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Biomedical subjects

Claudio L Bassetti

Publications and source records attributed to Claudio L Bassetti.

At least 19 recordsLinked to original sources
PubMed2006

Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways.

Based on its trophic effects on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of neurodegenerative diseases. To evaluate the therapeutic potential of VEGF, we here examined effects of this growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS-derived neurons, offer themselves in an excellent way to study neuroprotection in vivo. Making use of a transgenic mouse line that constitutively expresses human VEGF under a neuron-specific enolase promoter, we show that (1) the VEGF-transgenic retina overexpresses human VEGF, (2) RGCs carry the VEGF receptor-2, and (3) vascular networks in normal and axotomized VEGF-transgenic (tg) retinas do not differ from control animals. After axotomy, RGCs of VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated caspase-3 levels in axotomized VEGF-transgenic retinas. Intravitreous injections of pharmacological ERK-1/2 (PD98059) or Akt (LY294002) inhibitors showed that VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of VEGF in neurodegenerative diseases of both brain and retina.

Animals↗
PubMed2006

The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia.

Based on its trophic influence on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for stroke treatment. VEGF's survival-promoting effects are purchased at the expense of an increased blood brain barrier permeability, which potentially compromises tissue survival. The mechanisms via which VEGF protects the brain against ischemia remained unknown. We examined signaling pathways underlying VEGF's neuroprotective activity in our transgenic mouse line, which expresses human VEGF165 under a neuron-specific enolase (NSE) promoter. We show that VEGF receptor-2 (Flk-1) is expressed on ischemic neurons and astrocytes and is activated by VEGF. Following 90-min episodes of middle cerebral artery occlusion, VEGF increased phosphorylated (but not total) Akt and ERK-1/-2 and reduced phosphorylated mitogen activated protein kinase/p38 and c-Jun NH2-terminal kinase (JNK)-1/-2 levels, at the same time decreasing inducible NO synthase expression in ischemic neurons. Inhibition of Akt with Wortmannin reversed VEGF's neuroprotective properties, diminished brain swelling, and restored the vascular permeability induced by VEGF to below levels in WT animals. The aggravation of brain injury by Wortmannin was associated with the restitution of p38, but not of JNK-1/-2, ERK-1/-2, or inducible NOS (iNOS). Our data demonstrate that VEGF mediates both neuroprotection and blood brain barrier permeability via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Based on our observation that VEGF neuroprotection and vascular leakage depend on PI3K/Akt, which is putatively regulated by VEGF receptor-2, we predict that it may not easily be possible to make use of VEGF's neuroprotective function without accepting its unfavorable consequence, the increased vascular permeability.

Androstadienes↗
PubMed2006

CSF prostaglandin D synthase is reduced in excessive daytime sleepiness.

Lipocalin-type prostaglandin D synthase (L-PGDS) is a brain enzyme, which produces prostaglandin D(2), a substance with endogenous somnogenic effects. Using a standardized protocol for immunonephelometric determination of cerebrospinal fluid (CSF) L-PGDS levels, we show that CSF L-PGDS levels are significantly lower in 34 patients with excessive daytime sleepiness when compared with levels in 22 healthy controls. Thus, L-PGDS may represent the first neurochemical measure of excessive daytime sleepiness.

Adult↗
PubMed2006

Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia.

The blood-brain barrier possesses active transporters carrying brain-permeable xenobiotics back into the blood against concentration gradients. We demonstrate that multidrug resistance transporter (Mdr)-1 is upregulated on capillary endothelium after focal cerebral ischemia; moreover, Mdr-1 deactivation by pharmacological inhibition or genetic knockout preferably enhances the accumulation and efficacy of two neuroprotectants known as Mdr-1 substrates in the ischemic brain. We predict that Mdr-1 inhibition may greatly facilitate neuroprotective therapies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Epilepsy and obstructive sleep apnea.

A few publications documented the coexistence of epilepsy and obstructive sleep apnea (OSA). The extent, nature, and clinical relevance of this association remain poorly understood. We retrospectively reviewed the database of our sleep center to identify patients with both sleep apnea and epilepsy. Characteristics of epilepsy, sleep history, presence of excessive daytime sleepiness [Epworth Sleepiness Scale (ESS)] and polysomnographic data were assessed. The effect of continuous positive airway pressure (CPAP) on seizure reduction was prospectively analyzed after a median interval of 26 months (range: 2-116 months) from the diagnosis of OSA. OSA was found in 29 epilepsy patients (25 men and 4 women) with a median age of 56 years (range: 37-79). The median apnea hypopnea index was 33 (range: 10-85), the oxygen desaturation index was 12 (range 0-92), and 52% of the patients had an ESS score >10. In 27 patients, epilepsy appeared 1 month to 44 years prior to the diagnosis of OSA. In 21 patients, the appearance of OSA symptoms coincided with a clear increase in seizure frequency or the first appearance of a status epilepticus. Treatment with CPAP was continued with good compliance in 12 patients and led to a significant reduction of both ESS scores and seizure frequency in 4 patients. Our data suggest the importance of considering diagnosis and treatment of OSA in epilepsy patients with poor seizure control and/or reappearance of seizures after a seizure-free interval.

Adult↗
PubMed2006

Sleep-wake habits and disorders in a series of 100 adult epilepsy patients--a prospective study.

The aim of the study was to assess sleep-wake habits and disorders and excessive daytime sleepiness (EDS) in an unselected outpatient epilepsy population. Sleep-wake habits and presence of sleep disorders were assessed by means of a clinical interview and a standard questionnaire in 100 consecutive patients with epilepsy and 90 controls. The questionnaire includes three validated instruments: the Epworth Sleepiness Scale (ESS) for EDS, SA-SDQ for sleep apnea (SA), and the Ullanlinna Narcolepsy Scale (UNS) for narcolepsy. Sleep complaints were reported by 30% of epilepsy patients compared to 10% of controls (p=0.001). The average total sleep time was similar in both groups. Insufficient sleep times were suspected in 24% of patients and 33% of controls. Sleep maintenance insomnia was more frequent in epilepsy patients (52% vs. 38%, p=0.06), whereas nightmares (6% vs. 16%, p=0.04) and bruxism (10% vs. 19%, p=0.07) were more frequent in controls. Sleep onset insomnia (34% vs. 28%), EDS (ESS >or=10, 19% vs. 14%), SA (9% vs. 3%), restless legs symptoms (RL-symptoms, 18% vs. 12%) and most parasomnias were similarly frequent in both groups. In a stepwise logistic regression model loud snoring and RL-symptoms were found to be the only independent predictors of EDS in epilepsy patients. In conclusion, sleep-wake habits and the frequency of most sleep disorders are similar in non-selected epilepsy patients as compared to controls. In epilepsy patients, EDS was predicted by a history of loud snoring and RL-symptoms but not by SA or epilepsy-related variables (including type of epilepsy, frequency of seizures, and number of antiepileptic drugs).

Adult↗
PubMed2006

Sleep-disordered breathing and acute ischemic stroke: diagnosis, risk factors, treatment, evolution, and long-term clinical outcome.

BACKGROUND AND PURPOSE: Sleep-disordered breathing (SDB) is frequent in stroke patients. Risk factors, treatment response, short-term and long-term outcome of SDB in stroke patients are poorly known. METHODS: We prospectively studied 152 patients (mean age 56+/-13 years) with acute ischemic stroke. Cardiovascular risk factors, Epworth sleepiness score (ESS), stroke severity/etiology, and time of stroke onset were assessed. The apnea-hypopnea index (AHI) was determined 3+/-2 days after stroke onset and 6 months later (subacute phase). Continuous positive airway pressure (CPAP) treatment was started acutely in patients with SDB (AHI > or =15 or AHI > or =10+ESS >10). CPAP compliance, incidence of vascular events, and stroke outcome were assessed 60+/-16 months later (chronic phase). RESULTS: Initial AHI was 18+/-16 (> or =10 in 58%, > or =30 in 17% of patients) and decreased in the subacute phase (P<0.001). Age, diabetes, and nighttime stroke onset were independent predictors of AHI (r2=0.34). In patients with AHI > or =30, age, male gender, body mass index, diabetes, hypertension, coronary heart disease, ESS, and macroangiopathic etiology of stroke were significantly higher/more common than in patients with AHI <10. Long-term incidence of vascular events and stroke outcome were similar in both groups. CPAP was started in 51% and continued chronically in 15% of SDB pts. Long-term stroke mortality was associated with initial AHI, age, hypertension, diabetes, and coronary heart disease. CONCLUSIONS: SDB is common particularly in elderly stroke male patients with diabetes, nighttime stroke onset, and macroangiopathy as cause of stroke; it improves after the acute phase, is associated with an increased poststroke mortality, and can be treated with CPAP in a small percentage of patients.

Acute Disease↗
PubMed2006

Role of drug efflux carriers in the healthy and diseased brain.

The blood-brain barrier is a natural diffusion barrier, which expresses active carriers extruding drugs on their way to the brain back into the blood against concentration gradients. Whereas these so-called adenosine triphosphate-binding cassette (ABC) transporters prevent the brain entry of toxic compounds under physiological conditions, they complicate pharmacotherapies in neurological disease. Recent observations in animal models of ischemic stroke, drug-resistant epilepsy, and brain cancer showed that the prototype of ABC transporters, ABCB1, is upregulated on brain injury, deactivation of this carrier considerably enhancing the accumulation of neuroprotective, antiepileptic, and chemotherapeutic compounds. These studies provide the proof of concept that the efficacy of brain-targeting drugs may significantly be improved when drug efflux is blocked. Under clinical conditions, efforts currently are made to enhance drug accumulation by selecting new compounds that do not bind to efflux carriers or deactivating ABC transporters by targeted downregulation or pharmacological inhibition. We predict that strategies aiming at circumventing drug efflux may greatly facilitate progress in neurological therapies.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Facial pain: clinical differential diagnosis.

Differential diagnosis of pain in the face as the presenting complaint can be difficult. We propose an approach based on history and neurological examination, which allows a working diagnosis to be made at the bedside, including aetiological hypotheses, leading to a choice of investigations. Neuralgias are characterised by stabs of short lasting, lancinating pain, and, although neuralgias are often primary, imaging may be needed to exclude symptomatic forms. Facial pain with cranial nerve symptoms and signs is almost exclusively of secondary origin and requires urgent examination. Facial pain with focal autonomic signs is mostly primary and belongs to the group of the idiopathic trigeminal autonomic cephalalgias, but can occasionally be secondary. Pure facial pain is most often due to sinusitis and the chewing apparatus, but also a multitude of other causes. The pain can also be idiopathic. Imaging as well as non-neurological specialist assessment is often necessary in these cases.

Diagnosis, Differential↗
PubMed2006

Sleep EEG changes after middle cerebral artery infarcts in mice: different effects of striatal and cortical lesions.

STUDY OBJECTIVES: Hemispheric stroke in humans is associated with sleep-wake disturbances and sleep electroencephalogram (EEG) changes. The correlation between these changes and stroke extent remains unclear. In the absence of experimental data, we assessed sleep EEG changes after focal cerebral ischemia of different extensions in mice. DESIGN: Following electrode implantation and baseline sleep-wake EEG recordings, mice were submitted to sham surgery (control group), 30 minutes of intraluminal middle cerebral artery (MCA) occlusion (striatal stroke), or distal MCA electrocoagulation (cortical stroke). One and 12 days after stroke, sleep-wake EEG recordings were repeated. The EEG recorded from the healthy hemisphere was analyzed visually and automatically (fast Fourier analysis) according to established criteria. MEASUREMENTS AND RESULTS: Striatal stroke induced an increase in non-rapid eye movement (NREM) sleep and a reduction of rapid eye movement sleep. These changes were detectable both during the light and the dark phase at day 1 and persisted until day 12 after stroke. Cortical stroke induced a less-marked increase in NREM sleep, which was present only at day 1 and during the dark phase. In cortical stroke, the increase in NREM sleep was associated in the wake EEG power spectra, with an increase in the theta and a reduction in the beta activity. CONCLUSION: Cortical and striatal stroke lead to different sleep-wake EEG changes in mice, which probably reflect variable effects on sleep-promoting and wakefulness-maintaining neuronal networks.

Animals↗
PubMed2006

Effects of sleep fragmentation on the arousability to resistive loading in NREM and REM sleep in normal men.

STUDY OBJECTIVE: In healthy subjects, arousability to inspiratory resistive loading is greater during rapid eye movement (REM) sleep compared with non-REM (NREM) sleep but is poorest in REM sleep in patients with sleep apnea. We therefore examined the hypothesis that sleep fragmentation impairs arousability, especially from REM sleep. DESIGN: Two blocks of 3 polysomnographies (separated by at least 1 week) were performed randomly. An inspiratory-loaded night followed either 2 undisturbed control nights (LN(C)) or 2 acoustically fragmented nights (LN(F)) SETTING: Sleep laboratory. PARTICIPANTS: Sixteen healthy men aged 20 to 29 years. INTERVENTIONS: In both loaded nights, an inspiratory resistive load was added via a valved facemask every 2 minutes during sleep and turned off either when arousal occurred or after 2 minutes. MEASUREMENTS AND RESULTS: During LN(F), arousability remained significantly greater in REM sleep (71% aroused within 2 minutes) compared with stage 2 (29%) or stage 3/4 (16%) sleep. After sleep fragmentation, arousability was decreased in stage 2 sleep (LN(F): 29%; LN(C): 38%; p < .05) and low in early REM sleep, increasing across the night (p < .01). In stage 3/4 sleep, neither an attenuation nor a change across the night was seen after sleep fragmentation. CONCLUSIONS: Mild sleep fragmentation is already sufficient to attenuate arousability in stage 2 sleep and to decrease arousability in early, compared with late, REM sleep. This means that sleep fragmentation affects the arousal response to increasing resistance and that the effects are different in stage 2 and REM sleep. The biologic reason for this increase in the arousal response in REM sleep across the night is not clear.

Adult↗
PubMed2005

Blood pressure evolution after acute ischemic stroke in patients with and without sleep apnea.

BACKGROUND AND PURPOSE: Sleep apnea (SA) is an independent risk factor for arterial hypertension and is present in 50% to 70% of patients with ischemic stroke. The effects of SA on blood pressure (BP) and stroke outcome in the acute stroke phase are essentially unknown. METHODS: We studied 41 consecutive patients admitted within 96 hours after stroke onset. Stroke severity on admission (National Institutes of Health Stroke Scale [NIHSS]) and stroke outcome at discharge (modified Rankin Disability Scale [mRS]) were assessed. Nocturnal breathing was assessed with an ambulatory device the first night after admission. SA was defined by an apnea-hypopnea-index (AHI) > or =10/hour, and moderate-severe SA (MSSA) was defined by an AHI >30/hour. BP monitoring was performed during the first 36 hours after admission. A nondipping status (NDS) was defined by a ratio >0.9 of mean systolic BP during nights 1 to 2/mean systolic BP during day 2. RESULTS: SA was found in 28 (68%) and MSSA in 11 (27%) of 41 patients. A correlation was found between AHI and both NIHSS (r=0.331; P=0.035) and mRS (r=0.341; P=0.031). Patients with MSSA had higher systolic and diastolic BP values during night 1 (P=0.003), day 2 (P=0.004), and night 2 (P=0.03). NDS was found in 26 (63%) patients. Nondippers had a similar AHI but higher NIHSS (P=0.004) and mRS (P=0.005) than dippers. AHI and NDS were confirmed to be independent predictors for both stroke severity and stroke outcome in a multiple stepwise linear regression model. CONCLUSIONS: SA severity is associated with high 24-hour BP values but only weakly with stroke severity and outcome. Conversely, NDS is linked with a more severe stroke and a poorer evolution but not with SA severity. These data suggest different, although overlapping, pathophysiological and clinical implications of circadian and nocturnal BP values in acute stroke.

Adult↗
PubMed2005

Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways.

Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective functions in brain hypoxia and ischemia. To examine the mechanisms mediating Epo's neuroprotective activity in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo in brain without inducing excessive erythrocytosis. We show that human Epo is expressed in tg21 brains and that cortical and striatal neurons carry the Epo receptor. After middle cerebral artery occlusion, human Epo potently protected brains of tg21 mice against ischemic injury, both when severe (90 min) and mild (30 min) ischemia was imposed. Histochemical studies revealed that Epo induced an activation of JAK-2, ERK-1/-2, and Akt pathways in the ischemic brain. This activation was associated with elevated Bcl-XL and decreased NO synthase-1 and -2 levels in neurons. Intracerebroventricular injections of selective inhibitors of ERK-1/-2 (PD98059) or Akt (wortmannin) pathways revealed that both ERK-1/-2 and Akt were required for Epo's neuroprotective function, antagonization of either pathway completely abolishing tissue protection. On the other hand, ERK-1/-2 and Akt blockade did not reverse the neuronal NO synthase-1/-2 inhibition, indicating that Epo down-regulates these NO synthases in an ERK-1/-2 and Akt independent manner. On the basis of our data, the dual activation of ERK-1/-2 and Akt is crucial for Epo's neuroprotective activity.

Androstadienes↗