Rest-activity patterns associated with delirium in patients with intracerebral hemorrhage.

BACKGROUND: Delirium is an acute cognitive disturbance frequently characterized by abnormal psychomotor activity and sleep-wake cycle disruption. However, the degree to which delirium affects activity patterns in the acute period after stroke is unclear. We aimed to examine these patterns in a cohort of patients with intracerebral hemorrhage (ICH). METHODS: We enrolled 40 patients with intracerebral hemorrhage (ICH) who had daily DSM-5-based delirium assessments. Continuous activity measurements were captured using bilateral wrist actigraphs throughout each patient's admission. Activity data were collected in 1-min intervals, with "rest" defined as periods with zero activity. We compared differences in activity based on delirium status across multiple time intervals using multivariable models adjusted for age, ICH severity, and mechanical ventilation. RESULTS: There were 279 days of actigraphy monitoring, of which 199 (71%) were rated as days with delirium. In multivariable analyses, delirium was associated with 98.4 (95% CI 10.4-186.4) fewer daily minutes of rest, including 5.3% (95% CI -0.1-10.1%) fewer minutes during daytime periods (06:00-21:59) and 10.2% (95% CI 1.9-18.4%) fewer minutes during nocturnal periods (22:00-5:59), with higher levels of activity across multiple individual hourly intervals (18:00-21:00, 23:00-03:00, and 04:00-08:00). These differences were even more pronounced in hyperactive or mixed delirium, although even hypoactive delirium was associated with more activity during multiple time periods. CONCLUSIONS: Post-stroke delirium is associated with less rest and higher overall levels of activity, especially during nocturnal periods.

A blood biomarker test for brain amyloid impacts the clinical evaluation of cognitive impairment.

OBJECTIVE: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. METHODS: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. RESULTS: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). INTERPRETATION: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

Delirium detection using wearable sensors and machine learning in patients with intracerebral hemorrhage.

Objective: Delirium is associated with worse outcomes in patients with stroke and neurocritical illness, but delirium detection in these patients can be challenging with existing screening tools. To address this gap, we aimed to develop and evaluate machine learning models that detect episodes of post-stroke delirium based on data from wearable activity monitors in conjunction with stroke-related clinical features. Design: Prospective observational cohort study. Setting: Neurocritical Care and Stroke Units at an academic medical center. Patients: We recruited 39 patients with moderate-to-severe acute intracerebral hemorrhage (ICH) and hemiparesis over a 1-year period [mean (SD) age 71.3 (12.20), 54% male, median (IQR) initial NIH Stroke Scale 14.5 (6), median (IQR) ICH score 2 (1)]. Measurements and main results: Each patient received daily assessments for delirium by an attending neurologist, while activity data were recorded throughout each patient's hospitalization using wrist-worn actigraph devices (on both paretic and non-paretic arms). We compared the predictive accuracy of Random Forest, SVM and XGBoost machine learning methods in classifying daily delirium status using clinical information alone and combined with actigraph data. Among our study cohort, 85% of patients (n = 33) had at least one delirium episode, while 71% of monitoring days (n = 209) were rated as days with delirium. Clinical information alone had a low accuracy in detecting delirium on a day-to-day basis [accuracy mean (SD) 62% (18%), F1 score mean (SD) 50% (17%)]. Prediction performance improved significantly (p < 0.001) with the addition of actigraph data [accuracy mean (SD) 74% (10%), F1 score 65% (10%)]. Among actigraphy features, night-time actigraph data were especially relevant for classification accuracy. Conclusions: We found that actigraphy in conjunction with machine learning models improves clinical detection of delirium in patients with stroke, thus paving the way to make actigraph-assisted predictions clinically actionable.

The development of an eco-friendly cold mix asphalt using wastewater sludge ash.

The aim of this research was to develop a sustainable and ecologically sound, non-traditional cold mix asphalt (CMA) that can be used in the construction industry. This new type of CMA incorporates wastewater sludge fly ash (UFA) and bottom ash (UBA) as a replacement filler for ordinary Portland cement and limestone. Silica fume (SF) was also used as an additional filler. The mechanical and durability characteristics of the new CMAs were examined in terms of indirect tensile stiffness modulus (ITSM), and rutting, fatigue, water and fuel resistance. The results showed that CMA with 2.1% OPC +3.9% UFA at 3 days of age, had ITSM values 11 times that of traditional CMA, while CMA with 2.1% OPC+ 3.3% UFA +0.6% UBA, had ITSM values 5 times that of traditional CMA at 28 days of age. SF activated hydration for both mixes, significantly increasing ITSM. These results indicate that CMA has a comparable mechanical performance to standard Hot Mix Asphalt (HMA) mixtures for use as surface pavement layers. This study offers a novel CMA with improved mechanical performance. It is economically effective and ecologically beneficial, compared to HMA, due to its ability to accommodate wastewater sludge ashes that are often disposed of in landfill sites.

A Pilot Study of the Fluctuating Mental Status Evaluation: A Novel Delirium Screening Tool for Neurocritical Care Patients.

BACKGROUND: Delirium occurs frequently in patients with stroke and neurocritical illness but is often underrecognized. We developed a novel delirium screening tool designed specifically for neurocritical care patients called the fluctuating mental status evaluation (FMSE) and aimed to test its usability and accuracy in a representative cohort of patients with intracerebral hemorrhage (ICH). METHODS: We performed a single-center prospective study in a pilot cohort of patients with ICH who had daily delirium assessments throughout their admission. Reference-standard expert ratings were performed each afternoon using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and were derived from bedside assessments and clinical data from the preceding 24 h. Paired FMSE assessments were performed by patients' clinical nurses after receiving brief one-on-one training from research staff. Nursing assessments were aggregated over 24-h periods (including day and night shifts), and accuracy of the FMSE was analyzed in patients who were not comatose to determine optimal scoring thresholds. RESULTS: We enrolled 40 patients with ICH (mean age 71.1 ± 12.2, 55% male, median National Institutes of Health Stroke Scale score 16.5 [interquartile range 12-20]), of whom 85% (n = 34) experienced delirium during their hospitalization. Of 308 total coma-free days with paired assessments, 208 (68%) were rated by experts as days with delirium. Compared with expert ratings, FMSE scores ≥ 1 had 86% sensitivity and 73% specificity on a per-day basis, whereas FMSE scores ≥ 2 had 68% sensitivity and 82% specificity. Accuracy remained high in patients with aphasia (FMSE scores ≥ 1: 83% sensitivity, 77% specificity; FMSE scores ≥ 2: 68% sensitivity, 85% specificity) and decreased arousal (FMSE scores ≥ 1: 80% sensitivity, 100% specificity; FMSE scores ≥ 2: 73% sensitivity, 100% specificity). CONCLUSIONS: In this pilot study, the FMSE achieved a high sensitivity and specificity in detecting delirium. Follow-up validation studies in a larger more diverse cohort of neurocritical care patients will use score cutoffs of ≥ 1 as "possible" delirium and ≥ 2 as "probable" delirium.

Cognitive Complications of COVID-19 Infection.

SARS-CoV-2 is associated with a post-infectious neurocognitive syndrome characterized by fatigue and deficits in attention, memory, and executive function. As screening cognitive testing generally remains normal, the pathophysiologic basis of these symptoms remains controversial and there is no standardized treatment paradigm. We present a clinical case demonstrative of typical neurocognitive sequelae of SARS-CoV-2 infection, highlighting medical and social factors that may have contributed to the severity of symptoms. We discuss the pathophysiologic evidence for cognitive "brain fog" following COVID-19 infection as well as lifestyle changes and rehabilitation strategies that may improve recovery. As the benefits of pharmacologic therapy remain unproven, we close with a brief discussion of medication options that might be appropriate targets for future clinical trials in the context of rehabilitative treatment.

Novel blood test for early biomarkers of preeclampsia and Alzheimer's disease.

A non-invasive and sensitive blood test has long been a goal for early stage disease diagnosis and treatment for Alzheimer's disease (AD) and other proteinopathy diseases. We previously reported that preeclampsia (PE), a severe pregnancy complication, is another proteinopathy disorder with impaired autophagy. We hypothesized that induced autophagy deficiency would promote accumulation of pathologic protein aggregates. Here, we describe a novel, sensitive assay that detects serum protein aggregates from patients with PE (n = 33 early onset and 33 late onset) and gestational age-matched controls (n = 77) as well as AD in both dementia and prodromal mild cognitive impairment (MCI, n = 24) stages with age-matched controls (n = 19). The assay employs exposure of genetically engineered, autophagy-deficient human trophoblasts (ADTs) to serum from patients. The aggregated protein complexes and their individual components, including transthyretin, amyloid ß-42, α-synuclein, and phosphorylated tau231, can be detected and quantified by co-staining with ProteoStat, a rotor dye with affinity to aggregated proteins, and respective antibodies. Detection of protein aggregates in ADTs was not dependent on transcriptional upregulation of these biomarkers. The ROC curve analysis validated the robustness of the assay for its specificity and sensitivity (PE; AUC: 1, CI: 0.949-1.00; AD; AUC: 0.986, CI: 0.832-1.00). In conclusion, we have developed a novel, noninvasive diagnostic and predictive assay for AD, MCI and PE.

Common biomarkers of physiologic stress and associations with delirium in patients with intracerebral hemorrhage.

PURPOSE: To examine associations between physiologic stress and delirium in the setting of a direct neurologic injury. MATERIALS AND METHODS: We obtained initial neutrophil-to-lymphocyte ratio (NLR), glucose, and troponin in consecutive non-comatose patients with non-traumatic intracerebral hemorrhage (ICH) over 1 year, then used multivariable regression models to determine associations between each biomarker and incident delirium. Delirium diagnoses were established using DSM-5-based methods, with exploratory analyses further categorizing delirium as first occurring <24 h ("early-onset") or > 24 h after presentation ("later-onset"). RESULTS: Of 284 patients, delirium occurred in 55% (early-onset: 39% [n = 111]; later-onset: 16% [n = 46]). Patients with delirium had higher NLR (mean 9.0 ± 10.4 vs. 6.4 ± 5.5; p = 0.01), glucose (mean 146.5 ± 59.6 vs. 129.9 ± 41.4 mg/dL; p = 0.008), and a higher frequency of elevated troponin (>0.05 ng/mL; 21% vs. 10%, p = 0.02). In adjusted models, elevated NLR (highest quartile: OR 3.4 [95% CI 1.5-7.8]), glucose (>180 mg/dL: OR 3.1 [95% CI 1.1-8.2]), and troponin (OR 3.0 [95% CI 1.2-7.2]) were each associated with delirium, but only initial NLR was specifically associated with later-onset delirium and with delirium in non-mechanically ventilated patients. CONCLUSIONS: Stress-related biomarkers corresponding to multiple organ systems are associated with ICH-related delirium. Early NLR elevation may also predict delayed-onset delirium, potentially implicating systemic inflammation as a contributory delirium mechanism.

Pilot study of an Alzheimer's disease risk assessment program in a primary care setting.

INTRODUCTION: The goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting. METHODS: Primary care providers (PCPs; N = 6) referred patients (N = 94; M = 63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification. RESULTS: Compared to the Registry as a whole, participants were younger, more likely to be non-White, and had lower cognitive screening scores. Mild cognitive impairment participants correctly reported a higher perceived risk of developing AD. Patients who recalled being counseled about modifiable risk factors were more likely to report positive health behavior changes. DISCUSSION: A referral-based program for cognitive and genetic AD risk assessment in a primary care setting is feasible, acceptable to patients, and yielded a more demographically diverse sample than an AD prevention registry.

The relationship between cerebral and retinal microbleeds in cerebral amyloid angiopathy (CAA): A pilot study.

BACKGROUND: The standard in vivo diagnostic imaging technique for cerebral amyloid angiopathy (CAA) is costly and thereby of limited utility for point-of-care diagnosis and monitoring of treatment efficacy. Recent recognition that retinal changes may reflect cerebral changes in neurodegenerative disease provides an ideal opportunity for development of accessible and cost-effective biomarkers for point-of-care use in the detection and monitoring of CAA. In this pilot study, we examined structural and angiographic retinal changes in CAA patients relative to a control group, and compared retinal and cerebral pathology in a group of CAA patients. METHODS: We used spectral domain optical coherence tomography (SD-OCT) to image the retina and compared retinal microbleeds to both cerebral microbleeds and white matter hyperintensities (WMH) in CAA patients, as seen on MRI. We compared retinal angiographic changes, along with structural retinal neuronal layer changes in CAA patients and cognitively normal older adults, and examined the relationship between retinal and cerebral microbleeds and cognition in CAA patients. RESULTS: We found a trend level correlation between retinal and cerebral microbleeds in CAA patients. Moreover, we found a significant correlation between retinal microbleeds and episodic memory performance in CAA patients. There were no significant group differences between CAA patients and cognitively normal older adults on retinal angiographic or structural measurements. CONCLUSION: Retinal microbleeds may reflect degree of cerebral microbleed burden in CAA. This picture was complicated by systolic hypertension in the CAA group, which is a confounding factor for the interpretation of these data. Our results stimulate motivation for pursuit of a more comprehensive prospective study to determine the feasibility of retinal biomarkers in CAA.

Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer's Disease.

BACKGROUND: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer's disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. OBJECTIVE: We utilized Alzheimer's Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. METHODS: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). RESULTS: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-ß (Aß42), total tau, phosphorylated tau (P-tau), or P-tau/Aß42 (all < p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. CONCLUSION: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

Classification of aerosol-generating procedures: a rapid systematic review.

In the context of covid-19, aerosol generating procedures have been highlighted as requiring a higher grade of personal protective equipment. We investigated how official guidance documents and academic publications have classified procedures in terms of whether or not they are aerosol-generating. We performed a rapid systematic review using preferred reporting items for systematic reviews and meta-analyses standards. Guidelines, policy documents and academic papers published in english or french offering guidance on aerosol-generating procedures were eligible. We systematically searched two medical databases (medline, cochrane central) and one public search engine (google) in march and april 2020. Data on how each procedure was classified by each source were extracted. We determined the level of agreement across different guidelines for each procedure group, in terms of its classification as aerosol generating, possibly aerosol-generating, or nonaerosol-generating. 128 documents met our inclusion criteria; they contained 1248 mentions of procedures that we categorised into 39 procedure groups. Procedures classified as aerosol-generating or possibly aerosol-generating by ≥90% of documents included autopsy, surgery/postmortem procedures with high-speed devices, intubation and extubation procedures, bronchoscopy, sputum induction, manual ventilation, airway suctioning, cardiopulmonary resuscitation, tracheostomy and tracheostomy procedures, non-invasive ventilation, high-flow oxygen therapy, breaking closed ventilation systems, nebulised or aerosol therapy, and high frequency oscillatory ventilation. Disagreements existed between sources on some procedure groups, including oral and dental procedures, upper gastrointestinal endoscopy, thoracic surgery and procedures, and nasopharyngeal and oropharyngeal swabbing. There is sufficient evidence of agreement across different international guidelines to classify certain procedure groups as aerosol generating. However, some clinically relevant procedures received surprisingly little mention in our source documents. To reduce dissent on the remainder, we recommend that (a) clinicians define procedures more clearly and specifically, breaking them down into their constituent components where possible; (b) researchers undertake further studies of aerosolisation during these procedures; and (c) guideline-making and policy-making bodies address a wider range of procedures.

Testing Application of Geographical Information Systems, Forensic Geomorphology and Electrical Resistivity Tomography to Investigate Clandestine Grave Sites in Colombia, South America.

Colombian forensic investigators required assistance locating clandestine burials of missing persons related to human right atrocities from 14 years ago. Geoscientific search methods were trialled, including a predictive spatial statistical model, using various input and database information, to select the most likely grave locations in difficult mountainous terrain. Groundwork using forensic geomorphology, near-surface geophysics (ERT) and subsequent probing identified suspect burial positions. One site was in mountainous terrain and the other in former school grounds, both difficult to access and in poor weather conditions. In the mountainous area, a negative resistivity anomaly area was identified and intrusively investigated, found to be a buried rock. In school grounds, after MESP and intelligence were used to identify a burial site, surface depressions were identified, and ERT datasets collected over the highest priority depression; intrusive investigations discovered a hand-dug pit containing animal bones. This approach is suggested for Latin American searches.

Deconstructing Poststroke Delirium in a Prospective Cohort of Patients With Intracerebral Hemorrhage.

OBJECTIVES: Poststroke delirium may be underdiagnosed due to the challenges of disentangling delirium symptoms from underlying neurologic deficits. We aimed to determine the prevalence of individual delirium features and the frequency with which they could not be assessed in patients with intracerebral hemorrhage. DESIGN: Prospective observational cohort study. SETTING: Neurocritical Care and Stroke Units at a university hospital. PATIENTS: Consecutive patients with intracerebral hemorrhage from February 2018 to May 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An attending neurointensivist performed 257 total daily assessments for delirium on 60 patients (mean age 68.0 [SD 18.4], 62% male, median intracerebral hemorrhage score 1.5 [interquartile range 1-2], delirium prevalence 57% [n = 34]). Each assessment included the Confusion Assessment Method for the ICU, Intensive Care Delirium Screening Checklist, a focused bedside cognitive examination, chart review, and nurse interview. We characterized individual symptom prevalence and established delirium diagnoses using Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria, then compared performance of the Confusion Assessment Method for the ICU and Intensive Care Delirium Screening Checklist against reference-standard expert diagnosis. Symptom fluctuation (61% of all assessments), psychomotor changes (46%), sleep-wake disturbances (46%), and impaired arousal (37%) had the highest prevalence and were never rated "unable to assess," while inattention (36%), disorientation (27%), and disorganized thinking (18%) were also common but were often rated 'unable to assess' (32%, 43%, and 44% of assessments, respectively), most frequently due to aphasia (32% of patients). Including nonverbal assessments of attention decreased the frequency of 'unable to assess' ratings to 11%. Since the Intensive Care Delirium Screening Checklist may be positive without the presence of symptoms that require verbal assessment, it was more accurate (sensitivity = 77%, specificity = 97%, area under the receiver operating characteristic curve, 0.87) than the Confusion Assessment Method for the ICU (sensitivity = 41%, specificity = 88%, area under the receiver operating characteristic curve, 0.64). CONCLUSIONS: Delirium is common after intracerebral hemorrhage, but severe neurologic deficits may confound its assessment and lead to underdiagnosis. The Intensive Care Delirium Screening Checklist's inclusion of nonverbal features may make it more accurate than the Confusion Assessment Method for the ICU in patients with neurologic deficits, but novel tools designed for such patients may be warranted.

Abnormal involuntary movement (AIM) expression following D2 dopamine agonist challenge is determined by the nature of prior dopamine receptor stimulation (priming) in 6-hydroxydopamine lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions show sensitization (priming) of rotational behavior upon repeated treatment with dopamine agonists. To relate these observations to dyskinesias exhibited by Parkinson's Disease patients, we assessed abnormal involuntary movements (AIMs) in 6-OHDA rats, which were primed with three injections of either the following: water, D1/D2 agonist apomorphine (Apo) (0.5mg/kg), D1 agonist SKF38393 (SKF) (10mg/kg) or D2 agonist quinpirole (Quin) (1 or 2.5mg/kg). The rats were challenged one week later with Quin (0.25mg/kg). Axial, limb, orolingual, locomotor, and grooming AIMs were scored (0-4) every 5min. Priming with water did not produce AIMs. Priming with Quin (1mg/kg) produced axial and locomotor AIMs, while priming with Apo, SKF or Quin (2.5mg/kg) produced axial, locomotor, limb, and grooming AIMs. The disparity in AIM profiles between Quin (1mg/kg) and (2.5mg/kg) was not the result of D1 receptor stimulation since there was little striatal Fos expression following the third priming injection with Quin (1 or 2.5mg/kg) compared to following SKF, which led to robust striatal Fos expression. Challenge with Quin (0.25mg/kg) essentially reproduced the categories of AIMs exhibited during priming, with no AIMs in water-primed 6-OHDA rats, mild, non-significant, axial and locomotor AIMs in Quin (1 and 2.5mg/kg)-primed 6-OHDA rats, and axial, limb, locomotor, and grooming AIMs in Apo- and SKF-primed 6-OHDA rats. These data suggest that the types of AIMs expressed following challenge with Quin depend on the dopamine receptor subtype and dose of dopamine agonist used during priming.

Prior treatment (priming) with caffeine sensitizes D2-dopamine-mediated contralateral rotational behavior in 6-hydroxydopamine-lesioned rats.

BACKGROUND/AIMS: In unilaterally dopamine-depleted rats, repeated treatment with dopamine agonists sensitizes contralateral rotational behavior. Since A2a adenosine receptors are co-localized with D2 dopamine receptors in the brain, it was hypothesized that repeated treatment with the adenosine antagonist caffeine could sensitize D2 dopamine-mediated rotational behavior. METHODS: Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA), and pretreated (primed) with 3 injections of caffeine or water. One week later, rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). RESULTS: 6-OHDA rats primed with caffeine (50 mg/kg) displayed contralateral rotational behavior following challenge with quinpirole - an effect not observed with caffeine (10 or 75 mg/kg) or water. CONCLUSIONS: These results suggest that prior administration of caffeine can sensitize D2 dopamine-mediated rotational behavior in dopamine-depleted rats.

Susceptibility of human corneal endothelial cells to HSV-1 infection.

PURPOSE: The purpose of this study was to examine the intrinsic susceptibility of cultured human corneal endothelial cells (HCEC) to herpes simplex virus-1 (HSV-1) infection. We compared HSV-1 adsorption, kinetics of HSV-1 production, and pattern of viral plaque formation in cultured HCEC with those of a cell line used routinely for laboratory HSV propagation (African green monkey kidney fibroblast CV-1 cells). METHODS: Cultured HCEC and CV-1 cells were exposed to the McKrae strain of HSV-1 at 5 and 0.0001 multiplicities of infection (MOI). Using the 50% tissue culture infectious dose (TCID(50)) titration method, viral adsorption (at 5 MOI) and total virus production (at 5 and 0.0001 MOI) were compared to assess both susceptibility to viral attachment and productive viral infection, respectively. Additionally, visual observations were made at 0.0001 MOI using bright-field microscopy and immunofluorescence staining of viral antigens to compare patterns of viral spread in confluent monolayers of both cell types. RESULTS: The percentage of HSV-1 virion particles adsorbed by cultured HCEC and CV-1 cells was similar (35.9% and 33.0%, respectively, p = 0.07, NS), indicating similar susceptibility of the two cell types to initial HSV-1 attachment and adsorption. However, maximum total virus production was more than 3-fold higher for HCEC than for CV-1 cells (p < 0.005), suggesting higher susceptibility of HCEC cells to productive viral infection. Immunofluorescence studies of infected cell monolayers corroborated these quantitative findings, with HCEC monolayers demonstrating more rapid progression of cytopathic effect than CV-1 monolayers. CONCLUSIONS: In comparison to reference CV-1 cells, cultured HCEC show similar susceptibility to HSV-1 adsorption, but higher capacity to support productive HSV-1 infection. Our results suggest that human corneal endothelial cells may be inherently susceptible to HSV-1 infection.