Dynamic perfusion-CT assessment of early changes in blood brain barrier permeability of acute ischaemic stroke patients.

BACKGROUND AND PURPOSE: Damage to the blood brain barrier (BBB) may lead to haemorrhagic transformation after ischaemic stroke. The purpose of this study was to evaluate the effect of patient characteristics and stroke severity on admission BBB permeability (BBBP) values measured with perfusion-CT (PCT) in acute ischaemic stroke patients. METHODS: We retrospectively identified 65 patients with proven ischaemic stroke admitted within 12 hours after symptom onset. Patients' charts were reviewed for demographic variables and vascular risk factors. The Patlak's model was applied to calculate BBBP values from the PCT data in the infarct core, penumbra and non-ischaemic tissue in the contralateral hemisphere. Mean BBBP values and their 95% confidence intervals (CI) were calculated in the different tissue types. Effects of demographic variables and risk factors on BBBP were analyzed using a multivariate, generalized estimating equations (GEE) model. RESULTS: BBBP values in the infarct core (mean [95%CI]: 2.48 [2.16-2.85]) and penumbra (2.48 [2.21-2.79]) were significantly higher than in non-ischaemic tissue (2.12 [1.88-2.39]). Multivariate analysis demonstrated that collateral filling has effect on BBBP. Less elevated BBBP values were associated with more than 50% collateral filling. CONCLUSIONS: BBBP values are increased in ischaemic brain tissue on the admission PCT scan of acute ischaemic stroke patients. Less abnormally elevated BBBP values were observed in patients with more than 50% collateral filling, possibly explaining why there is a relationship between more collateral filling and a lower incidence of haemorrhagic transformation.

Macroclimate associated with urbanization increases the rate of secondary succession from fallow soil.

To examine the impact of projected climate changes on secondary succession, we exposed the same fallow soil with a common seed bank to an in situ gradient of urban to rural macroenvironments that differed in temperature and CO2 concentration ([CO2]). This gradient was established at three locations: Baltimore city center (urban), a city park on the outskirts of Baltimore (suburban), and an organic farm 87 km from the Baltimore city center site (rural). Over a five-year period, the urban site averaged 2.1 degrees C warmer and had a [CO2] that was ~20% higher than at the rural location, indicating that this gradient was a reasonable surrogate for projected changes in those variables for this century. Previous work had demonstrated that other abiotic variables measured across the transect, including tropospheric ozone and nitrogen deposition, did not differ consistently. The first year of exposure resulted in (two- to threefold) greater aboveground biomass in the urban relative to the rural site, but with uniform species composition across sites. Simple regression of abiotic variables indicated that temperature and vapor pressure deficit (VPD) were the best predictors of plant biomass among locations. Stepwise multiple regressions were also performed to analyze the effect of more than one macroenvironmental variable on total plant biomass. The combination of daily CO2 concentration and nighttime temperature explained 87% (P < 0.01) of the variability in total biomass between sites. After five years, the species demography of the plant communities had changed significantly, with a greater ratio of perennials to annuals for the urban relative to the rural location. Greater first-year biomass and litter accumulation at the urban site may have suppressed the subsequent seed germination of annual species, accelerating changes in species composition. If urban macroenvironments reflect future global change conditions, these data suggest a faster rate of secondary succession in a warmer, higher [CO2] world.

Age- and anatomy-related values of blood-brain barrier permeability measured by perfusion-CT in non-stroke patients.

BACKGROUND AND PURPOSE: The goal of this study was to determine blood-brain barrier permeability (BBBP) values extracted from perfusion-CT (PCT) using the Patlak model and possible variations related to age, gender, race, vascular risk factors and their treatment and anatomy in non-stroke patients. MATERIALS AND METHODS: We retrospectively identified 96 non-stroke patients who underwent a PCT study using a prolonged acquisition time up to 3 minutes. Patients' charts were reviewed for demographic data, vascular risk factors and their treatment. The Patlak model was applied to calculate BBBP values in regions of interest drawn within the basal ganglia and the gray and white matter of the different cerebral lobes. Differences in BBBP values were analyzed using a multivariate analysis considering clinical variables and anatomy. RESULTS: Mean absolute BBBP values were 1.2 ml 100 g(-1) min(-1) and relative BBBP/CBF values were 3.5%. Statistical differences between gray and white matter were not clinically relevant. BBBP values were influenced by age, history of diabetes and/or hypertension and aspirin intake. CONCLUSION: This study reports ranges of BBBP values in non-stroke patients calculated from delayed phase PCT data using the Patlak model. These ranges will be useful to detect abnormal BBBP values when assessing patients with cerebral infarction for the risk of hemorrhagic transformation.

Development of multiplex PCR-ligase detection reaction assay for detection of West Nile virus.

We have developed a novel multiplex reverse transcription-PCR ligase detection reaction (RT-PCR/LDR) assay for the detection of West Nile virus (WNV) in both clinical and mosquito pool samples. The method relies on the amplification of three different genomic regions, one in the coding sequence of nonstructural protein NS2a and two in nonstructural protein NS5, to minimize the risk of detection failure due to genetic variation. The sensitivity of the PCR is complemented by the high specificity of the LDR step, and the detection of the LDR products can be achieved with capillary electrophoresis (CE) or a universal DNA microarray. We evaluated the limit of detection by both one-step and two-step multiplex RT-PCR/LDR/CE approaches, which reached, respectively, 0.005 and 0.017 PFU. The assay demonstrated 99% sensitivity when mosquito pool samples were tested and 100% sensitivity with clinical samples when the one-step approach was used. The broad strain coverage was confirmed by testing 34 WNV isolates belonging to lineages 1 and 2, and the high specificity of the assay was determined by testing other flaviviruses, as well as negative mosquito pool and clinical samples. In summary, the multiplex RT-PCR/LDR assay could represent a valuable complement to WNV serological diagnosis, especially in early symptomatic patients. In addition, the multiplexing capacity of the technique, which can be coupled to universal DNA microarray detection, makes it an amenable tool to develop a more comprehensive assay for viral pathogens.

The amyloidogenic peptide human amylin augments the inflammatory activities of eosinophils.

The amyloidogenic peptides, amyloid-beta (A beta) and human amylin, are the major constituents of amyloid deposits found in patients with the chronic degenerative disorders Alzheimer's disease (AD) and type 2 diabetes, respectively. Recent studies have shown that a variety of inflammatory proteins such as cytokines are associated with the amyloid deposits of AD brain tissues. Therefore, in the present study, we sought to determine whether A beta and/or human amylin could modulate the various inflammatory activities of eosinophils. We observed that human amylin but not A beta peptides inhibited the in vitro interleukin-5 (IL-5)-mediated survival of cord blood-derived eosinophils (CBEs) in a concentration-dependent manner. By contrast, rat amylin, a nonamyloidogenic peptide that is highly homologous to human amylin, failed to affect the IL-5-mediated survival of CBEs. Similar inhibitory effects of human amylin were observed for peripheral blood eosinophils. Human amylin also enhanced the release of the cytokine granulocyte-macrophage colony-stimulating factor by CBEs that were stimulated with the calcium ionophore A23187 but was incapable of directly stimulating CBEs to release cytokines. In addition, the A23187-induced release of the inflammatory lipid mediator leukotriene C4 by CBEs was augmented by human amylin. These results suggest that the amyloidogenic peptide human amylin is capable of amplifying the various inflammatory activities of eosinophils.

Dissociation of affinity and efficacy in KOR-3 chimeras.

KOR-3 chimeras were constructed in which the first coding exon of KOR-3 was exchanged for the corresponding first coding exon of either MOR-1 (MOR-1/KOR-3) or DOR-1 (DOR-1/KOR-3). All three clones were expressed in CHO cells and characterized with regards to their binding profiles for orphanin FQ/nociceptin (OFQ/N) and a variety of opioids as well as their functional activities in cyclase studies. 125I[Tyr14]OFQ/N labels both KOR-3 (KD 37 pM) and the MOR-1/KOR-3 chimera (KD 39 pM) equally well. Although its affinity for the DOR-1/KOR-3 chimera is quite good (KD 135 pM), it is slightly lower than the other two. Competition studies confirm the high affinity of OFQ/N for all three clones. However, several competitors clearly distinguish the chimeras from KOR-3. OFQ/N(1-11) competes KOR-3 (Ki 55 nM) over 6-fold more potently than either of the chimeras. (Ki values > 350 nM). Conversely, the modest affinity of naloxone benzoylhydrazone for KOR-3 (310 nM) is greatly increased in both the MOR-1/KOR-3 (Ki 69 nM) and DOR-1/KOR-3 (Ki 74 nM) chimeras. The remainder of the opioids tested have no appreciable affinity against any of the clones. Functionally, OFQ/N inhibits forskolin-stimulated cAMP accumulation in both the KOR-3 and the MOR-1/KOR-3 chimera by almost 40%, with IC50 values in the low nanomolar range. Little activity is seen against the DOR-1/KOR-3 chimera. Naloxone benzoylhydrazone inhibits cAMP accumulation in the KOR-3 and the DOR-1/KOR-3 chimera. Although naloxone benzoylhydrazone has higher affinity for the MOR-1/KOR-3 chimera in binding studies than KOR-3 itself, it is inactive in cyclase studies using the MOR-1/KOR-3 chimera, implying that the replacement of the first coding exon increases affinity while decreasing intrinsic activity.

Single photon tomography in Alzheimer's disease and the dementias.

Measurements of brain blood flow has evolved over the past 50 years, and during the latter half of that time radionuclide techniques have been used to study this important function. Using Xenon 133 and scintillation multiprobe systems, several teams of investigators measured regional cerebral blood flow (rCBF), and noted that under many circumstances it could be equated with local brain physiological activity. The dementias were investigated using the scintillation multiprobe method, and posterior flow deficits were described in patients who were thought to have Alzheimer's disease. The multiprobe technique gave way first to planar, and then tomographic imaging, with initial favorable results achieved by positron emission tomography (PET). Soon investigators learned to measure rCBF with single-photon emission computed tomography (SPECT) using high-sensitivity systems and 133Xe as a tracer, or high-resolution systems with 123I-iodoamphetamine (IMP), and later, 99mTc-HMPAO. Three-dimensional tomographic imaging shows to advantage the flow patterns that characterize Alzheimer's disease, with rCBF reductions in temporal, parietal, and sometimes frontal areas, as opposed to randomly distributed deficits in multiinfarct dementia, reduced frontal flow in entities such as Pick's disease, and others. Herein we will review our own experience with high-sensitivity rCBF SPECT in 119 patients with dementia, and with high-resolution SPECT, using a new, three-camera scanner and 99mTc-HMPAO in an additional 39 patients. SPECT rCBF study of patients with dementia and Alzheimer's disease, will aid in separating patients with untreatable Alzheimer's from those patients who may have treatable causes of dementia, and will be useful in evaluating experimental drugs for the treatment of Alzheimer's disease.

Experiences with depression in a dementia clinic.

Of 317 consecutive cases seen in a dementia clinic, 19 (6%) had little or no objective evidence of cognitive impairment on clinical examination and extensive neuropsychological testing. Of the remaining 298 cases, 192 (64%) were diagnosed as probable or possible Alzheimer's disease (AD). Of the 19 nondemented cases, 8 (42%) were thought to have cognitive difficulty due to depression. In the AD group, only 4 cases (2%) were thought to be depressed and only 2 of the 4 met DSM-III-R criteria for major depression. There was no relationship between Hamilton Rating Scale for Depression scores and either cognitive or behavioral measurements of dementia severity, suggesting that the difference between the two groups was not due to underreporting by AD patients. The authors concluded that a tertiary care setting, depression is a common cause of cognitive complaints in persons without organic disease and a rare cause of excess morbidity in AD.

The effect of acetazolamide on regional cerebral blood flow in patients with Alzheimer's disease or stroke as measured by single-photon emission computed tomography.

Regional cerebral blood flow (rCBF) was assessed in 35 patients with possible or probable Alzheimer's disease (AD) and in 16 patients known to have had at least one stroke. Patients were evaluated before and after the administration of 1 g acetazolamide (ACZ) by means of a rotating four-detector single-photon emission computed tomograph (SPECT) and inhaled Xe-133. RCBF values in mL/minute/100 g were derived from eight cortical regions of interest (ROI), and from the whole transverse section as a measure of whole brain flow (WBF). ROI/WBF ratios were calculated for each ROI in paired determinations done before and 15 minutes after the administration of ACZ. Results were compared with those previously obtained in a study of 15 normal, healthy volunteer subjects. ROI/WBF ratios greater than 2 standard deviations (SD) below the mean for a given ROI in the normal group were regarded as probably abnormal, whereas ratios greater than 4 SD below the mean were considered definitely abnormal. After ACZ administration, the number of ROI greater than 2 SD below the normal mean decreased significantly in the AD group and was unchanged in the stroke patients. However, the number of ROI/WBF ratios greater than 4 SD below the normal mean fell in the AD group and rose in the stroke group, with the difference in behavior highly statistically significant. Thus, the response of low-flow areas to ACZ differs in AD and in stroke, which could be of ultimate diagnostic significance.

Merkel cell carcinoma of the vulva.

The authors describe the clinical and histologic findings in a case of Merkel cell carcinoma of the vulva, which was associated with squamous cell carcinoma in situ and lichen sclerosus. Electron microscopy of the tumor revealed membrane-bound granules. At postmortem examination, metastases from this primary skin tumor were found in the pelvic lymph nodes, in paraortic lymph nodes, in the liver, and in vertebral bodies. The case is unusual because Merkel cell tumors are usually found on the face or the extremities and seldom metastasize widely.

Neuroprotection with herpes simplex vectors expressing virally derived anti-apoptotic agents.

A large body of literature dealing with neurotoxicity has focused on trying to define the exact nature of cell death following a neurological insult. While there is some debate in the field, it has been shown that a number of neurons in a given population can respond to an acute insult stimulus by activating the apoptotic cascade. To what extent, however, these insults result in the classical manifestations of either apoptosis or necrosis, or whether a mixture of the two results, is highly controversial, in part dependent on the particular system utilized. In this paper, we investigate the role of particular apoptotic signals in cultured rat hippocampal neurons, following acute excitotoxicity, metabolic poisoning, and heat stress. In particular, we examine these effects by utilizing a modified herpes simplex viral vector to specifically deliver viral anti-apoptotic genes. We have selected a battery of viral genes (crmA, p35, gamma34.5, KsBcl-2) that have evolved to suppress suicidal host responses to infection. We examine these inhibitors in the face of the above classes of insults and report that each viral agent tested has a unique profile in its ability to protect hippocampal neurons following acute neurological insults. Specifically, the effects of domoic acid excitotoxicity can be alleviated only with crmA, p35 and gamma34.5 whereas all genes tested can protect against heat stress. Conversely, no genes tested can protect against metabolic poisoning by cyanide. Such a study helps us to further understand the nature of apoptotic signals in different insults.

Human cortical neuronal (HCN) cell lines: a model for amyloid beta neurotoxicity.

Human cortical neuronal cell lines HCN-1A and HCN-2 are killed for following exposure of the differentiated cells to amyloid beta-peptide(1-40), a component of senile plaques and other amyloid deposits in brains from Alzheimer's patients. We present a model of A beta toxicity uncomplicated by the presence of other cell types that can be used to address the mechanism of A beta neurotoxicity. This model will be useful in the evaluation of neuroprotective compounds which may attenuate cortical neuronal loss in Alzheimer's disease.

General and specific cognitive dysfunctions in patients with Alzheimer's disease.

The purpose of the present study was to investigate the effect of Alzheimer's disease (AD) on general and specific neuropsychological function. Thirty-five subjects diagnosed with AD were compared to 30 medically normal aging control subjects using measures from the Halstead-Reitan Battery (HRB). All AD subjects were classified as "probable" AD (NINCDS-ADRDA) and found to be in the "late confusional" to "early dementia" stages of the disease (Global Deterioration Scale, GDS = 4-5). The AD group performed significantly worse than the controls on all measures of general neuropsychological function and almost all measures of specific functions. However, no differences were found between groups on motor abilities or many simple sensory functions. The findings demonstrate dramatic brain-behavior changes involving both general and specific cognitive functions which go beyond memory dysfunction even in the earlier stages of the disease. The neuropsychological pattern found may be the basis of a useful clinical-behavioral AD pattern in the earlier stages of the disease.

Neuropsychological correlates of Gulf War syndrome.

As part of a comprehensive multispecialty project, the present study reports on the neurocognitive and psychological function of veterans who report Persian Gulf War-related symptoms. The neuropsychological and psychological performances of 26 ill Gulf War veterans were compared to 20 well veterans from the same military unit. Neurocognitive functions assessed included intelligence, abstraction and problem-solving, attention and concentration, memory and learning, language and visual-spatial function, and sensorimotor abilities. Psychological function was measured by self-report questionnaires. Results indicated global and consistently poorer intellectual and neurocognitive function among the ill veterans compared to the control veterans. A generalized pattern of neuropsychological deficit was evident for the ill veterans. Psychological profiles of the ill veterans were similar to those in general medical patients. Based on these findings and results from the multispecialty investigation, we conclude that some of the ill veterans have experienced neurotoxic injury resulting in chronic neuropsychological impairment that is related to their service in the Persian Gulf War.

Adenocarcinoma with a neuroendocrine component arising in the urachus. A case report.

The clinical, cytologic, histologic and ultrastructural findings in a mixed adenocarcinoma and neuroendocrine carcinoma of the urinary bladder urachus, an extremely rare tumor only recently described, are presented for a 31-year-old woman who died of widespread metastatic disease six months following the initial diagnosis and treatment. Cytologic study of voided urine and bladder washings disclosed the presence of malignant cells with the features of a small cell carcinoma; retrospectively, scarce adenocarcinoma cells were also identified in those specimens. Histologic study of resection specimens, including the use of special stains and electron microscopy, confirmed the presence of a small cell component, consistent with the poor prognosis in this case. Image analysis measurements of the malignant cells suggested a high proliferation rate.

[The effect of ivermectin on the longevity of Simulium damnosum]. / Etude de l'effet de l'ivermectine sur la longévité de Simulium damnosum.

Studies on various blood-sucking arthropods have shown an increased mortality after feeding on hosts previously treated with ivermectin. We investigated in Cameroon the survival of blackflies (Simulium damnosum s.s. and S. sirbanum) fed on patients who had been treated at a dose of 150 micrograms/kg 3-13 days before the blood meal. The mortality rates were not significantly reduced when compared with those of flies fed on untreated individuals.

Delay correction for the assessment of blood-brain barrier permeability using first-pass dynamic perfusion CT.

SUMMARY: Hemorrhagic transformation is a serious potential complication of ischemic stroke with damage to the BBB as one of the contributing mechanisms. BBB permeability measurements extracted from PCT by using the Patlak model can provide a valuable assessment of the extent of BBB damage. Unfortunately, Patlak assumptions require extended PCT acquisition, increasing the risk of motion artifacts. A necessary correction is presented for obtaining accurate BBB permeability measurements from first-pass PCT.

Blood-brain barrier permeability assessed by perfusion CT predicts symptomatic hemorrhagic transformation and malignant edema in acute ischemic stroke.

BACKGROUND AND PURPOSE: SHT and ME are feared complications in patients with acute ischemic stroke. They occur >10 times more frequently in tPA-treated versus placebo-treated patients. Our goal was to evaluate the sensitivity and specificity of admission BBBP measurements derived from PCT in predicting the development of SHT and ME in patients with acute ischemic stroke. MATERIALS AND METHODS: We retrospectively analyzed a dataset consisting of 32 consecutive patients with acute ischemic stroke with appropriate admission and follow-up imaging. We calculated admission BBBP by using delayed-acquisition PCT data and the Patlak model. Collateral flow was assessed on the admission CTA, while recanalization and reperfusion were assessed on the follow-up CTA and PCT, respectively. SHT and ME were defined according to ECASS III criteria. Clinical data were obtained from chart review. In our univariate and forward selection-based multivariate analysis for predictors of SHT and ME, we incorporated both clinical and imaging variables, including age, admission NIHSS score, admission blood glucose level, admission blood pressure, time from symptom onset to scanning, treatment type, admission PCT-defined infarct volume, admission BBBP, collateral flow, recanalization, and reperfusion. Optimal sensitivity and specificity for SHT and ME prediction were calculated by using ROC analysis. RESULTS: In our sample of 32 patients, 3 developed SHT and 3 developed ME. Of the 3 patients with SHT, 2 received IV tPA, while 1 received IA tPA and treatment with the Merci device; of the 3 patients with ME, 2 received IV tPA, while 1 received IA tPA and treatment with the Merci device. Admission BBBP measurements above the threshold were 100% sensitive and 79% specific in predicting SHT and ME. Furthermore, all patients with SHT and ME--and only those with SHT and ME--had admission BBBP measurements above the threshold, were older than 65 years of age, and received tPA. Admission BBBP, age, and tPA were the independent predictors of SHT and ME in our forward selection-based multivariate analysis. Of these 3 variables, only BBBP measurements and age were known before making the decision of administering tPA and thus are clinically meaningful. CONCLUSIONS: Admission BBBP, a pretreatment measurement, was 100% sensitive and 79% specific in predicting SHT and ME.

Optimal duration of acquisition for dynamic perfusion CT assessment of blood-brain barrier permeability using the Patlak model.

BACKGROUND AND PURPOSE: A previous study demonstrated the need to use delayed acquisition rather than first-pass data for accurate blood-brain barrier permeability surface product (BBBP) calculation from perfusion CT (PCT) according to the Patlak model, but the optimal duration of the delayed acquisition has not been established. Our goal was to determine the optimal duration of the delayed PCT acquisition to obtain accurate BBBP measurements while minimizing potential motion artifacts and radiation dose. MATERIALS AND METHODS: We retrospectively identified 23 consecutive patients with acute ischemic anterior circulation stroke who underwent a PCT study with delayed acquisition. The Patlak model was applied for the full delayed acquisition (90-240 seconds) and also for truncated analysis windows (90-210, 90-180, 90-150, 90-120 seconds). Linear regression of Patlak plots was performed separately for the full and truncated analysis windows, and the slope of these regression lines was used to indicate BBBP. The full and truncated analysis windows were compared in terms of the resulting BBBP values and the quality of the Patlak fitting. RESULTS: BBBP values in the infarct and penumbra were similar for the full 90- to 240-second acquisition (95% confidence intervals for the infarct and penumbra: 1.62-2.47 and 1.75-2.41 mL x100 g(-1) x min(-1), respectively) and the 90- to 210-second analysis window (1.82-2.76 and 2.01-2.74 mL x 100 g(-1) x min(-1), respectively). BBBP values increased significantly with shorter acquisitions. The quality of the Patlak fit was excellent for the full 90- to 240-second and 90- to 210-second acquisitions, but it degraded with shorter acquisitions. CONCLUSIONS: The duration for the delayed PCT acquisition should be at least 210 seconds, because acquisitions shorter than 210 seconds lead to significantly overestimated BBBP values.