short periods may lead to the loss of a career. The epidemic of repetitive strain injury …

1 Cerebral blood flow (CBF) was measured by the 133xenon inhalation method in 33 newly-diagnosed hypertensive patients prior to commencing therapy. 2 Blood pressure was treated by using a varying sequence of four different drugs, namely labetalol, metoprolol, oxprenolol and sotalol, each of which is a beta-adrenergic receptor blocking agent, but with differing additional properties. 3 CBF measurements were repeated when blood pressure was controlled. No significant change in CBF was found with any of the four drugs, in contrast to the fall which has been reported when drugs of this type are administered acutely.

Three of six patients with chronic hepatic encephalopathy treated with levodopa showed a significant improvement. One patient was probably improved whilst the remaining two patients failed to show any benefit. Serial electroencephalography did not demonstrate significant changes. Treatment with levodopa was associated with an improvement in `speed-based' tasks as assessed by computerized psychometry. A significant rise in cerebral oxygen consumption was found during levodopa therapy. Gastrointestinal side effects were dose limiting. It is concluded that a therapeutic trial of levodopa in patients with chronic hepatic encephalopathy is indicated when the response to conventional therapy has been poor.

The pharmacokinetics of acebutolol have been studied in eight healthy male volunteers following the oral administration of acebutolol hydrochloride (‘Sectral’, May & Baker) as a single dose (400 mg), and during and after repeated oral dosing (400 mg, b.d. for 56 days). Following single dose administration, considerable inter-subject variation in plasma levels of parent drug and the major metabolite, diacetolol. was evident. Acebutolol appeared to be eliminated from plasma in a bi-phasic manner, and this was confirmed from urinary excretion rate data. Mean initial and terminal half-lives of about 2 and 11 h, respectively, were determined. Plasma levels of diacetolol were greater than those of parent drug from 3 to 4 h following dose administration. Total urinary excretion of diacetolol was generally greater than that of acebutolol. During repeated dosing, steady-state plasma levels of acebutolol and diacetolol were achieved in 6 volunteers. Acebutolol did not appear to stimulate or inhibit its metabolism.

Patients with chronic liver disease, yet without severe encephalopathy, were found to show evidence of increased brain utilization of glucose. The changes were abolished after an intravenous infusion of 15 g ornithine alpha oxoglutarate, given over a period of 15 minutes. The possible implications of these observations are discussed.