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Background: Video consultations between hospital-based neurologists and Emergency Medical Services (EMS) have potential to increase precision of decisions regarding stroke patient assessment, management and transport. In this study we explored the use of real-time video streaming for neurologist-EMS consultation from the ambulance, using highly realistic full-scale prehospital simulations including role-play between on-scene EMS teams, simulated patients (actors), and neurologists specialized in stroke and reperfusion located at the remote regional stroke center., Methods: Video streams from three angles were used for collaborative assessment of stroke using the National Institutes of Health Stroke Scale (NIHSS) to assess symptoms affecting patient's legs, arms, language, and facial expressions. The aim of the assessment was to determine appropriate management and transport destination based on the combination of geographical location and severity of stroke symptoms. Two realistic patient scenarios were created, with severe and moderate stroke symptoms, respectively. Each scenario was simulated using a neurologist acting as stroke patient and an ambulance team performing patient assessment. Four ambulance teams with two nurses each all performed both scenarios, for a total of eight cases. All scenarios were video recorded using handheld and fixed cameras. The audio from the video consultations was transcribed. Each team participated in a semi-structured interview, and neurologists and actors were also interviewed. Interviews were audio recorded and transcribed., Results: Analysis of video-recordings and post-interviews (n = 7) show a more thorough prehospital patient assessment, but longer total on-scene time, compared to a baseline scenario not using video consultation. Both ambulance nurses and neurologists deem that video consultation has potential to provide improved precision of assessment of stroke patients. Interviews verify the system design effectiveness and suggest minor modifications., Conclusions: The results indicate potential patient benefit based on a more effective assessment of the patient's condition, which could lead to increased precision in decisions and more patients receiving optimal care. The findings outline requirements for pilot implementation and future clinical tests., (© 2024. The Author(s).)

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with ~40-50% of patients diagnosed with non-metastatic disease (stages IA-IIIC). The treatment landscape is evolving rapidly as immunotherapies and targeted therapy are introduced in the non-metastatic setting, creating a need to assess patient outcomes prior to their introduction. This real-world study using Swedish National Lung Cancer Registry data examined outcomes (overall survival (OS) and time to next treatment or death (TTNTD)) and treatment patterns for adults diagnosed with non-metastatic NSCLC. Baseline characteristics and OS from diagnosis were described for all patients; OS, treatment patterns, and TTNTD from treatment start were described for the treatment subgroup (patients diagnosed from 2014 onwards), stratified by disease stage and initial treatment. OS and TTNTD were described using the Kaplan-Meier estimator. The overall population (2008-2019) included 17,433 patients; the treatment subgroup included 5147 patients. Median OS (interquartile range) overall ranged from 83.3 (31.6-165.3) months (stage I patients) to 10.4 (4.3-24.2) months (stage IIIB patients). Among the treatment subgroup, median OS and TTNTD were longest among patients receiving surgery versus other anticancer treatments. These findings provide a baseline upon which to evaluate the epidemiology of non-metastatic NSCLC as newer treatments are introduced.

Johne's disease is an insidious infectious disease of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease can have important implications for animal welfare and risks causing economic losses in affected herds due to reduced productivity, premature culling and replacement, and veterinary costs. Despite the limited accuracy of diagnostic tools, testing and culling is the primary option for controlling Johne's disease in beef herds. However, evidence to inform specific test and cull strategies is lacking. In this study, a stochastic, continuous-time agent-based model was developed to investigate Johne's disease and potential control options in a typical western Canadian cow-calf herd. The objective of this study was to compare different testing and culling scenarios that included varying the testing method and frequency as well as the number and risk profile of animals targeted for testing using the model. The relative effectiveness of each testing scenario was determined by the simulated prevalence of cattle shedding MAP after a 10-year testing period. A second objective was to compare the direct testing costs of each scenario to identify least-cost options that are the most effective at reducing within-herd disease prevalence. Whole herd testing with individual PCR at frequencies of 6 or 12 months were the most effective options for reducing disease prevalence. Scenarios that were also effective at reducing prevalence but with the lowest total testing costs included testing the whole herd with individual PCR every 24 months and testing the whole herd with pooled PCR every 12 months. The most effective method with the lowest annual testing cost per unit of prevalence reduction was individual PCR on the whole herd every 24 months. Individual PCR testing only cows that had not already been tested 4 times also ranked well when considering both final estimated prevalence at 10 years and cost per unit of gain. A more in-depth economic analysis is needed to compare the cost of testing to the cost of disease, taking into account costs of culling, replacements and impacts on calf crops, and to determine if testing is an economically attractive option for commercial cow-calf operations., Competing Interests: Author LR is the owner of the company Rosengren Epidemiology Consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Johnson, McLeod, Qin, Osgood, Rosengren, Campbell, Larson and Waldner.)

Parkinson's disease (PD) is a complex, progressive neurological condition that impacts daily life and reduces life satisfaction (LS). To achieve and maintain high LS, persons with PD (PwPD) must go through a process of change to adapt to their new life situation. However, our knowledge about this process is very limited. The aim of this study was to investigate the process of change, and the main concern in this process, in PwPD. To study the transitional experience of PwPD, an inductive qualitative approach, using Grounded Theory (GT), was employed. Thirteen participants (9 women, 3 men and 1 non-binary), with a mean age of 54 years (range from 47-62 years), participated in in-depth interviews. Data showed that social belonging is the main concern in the process of change for PwPD. In this process of change, they use strategies to comprehend, accept, adapt, and balance in their strive for social belonging, which in turn can enhance LS. Health care professionals can use this model with an interdisciplinary approach to support PwPD through a successful process of change to achieve social belonging, and thereby achieving and maintaining LS.

Persons with Parkinson's disease (PD) need to adapt to their progressive disability to achieve and maintain a high degree of life satisfaction (LS), but little is known about the meaning of LS and adaptation. This study aimed to gain an in-depth understanding of the meaning of LS and adaptation in persons with PD. Open-ended in-depth interviews were performed with 13 persons diagnosed with PD, 9 women, 3 men, and one non-binary person (mean age 54 years, mean time since diagnosis 3.4 years). The interviews were analyzed using a phenomenological-hermeneutic approach. The participants were in the process of adapting to their new health situation. There were two quite distinct groups: one that adapted through acceptance and one that struggled to resist the disease and the profound impact it had on their lives. The thematic structural analysis covers eight themes illustrating the meaning of LS and adaptation, through either acceptance or resistance. Adaptation to PD involves a transitional process characterized by either acceptance or resistance, which influences a person's LS. Acceptance makes LS possible, whereas resistance constitutes a behavioral barrier to adaptation and LS. Rehabilitation professionals need to understand this individual process to be able to support a person with PD to reach and maintain a high level of LS. Understanding the link between LS and adaptation can support rehabilitation professionals to provide targeted interventions for people with PD.

Background: The Swedish Healthcare Act states that patients should have equal access to healthcare. This study addresses at how this translates to pharmacological treatment of adult spasticity, including injections with botulinum toxin A (BoNT-A) and pumps for intrathecal baclofen (ITB). To address potential economic incentives for treatment differences, the results are also set into a health economic perspective. Thus, the current study provides a detailed and comprehensive overview for informed decision- and policymaking., Methods: Botulinum toxin use was retrieved from sales data. Clinical practice regarding mean BoNT-A treatment dose and proportion used for spasticity indication were validated in five county councils, while the number of ITB pumps were mapped for all county councils. Published costs and quality of life data was used for estimating required responder rates for cost-balance or cost-effectiveness., Results: The proportion of patients treated with BoNT-A varied between 5.8% and 13.6% across healthcare regions, with a mean of 9.2% on a national level. The reported number of ITB pumps per 100,000 inhabitants varied between 3.6 and 14.1 across healthcare regions, with a national mean of 6/100,000. The estimated incremental cost for reaching treatment equity was EUR 1,976,773 per year for BoNT-A and EUR 3,326,692 for ITB pumps. Based on expected cost-savings, responder rates ranging between 4% and 15% cancelled out the incremental cost for BoNT-A. Assuming no cost-savings, responder rates of 14% or 36% was required for cost-effectiveness., Conclusions: There is a marked variation in pharmacologic treatment of adult spasticity in Sweden. Overall, the results indicate an underuse of treatment and need for harmonisation of clinical practice. Furthermore, the incremental cost for reaching treatment equity is likely to be offset by spasticity-associated cost-savings.

Stable isotope-labeled standard (SIS) peptides are used as internal standards in targeted proteomics to provide robust protein quantification, which is required in clinical settings. However, SIS peptides are typically added post trypsin digestion and, as the digestion efficiency can vary significantly between peptides within a protein, the accuracy and precision of the assay may be compromised. These drawbacks can be remedied by a new class of internal standards introduced by the Human Protein Atlas project, which are based on SIS recombinant protein fragments called SIS PrESTs. SIS PrESTs are added initially to the sample and SIS peptides are released on trypsin digestion. The SIS PrEST technology is promising for absolute quantification of protein biomarkers but has not previously been evaluated in a clinical setting. An automated and scalable solid phase extraction workflow for desalting and enrichment of plasma digests was established enabling simultaneous preparation of up to 96 samples. Robust high-precision quantification of 13 apolipoproteins was achieved using a novel multiplex SIS PrEST-based LC-SRM/MS Tier 2 assay in non-depleted human plasma. The assay exhibited inter-day coefficients of variation between 1.5% and 14.5% (median = 3.5%) and was subsequently used to investigate the effects of omega-3 carboxylic acids (OM3-CA) and fenofibrate on these 13 apolipoproteins in human plasma samples from a randomized placebo-controlled trial, EFFECT I (NCT02354976). No significant changes were observed in the OM3-CA arm, whereas treatment with fenofibrate significantly increased apoAII and reduced apoB, apoCI, apoE and apoCIV levels. The reduction in apoCIV following fenofibrate treatment is a novel finding. The study demonstrates that SIS PrESTs can facilitate the generation of robust multiplexed biomarker Tier 2 assays for absolute quantification of proteins in clinical studies., (© 2019 Hober et al.)

Background: The discovery that not all patients who call for the emergency medical service (EMS) require transport to hospital has changed the structure of prehospital emergency care. Today, the EMS clinician at the scene already distinguishes patients with a time-critical condition such as stroke/transitory ischemic attack (TIA) from patients without. This highlights the importance of the early identification of stroke/TIA., Aim: To describe patients with a final diagnosis of stroke/TIA whose transport to hospital was interrupted either due to a lack of suspicion of the disease by the EMS crew or due to refusal by the patient or a relative/friend., Methods: Data were obtained from a register in Gothenburg, covering patients hospitalised due to a final diagnosis of stroke/TIA. The inclusion criterion was that patients were assessed by the EMS but were not directly transported to hospital by the EMS., Results: Among all the patients who were assessed by the EMS nurse and subsequently diagnosed with stroke or TIA in 2015, the transport of 34 of 1,310 patients (2.6%) was interrupted. Twenty-five of these patients, of whom 20 had a stroke and five had a TIA, are described in terms of initial symptoms and outcome. The majority had residual symptoms at discharge from hospital. Initial symptoms were vertigo/disturbed balance in 11 of 25 cases. Another three had symptoms perceived as a change in personality and three had a headache., Conclusion: From this pilot study, we hypothesise that a fraction of patients with stroke/TIA who call for the EMS have their direct transport to hospital interrupted due to a lack of suspicion of the disease by the EMS nurse at the scene. These patients appear to have more vague symptoms including vertigo and disturbed balance. Instruments to identify these patients at the scene are warranted., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Cerebrospinal fluid (CSF) biomarkers reflect ongoing processes in the brain. Growth-associated protein 43 (GAP-43) is highly upregulated in brain tissue shortly after experimental ischemia suggesting the CSF GAP-43 concentration may be altered in ischemic brain disorders. CSF GAP-43 concentration is elevated in Alzheimer's disease patients; however, patients suffering from stroke have not been studied previously., Methods: The concentration of GAP-43 was measured in longitudinal CSF samples from 28 stroke patients prospectively collected on days 0-1, 2-4, 7-9, 3 weeks, and 3-5 months after ischemia and cross-sectionally in 19 controls. The stroke patients were clinically evaluated using a stroke severity score system. The extent of the brain lesion, including injury size and degrees of white matter lesions and atrophy were evaluated by CT and magnetic resonance imaging., Results: Increased GAP-43 concentration was detected from day 7-9 to 3 weeks after stroke, compared to day 1-4 and to levels in the control group (P = 0.02 and P = 0.007). At 3-5 months after stroke GAP-43 returned to admission levels. The initial increase in GAP-43 during the nine first days was associated to stroke severity, the degree of white matter lesions and atrophy and correlated positively with infarct size (r s  = 0.65, P = 0.001)., Conclusions: The transient increase of CSF GAP-43 is important to take into account when used as a biomarker for other neurodegenerative diseases such as Alzheimer's disease. Furthermore, GAP-43 may be a marker of neuronal responses after stroke and additional studies confirming the potential of CSF GAP-43 to reflect severity and outcome of stroke in larger cohorts are warranted.

Background and purpose Recent randomized clinical trials have proved the efficacy of endovascular treatment of acute ischemic stroke in the anterior circulation. However, the benefit of endovascular treatment of ischemic stroke in the posterior circulation remains to be proven since it was excluded from these trials. We evaluate the benefit of endovascular treatment in posterior circulation strokes. Methods A total of 110 consecutive patients with posterior circulation stroke who underwent endovascular treatment in our institute in the period 1991-2015 were included. Recanalization rate according to modified Treatment in Cerebral Ischemia score and neurological outcome at three months according to modified Rankin Scale were the main outcomes. Collateral circulation, procedural complications and radiological outcome were evaluated in the radiological examinations. Results The median National Institutes of Health Stroke Scale was 31 (IQR: 13-31) and median time from symptom onset to groin puncture was 300 (IQR: 175-463) minutes. Successful recanalization was seen in 80 of 110 patients (73%). Favorable outcome (modified Rankin Scale ≤2) was seen in 38 patients (35%) while moderate favorable outcome (≤3) was seen in 48 patients (44%). Symptomatic intracerebral hemorrhage occurred in 10 patients (9%). An association between collateral circulation, recanalization rate and outcome was seen. Conclusion Endovascular treatment for posterior circulation stroke in this single-center cohort is relatively safe and effective with decreased mortality and increased favorable outcome compared to natural history.

Objective/background: The aim of the Carotid Alarm Study was to compare the procedural risk of carotid endarterectomy (CEA) performed within 48 hours with that after 48 hours to 14 days following an ipsilateral cerebrovascular ischaemic event., Methods: Consecutive patients with symptomatic carotid stenosis undergoing CEA were prospectively recruited. Time to surgery was calculated as time from the most recent ischaemic event preceding surgery. A neurologist examined patients before and, after CEA. The primary endpoint was the composite endpoint of death and/or any stroke within 30 days of the surgical procedure. The study was designed to include 600 patients, with 150 operated on within 48 hours., Results: From October 2010 to December 2015, 418 patients were included, of whom 75 were operated within 48 hours of an ischaemic event. The study was prematurely terminated owing to the slow recruitment rate in the group operated on within 48 hours. Patients undergoing CEA within 48 hours had a higher risk of reaching the primary endpoint than those operated on later (8.0% vs. 2.9%). Multivariate logistic regression analyses showed that CEA performed within 48 h (odds ratio [OR] 3.07; 95% confidence interval [CI] 1.04-9.09), CEA performed out of office hours (OR 3.65; 95% CI 1.14-11.67), and use of shunt (OR 4.02; 95% CI 1.36-11.93) were all independently associated with an increased risk of reaching the primary endpoint., Conclusion: CEA performed within 48 hours was associated with a higher risk of complications compared with surgery performed 48 hours-14 days after the most recent ischaemic event., (Copyright © 2017. Published by Elsevier Ltd.)

Background and Purpose: Retrospective studies have found that patients receiving general anesthesia for endovascular treatment in acute ischemic stroke have worse neurological outcome compared with patients receiving conscious sedation. In this prospective randomized single-center study, we investigated the impact of anesthesia technique on neurological outcome in acute ischemic stroke patients., Methods: Ninety patients receiving endovascular treatment for acute ischemic stroke in 2013 to 2016 were included and randomized to general anesthesia or conscious sedation. Difference in neurological outcome at 3 months, measured as modified Rankin Scale score, was analyzed (primary outcome) and early neurological improvement of National Institutes of Health Stroke Scale and cerebral infarction volume. Age, sex, comorbidities, admission National Institutes of Health Stroke Scale score, intraprocedural blood pressure, blood glucose, Paco 2 and Pco 2 modified Thrombolysis in Cerebral Ischemia score, and relevant time intervals were recorded., Results: In the general anesthesia group 19 of 45 patients (42.2%) and in the conscious sedation group 18 of 45 patients (40.0%) achieved a modified Rankin Scale score ≤2 ( P =1.00) at 3 months, with no differences in intraoperative blood pressure decline from baseline ( P =0.57); blood glucose ( P =0.94); PaCO2 ( P =0.68); time intervals ( P =0.78); degree of successful recanalization, 91.1% versus 88.9% ( P =1.00); National Institutes of Health Stroke Scale score at 24 hours 8 (3-5) versus 9 (2-15; P =0.60); infarction volume, 20 (10-100) versus 20(10-54) mL ( P =0.53); and hospital mortality (13.3% in both groups; P =1.00)., Conclusions: In endovascular treatment for acute ischemic stroke, no difference was found between general anesthesia and conscious sedation in neurological outcome 3 months after stroke., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01872884., (© 2017 American Heart Association, Inc.)

Background and Purpose: In retrospective studies, patients receiving general anesthesia for endovascular treatment for acute ischemic stroke have worse neurological outcome compared with patients receiving conscious sedation. It has been suggested that this is caused by general anesthesia-associated hypotension. We investigated the effect of intraprocedural hypotension on neurological outcome., Methods: One hundred eight patients with acute ischemic stroke, who underwent endovascular treatment in general anesthesia between 2007 and 2012, were included. Analyzed predictors of neurological outcome were age, sex, comorbidities, baseline National Institutes of Health Stroke Scale, intraprocedural relative changes in mean arterial blood pressure from baseline, blood glucose, modified Thrombolysis in Cerebral Infarction score, and elapsed time from stroke to computed tomography, groin puncture, and recanalization/end of procedure., Results: A fall in mean arterial blood pressure of >40% was an independent predictor for poor neurological outcome (P=0.032), as were higher admission National Institutes of Health Stroke Scale score (P=0.008) and lack of recanalization (P=0.003)., Conclusions: Profound intraprocedural hypotension is an independent predictor for poor neurological outcome in patients with acute ischemic stroke undergoing endovascular therapy in general anesthesia., (© 2015 American Heart Association, Inc.)

Background: Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL) in CSF with a novel, sensitive method., Methods: With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL) (marker of neuronal injury), neopterin (intrathecal immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity) were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n = 204). 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation., Results: While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups., Conclusions: Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

Background: Frontotemporal dementia (FTD) is recognised as a clinically and morphologically heterogeneous group of interrelated neurodegenerative conditions. One of the subtypes within this disease spectrum is the behavioural variant FTD (bvFTD). This is known to be a varied disorder with a mixture of tau-positive and tau-negative underlying pathologies. The other subtypes include semantic dementia (SD), which generally exhibits tau-negative pathology, and progressive non-fluent aphasia (PNFA), which is usually tau-positive. As the clinical presentation of these subtypes may overlap, a specific diagnosis can be difficult to attain and today no specific biomarker can predict the underlying pathology. Neurofilament light chain protein (NFL), a cytoskeletal constituent of intermediate filaments, is thought to reflect neuronal and axonal death when appearing in the cerebrospinal fluid (CSF). NFL has been shown to be elevated in CSF in patients with FTD compared with AD and controls. Our hypothesis was that the levels of NFL also differ between the subtypes of FTD and may indicate the underlying pathological subtype., Methods: We retrospectively analysed data from previous CSF analyses in 34 FTD cases (23 bvFTD, seven SD, four PNFA), 20 AD cases, and 26 healthy controls. A separate group of 10 neuropathologically verified and subtyped FTD cases (seven tau-negative, three tau-positive) were also analysed., Result: NFL levels were significantly higher in FTD compared with both AD (p<0.001) and controls (p<0.001). The NFL levels of SD and bvFTD were significantly higher (p<0.001) compared with AD. The biomarker profiles of PNFA and AD were similar. In the neuropathologically verified FTD cases, NFL was higher in the tau-negative than in the tau-positive cases (exact p=0.017)., Conclusions: The marked NFL elevation in some but not all FTD cases is likely to reflect the different underlying pathologies. The highest NFL values found in the SD group as well as in the neuropathologically verified tau-negative cases may be of subtype diagnostic value, if corroborated in larger patient cohorts. In bvFTD, a mixture of tau-positive and tau-negative underlying pathologies could possibly explain the intermediate NFL values.

One study described the frequency of pre-breeding vaccination for leptospirosis in 205 cow-calf herds from across western Canada and the prevalence of positive Leptospira antibody titers in unvaccinated, weaned calves from 61 of these herds. The percentages of herds vaccinated for leptospirosis were 13.7% in 2001 and 8.4% in 2002. Of 1539 calves examined, 13 (0.8%) had a positive antibody titer for a Leptospira serovar; the most common serovar detected was hardjo. A second study examined the prevalence of positive Leptospira antibody titers during the summer grazing season in 313 vaccinated and 478 unvaccinated cows from 40 cow-calf herds in southern Saskatchewan. Antibody titers for 7 Leptospira serovars were measured during the grazing season. Of the non-vaccinated cows, 9.6% were positive in the spring for serovar pomona, 6.7% for serovar grippotyphosa, and 6.1% for serovar icterohaemorrhagiae; the corresponding percentages for the fall were 5.5%, 3.0%, and 1.3%, respectively. Of 781 vaccinated and unvaccinated cows that were sampled twice, 11.3% of vaccinated cows and 2.3% of unvaccinated cows had increases in Leptospira antibody titers during the grazing season.

Background: Alzheimer's disease (AD) and cerebrovascular disease (CVD) including chronic small vessel disease of the brain (SVD) are the most frequent causes of dementia. AD is associated with metabolism of amyloid precursor protein (APP) and low levels of amyloid-beta peptide (Abeta) X-42 in the cerebrospinal fluid (CSF). CVD and SVD are established risk factors for AD, brain white matter lesions (WML) are established surrogate markers for SVD and are also associated with reduced CSF AbetaX-42.A cohort survey was performed to examine whether SVD or acute CVD affects APP metabolism and to explore a potential association between WML and APP metabolism in two groups; cognitively impaired patients, subjective and mild (SCI and MCI) and stroke patients. Through measurements of CSF APP metabolite levels in patients with a wide range of WML volumes, this study aimed to determine how SVD influences APP metabolism., Methods: Sixty-three patients were included: 37 with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI) without stroke, and 26 after acute stroke. Chronic and acute WML volume and infarct volume were determined by magnetic resonance imaging (MRI) post-scan processing, and CSF levels of alpha- and beta-cleaved soluble APP (sAPP-alpha and sAPP-beta, AbetaX-38, AbetaX-40 and AbetaX-42) were determined. The Mann-Whitney test was used to compare the patient groups. Chronic and acute WML volumes, infarct volume, age, and sex were used as predictors for CSF biomarker levels in linear regression analysis., Results: CSF levels of sAPP-alpha and sAPP-beta were strongly correlated (r = 0.95, p < 0.001) and lower levels of these biomarkers were found in the stroke group than in the SCI/MCI group; median sAPP-alpha 499.5 vs. 698.0 ng/mL (p < 0.001), sAPP-beta 258.0 vs. 329.0 ng/mL (p < 0.005). CSF levels of sAPP-alpha, sAPP-beta, AbetaX-38, AbetaX-40 and AbetaX-42 were inversely correlated with chronic WML volume (p

The study objectives were to investigate Salmonella prevalence, serovar distribution, and risk factors for shedding in 10 purposively selected farrow-to-finish farms in Saskatchewan and Alberta. Pooled fecal samples from the breeding and grow-finish phases and individual fecal samples from breeding, nursery, and grow-finish pigs were cultured for Salmonella; serotyping of isolates was performed. Pig and pen characteristics were recorded for each pig and pen sampled.Overall, 407/1143 (36%) of samples were Salmonella positive; within-farm prevalence ranged from 1% to 79%. Sows, nursery, and grow-finish pigs accounted for 43%, 29%, and 28% of positive samples, respectively. More Salmonella were detected in pooled pen than individual pig samples (P < 0.001). Among 418 Salmonella isolates, there were 19 distinct serovars; the most common were S. Derby (28.5%), S. Typhimurium, var. Copenhagen (19.1%), S. Putten (11.8%), S. Infantis (6.8%), and S. Mbandaka (6.1%). Sows were more likely to shed Salmonella than nursery or grow-finisher (OR 2.9, P < 0.001) pigs. Pelleted feed (OR 8.2, P < 0.001) and nose-to-nose pig contact through pens (OR 2.2, P = 0.005) were associated with increased Salmonella prevalence. Significant differences in serovar distribution were detected among production phases. The use of pooled pen samples is recommended as a more efficient means for accurate evaluation of Salmonella status in different phases of pig production. The breeding herd might be an important source of Salmonella persistence within farrow-to-finish farms and should be targeted in control efforts. The latter might also apply to the use of pelleted feed, which remains the most consistently reported significant risk factor for Salmonella shedding in pigs.

Background: Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients., Methods: In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease., Results: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections., Conclusions: Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.

The objectives were to describe the pattern of losses through culling, sales of breeding stock, mortality, and disappearance, and to characterize the causes of mortality of cows and replacement heifers of breeding age from Western Canadian beef herds. Cows and replacement heifers from 203 herds were observed for a 1-year period starting June 1, 2001. Veterinarians examined dead animals on-farm using a standard postmortem protocol. The incidence of culling in cows and replacements heifers was 14.3 per 100 cow-years at risk, and the frequencies of sales for breeding stock, mortality, and cows reported missing per cow-years at risk were 4.0, 1.1, and 0.4, respectively. During the study, 355 animals died or were euthanized, 209 were examined postmortem, and the requested tissues were submitted for histopathologic examination from 184. A cause of death was determined for 70% (128/184) of the cows with complete gross postmortem and histopathologic examinations. Hardware disease (traumatic reticuloperitonitis), malignant neoplasia (cancer), calving-associated injury, rumen tympany (bloat), myopathy, and pneumonia accounted for 56% (72/128) of the animals where a cause of death was determined. Twenty-three other causes of death accounted for the remaining 44% (56/128). Factors relating to cow nutrition accounted for 25% of the deaths, emphasizing the importance of feeding management as a determinant of cow health in western Canada.

Objective: To test the hypothesis that the arachodinic acid metabolites prostaglandin E2 (PGE2) and 15-(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in cerebrospinal fluid (CSF) are elevated and reflect neuroinflammation and degenerative changes in multiple sclerosis (MS)., Patients and Methods: We measured PGE2 and 15(S)-HETE concentrations, as well as markers of axonal and astroglial injury in CSF from 46 MS patients, 46 healthy siblings and 50 controls., Results: We found elevated levels of both PGE2 and 15(S)-HETE in MS compared with the control and sibling groups. Siblings had lower PGE2 levels and higher 15(S)-HETE levels than controls. There were no correlations between either PGE2 or 15(S)-HETE and clinical scores of MS severity or biochemical markers of axonal or astroglial injury., Conclusion: These data suggest no direct involvement of PGE2 and 15(S)-HETE in the MS disease process. Rather, the elevated levels reflect a general up-regulation of arachidonic acid metabolism and neuroinflammation.

Introduction: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV., Purpose: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model., Materials and Methods: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay., Results: Mice treated with PPP, administered intraperitoneally or orally, showed 22-32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter., Conclusions: PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.

Background. @nbsp; Cerebrovascular complications (CVCs) have remained a major therapeutic and prognostic challenge associated with infective endocarditis, and definite risk factors have not been fully elucidated. This prospective study was designed to the evaluate the total incidence of CVC associated with infective endocarditis and major risk factors. Methods. @nbsp; During 2 study periods, from June 1998 through April 2001 and from September 2002 through January 2005, patients were prospectively enrolled in the study regardless of neurological symptoms. Study patients underwent neurological examinations and magnetic resonance imaging of the brain, and cerebrospinal fluid analyses of inflammatory and neurochemical markers of brain damage (neurofilament protein and glial fibrillary acidic protein) were performed. Results. @nbsp; Sixty patients who experienced episodes of left-sided infective endocarditis were evaluated; 35% of these patients experienced a symptomatic CVC. Silent cerebral complications were detected in another 30% of the patients, and the total CVC rate was 65% (95% confidence interval, 58%-72%). Five percent of patients experienced their first neurological symptom after the initiation of antibiotic treatment without prior surgery. No new symptomatic CVCs were detected after 10 days of antibiotic treatment. No neurological deterioration was observed after surgery in patients who were established to have a symptomatic CVC preoperatively. A larger heart valvular vegetation size was a risk factor for both symptomatic and silent CVCs; Staphylococcus aureus etiology conferred a higher risk for symptomatic cerebral complication only. Conclusions. @nbsp; The use of sensitive methods of detection indicates that the incidence of CVC associated with infective endocarditis is high, but the risk for neurological deterioration during cardiac surgery after a CVC is lower than previously assumed. The major mechanism behind cerebral complications associated with infective endocarditis is cerebral embolization, although the dominant neurological symptoms vary considerably.

The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth and survival of malignant cells. Experience in targeting IGF-1R in cancer models has shown that strategies promoting downregulation of the receptor are much more efficient in inducing apoptosis than those inhibiting the IGF-1R activity. Recently, we found that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation of downstream signaling without interfering with the highly homologous insulin receptor (IR). Furthermore, PPP treatment caused strong regression of tumor grafts and prolonged survival of animals with systemic tumor disease. Here we demonstrate that PPP also downregulates the IGF-1R, whereas the IR and several other receptors were not affected. PPP-induced IGF-1R downregulation required expression of the MDM2 E3 ligase, which recently was found to ubiquitinate and cause degradation of the IGF-1R. In addition knockdown of beta-arrestin1, the adaptor molecule known to bridges MDM2 and IGF-1R, prevented downregulation of the receptor and significantly decreased PPP-induced cell death. All together these data suggest that PPP downregulates IGF-1R by interfering with the action of beta-arrestin1/MDM2 as well as the achieved receptor downregulation contributes to the apoptotic effect of PPP.

Objectives: S100B is an established marker of brain damage. Used in the context as a biochemical marker, S100B denotes a measurement of all S100 proteins, including at least one S100B monomer, i.e. the sum of the two dimers S100A1B and S100BB. Almost all published studies are based on this "sum concentration". However, the brain specificity of S100B has been questioned and increased serum levels have also been reported after trauma without head injury. Since the S100B monomer dominates in the brain, we hypothesised that the S100BB dimer should be better related to outcome after severe traumatic brain injury than S100A1B or the "sum concentration"., Methods: Daily serum samples were collected from 59 patients with severe traumatic brain injury. Three different ELISA methods were used for measurements of S100B, S100A1B and S100BB respectively. Outcome was assessed after one year and categorised according to the Glasgow Outcome Scale., Results: Serum levels of S100B, S100A1B and S100BB followed the same temporal course, with early maximum and rapidly decreasing values over the first days after the trauma. Maximum serum concentrations of each of the parameters were increased in the patient group with an unfavourable outcome compared with those with a favourable outcome (p = 0.01, 0.006 and 0.004, respectively)., Conclusion: Both S100A1B and S100BB were related to outcome after severe traumatic brain injury. Even though this study is small, it seems unlikely that separate analyses of the dimers are of any advantage compared with measuring S100B alone.

Objective: We explored the relationship between adiposity factors measured during mid-life and blood-brain barrier (BBB) integrity measured via the cerebrospinal fluid/serum (CSF/S) albumin ratio in late life. Adiposity factors included body mass index and blood levels of sex hormone binding globulin (SHBG) and leptin. Design. Retrospective analyses over 24 years within a longitudinal study., Setting: Population-based sample. Subjects. Eighty-one women., Main Outcome Measures: CSF/S albumin ratio., Results: The CSF/S albumin ratio measured at age 70-84 years was higher amongst women who were overweight or obese (6.50 +/- 2.79 vs. 5.23 +/- 1.61, age-adjusted P = 0.012), and was inversely correlated with SHBG (age-adjusted r = -0.321, P < 0.005) at age 46-60 years. In stepwise regression models, SHBG predicted the CSF/S albumin ratio (beta = -0.017, R2 = 0.107, P = 0.007). The best model (R2 = 0.187) predicting CSF/S albumin ratio included SHBG, age group (age 46 years versus >46), overweight or obesity, and an age group by SHBG interaction., Conclusions: Lower levels of SHBG in mid-life were related to worse BBB integrity in women after 24 years in late life, even considering other adiposity factors. SHBG may be important for understanding sex hormone-mediated mechanisms in brain health or as an independent marker of adipose tissue, the largest endocrine organ.

Background: The possible injurious effect to the brain of heading in soccer is a matter of discussion., Objective: To determine whether standardised headings in soccer are associated with increased levels of biochemical markers for neuronal injury in cerebrospinal fluid (CSF) and serum., Methods: 23 male amateur soccer players took part in a heading training session involving heading a ball kicked from a distance of 30 m at least 10 m forward. Ten players performed 10 and 13 players performed 20 approved headings. The players underwent lumbar puncture and serum sampling 7-10 days after the headings. The study also included 10 healthy male non-athletic control subjects. CSF was analysed for neurofilament light protein, total tau, glial fibrillary acidic protein, S-100B and albumin concentrations. Serum was analysed for S-100B and albumin., Results: None of the biomarker levels were abnormal and there were no significant differences between any of the three groups, except for a slightly increased CSF S-100B concentration in controls compared with headers. Biomarker levels did not correlate with the number of headings performed., Conclusion: Repeated low-severity head impacts due to heading in soccer are not associated with any neurochemical signs of injury to the brain.

The light subunit of neurofilament protein (NFL) is a sensitive indicator of central nervous system axonal injury. We retrospectively identified 9 subjects participating in a longitudinal cohort study who developed acquired immunodeficiency syndrome dementia complex (ADC) and who had had a lumbar puncture performed within 2 years before presentation. Elevated cerebrospinal fluid (CSF) NFL concentrations were found in 7 (78%) of the 9 case patients who later developed ADC, compared with 9 (33%) of 27 CD4 cell count-matched HIV-1-infected control subjects. By contrast, no differences were found in CSF HIV-1 RNA or neopterin concentrations between the 2 groups. CSF NFL may prove to be a useful predictive marker for ADC.

Background and Purpose: Aneurysmal subarachnoid hemorrhage (aSAH) stands out from other subtypes of stroke because of the high early mortality and the risk of complications. Serum glial fibrillary acidic protein (s-GFAP) concentrations are increased after stroke. The aim of this study was to investigate whether s-GFAP could be used as a marker of brain damage and outcome after aSAH., Methods: Serum samples were obtained on a regular basis from 116 adults during a 2-week period after aSAH and analyzed using an enzyme-linked immunosorbent assay. The World Federation of Neurological Surgeons scale was used for neurological evaluation. Outcome was assessed after 1 year and categorized according to the Extended Glasgow Outcome Scale., Results: Increased s-GFAP levels were seen in 81 of the 116 patients. Maximum s-GFAP correlated with World Federation of Neurological Surgeons scale on arrival and on days 10 to 15 (r=0.37, P<0.001 and r=0.47, P<0.001, respectively). Furthermore, maximum s-GFAP levels were increased in the patient group with radiological signs of focal lesions acute or at 1 year, compared with the group without focal lesions (P<0.001 in both comparisons). Patients with secondary events (re-bleeding or ischemia) reached maximum levels later in the series and both maximum and final s-GFAP levels increased compared with the levels in patients without secondary events (P<0.001 in all 3 comparisons). Finally, maximum s-GFAP correlated with outcome (r=-0.48, P<0.001) and s-GFAP was an independent predictor of dichotomized outcome., Conclusions: s-GFAP provides information about brain injury severity and outcome after aSAH, which can be useful as a complement to clinical data.

Background: Low levels of cerebrospinal fluid (CSF) beta-amyloid 1-42 (Abeta42) and high total tau (T-tau) are diagnostic for manifest Alzheimer's disease. It is not known, however, whether these biomarkers may be risk indicators for cognitive decline in otherwise healthy older people., Methods: The longitudinal relationship between CSF markers, Abeta42 and T-tau, measured in 1992, and change in Mini-Mental State Examination (deltaMMSE) score between 1992 and 2002 were investigated in 55 women (aged 70-84 years, mean (SD) MMSE score = 28.3 (1.5)), who were participants in the Prospective Population Study of Women in Gothenburg, Sweden. These women did not have dementia when they experienced lumbar puncture in 1992-3., Results: Over the 8-year follow-up period, deltaMMSE (range = +3 to -21 points) was correlated with Abeta42 (Spearman's r = 0.40, p = 0.002), such that lower levels of Abeta42 were related to greater decline. This was also observed after excluding 4 women who developed dementia between 1992 and 2002 (Spearman's r = 0.34, p = 0.019). A multivariate logistic regression model predicting a decline of > or = 5 points on the MMSE (observed in six women), or a risk of developing dementia over the 8-year follow-up period (observed in four women), including age, education, Abeta42 and T-tau as covariates, showed that Abeta42 was the sole predictor of significant cognitive decline or dementia (OR per 100 pg/ml Abeta42 = 2.24, 95% CI 1.19 to 4.22, p = 0.013)., Conclusions: Low levels of CSF Abeta42 may predict cognitive decline among older women without dementia.

Objective: Multilevel somatosensory evoked potentials (SSEP) and the release of biochemical markers in cerebrospinal fluid (CSF) were investigated to identify patients with spinal cord ischemia during thoracoabdominal aortic repair and/or a vulnerable spinal cord during the postoperative period., Methods: Thirty-nine consecutive patients undergoing elective aneurysm repair using distal aortic perfusion and cerebrospinal fluid drainage were studied. Continuous SSEP were monitored using nerve stimulation of the right and left posterior tibial nerves with signal recording at the level of both common peroneal nerves, the cervical cord and at the cortical level. CSF concentrations of the markers glial fibrillary acidic protein (GFAp), the light subunit of neurofilament triplet protein (NFL), and S100B were determined at different time points from before surgery until 3 days postoperatively., Results: SSEP indicated spinal cord ischemia in two patients leading to additional intercostal artery reattachments. In one of them the signal loss was permanent and the patient woke up with paraplegia. In the other the signal returned but the patient later developed delayed paraplegia. Three patients without SSEP indications of spinal cord ischemia during surgery later developed delayed paraplegia. The patients with spinal cord symptoms had significant increases, during the postoperative period of CSF biomarkers GFAp (571-fold), NFL (14-fold) and S100B (18-fold) compared to asymptomatic patients. GFAp increased before or in parallel to onset of symptoms in the patients with delayed paraplegia., Conclusions: Peroperative multilevel SSEP has a high specificity in detecting spinal cord ischemia but does not identify all patients with a postoperative vulnerable spinal cord. Biochemical markers in CSF increase too late for intraoperative monitoring but GFAp is promising for identifying patients at risk for postoperative delayed paraplegia.

Background: Since the introduction of HAART the incidence of HIV dementia has declined and HAART seems to improve neurocognitive function in patients with HIV dementia. Currently, HIV dementia develops mainly in patients without effective treatment, though it has also been described in patients on HAART and milder HIV-associated neuropsychological impairment is still frequent among HIV-1 infected patients regardless of HAART. Elevated cerebrospinal fluid (CSF) levels of markers of neural injury and immune activation have been found in HIV dementia, but neither of those, nor CSF HIV-1 RNA levels have been proven useful as diagnostic or prognostic pseudomarkers in HIV dementia., Case Presentation: We report a case of HIV dementia (MSK stage 3) in a 57 year old antiretroviral naïve man who was introduced on zidovudine, lamivudine and ritonavir boosted indinavir, and followed with consecutive lumbar punctures before and after two and 15 months after initiation of HAART. Improvement of neurocognitive function was paralleled by normalisation of CSF neural markers (NFL, Tau and GFAP) levels and a decline in CSF and serum neopterin and CSF and plasma HIV-1 RNA levels., Conclusion: The value of these CSF markers as prognostic pseudomarkers of the effect of HAART on neurocognitive impairment in HIV dementia ought to be evaluated in longitudinal studies.

The rapid rise in the use of mobile communications has raised concerns about health issues related to low-level microwave radiation. The head and brain are usually the most exposed targets in mobile phone users. In the brain, two types of glial cells, the astroglial and the microglial cells, are interesting in the context of biological effects from microwave exposure. These cells are widely distributed in the brain and are directly involved in the response to brain damage as well as in the development of brain cancer. The aim of the present study was to investigate whether 900 MHz radiation could affect these two different glial cell types in culture by studying markers for damage-related processes in the cells. Primary cultures enriched in astroglial cells were exposed to 900 MHz microwave radiation in a temperature-controlled exposure system at specific absorption rates (SARs) of 3 W/kg GSM modulated wave (mw) for 4, 8 and 24 h or 27 W/kg continuous wave (cw) for 24 h, and the release into the extracellular medium of the two pro-inflammatory cytokines interleukin 6 (Il6) and tumor necrosis factor-alpha (Tnfa) was analyzed. In addition, levels of the astroglial cell-specific reactive marker glial fibrillary acidic protein (Gfap), whose expression dynamics is different from that of cytokines, were measured in astroglial cultures and in astroglial cell-conditioned cell culture medium at SARs of 27 and 54 W/kg (cw) for 4 or 24 h. No significant differences could be detected for any of the parameters studied at any time and for any of the radiation characteristics. Total protein levels remained constant during the experiments. Microglial cell cultures were exposed to 900 MHz radiation at an SAR of 3 W/kg (mw) for 8 h, and I16, Tnfa, total protein and the microglial reactivity marker ED-1 (a macrophage activation antigen) were measured. No significant differences were found. The morphology of the cultured astroglial cells and microglia was studied and appeared to be unaffected by microwave irradiation. Thus this study does not provide evidence for any effect of the microwave radiation used on damage-related factors in glial cells in culture.

Background: The neurofilament is a major structural component of myelinated axons. Increased cerebrospinal fluid (CSF) concentrations of the light chain of the neurofilament protein (NFL) can serve as a sensitive indicator of central nervous system (CNS) injury. To assess whether interrupting antiretroviral treatment of HIV infection might have a deleterious effect on the CNS, we measured NFL levels in HIV-infected subjects interrupting therapy. We identified subjects who had CSF HIV RNA concentrations below 50 copies/mL at the time combination antiretroviral therapy was interrupted, and for whom CSF samples were available before and after the interruption., Results: A total of 8 subjects were studied. The median (range) CSF NFL level at baseline was <125 (<125-220) ng/L (normal <250 ng/L). All 8 subjects exhibited an increase in CSF and plasma HIV RNA after stopping therapy, accompanied by intrathecal immunoactivation as evidenced by CSF lymphocytic pleocytosis (7/8 patients) and increased CSF neopterin concentration (5/6 patients). Three subjects showed a consistent increase in CSF NFL, rising from <125 ng/L to a maximum of 880 (at day 148), 1,010 (day 58) and 10,930 ng/L (day 101). None exhibited new neurological symptoms or signs, or experienced functional deterioration during the period off treatment; of 5 who underwent brief quantitative neurological testing, none showed worsening performance., Conclusion: These findings suggest that resurgence of active HIV replication may result in measurable, albeit subclinical, CNS injury. Further studies are needed to define the frequency and pathobiological importance of the increase in CSF NFL.

The growth-promoting effect of growth hormone (GH) is primarily mediated by insulin-like growth factor-1 (IGF-1). The liver is the main source of circulating IGF-I. The authors have used rodent primary hepatocytes for studies on pharmacological intervention of IGF-I mRNA expression. A 96-well nonradioactive IGF-1 mRNA quantification assay was developed, based on the hybridization of sense and antisense RNA probes, to replicate membranes with crude hepatocyte lysates. The sense hybridization was used as an internal standard. The antagonistic properties of a set of GH-receptor binding compounds were evaluated. Two compounds were found to down-regulate IGF-I mRNA. Effects due to metabolic inhibition or toxicity were excluded using a cell proliferation assay. To investigate potential unspecific transcriptional effects, the mRNA levels of the housekeeping genes, beta-actin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were determined. Two other GH-regulated genes, cytochrome P450 2C12 (CYP2C12) and a rat homologue to the human alpha1B-glycoprotein (A1BG), were quantified by RNase protection assays and found to be down-regulated, confirming the antagonistic property of 1 compound. In conclusion, a direct filter hybridization assay of hepatocyte lysates using nonradioactive sense and antisense probes can be used for quantitative mRNA measurements and could constitute a valuable tool in screening for pharmacologically active compounds.

Background: To simultaneously study several biomarkers for Alzheimer disease (AD), we used the xMAP technology to develop and evaluate a multiparametric bead-based assay for quantification of beta-amyloid((1-42)) [Abeta((1-42))], total tau (T-TAU), and hyperphosphorylated tau [P-TAU((181P))] in cerebrospinal fluid (CSF)., Methods: We compared the new multianalyte assay format with established ELISA techniques for the same proteins. We then performed a clinical study using CSF samples from patients with AD or mild cognitive impairment with progression to AD, healthy controls, and patients with other neurologic disorders., Results: The INNO-BIA AlzBio3 selectively and specifically measured Abeta((1-42)), T-TAU, and P-TAU((181P)) in the CSF. The new assay format had intra- and interassay CVs <10% for all analytes, even at low concentrations. The measurement range of the new assay was 3 to 4 logs compared with 1 to 2 logs for ELISAs. By plotting the mean of the values obtained in ELISA and the xMAP technology against the difference, we found that a correction factor could be used to convert xMAP results to ELISA values. The clinical study demonstrated that the new multiparametric assay could accurately distinguish patients with AD from patients with other neurologic disorders or control patients, with the diagnostic accuracy reaching recommended consensus criteria for specificity and sensitivity., Conclusion: The new multiparametric method may be able to replace the corresponding ELISA methods.

Clinical examination is the only tool available to assess the extent of the nerve tissue damage after a spinal cord injury, and it is well known that the reliability of classification based on clinical examination is not satisfactory, especially in cases with incomplete motor injuries. There is a need to evaluate new methods in order to improve the possibilities of classifying and prognosticating spinal cord injuries. Methods for assessing central nervous system (CNS) damage using markers in cerebrospinal fluid (CSF) have recently been developed. Previous studies have reported glial fibrillary acidic protein (GFAp) and neurofilament protein (NFL) levels in non-traumatic diseases in the central nervous system. The present study is the first report of GFAp and NFL levels in CSF after trauma to the cervical spine. Six cases with cord damage and pronounced neurological deficit showed significantly increased concentrations of both GFAp and NFL in the CSF. Patients with tetrapareses showed higher values than those with incomplete injuries. Three of the 17 whiplash cases had increased levels of NFL, but normal GFAp. Assessment of nervous tissue markers in CSF will probably improve possibilities to classify and prognosticate spinal cord injuries and also to evaluate pharmacological intervention. The increased levels of NFL in three whiplash cases indicate neural damage in a proportion of the cases with neurological deficit. Neurological examinations are presently the only tools for grading and prognostication of spinal cord injuries. Assessment of nervous tissue markers in CSF makes it possible to quantify the degree of nerve cell damage after different types of cervical spine injury ranging from spinal cord lesions to whiplash injuries.

Concentrations of glial fibrillary acidic protein (GFAp) and light subunit neurofilament protein (NFL) in cerebrospinal fluid (CSF) were measured in patients with second-stage Trypanosoma brucei gambiense sleeping sickness. Correlations between GFAp and NFL in CSF as markers for astrogliosis and neurodegeneration, and clinical and biological data were investigated. Abnormal levels of GFAp and NFL were significantly associated with increasing CSF cell number and protein concentration, and with the absence of lymph nodes or the absence of trypanosomes in lymph node aspirate. A significant association was found between abnormal NFL and presence of trypanosomes in CSF, abnormal limb movements, difficulties in gait and coordination, and low Karnofsky index. By multivariate analysis, it was shown that increasing CSF cell number, increasing CSF protein concentration, and the absence of lymph nodes or the absence of trypanosomes in the lymph node aspirate were the best predictors for astrogliosis and neurodegeneration among the variables tested. These results demonstrate the importance of CSF cell count and protein determination in assessment of the severity of central nervous system involvement and reinforces the importance of laboratory diagnosis to assess the stage of the disease. The clinical symptoms studied were less useful in predicting astrogliosis or neurodegeneration.