Akinetic crisis in dementia with Lewy bodies.

BACKGROUND AND PURPOSE: Dementia with Lewy bodies (DLB) is characterised by neuroleptic hypersensitivity. It is unclear, however, whether the neuroleptic hypersensitivity implies an increased incidence of neuroleptic malignant syndrome (NMS) or of akinetic crisis (AC), which are expressions of the same possibly lethal clinical event, and whether AC in DLB can appear independently of neuroleptic treatment. In our prospective study, we assessed the incidence of AC in a cohort of DLB as compared with that in patients with Parkinson disease (PD). METHODS: In total, 614 patients with PD and 236 DLB were recruited and followed during 2005-2013. AC was diagnosed as sudden akinetic state unresponsive to dopaminergic rescue drugs, dysphagia and serological alterations without recovery for 48 h or more requiring hospital admission. Exposure to neuroleptics was specifically evaluated, because of the high implicit risk in DLB. RESULTS: 24 patients with PD (3.9%) and 16 patients with DLB (6.8%) developed AC. 77 (32.6%) DLB and 32 (5.2%) PD were exposed to typical neuroleptics, but only 8 DLB and 3 PD presented with AC. Disease duration before AC was lower in DLB than in PD group (p<0.01). Outcome was fatal in 8 patients with (50%) DLB and 3 (12.5%) PD (p=0.05). When age and use of neuroleptics were adjusted for into a Cox proportional hazards model predicting time to AC, the HR of patients with DLB was 13.0 (95% CI 4.23 to 39.9; p<0.001). CONCLUSIONS: AC in DLB can appear independently of neuroleptic treatment, occurs earlier and is more frequently fatal than in PD.

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain.

New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc.

The molecular determinants of Alzheimer's (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca(2+)) and zinc (Zn(2+)). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-ß dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca(2+) and Zn(2+) dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca(2+) and Zn(2+) rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca(2+) and Zn(2+) dyshomeostasis may offer a great opportunity for disease-modifying strategies.

Oxidative stress and brain aging: is zinc the link?

Zn(2+) dyshomeostasis has been strongly linked to neuronal injury in many neurological conditions. Toxic accumulation of intracellular free Zn(2+) ([Zn(2+)](i)) may result from either flux of the cation through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn(2+)-sensitive membrane transporters. Injurious [Zn(2+)](i) rises can also result from release of the cation from intracellular sites such as metallothioneins (MTs) and mitochondria. Chronic inflammation and oxidative stress are hallmarks of aging. Zn(2+) homeostasis is affected by oxidative stress, which is a potent trigger for detrimental Zn(2+) release from MTs. Interestingly, Zn(2+) itself is a strong inducer of oxidative stress by promoting mitochondrial and extra-mitochondrial production of reactive oxygen species. In this review, we examine how Zn(2+) dyshomeostasis and oxidative stress might act synergistically to promote aging-related neurodegeneration.

Epistaxis: vascular anatomy, origins, and endovascular treatment.

Embolization can play an important role in controlling epistaxis. However, one must be careful to avoid nontarget embolization via the dangerous anastomoses between the ECA branches, the carotid siphon, and ophthalmic arteries.

The safety of intraoperative lumbar subarachnoid drainage for acutely ruptured intracranial aneurysm: technical note.

Recently, some concern has arisen regarding the safety of intraoperative spinal drainage for brain relaxation in aneurysm surgery, due to anecdotal association with both aneurysmal rebleeding and increases in symptomatic vasospasm. To address these concerns, we reviewed our experience with frequent spinal drainage and early surgery in 432 consecutive cases of surgically treated aneurysmal subarachnoid hemorrhage. Unless contraindicated by mass effect or associated pathology, all grade I-III patients referred within 14 days were treated with spinal drainage at surgery. In this cohort (n = 314), there were no cases of meningitis or nerve root injury. Only one case of intraoperative rebleeding could be associated with spinal drain placement (0.3%). In grade IV-V patients, 47% required preoperative ventriculostomy, and 11% were ineligible for spinal drainage due to mass effect. There were, however, no complications related to spinal drainage in the remaining 23 patients. Permanently-shunted hydrocephalus (8%) and symptomatic vasospasm (19%) were infrequent overall. When analyzed by grade, spinal drains were generally associated with equal or reduced incidence of these developments when compared to patients without spinal drainage. We conclude that brain relaxation can be safely and effectively obtained using intraoperative spinal drains during early aneurysm surgery.

Internally stabilized spine: optimal choice of frequency-encoding gradient direction during MR imaging minimizes susceptibility artifact from titanium vertebral body screws.

In 18 vertebral bodies with titanium fixation screws and in a phantom model, visualization of the vertebral body marrow was improved and susceptibility artifact was reduced on T1-weighted spin-echo magnetic resonance images when the direction of the frequency-encoding gradient was parallel to the long axis of the screw. A perpendicular direction improved image quality only when the region of interest was adjacent to the tip of the screw. In the phantom, the length of the screw was statistically significantly increased and the width and area were reduced (P <.001) when the gradient was parallel to the long axis of the screw.

Case report. Small bowel obstruction due to phytobezoar formation within Meckel diverticulum: CT findings.

Intestinal obstruction due to a phytobezoar within a Meckel diverticulum is exceedingly rare, with only seven reported cases in the surgical literature. The most important precipitating factor is the ingestion of agents high in fiber and cellulose. Small bowel obstruction in all but one case was due to retrograde propagation of the bezoar into the small bowel lumen. We report the clinical and CT findings in such a patient following a vegetarian diet.

Intraischemic hypothermia decreases the release of glutamate in the cores of permanent focal cerebral infarcts.

The cerebroprotective effects of hypothermia in focal models of ischemia are well established, but little is known about the underlying mechanisms of this form of brain protection. Cortical cooling in global transient ischemic models suggests that hypothermia limits glutamate excitotoxicity by decreasing the release of glutamate during ischemia. Few studies have examined glutamate release in the more physiological model of permanent focal ischemia. In this study, we used a rat model of middle cerebral artery occlusion (MCAO) of permanent focal ischemia. Extracellular glutamate concentration was analyzed bilaterally by microdialysis for 30 minutes before MCAO to 120 minutes after MCAO. Normothermic animals (n = 13) had a baseline glutamate concentration of 9.23 +/- 2.5 mumol/ml (mean +/- standard error of the mean) before MCAO. Extracellular glutamate rose quickly after vessel occlusion and peaked at 33.95 +/- 6.3 mumol/ml 30 minutes after MCAO. By 60 minutes after MCAO, this level had decreased to 25.14 +/- 6.3 mumol/ml; glutamate levels decreased slightly to 21.35 +/- 6.8 mumol/ml by 120 minutes. Hypothermic animals (n = 11) had an initial extracellular glutamate concentration of 5.22 +/- 1.3 mumol/ml before MCAO. This value rose gradually to a maximum of 10.69 +/- 3.3 microns/ml at 50 minutes after MCAO and then returned to a baseline value of 2.58 +/- 1.2 mumol/ml by 120 minutes. Contralateral control glutamate dialysates in the normothermic and hypothermic groups remained near baseline throughout the experimental period. The mean percentages of right hemispheric volumes occupied by infarcts were 11.96 +/- 1.68% in the hypothermic group and 19.77 +/- 2.03% in the normothermic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of mild hypothermia on nitric oxide synthesis during focal cerebral ischemia.

The cerebroprotective effects of mild hypothermia have been extensively studied in various animal models of ischemia, but the mechanism by which mild hypothermia diminishes ischemic injury is not well understood. Nitric oxide (NO) has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures, and its synthesis is acutely increased during focal ischemia in vivo. To evaluate possible mechanisms of hypothermic neuroprotection, we measured markers of NO synthesis--nitrite and cyclic guanosine monophosphate (cGMP) levels and NO synthase activity--during right middle cerebral artery occlusion (MCAO) in the rat under normothermic (36.5 degrees C) and mild hypothermic (33 degrees C) conditions. There was a significant increase in nitrite concentration in the right hemisphere versus the left under normothermic conditions at 10 and 20 minutes after MCAO (P < 0.01), with a return to baseline levels by 60 minutes. The increase in cortical nitrite levels in the right hemisphere versus the left was not observed with mild hypothermia. There was a threefold increase in cGMP synthesis in the normothermic right cortex 10 minutes after MCAO (P < 0.05). This rise in cGMP did not occur in hypothermic animals, and the right to left cortical disparity in cGMP production was abolished. Finally, the significant increase in NO synthase activity seen in the normothermic ischemic cortex was absent in hypothermic rats (P < 0.05). These results suggest that mild hypothermia (33 degrees C) modulates the burst of nitric oxide synthesis during cerebral ischemia and may account, at least partially, for its cerebroprotective effects.

Mild hypothermia and MK-801 have similar but not additive degrees of cerebroprotection in the rat permanent focal ischemia model.

Although not the sole factor, glutamate-mediated excitotoxicity is accepted as a major mechanism of ischemic neuronal damage. MK-801 and mild hypothermia, two cerebroprotective modalities, which have been documented to alter glutamatergic action, were tested in the rat middle cerebral artery occlusion (MCAO) model simulating permanent focal ischemia. We administered normothermic (37 degrees C) animals with either MK-801 (1.0 mg/kg 30 min before MCAO or 2.5 mg/kg 30 min before, immediately after, 4 hours, and 8 hours after MCAO) or saline vehicle (30 min before MCAO). Mildly hypothermic (33 degrees C) animals were administered either MK-801 (1.0 mg/kg) or saline vehicle 30 minutes before MCAO. Mild hypothermia was induced over a 20-minute period before MCAO in hypothermic animals. All animals were killed 24 hours after MCAO; their brains were sectioned and stained with 2,3,5-triphenyltetrazolium chloride and their infarct volumes were calculated. In normothermica animals given 1.0 mg/kg and multidose 2.5-mg/kg intraperitoneal injections of MK-801, the infarct volumes (as a percentage of right hemispheric volume) were 16.8 +/- 3.5% and 16.3 +/- 3.0%, respectively. These infarct volumes were significantly different (P < 0.05; single-variable analysis of variance) from the normothermic, drug-free control (26.8 +/- 1.9%), but not significantly different from each other. Analysis of the data using a nonparametric test (Kruskal-Wallis; P = 0.02) confirmed the same significant differences in infarct size. The infarct volumes from the mildly hypothermic groups were not different (1 mg/kg of MK-801, 15.5 +/- 2.3% and saline control, 15.4 +/- 1.1%).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide production during focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: Nitric oxide has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures. METHODS: A number of indicators of brain nitric oxide production (nitric and cyclic guanosine monophosphate [cGMP] concentrations and nitric oxide synthase activity) were examined after bilateral carotid ligation and right middle cerebral artery occlusion in adult rats. RESULTS: Brain nitrite was significantly increased in the right versus left cortex 5, 10, and 20 minutes after middle cerebral artery occlusion (P < .05), with a return to baseline at 60 minutes. There were no significant changes in cerebellar concentrations. Cortical levels of cGMP were increased at 10, 20, and 60 minutes after occlusion, with significant right-to-left differences (P < .05). Cerebellar concentrations of cGMP were also increased but without significant side-to-side differences. Nitric oxide synthase activity increased approximately 10-fold from baseline 10 minutes after occlusion in the right cortex but decreased markedly by 60 minutes from its peak at 10 minutes. The right-to-left difference in nitric oxide synthase activity was significant at 20 minutes (P < .05). Pretreatment of rats with NG-nitro-L-arginine, a nitric oxide synthase inhibitor, abolished the rise in nitrite and cGMP. CONCLUSIONS: These results suggest that a sharp transient increase in the activity of nitric oxide synthase occurs during the first hour of cerebral ischemia, which leads to a burst in nitric oxide production and activation of guanylate cyclase.

Insulin receptor number and binding affinity in newborn dogs.

The insulin resistance in newborn mammals may be caused by a receptor or postreceptor defect. Although liver and umbilical cord blood monocytes have increased numbers of insulin receptors, there is a paucity of information about other neonatal tissues. Glucose disposal takes place primarily in the skeletal muscle; therefore, it is important to evaluate this tissue for an insulin receptor defect. To determine the role of insulin receptors in neonatal insulin resistance, neonatal and adult canine skeletal muscle, heart, and liver were compared for numbers of insulin receptors and their affinity for insulin. Partially purified receptors from four animals in each group were obtained by wheat germ lectin affinity chromatography and used in competition binding studies. Specific binding (mean +/- SE) in the absence of cold insulin was increased in newborn skeletal muscle (9.7 +/- 0.8 versus 4.8 +/- 0.5%, p less than 0.001) and heart (8.1 +/- 1.2 versus 5.5 +/- 0.6%, p less than 0.05). High-affinity insulin receptor number (mean +/- SEM) was increased in newborn skeletal muscle (183 +/- 40 versus 120 +/- 29 pM, p less than 0.002) and heart (264 +/- 94 versus 157 +/- 51 pM, p less than 0.05) as estimated from the X intercept of the Scatchard plot. Using half-maximal binding to estimate affinity, there were no differences between adults and newborns among all tissues studied. High-affinity receptor number and percentage of specific binding were similar for newborn and adult liver tissue.(ABSTRACT TRUNCATED AT 250 WORDS)