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Biomedical subjects

R R Leker

Publications and source records attributed to R R Leker.

At least 19 recordsLinked to original sources
PubMed2003

Combination of dexanabinol and tempol in focal cerebral ischemia: is there a ceiling effect?

Because ischemic neuronal death is triggered by several parallel mechanisms, a combination of drugs active against individual death-promoting mechanisms may have synergistic effects. Dexanabinol is a noncompetitive NMDA antagonist with anti-inflammatory effects and tempol is a nitroxide antioxidant. Therefore, we explored whether their combined use results in smaller infarct volumes as compared with their individual administration. Rats underwent permanent middle cerebral artery occlusion (PMCAO) and were given vehicle, dexanabinol alone, tempol alone, or a combination of dexanabinol and tempol (n = 13 per group) 1 h later. Five animals in each group were evaluated with a motor rating scale 24 h after PMCAO and the infarct volumes were then measured. The remaining animals were examined with motor and behavioral scales up to 30 days after PMCAO and their infarct volumes were then determined. Motor disability and water maze latencies at all time points examined and infarct volumes at days 1 and 30 were significantly reduced in all active treatment groups when compared with vehicle. However, no significant differences were observed between the active treatment groups. In conclusions, combination therapy with dexanabinol and tempol does not appear to have additional neuroprotective effects compared to those conferred by each agent alone even when administered at optimal timing and dosing. Therefore, a ceiling neuroprotective effect that is impossible to overcome may exist.

Animals↗
PubMed2003

Anti-epileptic drugs as possible neuroprotectants in cerebral ischemia.

Many similarities exist between cerebral ischemia and epilepsy regarding brain-damaging and auto-protective mechanisms that are activated following the injurious insult. Therefore, drugs that are effective in minimizing seizure-induced brain damage may also be useful in minimizing ischemic injury. Use of such drugs in stroke victims may have important clinical and financial advantages. Therefore, the authors conducted a Medline search of studies involving the use of anti-epileptic drugs (AEDs) as possible neuroprotectants and summarize the data. Most AEDs have been tested in animal models of focal or global ischemia and some were already tested in humans, for a possible neuroprotective effect. The existing data is rather scant and insufficient but it appears that only drugs that have multiple mechanisms of action seem to have some potential in conferring a degree of neuroprotection that could be clinically applicable to stroke patients. In conclusion, some of the newer AEDs show promise as possible neuroprotectants in the setup of acute ischemic stroke but more studies are needed before clinical trials in humans could be undertaken.

Animals↗
PubMed2003

Seizures as a presenting symptom of phaeochromocytoma in a young soldier.

New onset of seizures in young adults is frequently related to alcohol withdrawal, toxic exposure, central nervous system trauma and neoplasm. We describe a young soldier presenting to the emergency department with seizures and transient coma. On admission, he had hypertension, marked leukocytosis, hyper-glycaemia, acidosis, elevated creatinine and elevated creatine phosphokinase of muscle origin. A thorough work-up revealed elevated urinary catecholamines, and a left adrenal mass was found on MRI and MIBG scan. The patient underwent laparoscopic adrenalectomy and completely recovered. This is the first description of seizures as a presenting symptom of phaeochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2002

The nitroxide antioxidant tempol is cerebroprotective against focal cerebral ischemia in spontaneously hypertensive rats.

Free radicals appear to participate in the final common pathway of neuronal death in ischemia and may therefore be an adequate target for therapy. Tempol is a nitroxide antioxidant with proven protective efficacy in several animal models, including myocardial ischemia, that has not been previously tested in models of permanent cerebral ischemia. Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Following dose-response and time-window-finding experiments rats were given vehicle or tempol (50 mg/kg) subcutaneously 1 h after PMCAO (n = 10/group). Five animals in each group were evaluated with a motor scale 24 h after the infarct and were then sacrificed and the injury volume was measured. The remaining animals were examined daily with the motor scale and also with a Morris water maze test on days 26-30 after PMCAO and sacrificed on day 30. Motor scores at all time points examined were significantly better in the tempol-treated animals (P < 0.05 for all). Significantly better performance in the water maze test for performance on days 26-30 was noted in the tempol group compared with the vehicle-treated group (P < 0.05). Injury volumes at days 1 and 30 were significantly reduced in the tempol group (9.83 +/- 1.05 vs 19.94 +/- 1.43% hemispheric volume, P = 0.0009, and 13.2 +/- 2.97 vs 24.4 +/- 2.38% hemispheric volume, P = 0.02, respectively). In conclusion, treatment with tempol led to significant motor and behavioral improvement and reduced injured tissue volumes both in the short and in the long term after stroke.

Animals↗
PubMed2002

Experimental models in focal cerebral ischemia: are we there yet?

Therapeutic options available for acute stroke management are sparse and inadequate. Therefore, new insights into stroke pathophysiology leading to new therapeutic targets are needed. In order to attain these goals, adequate animal models for cerebral ischemia are needed. In the following paper the authors will review the various animal models for stroke and emphasize their potential strengths and weaknesses.

Animals↗
PubMed2002

Experimental models of head trauma.

Traumatic brain injury is one of the most common causes for chronic disability in young people. Despite this there are currently no widely available modes of therapy that would limit the extent of brain damage secondary to trauma. Therefore, new insights into the pathological mechanisms involved in head trauma possibly leading to the identification of new therapeutic targets are urgently needed. In order to attain these goals adequate animal models for traumatic brain injury are needed. In the following paper the authors will review the various animal models for head trauma and emphasize their potential strengths and weaknesses.

Animals↗
PubMed2001

Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor.

Expressional patterns of the endothelial and neuronal forms of nitric oxide synthase (NOS) in cerebral ischemia were studied utilizing a permanent middle cerebral artery occlusion (PMCAO) model. Motor performance and infarct volumes were determined in the rats. Immunohistochemical staining for eNOS, nNOS and neurofilament were performed at 1, 2, 3, 5, 7 and 14 days after PMCAO. Vascular endothelial growth factor (VEGF) expression was determined by in-situ hybridization. PMCAO caused a reproducible cortical infarct with motor deficits in the rats. Double immunohistochemical stainings indicated that eNOS and nNOS were induced in ischemic neurons. Most stained neurons were positive for both NOS forms but some reacted with only one NOS antibody. nNOS expression peaked at 24-48 h after PMCAO, stained mainly the cytoplasm of core neurons, and disappeared after the 3rd day. eNOS expression increased until the 7th day, stained mainly the cytoplasm and membrane of penumbral cells and disappeared by the 14th day after PMCAO. VEGF expression was significantly induced in the penumbral zone in a similar distribution to eNOS. The anatomical and temporal pattern of VEGF and eNOS induction in the brain after permanent ischemia suggest that these mediators may play a role in protecting penumbral tissue from additional ischemic damage.

Animals↗
PubMed2001

Headache characteristics in patients after migrainous stroke.

Six patients who fulfilled strictly defined criteria for migrainous cerebral infarction and in whom other causes of stroke were ruled out were observed. All had a long-standing history of migraine with aura. In most, stroke was mild with good recovery and no recurrence. Headache frequency and severity decreased after the stroke. It is hypothesized that the improvement in migraine may be due to reduced nociceptive transmission as result of loss in vasoreactivity of the affected cerebral blood vessel.

Adolescent↗
PubMed2001

Long term cerebroprotective effects of dexanabinol in a model of focal cerebral ischemia.

In order to test the long-term cerebroprotective effects of dexanabinol, a synthetic non-competitive NMDA antagonist that also has anti-TNFalpha effects, spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Rats were given vehicle or dexanabinol (4.5 mg/kg) 1, 3 or 6 h after PMCAO. The research consisted of 2 stages. In the short-term set of experiments animals (n=5/group), were tested with a motor disability scale 24 h post PMCAO, then sacrificed and the infarct volume was measured using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. In the long-term set of experiments the rats (n=7/group) were examined daily with a motor disability scale up to 30 days after PMCAO and then sacrificed and infarct volumes were determined using TTC staining. Motor scores were significantly improved in the dexanabinol treated rats (P<0.05 for all groups) at all the time points examined. Infarct volumes were significantly reduced 24 h after PMCAO in the groups treated 1 or 3 h, but not 6 h after PMCAO compared with vehicle (Mean+/-S.D., 11.5+/-2.02, 12+/-3.2 and 14.4+/-2.4% vs. 20.8+/-1.3% hemispheric volume respectively). The lesions remained significantly smaller in the dexanabinol groups 30 days after PMCAO (Mean+/-S.D., 24.49+/-1.9% vs. 8.1+/-0.6, 11.1+/-2.3 and 13.8+/-2.5% hemispheric volume in animals treated with vehicle vs. dexanabinol 1, 3 or 6 h after PMCAO respectively; P<0.05 for all). In conclusion, the extended therapeutic window and the multi-mechanistic durable neuroprotective effects of dexanabinol make it a promising candidate for future stroke therapy.

Animals↗
PubMed2000

Prognostic factors in artificially ventilated stroke patients.

OBJECTIVES: To evaluate the reasons for implementing artificial ventilation (AV) in patients with acute ischemic stroke (AIS), determine their outcome and characterize prognostic variables in these patients. METHODS: Consecutive patients presenting with AIS were evaluated. All patients who received AV were treated in a neurological semi-intensive care setting. RESULTS: Of the 173 patients included in the study, 27 (16%) needed AV, 16 (9%) received AV and five of these patients (31%) survived. The mean NIH stroke scale score prior to AV was 14.5+/-5.6 (vs. 9.1+/-6.2 in non-intubated patients, P=0.001). Six patients were ventilated because of neurological deterioration. Most of these patients had large hemispheric infarctions with evident herniation and midline shift on CT scans. The only one who survived the acute hospitalization did not recover and died within 3 months. In the other 10 patients, AV was instituted during cardiopulmonary decompensation (CPD). These patients generally fared better; four of them survived and were discharged after a lengthier hospital stay when compared to non-intubated patients. Variables associated with survival among intubated patients were a lower neurological disability score on admission and on day 7 after the stroke, and intubation during CPD. CONCLUSIONS: Implementing AV in semi-intensive care settings does not seem to improve survival in AIS patients with neurological deterioration. Stroke patients who need AV during CPD and those that have less severe neurological deficits may have better chances for survival.

Aged↗
PubMed2000

Cognitive dysfunction following thalamic stroke: a study of 16 cases and review of the literature.

The thalamus is a relay center for afferent sensory pathways that regulates and transmits peripheral stimulation to various representative areas of the cortex. Aphasia, neglect and anosognosia were also reported to occur after thalamic lesions, in the absence of cortical pathology. However, considerable controversy exists as to the pathogenetic mechanisms, and incidence of cognitive abnormalities following thalamic lesions. We present a series of sixteen consecutive stroke patients with thalamic stroke (n=12) or hemorrhage (n=4), admitted to a university based neurology department. Dysphasia was observed in seven of eight patients with left thalamic strokes (five in the territory of the tuberothalamic artery, two inferior-lateral thalamic lesions and one in the area supplied by the anterior choroidal artery). Neglect and anosognosia appeared in five of eight patients with right side thalamic insults (two each in the territories of the tuberothalamic and thalamogeniculate arteries and one in the area supplied by the posterior choroidal artery). These findings reconfirm those found in previous studies and suggest that the thalamus is part of an integral neuronal network concerned with cognitive functions.

Adult↗
PubMed2000

Effects of sex hormones on experimental autoimmune myasthenia gravis.

To examine whether exacerbation of myasthenia gravis (MG) can be induced by changes in sex hormone levels we immunized 20 female Lewis rats with torpedo antigen to induce experimental autoimmune MG (EAMG). Ten of the animals underwent surgical ovariectomy prior to the induction of EAMG and 10 served as controls. Anti-acetylcholine receptor antibody (AChR-ab) titres and the degree of decrement on repetitive stimulation electromyography (REMG) at 3 Hz were obtained at base line and compared between rats with and without ovariectomy and a second control group of naïve rats. Three rats in each group were then injected with excess oestrogen and progesterone for one week, and three of the remaining rats in each group were given sham injections, and the degree of decrement on REMG and AchR-ab titres were re-evaluated. Immune reactivity of peripheral lymphocytes and splenic lymphocytes from all groups and controls was also determined. A comparable number of animals with and without ovariectomy developed clinical and electromyographic EAMG. The extent of decrement on REMG and AChR-ab titres did not change following hormonal replacement. Lymphocyte reactivity was similar for rats with and without ovariectomy. In conclusion, sex hormones do not appear to have an influence on the susceptibility to and the severity of MG.

Animals↗
PubMed2000

Activation of the adrenocortical axis by surgical stress: involvement of central norepinephrine and interleukin-1.

In the present study, we examined the mechanisms involved in the activation of the adrenocortical axis following surgical stress. Adult male rats underwent surgical laparotomy or craniotomy under ether anesthesia while control rats were only ether-anesthetized. Four hours following laparotomy or craniotomy, serum adrenocorticotropin (ACTH) and corticosterone (CS) were significantly increased and returned to almost basal levels after 24 h. Laparotomy also caused a significant depletion of corticotropin-releasing hormone (CRH-41) in the median eminence (ME). Pretreatment with dexamethasone 50 microg/kg completely abolished the pituitary-adrenal response while pretreatment with type II corticosteroid receptor antagonist caused a significant hypersecretion of both ACTH and CS and inhibited the effect of dexamethasone. The response to laparotomy was markedly attenuated in rats injected with 6-hydroxydopamine into the paraventricular nucleus (PVN) which significantly depletes norepinephrine (NE) PVN content. Intracerebroventricular injection of interleukin-1 receptor antagonist (IL-1ra) also inhibited the pituitary-adrenal response to laparotomy. The results suggest that (1) surgical stress activates the hypothalamo-pituitary-adrenal (HPA) axis via a mechanism which involves the release of CRH from the ME and NE input to the PVN; (2) the adrenocortical response is sensitive to the negative feedback of glucocorticoids via the mediation of type II glucocorticoid receptors, and (3) central IL-1 may be a mediator in the HPA axis response to surgical stress.

Adrenocorticotropic Hormone↗
PubMed1999

Dexanabinol; a novel neuroprotective drug in experimental focal cerebral ischemia.

The permanent middle cerebral artery occlusion (PMCAO) model was used to investigate the cerebroprotective effects of the synthetic cannabinoid, dexanabinol (HU-211). Dexanabinol is a noncompetitive N-methyl-D-aspartate antagonist, with antioxidant and anti-TNFalpha properties. Twenty hypertensive rats were subjected to PMCAO. Eight were given 4 mg/kg dexanabinol, i.v., 1 h after PMCAO, eight received vehicle and four were not injected Five rats underwent sham surgery. Infarct volumes were assessed, as well as TNFalpha concentrations and NOS activity in brain homogenates. Dexanabinol significantly decreased infarct volumes. It also significantly lowered TNFalpha levels in the ipsilateral hemisphere although not to the level of sham operated rats. No effect could be demonstrated on NOS activity. In conclusion, dexanabinol may be a pluripotent cerebroprotective agent.

Animals↗
PubMed1999

Subacute painful lumbosacral polyradiculoneuropathy in immunocompromised patients.

The syndrome of inflammatory subacute lumbosacral polyradiculoneuropathy (SLP) has been reported in acquired immunodeficiency syndrome (AIDS) patients in association with cytomegalovirus infection and is only partially amenable to anti-viral therapy. We report three cases of relatively benign inflammatory painful SLP in two non-AIDS, immunosuppressed patients and one who HIV-seroconversed at the time of clinical presentation. SLP developed: (1) in association with HIV seroconversion; (2) during ECHO virus infection in a patient with common variable immune deficiency; and (3) after a severe systemic infection that induced transient immunosuppression due to Epstein-Barr virus reactivation. This report expands the spectrum of viruses associated with acute and subacute lumbosacral polyradiculoneuropathy and may shed light on its possible pathogenesis.

Adult↗
PubMed1999

Features of dural sinus thrombosis simulating pseudotumor cerebri.

To characterize dural sinus thrombosis (DST) patients presenting with a syndrome simulating pseudotumor cerebri (PTC), medical records of patients initially diagnosed as having PTC between 1980 and 1995 were analysed. Inclusion criteria were intracranial hypertension (IH) and a normal initial computed tomography (CT) scan. All patients underwent angiography or magnetic resonance imaging (MRI) and magnetic resonance venography (MRV). Patients with IH secondary to a determined disorder were excluded from the study. Forty-six patients were included, 12 patients had MRI/MRV or angiography findings compatible with DST and the remaining 34 patients had no vascular pathology on neuroimaging studies and were considered to have PTC. No clinical or auxiliary findings differed between the two groups except for younger age, which delineated the PTC patients. Two patients with DST died during the study. Both were agitated, had a relatively rapid course of symptom progression, and a CSF pressure of over 40 cm water. We conclude that DST can be identified in 26% of patients presenting with symptoms and signs typical of PTC. It may be impossible to differentiate between patients with and without DST if MRI/MRV or angiography are not performed in this scenario.

Adult↗