Obstructive sleep apnea and atherosclerosis: "guilt by association".
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Arteriosclerosis↗
Biomedical subjects
Claudio L Bassetti
Publications and source records attributed to Claudio L Bassetti.
Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1.
The cellular isoform of prion protein, PrPc, may confer neuroprotection in the brain, according to recent studies. To elucidate the role of PrPc in stroke pathology, we subjected PrPc-knockout (Prnp(0/0)), wild-type and PrPc-transgenic (tga20) mice to 30 min of intraluminal middle cerebral artery occlusion, followed by 3, 24 or 72 h reperfusion, and examined how PrPc levels influence brain injury and cell signaling. In immunohistochemical experiments and Western blots, we show that PrPc expression is absent in the brains of Prnp(0/0) mice, detectable in wild-type controls and approximately 4.0-fold elevated in tga20 mice. We provide evidence that PrPc deficiency increases infarct size by approximately 200%, while transgenic PrPc restores tissue viability, albeit not above levels in wild-type animals. To elucidate the mechanisms underlying Prnp(0/0)-induced injury, we performed Western blots, which revealed increased activities of ERK-1/-2, STAT-1 and caspase-3 in ischemic brains of Prnp(0/0)mice. Our data suggest a role of cytosolic signaling pathways in Prnp(0/0)-induced cell death.
Animals↗
Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter.
Hypothalamic excitatory hypocretin (orexin) neurons have been discovered in 1998 and found to have widespread projections to basal forebrain, monoaminergic and cholinergic brainstem, and spinal cord regions. The hypocretin system is influenced both neuronally (e.g. suprachiasmatic nucleus, GABAergic, cholinergic and aminergic brainstem nuclei) as well as metabolically (e.g. glucose, ghrelin, and leptin). Physiologically the hypocretin system has been implicated in the regulation of behaviours that are associated with wakefulness, locomotion, and feeding. A role in REM sleep, neuroendocrine, autonomic and metabolic functions has also been suggested. Pathophysiologically a deficient hypocretin neurotransmission has been found in human narcolepsy and (engineered) animal models of the disorder. Different mechanisms are involved including (1) degeneration of hypocretin neurons (mice), (2) hypocretin ligand deficiency (humans, mice, dogs), (3) hypocretin receptor deficiency (mice, dogs). Reports of low hypocretin-1 cerebrospinal fluid levels in neurologic conditions (e.g. Guillain-Barré syndrome, traumatic brain injury, hypothalamic lesions) with and without sleep-wake disturbances and, on the other hand, observations of normal levels in about 11% of narcoleptics raise questions about the exact nature and pathophysiological base of the link between hypocretin deficiency and clinical manifestations in human narcolepsy.
Animals↗
Hypocretins (orexins) and sleep-wake disorders.
Since their discovery in 1998, the hypocretins (orexins)-peptides that are produced by a group of neurons situated in the posterolateral hypothalamus--have been shown to excite many CNS areas including many neuronal systems that regulate sleep and wakefulness. Animal studies indicate that hypocretins play a part in the regulation of various functions including arousal, muscle tone, locomotion, regulation of feeding behaviour, and neuroendocrine and autonomic functions. A link between hypocretin deficiency and narcoleptic symptoms was first shown in canine and rodent models of narcolepsy. Hypocretin deficiency, as shown by low or absent concentrations in CSF, was subsequently found in 90% of patients with sporadic narcolepsy-cataplexy, and less commonly in familial narcolepsy. In most other sleep-wake and neurological disorders, hypocretin concentrations are normal. Low concentrations were also found in hypothalamic disorders, acute traumatic brain injury, and a few other disorders. The exact function of the hypocretin system in sleep-wake regulation and its pathophysiological role in hypocretin-deficient and non-deficient narcolepsy as well as in non-narcoleptic, hypocretin-deficiency syndromes remain unclear.
Animals↗
Sleep-related painful erections.
BACKGROUND: A 45-year-old man presented with repeated awakenings at night caused by nocturnal painful erections, in sharp contrast with normal erections at other times, 2 years after surgical removal of a thoracic (Th6-7) ependymoma. INVESTIGATIONS: Physical examination, pharmaco-sensitized penile Doppler ultrasound, spinal and brain MRI, neurophysiological work-up (tibial and perineal somatosensory-evoked potential; hand, foot and perineal sympathetic skin response assessment), polysomnography with recording of nocturnal penile tumescence. DIAGNOSIS: Sleep-related painful erections, characterized by penile pain during nocturnal erection, typically during rapid eye movement sleep, in the presence of a residual thoracic spinal cord syndrome. MANAGEMENT: Amitriptyline, an antidepressant that suppresses rapid eye movement sleep, was ineffective. Treatments with other antidepressants, clozapine and beta-blockers were suggested, but the patient declined because of potential severe side effects.
Central Cord Syndrome↗
Sleep and stroke.
More than 50% of stroke patients have sleep-disordered breathing (SDB), mostly in the form of obstructive sleep apnea (OSA). SDB represents both a risk factor and a consequence of stroke. The presence of SDB has been linked with poorer long-term outcome and increased long-term stroke mortality. Continuous positive airway presure is the treatment of choice for OSA. Oxygen and other forms of ventilation may be helpful in other (e.g., central) forms of SDB. SDB can improve spontaneously after stroke. About 20 to 40% of stroke patients have sleep-wake disorders (SWD), mostly in form of insomnia, excessive daytime sleepiness/fatigue, or hypersomnia (increased sleep needs). Depression, anxiety, SDB, stroke complications, and medications may contribute to SWD and should be addressed first therapeutically. Brain damage per se, often at thalamic or brainstem level, can be also a cause of persisting SWD. In these patients, hypnotics, dopeminergic agents, and stimulants (e.g., modafinil) can be attempted.
Humans↗
Hypersomnia in an epilepsy patient treated with levetiracetam.
We report a patient with focal epilepsy in whom increased sleep needs (hypersomnia) developed in the absence of subjective excessive daytime sleepiness (EDS) during an add-on treatment with levetiracetam (LEV).
Adult↗
Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice.
Because of its favorable action profile in humans, melatonin is a particularly interesting candidate as a neuroprotectant in acute ischemic stroke. Until now, the signaling mechanisms mediating melatonin's neuroprotective actions remained essentially uninvestigated. Herein, we examined the effects of melatonin, administered either orally for 9 wk as a stroke prophylactic (4 mg/kg/day) or intraperitoneally immediately after reperfusion onset (4 mg/kg), on the activation of signal transduction pathways in mice submitted to 90 min of intraluminal middle cerebral artery occlusion, followed by 24 hr of reperfusion. In these studies, melatonin significantly reduced ischemic infarct size by approximately 30-35%, as compared with animals receiving diluent (sham) treatment, independent of whether the indole was administered prior to or after ischemia. Under both conditions, animals receiving melatonin exhibited elevated phosphorylated Akt levels in their brains, as determined by Western blots. Additionally, phosphorylation levels of mitogen-activated protein kinase/extracellular-regulated kinase (ERK)-1/-2 and Jun kinase (JNK)-1/-2 were increased following prophylactic, but not acute, melatonin treatment. Our data suggest a role of phosphatidyl inositol-3 kinase/Akt signaling in acute melatonin-induced neuroprotection, while ERK-1/-2 and/or JNK-1/-2 rather appear to be involved in melatonin's long-term effects.
Animals↗
Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin: role of iNOS and Akt.
In vivo studies showed that tissue-plasminogen activator (t-PA) may aggravate neuronal injury after focal cerebral ischemia. We hypothesized that t-PA impairs survival-promoting cell signaling in the ischemic brain, which may be reversed by a neuroprotectant, i.e. melatonin. We examined the effects of t-PA (10 mg/kg, i.v.), administered alone or in combination with melatonin (4 mg/kg, i.p.), on ischemic injury, inducible nitric oxide synthase (iNOS) expression as well as Akt, Bcl-X(L) and caspase-3 signaling following 90 min of intraluminal middle cerebral artery (MCA) occlusion in mice. t-PA, delivered immediately after reperfusion onset, increased infarct volume at 24 hr after MCA occlusion, in accordance with previous findings. Melatonin reduced infarct size when administered alone and reversed the t-PA-induced brain injury. Immunohistochemical studies showed that t-PA treatment was associated with an accumulation of iNOS positive cells in ischemic brain areas, which was abolished after co-delivery of melatonin. Western blots revealed that t-PA decreased phosphorylated Akt levels, but did not influence Bcl-X(L) expression and caspase-3 activity in ischemic brain lysates. Co-treatment with melatonin restored phosphorylated Akt levels, increased Bcl-X(L) expression and reduced caspase-3 activity. We provide evidence that t-PA-induced brain injury is accompanied by an activation of iNOS and inhibition of phosphatidylinositol-3 kinase/Akt. That melatonin reversed these signaling changes and the t-PA-induced brain injury makes this indole attractive as an add-on treatment with thrombolytics.
Animals↗
Reversible opsoclonus after diphenhydramine misuse.
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Adult↗
Aggravation of focal cerebral ischemia by tissue plasminogen activator is reversed by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor but does not depend on endothelial NO synthase.
BACKGROUND AND PURPOSE: It has repeatedly been reported that the thrombolytic tissue plasminogen activator (tPA) may aggravate ischemic injury after stroke. The underlying mechanisms, however, remain unknown. We hypothesized that tPA induces an inhibition of endothelial NO synthase (eNOS) after focal ischemia that is responsible for ischemic damage and may be restored by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. METHODS: We examined the effects of tPA, administered either alone or in combination with rosuvastatin, on ischemic injury, on eNOS expression, and cell signaling after 90 minutes of intraluminal middle cerebral artery occlusion. RESULTS: In wild-type mice, tPA delivered immediately after ischemia significantly increased infarct volume 24 hours after reperfusion. Coadministration of rosuvastatin completely reversed the tPA-induced brain damage. Western blots of ischemic brain lysates showed that tPA markedly diminished eNOS levels, increased extracellular regulated kinase (ERK)-2, and decreased MAP kinase/p38 activity. Cotreatment with rosuvastatin prevented the decrease in eNOS, reduced ERK-1/-2 and normalized p38 levels. To elucidate the role of eNOS in tPA-induced ischemic injury, we also evaluated tPA effects in eNOS knockout mice. In eNOS knockout animals, tPA again significantly increased infarct size after transient focal ischemia. CONCLUSIONS: In a mouse model of focal cerebral ischemia, tPA induces eNOS inhibition, ERK-2 activation, and p38 inhibition, possibly as part of a more complex signaling response exacerbating brain injury. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition reverses the effects of tPA by a mechanism independent of eNOS.
Animals↗
VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena.
Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) is a clinically promising strategy in ischaemic disease. The pathophysiological consequences of enhanced vessel formation, however, are poorly understood. We established mice overexpressing human VEGF165 under a neuron-specific promoter, which exhibited an increased density of brain vessels under physiological conditions and enhanced angiogenesis after brain ischaemia. Following transient intraluminal middle cerebral artery (MCA) occlusions, VEGF overexpression significantly alleviated neurological deficits and infarct volume, and reduced disseminated neuronal injury and caspase-3 activity, confirming earlier observations that VEGF has neuroprotective properties. Brain swelling was not influenced in VEGF-overexpressing animals, while sodium fluorescein extravasation was moderately increased, suggesting that VEGF induces a mild blood-brain barrier leakage. To elucidate whether enhanced angiogenesis improves regional cerebral blood flow in the ischaemic brain, [14C]iodoantipyrine autoradiography was performed. Autoradiographies revealed that VEGF induces haemodynamic steal phenomena with reduced blood flow in ischaemic areas and increased flow values only outside the MCA territory. Our data demonstrate that VEGF protects neurons from ischaemic cell death by a direct action rather than by promoting angiogenesis, and suggest that strategies aiming at increasing vascular density in the whole brain, e.g. by VEGF overexpression, may worsen rather than improve cerebral haemodynamics after stroke.
Animals↗
Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness.
Excessive daytime sleepiness, hallucinations and REM sleep behavior disorder are symptoms reported in both dementia with Lewy bodies (DLB) and narcolepsy. Considering the demonstration of low hypocretin-1/orexin A levels in the cerebrospinal fluid (CSF) of most patients with narcolepsy, we hypothesized the presence of a deficient hypocretinergic transmission in DLB. Hypocretin-1 was tested in the CSF of 10 DLB patients. Levels were found to be in the normal range (mean 521 pg/ml, range 382-667) when compared to controls (n = 20, mean 497 pg/ml, range 350-603) and Alzheimer's disease patients (n = 7, mean 474 pg/ml, range 333-564). In DLB, excessive daytime sleepiness, hallucinations and REM sleep behavior may occur in the absence of a detectable hypocretin deficiency.
Aged↗
CSF hypocretin levels in Guillain-Barré syndrome and other inflammatory neuropathies.
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Adult↗
Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway.
Narcolepsy with cataplexy is thought to be a hypocretin ligand or hypocretin receptor deficiency syndrome caused by genetic and environmental factors. We looked for an abnormality of the hypocretin pathway in HLA-DQB1*0602-positive monozygotic twins who were concordant for narcolepsy-cataplexy. They had normal cerebrospinal fluid concentrations of hypocretin-1, and we found no mutation in the prepro-hypocretin gene or either hypocretin receptor gene. Our finding points to the existence of presumably genetic forms of narcolepsy with cataplexy without any demonstrable defect in the hypocretin pathway.
Adult↗
Intravenously administered recombinant tissue-plasminogen activator attenuates neuronal injury after mild focal cerebral ischemia in mice.
Recombinant tissue-plasminogen activator (t-PA) increases brain injury after focal ischemias leading to overt tissue infarcts. The question arose, whether t-PA may also be detrimental after mild ischemias. To clarify this issue, we submitted mice to 30 min intraluminal thread occlusions and administered normal saline or t-PA (10 mg/kg, i.v.) after reperfusion onset. Thread occlusions resulted in reproducible ischemias, followed by hyperperfusion reactions immediately after thread withdrawal. Post-ischemic LDF did not differ between saline- and t-PA-treated animals. In contrast to earlier studies, where t-PA exacerbated injury, t-PA treatment did not increase, but attenuated disseminate neuronal death in the striatum, as shown by cresyl violet, TUNEL and activated caspase-3 staining 1 and 3 days after the ischemic event (p < 0.05). Our data argue against major detrimental actions of t-PA after mild focal ischemia.
Animals↗
Total dream loss: a distinct neuropsychological dysfunction after bilateral PCA stroke.
The term Charcot-Wilbrand syndrome (CWS) denotes dream loss following focal brain damage. We report the first case of CWS, in whom neuropsychological functions, extension of the underlying lesion, and sleep architecture changes were assessed. A 73-year-old woman reported a total dream loss after acute, bilateral occipital artery infarction (including the right inferior lingual gyrus), which lasted for over 3 months. In the absence of sleep-wake complaints and (other) neuropsychological deficits, polysomnography demonstrated an essentially normal sleep architecture with preservation of REM sleep. Dreaming was denied also after repeated awakenings from REM sleep. This observation suggests that CWS (1) can represent a distinct and isolated neuropsychological manifestation of deep occipital lobe damage, and (2) may occur in the absence of detectable REM sleep abnormalities.
Aged↗
Restless legs syndrome: clinical experience with long-term treatment.
BACKGROUND AND PURPOSE: There are limited data on long-term treatment efficacy, and almost none on predictors of treatment response in patients with restless legs syndrome (RLS). To assess: (1) long-term efficacy of RLS treatment in a clinical setting, (2) predictors of a good treatment response, and (3) the value of the RLS-severity score according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG). PATIENTS AND METHODS: Over three years 70 patients (36 men, 34 women; mean age: 59 years; range: 29-79) with RLS were prospectively assessed. Diagnosis of RLS was made according to international criteria Severity of RLS symptoms was were assessed at the outset by the IRLSSG rating scale. Treatment was chosen individually according to clinical judgement. After a mean follow-up time of 16 months (range: 1-106 months) evolution of symptoms was assessed by both overall clinical impression and IRLSSG rating scale. Clinical characteristics and treatment effect were compared between patients never treated for RLS before this study ('naïve'=N-pts) and those with previous treatment ('treated'=T-pts). Predictors of treatment response were sought for comparing patients with good treatment response (good, better or much better on follow-up) and those with bad (B-pts) treatment response. RESULTS: There were 40 N-pts and 30 T-pts. The mean IRLSSG score (hereinafter, IRLSSG) at baseline was 26 (range 12-38). No significant differences were found between N-and T-pts in age, gender, etiology and duration of RLS, positive family history, presenting sleep complaint, IRLSSG, or percentage of patients with periodic limb movements in sleep (PLMS) on polysomnography (PSG). At final follow-up 30 (76%) of 40 N-pts and 23 (77%) of 30 T-pts had a good (G-pts) treatment response. The mean IRLSSG at follow-up was 19 (range:1-36). There was a significant correlation between improvement of overall clinical impression (better or much better on final follow-up) and reduction of IRLSSG (P<0.0001). PLMS were more common in B- than G-pts (100 vs 58% of patients, P=0.02). In all other variables considered the two groups were similar. CONCLUSION: (1) A good long-term treatment response can be obtained and maintained in a clinical setting in about 80% of RLS patients. (2) Patients with RLS and without PLMS may have a better long-term treatment response, and (3) the IRLSSG is a useful tool for assessment of evolution of RLS symptoms over time in individual patients.
Adult↗