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Introduction Different mechanisms may underlie cryptogenic stroke, including subclinical atrial fibrillation (AF), nonstenotic carotid plaques (NCP), and aortic arch atherosclerosis (AAA). In a cohort of cryptogenic stroke patients, we aimed to: (1) evaluate the prevalence of subclinical AF, NCP, and AAA, and reclassify the etiology accordingly; (2) compare the clinical features of patients with reclassified etiology with those with confirmed cryptogenic stroke. Methods Data of patients hospitalized for cryptogenic stroke between January 2018 and February 2021 were retrospectively analyzed. Patients were included if they received implantable cardiac monitoring (ICM) to detect subclinical AF. Baseline computed tomography angiography (CTA) was re-evaluated to assess NCP and AAA. Since aortic plaques with ulceration/intraluminal thrombus were considered pathogenetic during the initial workup, only patients with milder AAA were included. Stroke etiology was reclassified as “cardioembolic”, “atherosclerotic”, or “mixed” based on the detection of AF and NCP/AAA. Patients with “true cryptogenic” stroke (no AF, ipsilateral NCP, or AAA detected) were compared with those with reclassified etiology. Results Among 63 patients included, 21 (33%) were diagnosed with AF (median follow-up time of 15 months), 12 (19%) had ipsilateral NCP, and 6 (10%) had AAA. Stroke etiology was reclassified in 30 patients (48%): cardioembolic in 14 (22%), atherosclerotic in 9 (14%), and mixed in 7 (11%). Patients with true cryptogenic stroke were younger compared to those with reclassified etiology (p = 0.001). Discussion One or more potential covert stroke sources can be recognized in half of the patients with a cryptogenic stroke through long-term cardiac monitoring and focused CTA re-assessment.

Background The early detection of patients at risk of post-stroke cognitive impairment (PSCI) may help planning subacute and long-term care. We aimed to determine the predictivity of two screening cognitive tests on the occurrence of mild cognitive impairment or dementia in acute stroke patients. Methods A cognitive assessment within a few days of ischemic or hemorrhagic stroke was performed in patients consecutively admitted to a stroke unit over 14 months by means of the Clock Drawing Test (CDT) and the Montreal Cognitive Assessment-Basic (MoCA-B). Results Out of 191 stroke survivors who were non-demented at baseline, 168 attended at least one follow-up visit. At follow-up (mean duration ± SD 12.8 ± 8.7 months), 28 (18.9%) incident cases of MCI and 27 (18%) cases of dementia were recorded. In comparison with patients who remained cognitively stable at follow-up, these patients were older, less educated, had more comorbidities, a higher score on the National Institutes of Health Stroke Scale (NIHSS) at admission, more severe cerebral atrophy, and lower MoCA-B and CDT scores at baseline. In multi-adjusted (for age, education, comorbidities score, NIHSS at admission and atrophy score) model, a pathological score on baseline CDT (p Conclusion A bedside cognitive screening with the CDT helps identifying patients at higher risk of PSCI.

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Background and Purpose— Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non–vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods— Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results— Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95–5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63–9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83–3.16), and CHA 2 DS 2 -VASc score (OR, 1.72 for each point increase; 95% CI, 1.58–1.88) were associated with ischemic events. Among the CHA 2 DS 2 -VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33–0.61). Conclusions— In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA 2 DS 2 -VASc score were associated with increased risk of cerebrovascular events.

Introduction Cognitive impairment is a common and disabling consequence of stroke. Its prevalence, the best way to screen for it in the acute setting, and its relation with premorbid status have not been thoroughly clarified. Materials and methods Ischemic and hemorrhagic stroke patients admitted to our stroke unit underwent a baseline assessment that included a clinical and neuroimaging assessment, two cognitive tests (clock-drawing test, CDT; Montreal Cognitive Assessment-Basic, MoCA-B) and measures of premorbid function (including the Clinical Dementia Rating Scale). A follow-up examination was repeated 3-4 months after the acute event. Results Two hundred and twenty-three patients (52.5% women, mean age ± SD 75.8 years ± 12.3) were evaluated. Prestroke cognitive impairment was present in 91 patients (40.8%). At follow-up, the prevalence of cognitive impairment was 49%, while its incidence among patients who did not have any prestroke cognitive impairment was 38.8%. Of the originally admitted 223 patients (71 were lost to follow-up), only 60 (26.9%) were still cognitively intact at follow-up. On regression analysis, age and baseline CDT were associated with worsening of cognitive status at follow-up. In patients without cognitive impairment at baseline, a cutoff of 23 for MoCA-B and of 8.7 for CDT scores predicted the diagnosis of post-stroke cognitive impairment with sufficient accuracy. Discussion and conclusion Prestroke and post-stroke cognitive impairment affect a large proportion of patients with stroke. Our findings suggest that a neuropsychological screening during the acute phase might be predictive of the development of post-stroke cognitive impairment.

In older patients with recurrent unexplained focal neurologic episodes, an EEG and brain MRI may reveal that they are a treatable manifestation of CAA.

Giant cell arteritis (GCA) is the most common vasculitis in patients older than 50 years, and it is occasionally a cause of ischemic stroke. GCA as a paraneoplastic manifestation has been rarely described. We describe a 77-year-old man with a sudden onset of dizziness, vomiting, and gait disturbances. Following imaging studies, a diagnosis of bulbar ischemic stroke with left vertebral artery stenosis was made. Based on a history of polymyalgia rheumatica, on laboratory tests, and brain digital subtraction angiography, a diagnosis of GCA was advanced and the patient underwent high-dose steroidal therapy. After a total body 18-FGD PET imaging, a pulmonary adenocarcinoma was found. Vertebral artery involvement is a rare but important occurrence in GCA as it carries a high mortality rate, and may require a vigorous therapeutic approach. The association of lung cancer and GCA is infrequent, and the relationship between malignancy and GCA remains unclear. Whereas the search for a malignancy in the setting of a GCA is not routinely performed, the use of total body PET when a large vessel vasculitis is suspected may provide useful information on disease and help recognize occult neoplasms.

Platypnea-orthodeoxia syndrome is a condition of dyspnea and hypoxia whilst in the upright position, which improves in the recumbent position. We present a case of platypnea-orthodeoxia due to a fenestrated atrial septal aneurysm that induced recurrent strokes and a recent condition of fluctuating confusion and cognitive impairment, modified by position, associated with rapid variations of O2 saturation position related. The suspect of platypnea-orthodeoxia syndrome may be hypothesized in case of patients with recurrent cerebral ischemia and fluctuating cognitive disturbances induced by change of position. In those cases a careful echocardiographic evaluation and O2 saturation determination in up and downright position are required.

Background and Purpose: About half of the dysphagic stroke patients have persistent swallowing dysfunction after 7 days from symptom onset. The aim of the study was to evaluate incidence, prognosis, clinical and neuroradiological correlates of post-stroke dysphagia. Methods: We prospectively examined consecutive patients with acute ischemic or hemorrhagic stroke. Patients' clinical and neuroradiological data were collected. Swallowing function was assessed by the water swallow test upon admission and after 14 days; patients were then classified as persistent dysphagic, non-persistent dysphagic or non-dysphagic. Results: We recruited 275 patients, 121 of whom were dysphagic upon admission and 254 patients attended follow-up at 14 days; 141 never presented dysphagia, 21 had a non-persistent pattern of dysphagia and 92 had a persistent one. Stroke type, leukoaraiosis degree, previous cognitive impairment and stroke severity upon admission independently predicted the occurrence of dysphagia after stroke and its persistence as well. At receiver operating characteristic (ROC) analysis, the National Institutes of Health Stroke Scale (NIHSS) score of 11.5 was the best predictive value of persistent dysphagia, with a specificity of 90.1% and a sensitivity of 72.4%. Conclusion: Stroke severity is an important predictor of a persistent pattern of dysphagia, with a suggested NIHSS cutoff value of ≥12. An independent correlation was observed with leukoaraiosis and with previous cognitive impairment.

Sleep and pain perception are two phylogenetically well-conserved functions, strictly influenced by environmental and psychological factors, and are able to interact reciprocally both in physiological and pathological situations. Sleep and head-pain perception share the involvement of several structures, such as the thalamus, the hypothalamus and brainstem nuclei, including the locus coeruleus and raphe nuclei. There ais clinical evidence indicating that sleep disorders can precede the appearance of certain headaches and that head pain, especially when frequent, can, in turn, affect sleep quality. In the present work the anatomy, physiology and pathology of sleep and head-pain perception will be reviewed with the aim of highlighting the points of contact and possible unifying treatment strategies.

Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid had been found in serum from patients with Alzheimer disease (AD). Folate concentration was evaluated in sera from 136 patients with cortical dementia [AD, n=108; frontotemporal dementia (FTD), n=28], 57 patients with subcortical dementia [Lewy body disease (LBD), n=9; corticobasal degeneration (CBD), n=5; progressive supranuclear palsy (PSP), n=6; Parkinson disease with dementia (PD-Dem), n=37], and 76 nondemented, healthy age-matched people. Serum folic acid levels were decreased in patients with AD and FTD as compared with either controls or patients with subcortical dementia (3.60+/-2.22 and 5.37+/-2.92 microg/L versus 6.87+/-3.50 microg/L, respectively; P

Alzheimer's disease (AD) is considered to be a conformational disease arising from the accumulation of misfolded and unfolded proteins in the endoplasmic reticulum (ER). SEL1L is a component of the ER stress degradation system, which serves to remove unfolded proteins by retrograde degradation using the ubiquitin-proteosome system. In order to identify genetic variations possibly involved in the disease, we analysed the entire SEL1L gene sequence in Italian sporadic AD patients. Here we report on the identification of a new polymorphism within the SEL1L intron 3 (IVS3-88 A>G), which contains potential binding sites for transcription factors involved in ER-induced stress. Our statistical analysis shows a possible role of the novel polymorphism as independent susceptibility factor of Alzheimer's dementia. (C) 2005 Published by Elsevier Ireland Ltd.

Sleep and headache are two realities known to be linked in a bidirectional way [01]. Clinical research correlates specific headache diagnoses and sleep disorders with chronobiologic patterns and sleep processes, implicating that common anatomic structures and neurochemical processes are involved in the regulation of both sleep and headache. Sleep and pain perception share several structures, such as the thalamus, the hypothalamus, and a number of mesencephalic, pontine and bulbar nuclei, some of which are also involved in breathing regulation. The respiratory parameters during sleep at night may play a important role in modifying susceptibility to various pathological conditions, including headache. Morning headache was found to be more frequent among Obstructive Sleep Apnea Syndrome (OSAS) patients with a direct relationship with the severity of the sleep breathing disorder: apnoea hypopnoea index (AHI) has been found higher in OSAS patients with morning headache compared with those without morning headaches and also mean oxygen saturation value (SpO2) during total sleep time has been found significantly lower in OSAS patients with morning headache [02]. Furthermore, it has been observed that morning headache may be largely resolved with nasal continuous positive airway pressure. The relevance of respiratory disturbances during sleep in subjects with primary headaches has not been clearly evaluated. Additionally, in a previous study we found that subjects with headache, and particularly those with headache-related cutaneous allodynia, had alterations in sleep behaviour [03]. Consequently, a possible link between sleep behavior disturbances, respiratory disorders during sleep and primary headaches may be hypothesized.

Sleep and headache are linked in a bidirectional way. Breathing quality during sleep may be a possible link between them. The objective of this study were to evaluate the prevalence of headache--and of allodynia--in a population of subjects who underwent cardiopulmonary monitoring during sleep for presumed respiratory problems; to evaluate the possible relationships between the presence of headaches--and of allodynia--and respiratory parameters. We studied 181 subjects, 112 without headache (mean age 59.4 ± 13.1 years, 97 men and 15 women); 69 with history of headache (42 men and 27 women; 41 migraineurs and 28 with tension type headache). Headache diagnosis was made according to ICHD-II criteria. A semi-structured ad hoc questionnaire was used to evaluate the presence of allodynia. Full cardiopulmonary monitoring was performed by SOMNO check(®) effort (WEINMANN) with SaO(2), T90 and AHI determination. Headache and headache-associated allodynia were particularly frequent in this population, suggesting a positive correlation between breathing problems during sleep and head pain, and allodynia. The observation that better respiratory parameters were found among headache sufferers with respect to those without headache, even in allodynic subjects, seems to reverse this point of view: headache and allodynia may possibly have an allostatic function preventing deep sleep and, in turn, avoiding prolonged apneas.

Cutaneous allodynia is a frequent complaint in migraine patients, possibly induced by central sensitisation of trigeminal nucleus. The objective of this study is to investigate if sleep quality is related to the presence of migraine-associated allodynia. A total of 175 consecutive migraineurs were included, 124 with episodic and 51 with chronic forms. As control group, 73 subjects free from any kind of headache were included (HC). The presence of allodynia and sleep disturbances was assessed by a set of semi-structured questions. Chi-square test was applied to compare frequencies among groups. Sleep quality was worse among migraineurs with respect to controls for each sleep item analysed. This difference was significant for all items but one (i.e. frequency in drug use to induce sleep). The frequency of sleep disturbances was higher than in controls in both allodynic and non-allodynic migraineurs, although statistical analysis showed that all these differences were still significant in allodynic migraineurs (also in this case for all the sleep items but one, i.e. frequency in drug use to induce sleep), whilst non-allodynic migraineurs were significantly different from controls only for one item (frequency of initial insomnia). These results suggest that allodynia is strongly related to sleep quality, in a bi-directional way: sleep disturbances may favour central sensitisation, and, in turn, allodynia may impair sleep.

Apolipoprotein E (APOE) genotype was determined in a population of patients with dementia, including 735 patients with Alzheimer's disease (AD), 75 with Frontotemporal Lobar Degeneration (FTLD), 97 with Vascular Dementia (VaD) and 40 with Lewy Body Dementia (LBD), as well as in 506 age- and gender-matched controls (CON). APOE ε2 allele frequency was lower in patients with AD (2.8%) than in CON (6.4%, P≤0.001, OR: 0.41). Similar results were obtained comparing AD with FTLD (6.7%, P≤0.01, OR: 0.37), at difference from VaD (5.6%, P>0.05) or LBD (5.0%, P>0.05). The frequency of the APOE ε4 allele was increased in patients with AD (25.1%) as compared with CON (8.2%, P≤0.001, OR: 4.24), FTLD (11.3%, P≤0.001, OR: 2.67), VaD (11.8%, P≤0.001, OR: 3.02), or LBD (13.8%, P=0.048, OR: 2.07). The frequency of the ε4/ε4 genotype was increased in AD patients compared with controls (6.3 versus 0.8%, P≤0.001, OR: 8.38). The presence of the ε2 allele is a protective factor for AD, whereas the ε4 allele acts as a risk factor for the disease. Both alleles do not influence the susceptibility to FTLD, LBD and VaD.

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 +/- 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 +/- 2.6 fmol/million cells; P less than 0.01) and sex- and age-matched controls (3.15 +/- 2.3 fmol/million cells; P less than 0.01). The affinity of glucocorticoid receptors (Kd) was strikingly decreased (9.36 +/- 3.44 nM in group 1; 3.2 +/- 1.5 nM in group 2; 2.0 +/- 0.8 nM in controls; P less than 0.01). [3H]Thymidine incorporation was decreased dose-dependently by dexamethasone in controls and patients; the effect was significantly blunted (P less than 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implies a complex change in immune-endocrine function, which may be important in the course of immunodeficiency syndrome.

Cutaneous allodynia is a frequent complain in headache patients, particularly in those with migraine. A stronger association is present in patients with migraine with aura and with chronic or transformed migraine. The aim of the present study was to investigate if the psychological profile may be related to the presence/absence of allodynia in a sample of headache patients. The psychological profile of patients was assessed by the SCL90R; the presence of allodynia was assessed by a set of semi-structured questions used in previous studies. For the purpose of the study, patients were divided into subgroups according to the headache type (ICDH-II diagnoses), as well as to the temporal pattern (episodic or chronic). A total of 213 consecutive headache patients were studied. Most patients had episodic migraine (116); 37 had tension-type headache. Overall, 156 patients had episodic headache forms, and 57 had chronic forms. As far as allodynia, 93 were non-allodynic; 120 presented allodynic symptoms during their headaches. No significant difference was found between allodynic and non-allodynic patients neither if studied in a whole group (t test, P = 0.10 NS) nor when patients were evaluated comparing different subgroups on the basis of headache type, and of the episodic/chronic pattern. Our results suggest that the presence/absence of allodynia may not be influenced by the psychological profile.

Allodynia, the perception of pain induced by a non-painful stimulus, is frequently associated with migraine, especially when chronic, and mainly in the aura subtype. Among migraineurs, allodynia is thought to be caused by the headache and the activation of nociceptors with the development of central sensitization in subjects with an altered regulation of the central nociceptive pathway. The persistence of pain sensation seems to be able to induce central sensitization in the caudal nucleus of the trigeminal nerve by lowering the neuronal pain threshold. Different pathogenetic mechanisms may be involved and genetic, environmental and psychological elements should be considered. The complaint of allodynia is more frequent during the headache attack (acute allodynia) than in-between attacks (interictal allodynia). Acute allodynia is generally referred to the painful region but may diffuse to other areas, cephalic or even extracephalic. Extracephalic allodynia could not be mediated by nucleus caudalis as its neurons do not express whole-body receptive fields. The likely mechanism is thalamic sensitization. This symptom must be carefully assessed because it may be as annoying and limiting in daily activities as pain itself, and because its presence seems to reduce the efficacy of drugs used for migraine attacks. Instrumental measures may be applied, and clinical questionnaires to assess the presence of allodynic symptoms have also been developed and validated. All these aspects will be discussed.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.

Activation of NADPH oxidase and Superoxide anion release in human neutrophils has been shown to be dependent on Na+/H+ exchange, and inhibition of intracellular alkalinisation has been proposed as a mechanism of action for some anti-inflammatory drugs. The effect of nimesulide, a novel nonsteroidal anti-inflammatory drug, on intracellular pH (pHi) regulation by the Na+/H+ antiport in human neutrophils was examined using the pH-sensitive fluorescent probe 2,7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). When stimulated by formylmethionylleucyl-phenylalanine (fMLP) or phorbol-12-myristate-13-acetate (PMA), neutrophils displayed changes in pHi consisting of an initial acidification followed by a sustained alkalinising phase indicative of antiport activation. Nimesulide did not change the pHi of resting neutrophils and did not affect the pHi response to stimulation. It is concluded that the anti-inflammatory effect of nimesulide is not directly linked to interactions with the Na+/H+ antiport or other pathways affecting the regulation of pHi.

β2-Adrenergic agonists inhibit the generation of Superoxide anions by neutrophils through action at β2-adrenoceptors. The aim of this study was to examine the characteristics of neutrophil β2-adrenoceptors after the activation of the respiratory burst by phorbol 12-myristate 13-acetate (PMA), which stimulates protein kinase C (PKC), and by drugs that are PKC antagonists. Binding of the hydrophilic adrenergic antagonist [3H]-(−)-CGP 12177 was rapid, reversible, of high affinity (Kd = 81 ± 12 pmol/L), stereospecific, of the β2 subtype and saturable, demonstrating a receptor density of 1.9 ± 0.1 fmol/million cells. Isoprenaline (isoproterenol) competition isotherms at 4°C showed 2 states of the affinity of the receptors. The high affinity state (pKiH 8.3 ± 0.05) was occupied by 24% of receptors and the low affinity state (pKiL 7.31 ± 0.06) by 76%. Preincubation of neutrophils with PMA did not affect the number of β2-adrenoceptors or their affinity for the radioligand, but was followed by a right shift of both the high and low affinity components (pKiH = 7.52 ± 0.05; pKiL = 6.22 ± 0.07; p < 0.05) of the (−)-isoprenaline competition isotherms. These phenomena were not produced by Superoxide anion per se since they were observed in the presence of Superoxide dismutase and catalase and in neutrophils from a patient with X-linked chronic granulomatous disease and were not observed in the presence of an exogenous source of Superoxide anion (xanthine-xanthine oxidase). Then we examined the effect of drugs that decrease the activity of PKC: 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), which antagonises the ATP binding site of the enzyme; staurosporine; and nimesulide, which affects the translocation of the enzyme from the cytosol to the plasma membrane. The effect of these drugs on PKC from human neutrophils was confirmed by the demonstration that H-7 and staurosporine (but not nimesulide) potently decreased PKC activity in the neutrophil cytosol, whereas nimesulide (but not H-7 or staurosporine) decreased PKC translocation from cytosol to neutrophil plasma membranes pretreated with phorbol diesters. These drugs decreased PMA-stimulated superoxide anion release in intact cells and antagonised the heterologous desensitisation of β2-adrenoceptors. Nimesulide decreased Superoxide production in PMA-treated cells when co-incubated with PMA, but not when added after sonication. Thus, the activation of neutrophils by respiratory burst stimulants that act through PKC is followed by a decrease in the isoprenaline agonist affinity states for β2-adrenoceptors, features that are consistent with heterologous desensitisation of neutrophil β2-adrenoceptors. Drugs affecting PKC are able to antagonise both Superoxide anion release and β2-adrenoceptor desensitisation.

Objective.— To investigate allodynia in patients with different primary headaches. Background.— Many migraineurs have allodynia during headache attacks; some may have allodynia outside attacks; allodynia may also be associated with other primary headaches. Methods.— A total of 260 consecutive primary headache patients presenting for the first time at a headache center, and 23 nonheadache controls answered written questions (subsequently repeated verbally) to determine the presence of acute and interictal allodynia. Results.— We divided the patients into: episodic migraine (N = 177), subdivided into only migraine without aura (N = 114) and those sometimes or always reporting migraine with aura (N = 63); episodic tension-type headache (N = 28); chronic headaches (headache ≥15 days/month, N = 52), including chronic migraine, chronic tension-type headache, and medication-overuse headache; and other headache forms (N = 3). Acute allodynia was present in 132 (50.7%), significantly more often in patients sometimes or always suffering migraine with aura, and those with chronic headache forms, compared to patients with migraine without aura and episodic tension-type headache. Interictal allodynia was present in 63 (24.2%) patients, with significantly higher frequency in those having migraine with aura attacks than controls and common migraine patients. Conclusions.— Allodynia is not specific to migraine but is frequent in all headache patients: acute allodynia was reported in half those interviewed and in over a third of patients in each headache category; interictal allodynia was reported by nearly 25%.

About 60% of patients complain of cutaneous allodynia during migraine episodes, often in the periorbitary region of the pain side. Pre-clinical studies have shown that the underlying mechanism is sensitisation of primary nociceptors and central trigeminovascular neurons and that patients have a lower pain threshold for mechanical stimulation compared to controls. The objective of this study was to determine the prevalence of allodynia during headache attacks in different forms of migraine. The subjects were 221 outpatients consecutively evaluated in the Headache Center of the L. Sacco Hospital in Milan: 114 had only attacks of migraine without aura (MO), 63 had also attacks with aura (MA) and 44 patients with chronic migraine with and without drug overuse (CM). Presence of head allodynia was investigated by a semistructured interview. Statistical analysis was performed by chi square test with Bonferroni correction for multiple comparisons. Forty-seven out of 114 MO patients (41.2%) complained of allodynia during headache episodes, 41 out of 63 MA patients (65.0%), and 29 out of 44 CM patients (65.9%). A higher frequency of allodynia in MA and CM with respect to MO patients was observed (p

the age of 30 of cerebral haemorrhage (not further investigated), and a patient’s son – a heterozygote twin – had died soon after birth for unknown causes. A brain CT scan performed at admission showed several hypodense areas within the cerebral parenchyma in both hemispheres. Brain MRI confirmed the presence of multiple T 1 -hypointense and T 2 -hyperintense lesions loDear Sir, Moyamoya disease is a clinical entity in which occlusion of intracranial large vessels, in particular carotid arteries, occurs in association with the development of an abnormal vascular network within the brain, especially in the basal ganglia. Clinical manifestations include hemiplegia of sudden onset, symptoms of intracranial bleeding and seizures [1] . Seven to 10% of cases occur with familial clustering, with variable patterns of inheritance (more often autosomal dominant with incomplete penetrance) [2, 3] . The disease, although present throughout the world, has a particularly high incidence in Eastern Asia, particularly in Japan [4] , as well as within close communities all around the world, such as the Amish and Mennonites. We describe the occurrence of moyamoya disease in a member of the community of Roma gypsies.

Nerve conduction velocity distribution (CVD) study is a newly-developed electrodiagnostic method for detecting alterations in the composition of nerve fibres according to their conduction velocity. The presence of subclinical neuropathy was evaluated in 138 diabetic patients by CVD study of four motor nerves (external popliteal and ulnar nerves bilaterally) and two sensory nerves (median nerve bilaterally), and the data obtained were compared with standard electrophysiological parameters in the same nerve segments. CVD studies revealed an altered distribution pattern in 106 of 129 evaluable patients for motor nerves (82%) and in 67 of 115 evaluable patients for sensory nerves (58%), while standard examination gave abnormal findings in 92 of 137 patients (67%) and in 33 of 118 patients (11%), respectively. Of the patients adequately evaluated by both techniques, 21 of 129 patients (16%) revealed altered CVD data unaccompanied by slowing of maximum nerve conduction velocity, and 37 patients of 101 (37%) showed similar findings for sensory nerves. Subclinical alterations of motor and sensory nerve CVD were not significantly related to age or to metabolic control expressed as glycated haemoglobin levels; a significantly longer duration of disease was found in patients with motor and mixed subclinical neuropathy with respect to non-neuropathic patients. The CVD study allowed us to detect subclinical abnormalities of motor and sensory nerve fibres; often this is a more sensitive method than the standard electrodiagnostic study. This method can be very useful as a diagnostic tool and in research in the study of the progression of diabetic neuropathy.

We compared plasma levels of beta-amyloid 1–42 (pg/ml) found for 146 sporadic Alzheimer (AD) patients, 89 subjects with mild cognitive impairment (MCI) and 89 age-matched controls (CT). AD patients had significantly lower levels (38, 54, 52; p < 0.01), unrelated to severity of the disease as assessed by MMSE score, age, sex or APOE4 status. Twenty cases investigated at two time points 18 months apart did not demonstrate further decreases. Thus, the reduction in beta-amyloid 1–42 may be a marker for AD status, specifically, a transition from normal status or MCI to AD, rather than a marker for neurodegenerative processes occurring in the disease.

Cerebral responses from the oesophagus were investigated in 16 normal male and female volunteers ranging in age from 20 to 54 years. The stimulus was applied by a naso-oesophageal probe equipped with bipolar ring electrodes. Short and long latency EP (SLEP and LLEP) were observed in all the subjects examined. SLEP consisted in a low threshold potential of 30 to 70 microV amplitude, biphasic or triphasic in shape and of approximately 5 to 10 ms duration; mean latency at the largest peak was 4.5 +/- 1.7 at 25 cm from the nostrils. Early components at about 2.5-3.5 ms and of small amplitude are also present. Recording from the neck at C7 with a common non-cephalic reference, SLEP components occurred from 2 to 6 ms earlier than that from the scalp, suggesting an oligo-synaptic transmission of the excitement via ganglion and lemniscal pathways to the cortex. SLEP was always followed by a complex potential formed of a succession of negative and positive waves with latencies ranging from 20 to 300 ms: the LLEP. This LLEP was usually not very stable and reproducible during the course of successive recordings and in the same subject because it tended to adjust. Preliminary observations concerning the topographical cortical distribution of oesophageal evoked potentials show a circumscribed localization of the SLEP in the parieto-temporal region of the hemisphere whereas LLEP was more widespread. It is the authors' opinion that oesophageal evoked potentials are generated both by the excitation of myelinic fibres with a wide range of conduction speed and of amyelinic fibres from the oesophageal mucosa and the paraoesophageal peripheral nerves of vagal origin.

Multiple system atrophy (MSA) is a heterogeneous group of central neurological degenerations often associated with diffuse deterioration of the hypothalamic cholinergic neurons. In the hypothesis of an altered cholinergic regulation of vasopressin release, we evaluated vasopressin response to metoclopramide (20 mg i.v.), a cholinomimetic agonist, in 12 MSA patients. In the same patients the hemodynamic and osmolal control of vasopressin was also evaluated. We found that MSA patients had significantly lower basal plasma vasopressin values and higher plasma osmolality than control subjects. However, they displayed a normal vasopressin response to osmotic stimulation. During head-up tilting, orthostatic hypotension occurred in all patients, and the vasopressin response to hypotension was severely blunted in 5 of 12 patients, thus demonstrating the presence of a lesion of the afferent noradrenergic pathways. Metoclopramide increased vasopressin in control subjects, whereas MSA patients did not display any increase in vasopressin. These results clearly indicate that cholinergic neurons that regulate vasopressin release are damaged in MSA. Such an alteration may be dissociated from the lesion of the afferent noradrenergic pathways. As a consequence of the altered vasopressin release, MSA patients show lower plasma vasopressin levels with consequent propensity to dehydration and hypovolemia, which may further aggravate their hypotension.

Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha-1 and beta-2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC), the density was examined of alpha-1 and beta-2 adrenoceptors with their affinity and coupling of beta-2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age-matched and sex-matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty-two HCC had a decrease of about 72% in alpha-1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha-1 adrenoceptor density compared with healthy livers. Twenty-three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase, as evidenced by a guanosine triphosphate-mediated right shift in (-)-isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (-)-isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha-1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the "healthy" part of the liver in HCC patients and that an increase in beta-2 and a decrease in alpha-1 adrenoceptor densities characterize the tumor part of the liver in human HCC.

We investigated the effect of respiratory-burst stimulants on beta-2 adrenoceptors in human polymorphonuclear leukocytes (PMNL). Pre-incubation of PMNL with these substances did not affect the number or affinity of the receptors but desensitized them, as shown by the "right-shift" in (-)-isoproterenol competition isotherms. H-7, an established protein kinase C inhibitor, and nimesulide, a new putative inhibitor of this enzyme, blunted both superoxide anion production and beta-2 adrenoceptor desensitization. A positive correlation was found between superoxide anion generation and the "right-shift" in isoproterenol competition isotherm (r = 0.92; p less than 0.01). Desensitization of beta-2 adrenoceptors was not due to superoxide anions per se since incubation of PMNL with superoxide anion scavengers (superoxide dismutase and catalase) did not modify the results.

Discontinuous density sucrose gradient centrifugation was used to isolate membrane vesicles from the left ventricle of three normal subjects (one prospective organ donor and two traffic victims whose hearts were obtained 1 hour after death) and nine patients undergoing cardiac transplantation as a consequence of idiopathic dilated cardiomyopathy. Sarcolemma-enriched subcellular fractions, detected in the interface between 8.55% and 25% sucrose, were identified by the increased activity of Na+,K+-ATPase and by enrichment in beta-adrenergic receptor density. The density of beta-adrenergic receptors was lower in vesicles from diseased hearts (610 +/- 71 fmol/mg protein) than in vesicles from normal hearts (1,410 +/- 226 fmol/mg protein; p less than 0.01). alpha 1-Adrenergic receptors were identified in these membrane vesicles by [3H]prazosin binding. Specific binding of [3H]prazosin was about 50% of the total binding at 1 nM, and alpha 1-adrenergic binding sites were saturable at approximately 3 nM. Scatchard analysis revealed 58 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.08 nM) in pathological hearts and 30 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.03 nM) in normal hearts (p less than 0.01). The displacement curve of (-)-norepinephrine in membrane vesicles from normal hearts delineated one subpopulation of alpha 1-adrenergic receptors; the addition of 0.1 mM GTP did not cause right shift. In membrane vesicles from diseased heart, the displacement curve of (-)-norepinephrine disclosed two subpopulations of alpha 1-adrenergic receptors. A right shift that occurred after addition of GTP showed that in this case alpha 1-adrenergic receptors were functionally coupled with GTP-binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for (125I)pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by (3H)prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas formore » the others alternative mechanisms should be considered.« less

The possibility that metoclopramide (MCP), a potent stimulator of aldosterone secretion, might influence vasopressin secretion in man was studied. MCP (10 mg, iv) increased plasma vasopressin (mean +/- SD) from 1.3 +/- 0.1 to 2.4 +/- 0.1 pg/ml at 10 min and to 2.65 +/- 0.1 pg/ml at 20 min (P less than 0.01) in 10 recumbent normal subjects. No changes in plasma osmolality or peripheral hemodynamics, which might have accounted for the increase in vasopressin, were found. Sulpiride (100 mg iv), haloperidol (2 mg, iv), and domperidone (20 mg, iv), three chemically unrelated antidopaminergic agents, as well as TRH (200 micrograms, iv), failed to modify plasma vasopressin, thus suggesting that the MCP effect on vasopressin is not linked to its antidopaminergic and/or PRL-releasing properties. MCP also was effective in releasing vasopressin in 5 dehydrated subjects, in whom plasma vasopressin increased from 1.9 +/- 0.2 to 3.1 +/- 4 pg/ml (P less than 0.05), and in 5 subjects during steady state water diuresis, in whom free water excretion decreased from 9 to 1 ml/min (P less than 0.01) and plasma vasopressin increased from 0.3 +/- 0.1 to 1.2 +/- 0.2 pg/ml (P less than 0.05). No changes in either vasopressin secretion or free water excretion occurred in 4 patients with severe central diabetes insipidus. These results suggest that MCP stimulates the release of biologically active vasopressin in man.