Effect of intrauterine growth pattern on serum visfatin concentrations in full-term infants at birth and at 6 months of life.

OBJECTIVE: Visfatin is a hormone discovered in fat cells and is directly related to diabetes. We aimed to investigate the relationship between intrauterine growth pattern and serum visfatin concentrations in full-term infants at birth and at 6 months of life. METHODS: Cord blood visfatin concentrations were assessed in 90 full-term neonates enrolled into; Group I: 30 appropriate for gestational age (AGA) neonates to healthy mothers, Group II: 30 intra-uterine growth restricted (IUGR) neonates, 19 were born to mothers with pre-eclampsia, Group III: 30 large for gestational age (LGA) neonates, 16 were infants of diabetic mothers (IDMs). Neonates were followed up at six months of age for visfatin concentrations. RESULTS: Cord blood visfatin concentrations were increased in IUGR compared to AGA group (p = 0.002). Cord blood visfatin concentrations were increased in LGA compared to AGA and IUGR groups (P <  0.001, P <  0.001). Cord blood visfatin concentrations were positively correlated to birth weight in AGA, LGA groups (r = 0.39, p = 0.045, r = 0.449, p = 0.013 respectively). Visfatin concentrations in neonates born to mothers with pre-eclampsia and IDMs were higher than in those born to mothers without pre-eclampsia and to non-diabetic mothers (p = 0.040, p = 0.002 respectively). At six months, serum visfatin concentrations decreased compared to cord blood visfatin concentrations in IUGR and LGA groups (p <  0.001). Levels in LGA were still higher than IUGR (p = 0.004). Serum visfatin concentrations were positively correlated to cord visfatin in IUGR neonates (r = 0.497, p = 0.005). CONCLUSION: Cord blood visfatin concentrations were increased in LGA and IUGR neonates. At six months, serum visfatin concentrations decreased compared to cord blood visfatin concentrations in LGA and IUGR groups, still higher in the former than the latter.

Central neurogenic mechanisms of migraine.

Evidence obtained from clinical studies, magnetoencephalography, and 31P magnetic resonance spectroscopy indicates that spreading depression is the underlying basis of migraine aura. Magnetoencephalographic and 31P magnetic resonance spectroscopic evidence also exists to explain interictal central neuronal hyperexcitability in migraine sufferers. A low intracellular brain magnesium concentration may be the link between the physiologic threshold for migraine and the attack itself.

Scintillating scotomata associated with internal carotid artery dissection: report of three cases.

We report three cases of cervical internal carotid artery (ICA) dissection, which presented with visual symptoms resembling the migraine aura. When prolonged and especially when associated with other neurologic symptoms, such transient and positive visual phenomena can be manifestations of ICA dissection that mimic migraine.

The Henry Ford Hospital Headache Disability Inventory (HDI).

To quantify the impact of headache of daily living, we developed a 25-item headache disability inventory (HDI). The alpha version of the HDI (alpha-HDI) consisted of 40 items, each requiring a "yes" (four points), "sometimes" (two points), or "no" (zero points) response based on items derived empirically from case history responses of subjects with headache. From the alpha-HDI, we derived a 25-item beta version (beta-HDI) with the items subgrouped into functional and emotional subscales. The internal consistency/reliability was strong, as was construct validity. The test-retest reliability for the beta-HDI was acceptable for the total score and functional and emotional subscale scores. A 29-point change (95% confidence interval) or greater in the total score from test-retest must occur before the changes can be attributed to treatment effects. The HDI is useful in assessing the impact of headache, and its treatment, on daily living.

Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine.

OBJECTIVES: We hypothesized that the hyperexcitability of occipital cortex neurons may predispose migraine subjects to develop spreading depression, the putative basis of migraine with aura (MwA). To date there is no direct physiologic correlate confirming this in patients. Accordingly, we evaluated the differences in the threshold of occipital cortex excitation between MwA patients and normal controls (C) using transcranial magnetic stimulation (TMS). METHODS: TMS was performed using the Cadwell MES 10 stimulator. A circular coil 9.5 cm in diameter was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulation intensity was then fine-tuned to determine the threshold at which phosphenes were just visualized. RESULTS: Eleven MwA patients, mean age 37 +/- 7 years, were compared with 11 C, mean age 37.7 +/- 7 years. The difference in the proportion of subjects with phosphene generation between MwA patients and C was significant (MwA patients 100% versus C 27.3%, p = 0.001). The mean threshold level for MwA patients was 44.2 +/- 8.6 versus 68.7 +/- 3.1 for C (p = 0.0001). All threshold levels for MwA patients were lower than the lowest threshold for C; the MwA patient with the lowest threshold had an aura after stimulation. CONCLUSIONS: The threshold for excitability of occipital cortex is lower in MwA patients compared with C. This is a direct neurophysiologic correlate for clinical observations that have indicated hyperexcitability of the occipital cortex in migraineurs.

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group.

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.

Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose range-finding study. The 017 Clinical Trial Study Group.

This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses > or = 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses > or = 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses < or = 2.5 mg than with those > or = 5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.

The nociceptive flexion reflex in humans -- review article.

The nociceptive flexion reflex (NFR) is a physiological, polysynaptic reflex allowing for painful stimuli to activate an appropriate withdrawal response. NFR is easily measurable in clinical setting, and is a reliable and objective tool for measurement of an individual's pain experience. An exhaustive review of the literature, covering multiple search engines, indicates that the NFR method is valuable in studying the impact of diverse pharmacological and non-pharmacological interventions on the flexion reflex, in conditions of acute pain and in healthy volunteers. More recently, the NFR method has gained particular attention as a research tool in studies of central sensitization and persistent or chronic pain.

Emerging trends in the pharmacotherapy of chronic pain.

The pharmacotherapy for pain is dominated by conventional analgesics such as the opioids and the non-steroidal anti-inflammatory drugs. Recent advances in the understanding of the mechanisms of pain in general and chronic pain in particular, opened the field of analgesic therapy to newer pharmacological targets, which are aimed at improved efficacy and enhanced tolerability over conventional antipain treatments. Many novel targets are still in preclinical development, but some have made it into human trials and have shown promise. Newer anticonvulsants, new generation cyclooxygenase inhibitors, better tolerated glutamate modulators and balanced serotonin/noradrenaline re-uptake inhibitors are some targets that have shown promise in the clinic. These and other compounds that are in advanced phases of development for chronic pain are reviewed in this paper. It is hoped that the decade of pain control and research will lead us to an arsenal of effective and safe analgesics that will conquer the problem of chronic pain.

Transcranial Doppler to evaluate the effects of antihypertensive medication on cerebral blood flow velocity.

The effect of oral nifedipine on cerebral blood flow velocity was studied in six elderly hypertensive patients using transcranial Doppler. Serial measurements of blood pressure (BP), middle cerebral artery (MCA) flow velocity and nifedipine serum concentrations were obtained over an 8-hour period. The authors found a significant inverse relationship between MCA velocities and nifedipine concentrations, independent of BP changes. These results are consistent with a direct vasodilatory effect of nifedipine on cerebral vessels and support the use of TCD in pharmacodynamic investigations of the cerebral vasculature.

Acute treatments: some blind alleys.

The introduction of sumatriptan, a selective 5-HT(1B/1D) agonist, for the treatment of migraine sparked a new era of drug research in this field. Many novel targets have since been developed, and tested in the clinic. The promise of these approaches is to deliver an anti-migraine compound with the optimal efficacy and safety profile. In this chapter, blind alleys in anti-migraine development are discussed. The failing soldiers have included the NK-1 antagonists, some second-generation 5-HT(1B/1D) agonists, CP-122,288, 4991W93, the neurosteroid ganaxolone, selective 5-HT(1F) (LY334370) and 5-HT(1D) agonists (PNU-142,633), and the endothelin-1 antagonist bosentan. Some of these promising targets failed to demonstrate clinical efficacy, while others were stopped for preclinical toxicity.

Acute treatments: future developments.

In Chapter 14, blind alleys in acute anti-migraine drug development were discussed. In this chapter, future therapies are covered. There is growing interest and support for the use of CGRP antagonists, nitric oxide synthase inhibitors, and ionotropic glutamate receptor antagonists. The hope is to strike the balance of high efficacy with minimal to no safety concern and good tolerability. Some of the targets discussed in this chapter have been in early efficacy trials and others are in first human dose stages. Large-scale efficacy and safety trials are eagerly awaited.

Mitochondria, magnesium and migraine.

The evidence for disordered mitochondrial oxidative phosphorylation and reduced intracellular free magnesium in brain and body tissue of migraine suffers both between and during an attack is reviewed. We propose that between attacks these metabolic shifts cause instability of neuronal function which enhances the susceptibility of brain to develop a migraine attack.

Age and carotid artery occlusive disease are important determinants of cerebral blood flow changes after antihypertensive therapy.

STUDY OBJECTIVE: To determine the short-term effects of antihypertensive therapy on cerebral blood flow (CBF). DESIGN: Prospective, observational study. SETTING: A university-affiliated teaching hospital. PATIENTS: Twenty-four patients (age range 53-85 yrs) with chronic hypertension, nine of whom had carotid artery occlusive disease (CAOD). INTERVENTIONS: The CBF (xenon-133 inhalation technique) and blood pressure were measured before and at 60 minutes after administration of antihypertensive therapy. MEASUREMENTS AND MAIN RESULTS: Age was inversely related to the change in CBF in patients with CAOD (p < 0.01). In all patients, the change in CBF after taking antihypertensive drugs was significantly inversely associated with baseline CBF (p < 0.01). Changes in regional CBF, measured by asymmetry scores, were significantly greater in patients with CAOD than in those without CAOD (p < 0.05). CONCLUSIONS: Elderly patients with occlusive extracranial cerebrovascular disease are at risk of drug-induced changes in both mean and regional CBF, and may benefit from a CBF assessment before being prescribed antihypertensive therapy.

Cerebral blood flow changes with enalapril.

Patients with carotid artery occlusive disease (CAOD) may be at increased risk of iatrogenic cerebral hypoperfusion. Using the 133xenon-inhalation technique, we evaluated the effects of enalapril on regional cerebral blood flow (CBF) in 14 patients with chronic hypertension, 7 with CAOD and 7 without CAOD (no CAOD). Regional CBF and blood pressure were measured before and 60 minutes after a single dose of enalapril. Changes in mean arterial pressure after enalapril were not significantly different between the two groups: CAOD -4.67 +/- 8.7 mm Hg, no CAOD -6.18 +/- 8.2 mm Hg. Changes in mean CBF after enalapril were also not statistically different: CAOD -1.0 +/- 3.9, no CAOD 1.0 +/- 2.8. In the CAOD group only, however, changes in CBF were significantly related to increasing age (r = -0.9253, p less than 0.01), such that in patients 65 years or older CBF tended to decrease, whereas in younger patients it increased. Elderly patients with CAOD may be at increased risk of iatrogenic cerebral hypoperfusion, and it may be appropriate to evaluate prospectively the effects of antihypertensive medications on CBF.

The concept of migraine as a state of central neuronal hyperexcitability.

This article explores the hypothesis that migraine with aura is associated with a state of central neuronal hyperexcitability. The authors propose that this central neuronal hyperexcitability involves overactivity of the excitatory amino acids, glutamate, and possibly aspartate. Stimuli that activate the migraine attack evoke neuronal depolarization, slow depolarization shifts, and spreading suppression of spontaneous neuronal activity possible by glutamate and K+ dependent mechanisms. A low brain Mg2+ and consequent reduced gating of glutamatergic receptors may provide the link between the physiologic threshold for a migraine attack and the mechanisms of the attack itself by promoting glutamate hyperactivity, neuronal hyperexcitability, and susceptibility to glutamate-dependent spreading depression.

Factors determining headache at onset of acute ischemic stroke.

Headache is a frequent accompaniment of acute ischaemic stroke. The predisposing factors and underlying mechanisms are currently incompletely defined. We analysed prospectively collected data relevant to headache occurring at ischaemic stroke onset in consecutive patients included in the Henry Ford Hospital Stroke Data Bank. Patients with headache (HA+) and without headache (HA-) were compared for demographic factors, medical history, medications, examination findings, laboratory findings, and stroke localization and subtype. Group comparisons for categorical data were performed with chi(2) test, and for continuous variables with two-sample t-tests. Stepwise logistic regression analysis, including all variables with P<0.25, was used to define the independent predictors of onset headache. Three hundred and seventy-five patients had complete headache and clinical datasets and were included in the analysis (HA+, N=118; HA-, N=257). Multivariate analysis revealed that the independent predictors of HA+ were: infarct in the distribution of the posterior circulation [P=0.0076, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.23, 3.77], absence of history of hypertension (P=0.0106, OR 0.48, 95% CI 0.27, 0.84), and treatment with warfarin at the time of the index stroke (P=0.0135, OR 4.89, 95% CI 1.39, 17.21). The occurrence of headache at onset of ischaemic stroke is determined by posterior circulation distribution of the ischaemic event, absence of history of hypertension and treatment with warfarin at the time of the index stroke. These results suggest that preserved elasticity and maintenance of the intracranial vasculature in a relaxed state, in combination with coagulation system derangements, and activation of dense perivascular afferent nerves, play a role in the pathogenesis of onset headache.