Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury.

BACKGROUND: Traumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase-5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8-week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8-week course of sildenafil on chronic TBI symptoms. METHODS: Forty-six subjects (31 chronic TBI, 15 matched healthy volunteers) were enrolled. Baseline CBF and CVR before and after administration of sildenafil were measured. Symptomatic TBI subjects then completed an 8-week double-blind, placebo-controlled, crossover trial of sildenafil. A neuropsychological battery and neurobehavioral symptom questionnaires were administered at each study visit. RESULTS: After a single dose of sildenafil, TBI subjects showed a significant increase in global CVR compared to healthy controls (P < 0.001, d = 0.9). Post-sildenafil CVR maps showed near-normalization of CVR in many regions where baseline CVR was low, predominantly within areas without structural abnormalities. Sildenafil was well tolerated. Clinical Global Impression (CGI) scale showed a trend toward clinical improvement while on sildenafil treatment. FINDINGS: Single-dose sildenafil improves regional CVR deficits in chronic TBI patients. CVR and ΔCVR are potential predictive and pharmacodynamic biomarkers of PDE5 inhibitor therapy for TCVI. Sildenafil is a potential therapy for TCVI.

Imaging of Cerebrovascular Function in Chronic Traumatic Brain Injury.

Traumatic cerebrovascular injury (TCVI) is a common pathologic mechanism of traumatic brain injury (TBI) and presents an attractive target for intervention. The aims of this study were to assess cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) using magnetic resonance imaging (MRI) to assess their value as biomarkers of TCVI in chronic TBI, characterize the spatial distribution of TCVI, and assess the relationships between each biomarker and neuropsychological and clinical assessments. Forty-two subjects (27 chronic TBI, 15 age- and gender-matched healthy volunteers) were studied cross-sectionally. CBF was measured by arterial spin labeling and CVR by assessing the MRI-blood oxygen level-dependent signal with hypercapnia challenge. A focused neuropsychological battery adapted from the TBI Common Data Elements and neurobehavioral symptom questionnaires were administered at the time of the imaging session. Chronic TBI subjects showed a significant reduction in mean global, gray matter (GM), and white matter (WM) CVR, compared with healthy volunteers (p < 0.001). Mean GM CVR had the greatest effect size (Cohen's d = 0.9). CVR maps in chronic TBI subjects showed patchy, multifocal CVR deficits. CBF discriminated poorly between TBI subjects and healthy volunteers and did not correlate with CVR. Mean global CVR correlated best with chronic neurobehavioral symptoms among TBI subjects. Global, GM, and WM CVR are reliable and potentially useful biomarkers of TCVI in the chronic stage after moderate-to-severe TBI. CBF is less useful as biomarker of TCVI. CVR correlates best with chronic TBI symptoms. CVR has potential as a predictive and pharmacodynamic biomarker for interventions targeting TCVI.

Heterozygous knockout of cytosolic phospholipase A2α attenuates Alzheimer's disease pathology in APP/PS1 transgenic mice.

Cytosolic phospholipase A2α (cPLA2α) is a key enzyme in regulation of inflammation process and neuromembrane homeostasis, both of which are critical in pathogenesis of Alzheimer's diseases. By hybride APP/PS1 Tg-AD mice with cPLA2α knockout mice, three lines of APP/PS1 Tg-AD mice were produced with genotypes of cPLA2α+/+, cPLA2α+/- and cPLA2α-/-. Compared to cPLA2α+/+ Tg-AD mice, the amyloid plaque formation was significantly downregulated in the brain of cPLA2α+/- Tg-AD mice, but not in cPLA2α-/- Tg-AD mice. The reactive gliosis were also significantly downregulated in both cPLA2α+/- and cPLA2α-/- Tg-AD mouse lines. The paradoxical effects of cPLA2α on the amyloid plaques reveal a complex role of cPLA2α in pathogenesis of AD and could be a potential target for prevention and treatment of AD.

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid ß up to 90 Days after Traumatic Brain Injury.

Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid ß peptide (Aß42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and Aß42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP (p < 0.0001 for all comparisons), tau (p < 0.0001, p < 0.0001, and p = 0.0044, at Days 0, 30, and 90, respectively), and Aß42 (p < 0.001, p < 0.0001, and p = 0.0203, respectively) in TBI cases compared with controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for Aß42. Area under curve (AUC) analyses for Day 0 GFAP and tau were excellent for discrimination of complicated mild TBI (cmTBI) from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for all three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of post-traumatic amnesia (PTA) correlated weakly with tau levels at 30 days (Spearman's r = 0.40; 95% CI 0.0003-0.60, p = 0.044). The Marshall CT Grade on admission correlated weakly with Day 30 tau levels (Spearman's r = 0.41; 95% CI 0.04-0.68, p = 0.027). Day 30 Aß42 correlated with GOSE (standardized ß -0.486, p = 0.042). GFAP, tau and Aß42 were increased up to 90 days after TBI compared with controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Plasma Aß42 correlated with clinical outcome. Combination of all three biomarkers at Days 0 and 30 can be used to differentiate controls from cmTBI populations, and may be useful as biomarkers of TBI in both acute and subacute phases.

Temporal lobe volume predicts Wada memory test performance in patients with mesial temporal sclerosis.

The Wada test is widely used in the presurgical evaluation of potential temporal lobectomy patients to predict postoperative memory function. Expected asymmetry (EA), defined as Wada memory lateralized to the nonsurgical hemisphere, or a higher score after injection of the surgical hemisphere would be considered favorable in terms of postoperative memory outcome. However, in some cases, nonlateralized memory (NM) results, with no appreciable asymmetry, may occur because of impaired scores after both injections, often leading to denial of surgery. The reason for such nonlateralized Wada memory in patients with intractable temporal lobe epilepsy (TLE) remains unclear. Given that quantitative morphometric magnetic resonance imaging studies in TLE patients have shown bilateral regional atrophy in temporal and extratemporal structures, we hypothesized that the volume loss in contralateral temporal structures could contribute to nonlateralized Wada memory performance. To investigate this, we examined the relationship between the volume changes of temporal structures and Wada memory scores in patients with intractable TLE with mesial temporal sclerosis (MTS) using an age- and gender-matched control group. Memory was considered nonlateralized if the absolute difference in the total correct recall scores between ipsilateral and contralateral injections was <11%. Among 21 patients, Wada memory was lateralized in 15 and nonlateralized in 6 patients, with all the nonlateralized scores being observed in left TLE. The recall scores after ipsilateral injection were significantly lower in patients with an NM profile than an EA profile (23 ± 14% vs. 59 ± 18% correct recall, p ≤ 0.001). However, the recall scores after contralateral injection were low but similar between the two groups (25 ± 17% vs. 25 ± 15% correct recall, p=0.97). Compared to controls, all the patients showed greater volume loss in the temporal regions. However, patients with a NM profile showed significantly more volume loss than those with a lateralized memory profile in both contralateral and ipsilateral temporal regions (p<0.05). Left hemispheric Wada memory performance correlated positively with the size of the left mesial and neocortical temporal structures (r=0.49-0.63, p=0.005-0.04). Our study suggests that volume loss in the nonsurgical temporal structures is associated with nonlateralized Wada memory results in patients with intractable TLE.

Preservation and enumeration of endothelial progenitor and endothelial cells from peripheral blood for clinical trials.

AIMS: Endothelial progenitor cells (EPCs) are markers of vascular repair. Increased numbers of circulating endothelial cells (ECs) are associated with endothelial damage. MATERIALS & METHODS: We enumerated EPC-EC by using Enrichment kit with addition of anti-human CD146-PE/Cy7 from peripheral blood mononuclear cell (PBMC) isolated either by red blood cell (RBC) lysing solution or by Ficoll centrifugation, and from fresh and preserved samples. PBMCs were quantified by flow cytometry. RESULTS: RBC lysis yielded higher percentage of PBMC (p = 0.0242) and higher numbers of PBMC/ml (p = 0.0039) than Ficoll. Absolute numbers of CD34(+)CD133(+)VEGFR2(+) and CD146(+)CD34(+)VEGFR2(+) were higher (p = 0.0117 for both), when isolated by RBC lysis than by Ficoll, when no difference in other subsets was found. Cryopreservation at -160°C and -80°C and short-term preservation at room temperature decreased EPC-EC. CONCLUSIONS: Our data support use of fresh samples and isolation of PBMC from human blood by RBC lysis for enumeration of EPC and EC.

[Effectiveness of integrated schistosomiasis control strategy in marshlands of Qixia District, Nanjing City].

OBJECTIVE: To evaluate the effectiveness of integrated schistosomiasis control strategy in marshlands of Qixia District from 2004 to 2013. METHODS: The endemic situation and integrated control data of schistosomiasis in Qixia District from 2004 to 2013 were collected, and the morbidity and Oncomelania hupensis snail status before and after the implementa- tion of integrated schistosomiasis control strategy were compared. RESULTS: Following 10-year integrated schistosomiasis control, the human schistosome infection rate gradually decreased in Qixia District, and no infection was detected since 2007. A gradual reduction was observed in the infection rate of domestic animals, and all bovine was eliminated from the regions along the Yangtze River since 2006. In addition, the snail area and the density of living snails in 2013 reduced by 42.25% and 82.56% as compared to those in 2004, and no infected snails were found since 2009. In 2010, the district achieved schistoso- miasis transmission control. CONCLUSION: The integrated schistosomiasis control strategy is effective to accelerate schistoso- miasis control process and achieve the criteria of schistosomiasis transmission control rapidly.

Beta-amyloid auto-antibodies are reduced in Alzheimer's disease.

Accumulation and cytotoxicity of amyloid beta (Aß) are understood as the major cause of Alzheimer's disease (AD). There is evidence that naturally occurring antibodies against amyloid beta (Aß) protein play a role in Aß-clearance, and such a mechanism appears to be impaired in AD. In the present study, the anti-Aß antibodies in the serum from individuals with and without late onset AD were measured using ELISA and dot-blot methods. Aß auto-antibodies in serum were mainly targeted to Aß1-15 epitope and its titer was significantly lower in AD patients than elderly non-AD controls (NC). The dot-blot analysis further demonstrated that auto-antibodies against fibrillar Aß42, Aß1-15 and Aß16-30 epitopes were all in a lower level in AD than in NC. The isotypes of the auto-antibodies were mainly non-inflammatory IgG2 type. We also analyzed the relationship of auto-Aß antibody levels with the genotypes of apolipoprotein E (ApoE) and ANKK1/DRD2 gene.

[Surveillance of schistosomiasis in a national surveillance site, Nanzhong Village, Nanjing City, 2010-2011].

OBJECTIVE: To understand the dynamic of schistosomiasis epidemic situation in a national surveillance site, Nanzhong Village, Qixia District, Nanjing City, 2010-2011, so as to provide the evidence for evaluating the control effect and formulating prevention countermeasures. METHODS: According to the National Schistosomiasis Monitoring Program, the Oncomelania snail status and the situation of endemic schistosomiasis were surveyed and the data were analyzed statistically. RESULTS: The emergence rate of frames with living Oncomelania snails decreased by 11.67% and the average density of living snails decreased by 95.49% in 2011 compared to those in 2010. No infected snail was found during the past 2 years. The infection rate of schistosome in the permernant residents decreased from 9.93% (95/957) in 2010 to 1.35% (7/519) in 2011, and no acute schistosomiasis case was found. All the stool tests of schistosome infection in domestic animals were negative. CONCLUSIONS: The schistosomiasis epidemic situation shows a decline trend year by year which demonstrates the routine comprehensive control measures are effective. However, the snail habitat area has not decreased significantly. Therefore, we should strengthen the snail control and continue the surveillance of snail status and infectious sources of schistosomiasis.

cPLA2α knockout mice exhibit abnormalities in the architecture and synapses of cortical neurons.

Cytosolic phospholipase A2α (cPLA2α) affects membrane fluidity and permeability by catalyzing the hydrolysis of membrane phospholipids. We hypothesize that cPLA2α deficiency induces rigidity and architectural changes in cell membranes, especially in large cortical neurons. These membrane changes are discernible using light and electron microscopy. Through careful comparison with wild-type counterparts, we observed significant morphological changes in cortical neurons of cPLA2α knockout mice. These changes included the following: (1) increased numbers of nucleoli and enlarged nuclei, (2) narrower spaces between the inner and outer nuclear membranes, (3) reduced numbers of nuclear pores and altered nuclear pore structure, and (4) morphological changes in synaptic clefts. These results further suggest that cPLA2α and its cleaved arachidonic acids play important roles in cortical neuronal maturation and in normal neurochemical processes.

pH-induced outward movement of star centers within coumarin-centered star-block polymer micelles.

A novel coumarin-centered amphiphilic star-block polymer of C-(PDMAEMA(80)-b-PS(8))(3) has been designed to investigate the pH-induced accompanying outward movement of hydrophobic coumarin centers within the polymer micelles upon protonation.

The relationship of cardiovascular risk factors to Alzheimer disease in Choctaw Indians.

OBJECTIVES: To test the hypothesis that cardiovascular risk factors (CRFs) influence predisposition to and the clinical course of Alzheimer disease (AD), the authors compared Choctaw Indians, a group with known high CRF with white persons with AD. In addition to CRF history, the authors investigated the frequency of apolipoprotein E4 (apoE4) genotype andplasma homocysteine (HC) levels. METHOD: The authors compared 39 Choctaw Indians with AD and 39 Choctaw Indians without AD to 39 white persons with AD with all groups similar in age. CRF history included diabetes, hypertension, high cholesterol or hypolipidemic agent use, or myocardial infarction. The authors also compared plasma HC concentration and apoE4 allele frequency. RESULTS: Choctaw persons with AD differed significantly from white persons with AD in history of hypertension, diabetes, and in HC values but not from Indians without AD. There was a significantly lower apoE4 allele frequency in Choctaw Indian AD than white persons with AD, and both AD groups had an affected first degree relative significantly more often than Indian controls. There was no relationship between the number of CRF and age at onset among Indians or whites, whereas HC concentration was associated with significantly earlier age of onset for Choctaw Indians but not for whites. CONCLUSIONS: This small study suggests that in Choctaw Indians modifiable risk factors may play more of a role in disease pathogenesis than in whites and that nonmodifiable risk factors such as apoE4 may play less of a role.

[Snail control effect of film covering method in fish ponds and ditches].

OBJECTIVE: To evaluate the snail control effect of a film covering method in fish ponds and ditches. METHODS: Two fish ponds and 2 ditches with Oncomelania snails were selected as pilots, and 1 fish pond as Group A1 and I ditch as Group B1 received niclosamide spraying + film covering, and another fish pond as Group A2 and another ditch as Group B2 received niclosamide spraying only. The snail control effects were observed at 15, 30, 90 d and 360 d after the test, and the fish and other aquatic were also observed. RESULTS: In Group A1, the adjusted mortality rates of snails were 92.31%, 99.36% and 100% at 15, 30 d and 90 d after the test, respectively; in Group B1, the adjusted mortality rates of snails were 91.45%, 95.84% and 100% at 15, 30 d and 90 d after the test, respectively; and there was no death of fish. The densities of snails were 0 and 0.07 snails/0.1 m2 one year after the test, respectively. In Group A2, the adjusted mortality rates of snails were 75.36%, 72.59% and 65.76% at 15 d, 30 d and 90 d after the test, respectively; in Group B2, the adjusted mortality rates of snails were 70.36%, 72.87% and 75.82% at 15, 30 d and 90 d after the test, respectively; and there was death of fish. The densities of snails were 0.11 snails/0.1 m2 and 0.13 snails/0.1 m2 one year after the test, respectively. CONCLUSION: In ponds and ditches with snails, the niclosamide spraying + film covering method is very effective and safe.

Brain MRI, apoliprotein E genotype, and plasma homocysteine in American Indian Alzheimer disease patients and Indian controls.

We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61-89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5-13 years in the AD group and 12-16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 micromol/L vs. 9.8 micromol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eepsilon4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).

Host genetic polymorphisms in human immunodeficiency virus-related neurologic disease.

The objective of this study was to determine whether host genetic polymorphisms influence the risk of developing human immunodeficiency virus (HIV) encephalitis and vacuolar myelopathy. Allelic association studies were carried out with common polymorphisms in candidate genes that are postulated to play a role in the pathogenesis of HIV-related neurologic complications. The authors studied brains and spinal cords from 270 patients who died of acquired immunodeficiency syndrome (AIDS) from 1989 to 1996. All had complete gross and microscopic pathologic evaluations, and the presence of microglial nodules, multinucleated giant cells, myelin pallor, and vacuolar myelopathy was assessed by an experienced neuropathologist who was blinded to the genotype. DNA was extracted from frozen brain samples, and determination of the presence of the APOE4, TNF-2, IL-1B*2, ILIRN*2 polymorphisms was determined by polymerase chain reaction (PCR) and restricted fragment length polymorphism (RFLP) mapping. The authors did not detect a consistent association between inheritance of candidate polymorphic alleles and the pathologic findings of HIV encephalitis or vacuolar myelopathy. Allelic association studies with candidate genes are powerful techniques that have the potential to contribute to understanding the pathophysiology of HIV-related neurodegeneration. This preliminary study, although including a substantial number of patients, was not sufficiently powered to exclude a modest but clinically significant effects. Future studies will require much larger sample sizes and technical advances to allow screening at larger number of candidate loci.

Increased risk of late posttraumatic seizures associated with inheritance of APOE epsilon4 allele.

BACKGROUND: Late posttraumatic seizures are a common complication of moderate and severe traumatic brain injury. Inheritance of the apolipoprotein E (APOE) epsilon4 allele is associated with increased risk of Alzheimer disease, progression to disability in multiple sclerosis, and poor outcome after traumatic brain injury. OBJECTIVE: To determine whether inheritance of APOE epsilon4 is associated with increased risk of developing late posttraumatic seizures. DESIGN: Prospective study. SETTING: Neurosurgical service at an urban level I trauma center.Patients Patients admitted with a diagnosis of moderate and severe traumatic brain injury were enrolled. METHODS: Six months after injury, patients were contacted to determine functional outcome (according to the Glasgow Outcome Scale-Expanded [GOS-E]) and the presence of late posttraumatic seizures. Genotype at the APOE locus was determined by restriction fragment length polymorphism analysis. RESULTS: DNA and outcome information was obtained from 106 subjects. Six months after injury, 31 (29%) had a poor outcome (GOS-E score, 1-4), 47 (44%) had an intermediate outcome (GOS-E score, 5-6), and 28 (26%) had a favorable outcome (GOS-E score, 7-8). Twenty-one patients (20%) had at least 1 late posttraumatic seizure. The relative risk of late posttraumatic seizures for patients with the epsilon4 allele was 2.41 (95% confidence interval, 1.15-5.07; P =.03). In this cohort, inheritance of APOE epsilon4 was not associated with an unfavorable GOS-E score 6 (P =.47). CONCLUSIONS: Inheritance of the APOE epsilon4 allele is associated with increased risk of late posttraumatic seizures. In this cohort, this risk appears to be independent of an effect of epsilon4 on functional outcome. A better understanding of the molecular role of APOE in neurodegenerative diseases may be helpful in developing antiepileptogenic therapies.