Recent research suggests that migraine results from the interplay of multiple factors, and many studies have considered the relationship of migraine to systemic abnormalities. This editorial comments on recent findings relating to migraine and metabolic syndrome, and suggests some possible causes.

Episodic brain disorders (EBD) form an intriguing group of neurological diseases in which at least some of the symptoms occur in attacks. The hypothalamus integrates many brain functions, including endocrine and autonomic control, and governs various body rhythms. It seems a likely site in which the initiation of attacks of EBD can be modulated. Indeed, the hypothalamus has a crucial role in EBD such as narcolepsy and cluster headache. The same may be true for migraine and depression. Here we summarise the evidence supporting an important role for the hypothalamus in the initiation of disease episodes in various EBD. Study of the various pathophysiological concepts of EBD within the context of the hypothalamus may prove a fruitful example of cross-fertilisation between various research areas.

We have designed this investigation to determine whether naftidrofuryl has an effect upon metabolism in vivo in man. Five subjects were studied during and after steady exercise on a bicycle ergometer. On the first occasion they received naftidrofuryl (300 mg orally) 20-40 min before exercise; and on the second they exercised without the drug to provide control observations. Blood samples were taken for the estimation of glucose, pyruvate, lactate, glycerol, acetoacetate and 3-hydroxybutyrate. Exercise with naftidrofuryl caused a significantly greater rise in blood pyruvate concentration during the exercise and post-exercise period compared with the controls. Changes in glucose, lactate, glycerol and ketone-bodies were not significantly different from the control values. Lactate/pyruvate ratios were significantly reduced with naftidrofuryl during the post-exercise period. Exercise causes a rise in intracellular anaerobic metabolism with associated increases in blood lactate/pyruvate ratios. This is followed by enhanced oxidative capacity during the recovery period as adduced from falling lactate/pyruvate ratios. The greater decline in lactate/pyruvate ratios with naftidrofuryl during the post-exercise period is evidence that naftidrofuryl is able to enhance cellular oxidative activity in vivo in man. Further studies in clinical situations are therefore indicated.

The clinical response of treatment with a chemical preparation of tyramine and tranylcypromine, a monoamine oxidase inhibitor, is described in six patients wit neurogenic orthostatic hypotension. Previous therapy with fluorocortisone, ephedrine, elastic garments, postural training and, in one patient, an anti-G suit was unsuccessful. Oral and intravenous tyramine produced no pressor response. However, after treatment with tranylcypromine five of the patients when supine showed a marked rise of blood pressure to intravenous tyramine which was sustained for over two hours when they stood up. Tyramine given orally with tranylcypromine produced a moderate rise of blood pressure in the supine position which was sustained for over 3-4 hours in the erect position enabling patients to walk about without symptoms of orthostatic hypotension. Measurement of circulating adrenaline and noradrenaline during therapy suggested that the pressor response was due to release of noradrenaline. Three patients have had marked improvement for four, fifteen and twenty-four months respectively. In a further patient, therapy has been successful in treating his orthostatic hypotension although his mobility has been restricted due to cerebellar ataxia. One patient developed a confusional state during treatment and the therapy was stopped. The only patient in whom the drugs produced no pressor response had orthostatic hypotension with evidence of adrenergic innervation of blood vessels, but failure of noradrenaline release. It is suggested that the pressor response to a monoamine oxidase inhibitor and tyramine should be examined in patients to a monoamine oxidase inhibitor and tyramine should be examined in patients with neurogenic orthostatic hypotension in whom conventional therapy is unsatisfactory and those who respond should receive a trial of this treatment.

Clonazepam was added to the treatment of patients with poorly controlled epilepsy in a double-blind trial and an open trial. Considerable improvement occurred with patients with myoclonic jerks and tonic-clonic convulsions, and with photosensitive epilepsy. Patients with atypical petit mal and focal epilepsies also improved. Drowsiness was initially common but lasted only a short time. No evidence was found for an action of clonazepam on the metabolism of other drugs, but treatment with phenobarbitone lowered serum concentrations of clonazepam. We conclude that clonazepam is particularly valuable in epilepsy with associated myoclonsu and in photosensitive epilepsy.

A 26 year old man is described with life-long orthostatic hypotension unrelated to autonomic nerve degeneration and apparently due to failure of peripheral noradrenaline realese. Tests of parasympathetic and sympathetic cholinergic nerve function were normal, but sympathetic adrenergic activity was defective. Thus blood pressure regulation was abnoraml. There was no pressor response to tyramine, an indirect sympathomimetic drug, but a marked pressor response to the directly acting sympathomimetic drugs phenylephrine and noradrenaline. On standing there was a progressive fall rather than a rise in circulating noradrenaline concentrations, although adrenaline levels rose normally. The pupils showed diminished responses to ephedrine and cocaine, and a normal response to phenylephrine. Fluorescence microscopy of blood bessels showed that they were innervated with adrenergic nerves. His orthostatic hypotenstion responded well to oral phenylephrine (50 mg five times daily) but not to other forms of therapy. It is suggested that this patient's symptoms were due to failure of noradrenaline release even though sympathetic adrenergic nerves were present. We therfore wish to draw attention to a further cause of orthostatic hypotension, failure of peripheral noradrenaline release without autonomic neuropathy.

Glucose tolerance tests have been performed on five patients with Huntington's chorea and no difference in response has been observed compared with seven controls. Insulin tolerance tests have been performed on 12 patients with Huntington's chorea and 10 controls. Blood samples were taken at regular intervals for 75 minutes and analysed for blood glucose, insulin, and growth hormone (HGH). There was no difference between the groups in the hypoglycaemia which developed. The patients, however, had an earlier elevation of HGH than the controls. The difference was highly significant (P less than 0.001, P less than 0.02) 30 and 35 minutes after the intravenous injection of insulin. The patients, although awake, ceased to have choreiform movements for at least the last 60 minutes of the insulin tolerance tests. Our observations of HGH release imply that hypothalamic activity is altered in Huntington's chorea. Further observations of HGH release may therefore be of value in its diagnosis.

Six patients with neurogenic orthostatic hypotension were treated with a chemical preparation of tyramine and tranylcypromine ("Parnate"), a monoamine oxidase inhibitor (M.A.O.I.). Four had autonomic failure with no other neurological deficit (idiopathic orthostatic hypotension), and in two patients other neuronal systems were also involved (Shy-Drager syndrome). Previous therapy with fludrocortisone, ephedrine, elastic garments, postural training, and, in one patient, an anti-G suit was unsatisfactory. Tyramine given orally with tranylcypromine produced a moderate rise in blood-pressure which was sustained for 2-4 hours, enabling patients to walk about without symptoms of orthostatic hypotension. Measurement of circulating adrenaline and noradrenaline during therapy suggested that release of noradrenaline caused the pressor response. In three patients there has been a pronounced improvement for 8, 20 and 30 months. In a further patient, therapy has been successful in treating the orthostatic hypotension, although his mobility has been restricted by cerebellar ataxia. In one patient a confusional state developed during treatment and therapy was stopped. The only patient in whom the drugs did not produce a pressor response had orthostatic hypotension with failure of noradrenaline release. It is suggested that the pressor response to a M.A.O.I. and tyramine should be examined in patients with neurogenic orthostatic hypotension and that this treatment should be tried in those who respond.

The growth hormone (hGH) and prolactin (hPRL) responses to oral bromocriptine were studied in two groups of patients with Huntington's chorea and in seven healthy control subjects. The patients included six patients who had previously been treated with phenothiazines and six patients who had not received phenothiazine treatment. All medication was stopped 72 hours before the investigation which involved taking blood samples for up to 210 minutes after taking bromocriptine (2.5 mg). Plasma samples were analysed for hGH and hPRL. There was no significant difference in basal hGH concentrations between the patients and control subjects. The hGH response to bromocriptine varied in the individual patients but the concentrations were significantly lower in the patients compared with the controls between 160 and 210 minutes. The basal concentrations of hPRL were also not different, apart from the findings of elevated hPRL concentrations in three patients previously treated with phenothiazines. The patients and control subjects showed a consistent fall in hPRL concentrations after taking bromocriptine. The lower peak hGH response to bromocriptine found in the patients suggests that there may be an alteration of dopaminergic neurones mediating hGH release.

Increasing uterine artery blood flow (UABF) may benefit fetal growth restriction where impaired uteroplacental perfusion prevails. Based on previous short-term results, we examined the long-term effects of adenovirus vector-mediated overexpression of vascular endothelial growth factor-A(165)(VEGF-A(165)) in the uterine artery (UtA). Transit-time flow probes were implanted around both UtAs of mid-gestation pregnant sheep (n=11) to measure UABF. A carotid artery catheter was inserted to measure maternal or fetal hemodynamics. Baseline UABF was measured over 3 days, before injection of adenovirus vector (5 × 10(11) particles) encoding the VEGF-A(165) gene (Ad.VEGF-A(165)) into one UtA and a reporter β-galactosidase gene (Ad.LacZ) contralaterally. UABF was then measured daily until term. At 4 weeks post injection, the increase in UABF was significantly higher in Ad.VEGF-A(165) compared with Ad.LacZ-transduced UtAs (36.53% vs 20.08%, P=0.02). There was no significant effect on maternal and fetal blood pressure. Organ bath studies showed significantly lesser vasoconstriction (E(max) 154.1 vs 184.7, P<0.001), whereas immunohistochemistry demonstrated a significantly increased number of adventitial blood vessels (140 vs 91, n=26, P<0.05) following Ad.VEGF-A(165) transduction. Local overexpression of VEGF-A(165) in the UtAs of pregnant mid-gestation sheep leads to a sustained long-term increase in UABF, which may be explained by neovascularization and altered vascular reactivity.Gene Therapy advance online publication, 20 October 2011; doi:10.1038/gt.2011.158.

This paper presents a general analysis and a concrete example of the catastrophic case of a discontinuity-induced bifurcation in so-called Filippov nonsmooth dynamical systems. Such systems are characterized by discontinuous jumps in the right-hand sides of differential equations across a phase space boundary and are often used as physical models of stick-slip motion and relay control. Sliding bifurcations of periodic orbits have recently been shown to underlie the onset of complex dynamics including chaos. In contrast to previously analyzed cases, in this work a periodic orbit is assumed to graze the boundary of a repelling sliding region, resulting in its abrupt destruction without any precursive change in its stability or period. Necessary conditions for the occurrence of such catastrophic grazing-sliding bifurcations are derived. The analysis is illustrated in a piecewise-smooth model of a stripline resonator, where it can account for the abrupt onset of self-modulating current fluctuations. The resonator device is based around a ring of NbN containing a microbridge bottleneck, whose switching between normal and super conducting states can be modeled as discontinuous, and whose fast temperature versus slow current fluctuations are modeled by a slow-fast timescale separation in the dynamics. By approximating the slow component as Filippov sliding, explicit conditions are derived for catastrophic grazing-sliding bifurcations, which can be traced out as parameters vary. The results are shown to agree well with simulations of the slow-fast model and to offer a simple explanation of one of the key features of this experimental device.

Context: Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH. Objective: The aim of this study was to investigate the impact of GHR blockade on substrate metabolism and insulin sensitivity during fasting. Design: We conducted a randomized, placebo-controlled, crossover study in 10 healthy young men. Intervention: After 36 h of fasting with saline or pegvisomant (GHR blockade), the subjects were studied during a 4-h basal period and 2.5-h hyperinsulinemic euglycemic clamp. Main Outcome: We measured whole-body and forearm glucose, lipid, and protein metabolism, peripheral insulin sensitivity, and acyl and desacyl ghrelin. Results: GHR blockade significantly suppressed circulating free fatty acids (1226 +/- 83 vs. 1074 +/- 65 mumol/liter; P = 0.03) and ketone bodies (3080 +/- 271 vs. 2015 +/- 235 mumol/liter; P </= 0.01), as well as forearm uptake of free fatty acids (0.341 +/- 0.150 vs. 0.004 +/- 0.119 mumol/100 ml . min; P < 0.01) and lipid oxidation (1.3 +/- 0.1 vs. 1.2 +/- 0.1 mg/kg . min; P = 0.03) in the basal period. By contrast, IGF-I levels in either serum or peripheral tissues were not impacted by GHR blockade, and protein metabolism was also unaffected. Basal glucose levels were elevated by GHR blockade, but insulin sensitivity was similar; this was associated with an increased acyl/desacyl ghrelin ratio. Conclusion: GHR blockade, without changes in circulating or tissue IGF-I levels, selectively suppresses lipid mobilization and oxidation after short-term fasting. This supports the notion that stimulation of lipolysis is a primary and important effect of GH.

PURPOSE: Diabetic ketoacidosis (DKA) and alcoholic ketoacidosis (AKA) are two medical emergencies characterized by elevated total ketone body concentration. We aimed to determine differences in pathogenesis of ketoacidosis and its metabolic consequences by comparing both at presentation and during treatment, the different metabolic products and hormones involved in the ketoacidotic state. MATERIALS AND METHODS: We studied 12 patients with DKA and 8 patients with AKA. On admission and every 4 hours for 24 hours during treatment, samples were drawn for determination of serum ketone bodies, lactate and pyruvate, insulin, and counterregulatory hormones (glucagon, cortisol, growth hormone, and catecholamines). RESULTS: At presentation, with a similar beta-hydroxybutyrate concentration, patients with DKA had a higher plasma glucose (32 mmol/L vs. 6.6 mmol/L), lower beta-hydroxybutyrate/acetoacetate ratio (3:1 vs. 7:1), and a lower lactate/pyruvate ratio (11:1 vs. 19:1) than patients with AKA (all, P <.01). The mean time to resolve ketoacidosis in patients with AKA (6 +/- 1 hour) was significantly shorter than in patients with DKA (16 +/- 2 hours). At presentation, the mean insulin concentration in patients with DKA and AKA were similarly decreased (7.8 +/- 2 and 10.3 +/- 3 microU/mL, P = not significant [NS]).The mean glucagon level before therapy was 203 +/- 15 pg/mL and 188 +/- pg/mL for patients with DKA and AKA, respectively (P = NS). Levels of cortisol, growth hormone, and epinephrine at presentation and during the first 8 hours of treatment were higher in patients with DKA; however, the difference in these values did not reach statistical significance. During therapy, levels of counterregulatory hormones declined at similar rates and returned to normal values after resolution of ketoacidosis. CONCLUSIONS: Our results indicate that, in addition to a history of diabetes or alcoholism, patients with DKA and AKA differ in their metabolic parameters more than in their hormonal profile. The metabolic profile of DKA is characterized by a higher plasma glucose concentration, and lower beta-hydroxybutyrate to acetoacetate and lactate to pyruvate ratios compared with patients with AKA. The initial hormonal profile in both ketoacidotic states is characterized by similarly decreased insulin levels and elevated levels of counterregulatory hormones.

To determine the role of fat-derived substrates in the regulation of glucose metabolism during fasting, glucose turnover, urea nitrogen production, alanine conversion to glucose, and substrate oxidation rates were measured in 34 normal 4-day-fasted volunteers treated with the antilipolytic drug acipimox or placebo for 8 h. The approximately 50% inhibition of lipolysis induced by acipimox increased glucose concentration and production, respectively, by approximately 35 and approximately 30%, whereas the protein breakdown and the amount of alanine converted to glucose were increased, respectively, by approximately 70 and approximately 85%. Insulin levels were reduced by approximately 40%, cortisol levels doubled, and growth hormone concentration increased sevenfold. The relative contribution of free fatty acid (FFA) and ketone body lowering to the observed response was evaluated in nine acipimox-treated subjects in whom ketone body concentration was clamped with an intravenous beta-hydroxybutyrate infusion. The results of these experiments suggest that, during fasting, both FFA and ketone bodies tend to suppress gluconceogenesis and to protect the protein stores. FFA seem to exert their effects mainly through their ability to modulate the hormonal milieu (especially insulin), whereas ketone bodies seem to act mainly by other mechanisms. Thus the widespread view according to which FFA exert a stimulatory role on gluconeogenesis does not apply to the fasting state in vivo.

To assess the metabolic disturbances, and, in particular, the occurrence of high blood ketone body concentration in post-absorptive Type 2 (non-insulin-dependent) diabetic patients as compared to a matched normal population, a study was carried out in a group of 78 Type 2 diabetic outpatients matched for age and sex and in 78 normal individuals. In all subjects we measured HbA1c, and fasting levels of glucose, FFA, lactate, pyruvate, glycerol, alanine, 3-hydroxybutyrate, acetoacetate, uric acid, total cholesterol, triglycerides, creatinine, growth hormone, cortisol, glucagon, free insulin, and C-peptide. Multistix strips were used for urine ketone determination. As expected HbA1c, and plasma glucose were higher in Type 2 diabetics. This was associated with multiple metabolic disturbances as shown by higher circulating concentrations of FFA, glycerol and gluconeogenic precursors. Similarly, blood levels of ketones (351 +/- 29 vs 159 +/- 15 umol/l; P < 0.0001) were increased, in spite of higher plasma free-insulin (77 +/- 7 vs. 49 +/- 14 pmol/l; p < 0.0001) and C-peptide concentration (0.63 +/- 0.03 vs. 0.46 +/- 0.07 nmol/l; P < 0.05) and no differences in plasma levels of cortisol, and growth hormone. Plasma glucagon levels were higher in Type 2 diabetics. Blood ketone body levels were directly correlated with both plasma glucose and FFA concentrations. These observations clearly show that Type 2 diabetes is a pathologic condition characterised by multiple metabolic disturbances which are fully apparent in the basal state. Furthermore, we emphasise that Type 2 diabetic patients, though not insulin deficient, may present a significant increase in their fasting levels of ketone bodies.

To elucidate the relationship between carnitine metabolism and plasma ketone body concentrations in moderately obese patients with mild glucose intolerance, the ketone body and carnitine levels in the basal state were determined in 72 obese patients: 20 with normal glucose tolerance (NGT), 29 with impaired glucose tolerance (IGT), and 23 with non-insulin-dependent diabetes mellitus (NIDDM) having a fasting plasma glucose (FPG) level of less than 200 mg/dl. Total ketone body (TKB) levels significantly (P < 0.05) increased in the order of NGT, IGT, NIDDM, while the FPG and free fatty acid (FFA) concentrations were significantly (P < 0.05) higher in the NIDDM group than in the other two groups. In contrast, the insulin, glucagon and glycerol levels were comparable in the three groups. The plasma short-chain acylcarnitine (SCAC) concentration and the acylcarnitine/free carnitine (AC/FC) ratio were similar in the IGT and NIDDM groups, and significantly (P < 0.05) greater than those in the NGT group. The AC/FC ratio correlated significantly with the FPG and FFA, but not with the TKB. These results suggest that the combination of IGT with simple obesity may trigger the acceleration of hepatic ketogenesis in conjunction with an elevated SCAC and an increased AC/FC ratio. In addition, the data also imply that, in patients with mild NIDDM, factors other than the carnitines may play a greater role in enhancing ketonemia.

Findings of studies of carbohydrate metabolism in anorexia nervosa are reviewed. Topics covered included fasting blood sugar concentrations; serum insulin concentrations, insulin receptor binding activity, insulin sensitivity, and insulin resistance; plasma ketone bodies and free fatty acids; glucose tolerance tests; growth hormone, cortisol, intestinal hormones, and norepinephrine. Metabolic changes reported in anorexia nervosa are similar to those found in human and animal studies of states of caloric and carbohydrate restriction. Restoration of normal body weight is associated with normalization of virtually all measures. It is concluded that published studies offer no conclusive evidence for a syndrome-specific impairment in carbohydrate metabolism in anorexia nervosa.

Intravenous administration of 500 ml of 50% glucose solution to 10 nonketotic dairy cows increased the blood glucose and insulin concentrations 7-fold immediately following administration. Blood glucose and insulin concentrations of ketotic cows were about 6- and 3-fold higher, respectively, immediately following glucose administration. Administration of 1000 ml of 25% xylitol (xylo-pentane-1,2,3,4,5-pentol) in nonketotic cows increased blood glucose and insulin concentrations 2- and 9-fold, respectively. Ketotic cows treated with xylitol exhibited blood insulin concentration 12-fold higher following administration. This insulin increase might be explained by a decrease in insulin degradation because of the diffusion of xylitol, which is not dependent on insulin in peripheral tissues. For ketotic cows given xylitol, serum concentrations of free fatty acid decreased, and triglyceride concentrations and aspartic acid aminotransferase activity increased, but values were unchanged by xylitol administration to nonketotic cows. Thus, for ketotic cows, the responses of the blood glucose and insulin concentrations to xylitol administration were better than those responses to glucose administration. Improvements in clinical signs, i.e., disappearance of urinary ketone bodies and recovery to normal feed consumption, also suggested the usefulness of xylitol administration for the treatment of ketosis.

Total and individual non-esterified fatty acids (NEFA), pyruvate, lactate, alpha ketoglutarate, acetoacetate, beta hydroxybutyrate, glucose and insulin were measured in horses during an 80 km endurance ride and during four days of food deprivation. In the latter group venous blood-gas and acid-base parameters, and plasma cortisol concentrations were also measured. During exercise and food deprivation the NEFA became considerably elevated, the predominant of which were oleic (35 per cent), palmitic (24 per cent), linoleic (19 per cent) and linolenic (10 per cent). By one hour after feeding total NEFA fell to approximately 20 per cent of 12 hour fasting concentrations. This was associated with a four fold rise in insulin. Small though significant increases occurred in lactate, acetoacetate and beta hydroxybutyrate after the 80 km endurance ride. It was concluded that a ketone pathway is relatively unimportant in the horse, probably due to the ability of the liver to maintain glycogenolysis.

In normal human subjects, when plasma insulin, glucagon and growth hormone were 'clamped' at basal concentrations (by infusion of somatostatin plus replacement infusion of these hormones), infusion of Intralipid and heparin increased plasma free fatty acid (FFA) concentrations to approx. 1.3 mM, and ketone body production increased 4-5 fold to approx. 11 mumol . kg -1 . min-1. Hyperglucagonaemia did not further increase ketogenesis. In conditions of combined insulin and glucagon deficiency (by infusion of somatostatin without insulin and glucagon), administration of Intralipid and heparin increased plasma FFA concentrations to approx. 2.2 mM but a further increase in ketone body production did not accompany this increase. In these conditions hyperglucagonaemia increased ketogenesis by 2-3 fold the increment seen in control studies. Infusion of adrenaline (epinephrine) in conditions in which insulin secretion was not inhibited caused only a transient increase in plasma FFA concentrations and in ketone body production. These data indicate:(1) that in humans increased FFA availability can markedly augment ketogenesis in the absence of insulin deficiency and without hyperglucagonaemia;(2) that glucagon can increase ketone body production during insulin deficiency but not in its absence; and (3) that insulin deficiency may be accompanied by increased ketogenesis only because of a lack of its restraint on lipolysis and because of the action of glucagon. Glucagon may be important in determining the magnitude of ketone body production for a given degree of FFA availability and insulin deficiency, and may be necessary for attainment of maximal rates of ketogenesis. Adrenaline increases ketone body production in humans, but whether this is primarily due to a direct effect on the liver or is mediated through enhancement of lipolysis remains to be determined.

The effect of fasting or suckling on blood glucose, circulating fuels, pancreatic hormones and liver glycogen concentration have been measured in newborn pigs during the first 48 h of life. Blood glucose concentrations fell to hypoglycaemic values after 48 h of fasting whereas for the same period of time, suckling piglets maintain a normal blood glucose. These differences are not due to hepatic glycogen mobilization, since liver is totally depleted from its high glycogen stores 24 h after birth, both in fasting and suckling piglets. Blood lactate is present at a high concentration during the first 48 h, both in fasting and suckling piglets. In contrast, blood pyruvate concentration is lower in suckling than in fasting newborn pigs. Colostrum intake leads to an increase in blood amino acid concentrations in the suckling piglets in comparison with the fasting newborn. Plasma non-esterified fatty acid levels and blood glycerol concentrations are lower in fasting piglets than in the suckling ones. In suckling newborn pigs, circulating ketone bodies are very low despite the increase in non-esterified fatty acids levels. The decrease in plasma insulin/glucagon molar ratio at birth, is due to a decrease in plasma insulin and an increase in plasma glucagon, both in fasting and suckling piglets. Plasma insulin and glucagon concentrations are higher during suckling than during fasting. The data suggest that gluconeogenesis could be impaired, in fasting newborn pigs, by a low plasma glucagon level and/or a limiting availability of non-esterified fatty acids.