BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies.

Brain-derived neurotrophic factor (BDNF), and full-length and truncated tyrosin kinase B receptor (TrkB) protein expression were examined by Western blotting and immunohistochemistry in the frontal cortex and hippocampus of individuals affected by long-lasting severe Alzheimer disease (AD) and age-matched controls. Since preliminary processing studies in the brains of rats have shown loss of immunoreactivity depending on the postmortem delay in tissue processing and on the type, duration, and temperature of the fixative solution, only human samples obtained up to 6 hours (h) after death for biochemical and morphological studies and fixed by immersion in 4% paraformaldehyde for 24 h for morphological studies were included in the present series. Decreased BDNF and full-length TrkB expression accompanied by increased truncated TrkB expression, as revealed by Western blotting, was observed in the frontal cortex of patients with AD. Immunohistochemistry disclosed reduced BDNF and full-length TrkB immunoreactivity in neurons. BDNF decrease was equally observed in tangle-bearing and non-tangle-bearing neurons, as revealed with double-labeling immunohistochemistry to BDNF and phosphorylated tau or phosphorylated neurofilament epitopes. Full-length TrkB immunoreactivity was largely decreased in tangle-bearing neurons, whereas only moderate decreases occurred in neurons with granulovacuolar degeneration. Strong BDNF immunoreactivity was observed in dystrophic neurites surrounding senile plaques, whereas strong TrkB expression occurred in reactive glial cells, including those surrounding senile plaques. Finally, truncated TrkB immunoreactivity was observed in individual neurons and in reactive glial cells in the cerebral cortex and white matter in AD. These results show decay in the expression of BDNF and TrkB in AD neurons, accompanied by altered BDNF, and full-length and truncated TrkB expression in dystrophic neurites and reactive glial cells, respectively, in this disease. The present results demonstrate selective decline of the BDNF/TrkB neurotrophic signaling pathway in the frontal cortex and hippocampus in AD and provide supplemental data that may be relevant in discussing the suitability of the use of BDNF as a therapeutic agent in patients with AD.     

Perfusion Deficits and Mismatch in Patients with Acute Lacunar Infarcts Studied with Whole-Brain CT Perfusion

BACKGROUND AND PURPOSE:The incidence and significance of perfusion abnormalities on brain imaging in patients with lacunar infarct are controversial. We studied the diagnostic yield of CTP and the type of perfusion abnormalities in patients presenting with a lacunar syndrome and in those with MR imaging–confirmed lacunar infarcts.MATERIALS AND METHODS:A cohort of 33 patients with lacunar syndrome underwent whole-brain CTP on admission. Twenty-eight patients had an acute ischemic lesion at follow-up MR imaging; 16 were classified as lacunar infarcts. Two independent readers evaluated NCCT and CTP to compare their diagnostic yield. In patients with DWI-confirmed lacunar infarcts and visible deficits on CTP, the presence of mismatch tissue was measured by using different perfusion thresholds.RESULTS:The symptomatic acute lesion was seen on CTP in 50% of patients presenting with a lacunar syndrome compared with only 17% on NCCT, and in 62% on CTP compared with 19% on NCCT, respectively, in patients with DWI-confirmed lacunar infarcts. CTP was more sensitive in supratentorial than in infratentorial lesions. In the nonblinded analysis, a perfusion deficit was observed in 12/16 patients with DWI-confirmed lacunar infarcts. The proportion of mismatch tissue was similar in patients with lacunar infarcts or nonlacunar strokes (32% versus 36%, P = .734).CONCLUSIONS:Whole-brain CTP is superior to NCCT in identifying small ischemic lesions, including lacunar infarcts, in patients presenting with a lacunar syndrome. Perfusion deficits and mismatch are frequent in lacunar infarcts, but larger studies are warranted to elucidate the clinical significance of these CTP findings.

Small-vessel disease is common and causes cognitive, psychiatric, and physical disability.¹ Lacunar infarcts (LIs) are one of the main manifestations of small-vessel disease, accounting for 10%–20% of all ischemic strokes, and they often present with the characteristic classic lacunar syndromes: pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, and dysarthria–clumsy hand syndrome. LIs are usually <1.5 cm wide and are often located in the territory of deep perforating arteries such as lenticulostriate, thalamoperforant, or paramedian territories. However, LIs can also result from in situ occlusion of single superficial perforators from pial arteries. LIs are thought to be related to arteriopathy of small blood vessels in the brain, either because of lipohyalinosis or microatheroma.² Less frequent causes are stenosis of a large vessel or microembolization.The sensitivity of neuroimaging techniques in acute LI is variable, ranging from 40% for NCCT scans,^3,4 80% for MR imaging,⁵ and up to 94% for DWI.⁶ Conflicting results have been reported regarding the presence of perfusion deficits in patients with LI,^7–11 with sensitivities varying from 0% to 68% in studies using MR imaging^12–14 and from 17% to 47% with CTP.^15,16 In fact, LI is considered one of the causes of false-negative CTP findings.^10,11 Some reports suggest that the presence of a perfusion deficit is associated with worse outcome in patients with LIs.^8,13 Regarding the presence of mismatch, a study using perfusion MR imaging did not find a mismatch between perfusion and diffusion sequences in strokes involving perforating arteries, but these results could be explained by the low resolution of their imaging methods.¹²In this study, we first assessed the clinical utility of CTP in the real-life scenario of patients presenting to the emergency department with a lacunar syndrome. Then, we studied the details of the perfusion abnormalities in a subgroup of patients with MR imaging–confirmed LIs and compared them with those of patients with nonlacunar infarcts.     

Antiviral activity of Spirulina maxima against herpes simplex virus type 2

Spirulina has been used in a variety of practical applications in biotechnology and medical sciences. This paper presents the antiviral activity found in a hot water extract (HWE) of a commercial preparation of Spirulina maxima, studied by a microplate inhibition assay, using several viruses. The HWE inhibited the infection for: herpes simplex virus type 2 (HSV-2), pseudorabies virus (PRV), human cytomegalovirus (HCMV), and HSV-1, and the 50% effective inhibition doses (ED(50)) were 0.069, 0.103, 0.142, and 0.333 mg/ml for each virus, respectively. For adenovirus the inhibition was less than 20%, and no inhibition was found for measles virus, subacute sclerosing panencephalitis virus (SSPE), vesicular stomatitis virus (VSV), poliovirus 1 and rotavirus SA-11, at concentrations of 2 mg/ml of the HWE. The highest antiviral activity was for HSV-2, with a selectivity index of 128. The antiviral activity was not due to a virucidal effect. Herpesvirus infection was inhibited at the initial events (adsorption and penetration) of the viral cycle. To initiate the isolation and identification of the compound that exhibits the antiviral activity of S. maxima, some extracts made by using several solvents with different polarity were evaluated by microplate inhibition assay using HSV-2. The highest antiviral activity was detected in the methanol-water 3:1, which suggests that the antiviral activity is probably due to highly polar compounds.     

Neuroprotective effect of Arthrospira (Spirulina) platensis against kainic acid-neuronal death

Context Arthrospira (Spirulina) platensis (SP) is a cyanobacterium which has attracted attention because of its nutritional value and pharmacological properties. It was previously reported that SP reduces oxidative stress in the hippocampus and protects against damaging neurobehavioural effects of systemic kainic acid (KA). It is widely known that the systemic administration of KA induces neuronal damage, specifically in the CA3 hippocampal region.

Objective The present study determines if the SP sub-chronic treatment has neuroprotective properties against KA.

Materials and methods Male SW mice were treated with SP during 24 d, at doses of 0, 200, and 800?mg/kg, once daily, and with KA (35?mg/kg, ip) as a single dose on day 14. After the treatment, a histological analysis was performed and the number of atrophic neuronal cells in CA3 hippocampal region was quantified.

Results Pretreatment with SP does not protect against seizures induced by KA. However, mortality in the SP 200 and the SP 800 groups was of 20%, while for the KA group, it was of 60%. A single KA ip administration produced a considerable neuronal damage, whereas both doses of SP sub-chronic treatment reduced the number of atrophic neurons in CA3 hippocampal region with respect to the KA group.

Discussion The SP neurobehaviour improvement after KA systemic administration correlates with the capacity of SP to reduce KA-neuronal death in CA3 hippocampal cells. This neuroprotection may be related to the antioxidant properties of SP.

Conclusion SP reduces KA-neuronal death in CA3 hippocampal cells.     

Hypolipidaemic and antiplatelet activity of phenoxyacetic acid derivatives related to alpha-asarone

The phenoxyacetic acid derivatives 1-6 [2-methoxy-4-(2-propenyl)phenoxyacetic acid (1); 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetic acid (2); methyl 2-methoxy-4-(2-propenyl)phenoxyacetate (3); ethyl 2-methoxy-4-(2-propenyl)phenoxyacetate (4); methyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate (5); ethyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate (6)] related to alpha-asarone have been reported previously as hypolipidaemic agents in diet-induced hyperlipidaemic mice. We have aimed to expand the pharmacological profile of these derivatives by investigating their hypolipidaemic activity in rats and mice under different experimental conditions. The antiplatelet activity was tested also in-vitro from blood derived from consenting healthy volunteers. In normolipidaemic rats, compounds 2, 3 and 5 at oral doses of 40 and 80 mg kg(-1) significantly decreased total cholesterol and LDL-cholesterol levels. Moreover, analogues 3 and 5 administered to hypercholesterolaemic rats at the same doses for seven days also produced a reduction in the content of these same lipoproteins. In neither case were the high-density lipoprotein cholesterol and triglyceride concentrations affected. However, practically all tested compounds were found to be hypocholesterolaemic agents, and were shown to effectively lower low-density lipoprotein cholesterol and triglyceride levels in Triton-induced hyperlipidaemic mice at oral doses of 50 and 100 mg kg(-1). In all tests, all animals appeared to be healthy throughout the experimental period in their therapeutic ranges. Triton-induced hypercholesterolaemic mice appeared to be a desirable model for this class of hypolipidaemic drugs. On the other hand, compounds 1, 2, 4 and 5 significantly inhibited ADP-induced aggregation in-vitro. These findings indicated that all of these compounds appeared to be promising for the treatment of human hyperlipidaemia and thrombotic diseases.     

Environmental lead contamination in Miami inner-city area

OBJECTIVES: The purpose of the study was to evaluate the magnitude of environmental lead contamination in the downtown area of Miami. Methods: Lead inspections took place at 121 homes in Little Haiti and Liberty City and involved the collection of representative samples from floors, window wells, tap water, soil and air. Community health workers (CHWs) trained in interview and safety techniques went from door to door to enlist participation. On-site investigations were tailored to areas most utilized by children under the age of 6 years. The presence of lead-containing paint was also investigated in situ via X-ray fluorescence (XRF) analysis. Results: Of the sampling areas, the window wells area had the most abundant occurrence of lead. On analysis, 24% of sites returned window well samples with lead levels above Department of Housing and Urban Development (HUD) guidelines. Of the soil samples, the playgrounds around the house had the highest concentration of lead. Soil sampling demonstrated that 27.5% of sites returned samples with lead levels (400 to 1600 ppm) in excess of HUD/Environmental Protection Agency (EPA) standards. Positive XRF readings in one or more components were returned by 18% of sites. Conclusions: More than half of the houses in these two neighborhoods exhibited unacceptably high levels of lead dust and soil in areas where children live and play. Limitations of this study did not allow the assessment of how many children in this area are affected. A more comprehensive study including other areas of Miami-Dade County with older housing stock is recommended.     

Quercetin and naringenin reduce abnormal development of mouse embryos produced by hydroxyurea

Objectives There is limited evidence about the impact of quercetin and naringenin on embryonic development. The purpose of this work was to evaluate in vitro their direct teratogenic potential as well as their protective activity against teratogenesis mediated by oxidative damage on mouse embryos. Methods Quercetin and naringenin toxicity on whole mouse cultured embryos, as well as their ability to protect embryos against hydroxyurea‐induced insult were evaluated. Key findings Quercetin 100 µm and naringenin 300 µm produced significant reduction of developmental and growth parameters, in comparison with those of the control group. Embryos exposed to the concurrent administration of quercetin or naringenin with hydroxyurea (2 µm , 2 h) were significantly protected from growth and developmental retardation, and abnormalities induced by hydroxyurea. Interestingly, embryos exposed to hydroxyurea and dimethyl sulfoxide 0.1%, the vehicle employed to dissolve flavonoids, also showed significant damage amelioration. Conclusions These results indicate that quercetin and naringenin have not only a minor toxic effect on development, but also a protective effect against hydroxyurea‐induced embryonic damage.     

Interaction between interleukin-6 and the natural anticoagulant system in acute stroke.

Inflammatory reactions mediated by cytokines are involved in the pathogenesis of acute stroke. Decrease in circulating levels of protein C (PC) and protein S (PS) induced by inflammatory cytokines has been postulated as a potential mechanism for a procoagulant tendency during acute stroke. The procoagulant state associated with impairments in natural anticoagulants may induce microvascular obstruction leading to a tissue perfusion reduction that worsens cerebral ischemia. Interleukin-6 (IL-6) regulate the synthesis of C4b-binding protein (C4BP), an acute-phase protein that also regulates PS plasma levels. We measured IL-6, C4BP, erythrocyte sedimentation rate (ESR), total and free PS and PC in 44 patients with acute ischemic stroke to determine if IL-6 decreases circulating levels of natural anticoagulants through the C4BP pathway and if these acute changes in natural anticoagulants may have clinical implications. Patients with higher levels of IL-6 had more severe neurologic deficits on admission, greater infarct size, higher levels of acute-phase reactants, and lower levels of free PS. IL-6 was significantly correlated with C4BP, ESR, and free PS levels. PC levels were also lower in the group of patients with greater IL-6, but differences were not statistically significant. No correlations were found between C4BP and natural anticoagulants. Severe neurologic deficit, greater infarct volume, atrial fibrillation, increased levels of inflammatory parameters (ESR and IL-6), and reduced levels of free PS were associated with disabling stroke at 3 months, but only neurologic severity and ESR remained as independent predictors of stroke disability on multiple regression analysis. Inflammatory reactions mediated by IL-6 during the acute phase of stroke influence the modulation of free PS. However, variations in free PS levels do not have implications for clinical outcome in stroke patients. The link between proinflammatory cytokines and free PS in the acute phase of stroke is not related to the C4BP pathway.     

Evolution of laparoscopic cholecystectomy in the regional hospitals of Catalonia.

OBJECTIVE: to assess the safety and effectiveness of laparoscopic cholecystectomy in the hands of surgeons with different amounts of experience in laparoscopic surgery at 15 regional hospitals, and to analyze the evolution of the current performance in comparison with results published in 1993. METHODS: prospective study of 1168 laparoscopic cholecystectomies done in 1996 in 15 regional hospitals in Catalonia. RESULTS: in 887 cases (76%) the indication was uncomplicated cholelithiasis. Preoperative cholangiography was done selectively in 12 of the 15 hospitals. Preoperative endoscopic retrograde cholangiopancreatography was positive in only 50 cases (57.4%), with 9 complications (10.3%). In 87 patients (7.4%) conversions to open surgery occurred. Postoperative complications (6. 3%), bile duct injury (0.4%), reintervention (0.4%) and postoperative stay (2.8 days) decreased in comparison with the year 1993. CONCLUSIONS: the current results suggest an overall improvement in comparison with the 1993 findings, since the rate of complications and length of stay decreased. However, the increasing number of conversions was notable; this may be due to the increasing complexity of the indications and the rise in the number of surgeons still on the learning curve. Laparoscopic cholecystectomy is, in our setting and for many surgeons, a safe and effective procedure that yields results similar to those in other multicenter studies.