Search

Glioblastoma (GBM) is the most aggressive glial tumor, where ion channels, including KCa1.1, are candidates for new therapeutic options. Since the auxiliary subunits linked to KCa1.1 in GBM are largely unknown we used electrophysiology combined with pharmacology and gene silencing to address the functional expression of KCa1.1/β subunits complexes in both primary tumor cells and in the glioblastoma cell line U-87 MG. The pattern of the sensitivity (activation/inhibition) of the whole-cell currents to paxilline, lithocholic acid, arachidonic acid, and iberiotoxin; the presence of inactivation of the whole-cell current along with the loss of the outward rectification upon exposure to the reducing agent DTT collectively argue that KCa1.1/β3 complex is expressed in U-87 MG. Similar results were found using human primary glioblastoma cells isolated from patient samples. Silencing the β3 subunit expression inhibited carbachol-induced Ca2+ transients in U-87 MG thereby indicating the role of the KCa1.1/β3 in the Ca2+ signaling of glioblastoma cells. Functional expression of the KCa1.1/β3 complex, on the other hand, lacks cell cycle dependence. We suggest that the KCa1.1/β3 complex may have diagnostic and therapeutic potential in glioblastoma in the future.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

Background Cross-education refers to increased motor output (i.e., force generation, skill) of the opposite, untrained limb following a period of unilateral exercise training. Despite extensive research, several aspects of the transfer phenomenon remain controversial. Methods A modified two-round Delphi online survey was conducted among international experts to reach consensus on terminology, methodology, mechanisms of action, and translational potential of cross-education, and to provide a framework for future research. Results Through purposive sampling of the literature, we identified 56 noted experts in the field, of whom 32 completed the survey, and reached consensus (75% threshold) on 17 out of 27 items. Conclusion Our consensus-based recommendations for future studies are that (1) the term ‘cross-education’ should be adopted to refer to the transfer phenomenon, also specifying if transfer of strength or skill is meant; (2) functional magnetic resonance imaging, short-interval intracortical inhibition and interhemispheric inhibition appear to be promising tools to study the mechanisms of transfer; (3) strategies which maximize cross-education, such as high-intensity training, eccentric contractions, and mirror illusion, seem worth being included in the intervention plan; (4) study protocols should be designed to include at least 13–18 sessions or 4–6 weeks to produce functionally meaningful transfer of strength, and (5) cross-education could be considered as an adjuvant treatment particularly for unilateral orthopedic conditions and sports injuries. Additionally, a clear gap in views emerged between the research field and the purely clinical field. The present consensus statement clarifies relevant aspects of cross-education including neurophysiological, neuroanatomical, and methodological characteristics of the transfer phenomenon, and provides guidance on how to improve the quality and usability of future cross-education studies.

Purpose We examined the possibility that wearing a below-knee compression garment (CG) reduces fatigue-induced strength loss and joint position sense (JPS) errors in healthy adults. Methods Subjects (n = 24, age = 25.5 +/- 4 years) were allocated to either one of the treatment groups that performed 100 maximal isokinetic eccentric contractions at 30 degrees(-1)with the right-dominant knee extensors: (1) with (EXPCG) or (2) without CG (EXP) or to (3) a control group (CONCG:CG, no exercise). Changes in JPS errors, and maximal voluntary isometric contraction (MVIC) torque were measured immediately post-, 24 h post-, and 1 week post-intervention in each leg. All testing was done without the CG. Results CG afforded no protection against JPS errors. Mixed analysis of variance (ANOVA) revealed that absolute JPS errors increased post-intervention in EXPCG and EXP not only in the right-exercised (52%,p = 0.013; 57%,p = 0.007, respectively) but also in the left non-exercised (55%,p = 0.001; 58%,p = 0.040, respectively) leg. Subjects tended to underestimate the target position more in the flexed vs. extended knee positions (75-61 degrees: - 4.6 +/- 3.6 degrees, 60-50 degrees: - 4.2 +/- 4.3 degrees, 50-25 degrees: - 2.9 +/- 4.2 degrees), irrespective of group and time. Moreover, MVIC decreased in EXP but not in EXPCG and CONCG at immediately post-intervention (p = 0.026,d = 0.52) and 24 h post-intervention (p = 0.013,d = 0.45) compared to baseline. Conclusion Altogether, a below-knee CG reduced fatigue-induced strength loss at 80 degrees knee joint position but not JPS errors in healthy younger adults.

BACKGROUND: There is evidence that physical exercise training (PET) conducted at the workplace is effective in improving physical fitness and thus health. However, there is no current systematic review available that provides high-level evidence regarding the effects of PET on physical fitness in the workforce.OBJECTIVES: To quantify sex-, age-, and occupation type-specific effects of PET on physical fitness and to characterize dose-response relationships of PET modalities that could maximize gains in physical fitness in the working population.DATA SOURCES: A computerized systematic literature search was conducted in the databases PubMed and Cochrane Library (2000-2019) to identify articles related to PET in workers.STUDY ELIGIBILITY CRITERIA: Only randomized controlled trials with a passive control group were included if they investigated the effects of PET programs in workers and tested at least one fitness measure.STUDY APPRAISAL AND SYNTHESIS METHODS: Weighted mean standardised mean differences (SMDwm) were calculated using random effects models. A multivariate random effects meta-regression was computed to explain the influence of key training modalities (e.g., training frequency, session duration, intensity) on the effectiveness of PET on measures of physical fitness. Further, subgroup univariate analyses were computed for each training modality. Additionally, methodological quality of the included studies was rated with the help of the Physiotherapy Evidence Database (PEDro) Scale.RESULTS: Overall, 3423 workers aged 30-56 years participated in 17 studies (19 articles) that were eligible for inclusion. Methodological quality of the included studies was moderate with a median PEDro score of 6. Our analyses revealed significant, small-sized effects of PET on cardiorespiratory fitness (CRF), muscular endurance, and muscle power (0.29 ≤ SMDwm ≤ 0.48). Medium effects were found for CRF and muscular endurance in younger workers (≤ 45 years) (SMDwm = 0.71) and white-collar workers (SMDwm = 0.60), respectively. Multivariate random effects meta-regression for CRF revealed that none of the examined training modalities predicted the effects of PET on CRF (R2 = 0). Independently computed subgroup analyses showed significant PET effects on CRF when conducted for 9-12 weeks (SMDwm = 0.31) and for 17-20 weeks (SMDwm = 0.74).CONCLUSIONS: PET effects on physical fitness in healthy workers are moderated by age (CRF) and occupation type (muscular endurance). Further, independently computed subgroup analyses indicated that the training period of the PET programs may play an important role in improving CRF in workers.

PurposeWe examined the possibility that old adults use flexibility in joint coordination as a compensatory mechanism for the age-related decline in muscle strength when performing the sit-to-stand (STS) task repeatedly under high force and balance demands.MethodYoung (n=14, 22.42.1) and old (n=12, 703.2) healthy adults performed repeated STSs under high and low force and balance demands. The balance demand was manipulated by reducing the base of support and the force demand by increasing body weight with a weight vest. Uncontrolled manifold analysis was used to quantify age differences in motor flexibility.Results p id= Par3 While there were age-typical differences in kinematic STS strategies, flexibility in joint coordination was independent of age and task difficulty during repeated STSs.Discussion p id=Par4That simple manipulations of force and balance demands did not affect flexibility in joint coordination in old and young adults suggests that motor flexibility acts as a compensatory mechanism only at the limits of available muscle strength and balance abilities during STS movements. Intervention studies should identify how changes in specific neuromuscular functions affect flexibility in joint coordination during activities of daily living such as STS.

PURPOSE: Limited evidence suggests that cross-education affords clinical benefits in the initial 8 weeks after anterior cruciate ligament (ACL) reconstruction, but it is unknown if such cross-education effects are reproducible and still present in later phases of rehabilitation. We examined whether cross-education, as an adjuvant to standard therapy, would accelerate the rehabilitation up to 26 weeks after ACL reconstruction by attenuating quadriceps weakness.METHODS: ACL-reconstructed patients were randomized into experimental (n = 22) and control groups (n = 21). Both groups received standard care after ACL reconstruction. In addition, the experimental group strength trained the quadriceps of the non-operated leg during weeks 1-12 after surgery (i.e., cross-education). Self-reported knee function was assessed with the Hughston Clinic Knee score as the primary outcome. Secondary outcomes were maximal quadriceps and hamstring strength and single leg hop distance. All outcomes were measured 29 ± 23 days prior to surgery, as a reference, and at 5-week, 12-week, and 26-week post-surgery.RESULTS: Both groups scored 12% worse on self-reported knee function 5-week post-surgery (95% CI 7-17) and showed 15% improvement 26-week post-surgery (95% CI - 20 to - 10). No cross-education effect was found. Interestingly, males scored 8-10% worse than females at each time point post-surgery. None of 33 secondary outcomes showed a cross-education effect. At 26-week post-surgery, both legs improved maximal quadriceps (5-14%) and hamstring strength (7-18%), and the non-injured leg improved 2% in hop distance. The ACL recovery was not affected by limb dominance and age.CONCLUSION: 26 weeks of standard care improved self-reported knee function and maximal leg strength relative to pre-surgery and adding cross-education did not further accelerate ACL recovery.LEVEL OF EVIDENCE: I.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION: This randomized controlled clinical trial is registered at the Dutch trial register ( http://www.trialregister.nl ) under NTR4395.

Comprehensive molecular characterization of and novel therapeutic approaches to glioblastoma have been explored as a result of advancements in biotechnologies. In this study, we aimed to bring basic research discoveries closer to clinical practice and ultimately incorporate molecular classification into the routine histopathological evaluation of grade IV gliomas. Integrated results of genome-wide sequencing, transcriptomic and epigenomic analyses by The Cancer Genome Atlas Network defined the classic, proneural, neural and mesenchymal subtypes of this tumor. In a retrospective cohort, we analyzed selected subgroup-defining molecular markers in formalin-fixed paraffin-embedded surgical specimens by immunohistochemistry. Quantitative and qualitative scores of marker expression were tested in hierarchical cluster analyses to evaluate segregations of the molecular subgroups, which then were correlated with clinical parameters including patients' age, gender and overall survival. Our study has confirmed the separation of molecular glioblastoma subgroups with clear trends regarding clinical correlations. Future analyses in a larger, prospective cohort using similar methods are expected to facilitate the development of a molecular diagnostic panel that may complement routine histological work up and support prognostication as well as treatment decisions in glioblastoma.

Alzheimer’s disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles and widespread neuronal loss in the brain. In recent years, blood biomarkers have emerged as a realistic prospect to highlight accumulating pathology for secondary prevention trials. Neurofilament light chain (NfL), a marker of axonal degeneration, is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. A strong relationship with cerebrospinal fluid (CSF) NfL suggests that these biomarker modalities reflect the same pathological process. Yet, the connection between blood NfL and brain tissue pathology has not been directly compared. In this study, longitudinal plasma NfL from cognitively healthy controls (n = 12) and AD participants (n = 57) were quantified by the Simoa platform. On reaching post-mortem, neuropathological assessment was performed on all participants, with additional frozen and paraffin-embedded tissue acquired from 26 participants for further biochemical (Aβ1–42, Aβ1–40, tau) and histological (NfL) evaluation. Plasma NfL concentrations were significantly increased in AD and correlated with cognitive decline, independent of age. Retrospective stratification based on Braak staging revealed that baseline plasma NfL concentrations were associated with higher neurofibrillary tangle pathology at post-mortem. Longitudinal increases in plasma NfL were observed in all Braak groupings; a significant negative association, however, was found between plasma NfL at time point 1 and both its rate of change and annual percentage increase. Immunohistochemical evaluation of NfL in the medial temporal gyrus (MTG) demonstrated an inverse relationship between Braak stages and NfL staining. Importantly, a significant negative correlation was found between the plasma NfL measurement closest to death and the level of NfL staining in the MTG at post-mortem. For the first time, we demonstrate that plasma NfL associates with the severity of neurofibrillary tangle pathology and neurodegeneration in the post-mortem brain. Electronic supplementary material The online version of this article (10.1186/s40478-018-0649-3) contains supplementary material, which is available to authorized users.

The embryonal tumor with abundant neuropil and true rosettes is a rare and highly malignant variant of embryonal brain tumors. It usually affects infants and young children under the age of 4 years and exhibits a very aggressive course with a dismal prognosis. For the 68 cases reported to date the mean age at diagnosis was 25.42 months (range 3-57 months). Survival data are available for 48 children (including our case): the median overall survival is 13.0 months, though 6 (9%) of the children have had a relative long survival (>30 months). The aggressive combined treatment, involving primary surgical tumor removal, adjuvant polychemotherapy, including high-dose chemotherapy with stem cell transplantation, radiotherapy and radiochemotherapy, might play an important role in the longer survival. We have performed a literature review and we present here a multimodal-treated case of a 2- year-old girl with a long survival, who was reoperated when recurrence occurred. The residual tumor demonstrated a good response to temozolomide radiochemotherapy (craniospinal axis + boost) and followed by maintenance temozolomide. The described complex aggressive treatment option might be considered for future cases of this tumor entity.

Optineurin (OPTN) is a multifunctional protein involved in vesicular trafficking, signal transduction and gene expression. OPTN mutations were described in eight Japanese patients with familial and sporadic amyotrophic lateral sclerosis (FALS, SALS). OPTN-positive inclusions co-localising with TDP-43 were described in SALS and in FALS with SOD-1 mutations, potentially linking two pathologically distinct pathways of motor neuron degeneration. We have explored the abundance of OPTN inclusions using a range of antibodies in postmortem tissues from 138 cases and controls including sporadic and familial ALS, frontotemporal lobar degeneration (FTLD) and a wide range of neurodegenerative proteinopathies. OPTN-positive inclusions were uncommon and detected in only 11/32 (34%) of TDP-43-positive SALS spinal cord and 5/15 (33%) of FTLD-TDP. Western blot of lysates from FTLD-TDP frontal cortex and TDP-43-positive SALS spinal cord revealed decreased levels of OPTN protein compared to controls (p < 0.05), however, this correlated with decreased neuronal numbers in the brain. Large OPTN inclusions were not detected in FALS with SOD-1 and FUS mutation, respectively, or in FTLD-FUS cases. OPTN-positive inclusions were identified in a few Alzheimer's disease (AD) cases but did not co-localise with tau and TDP-43. Occasional striatal neurons contained granular cytoplasmic OPTN immunopositivity in Huntington's disease (HD) but were absent in spinocerebellar ataxia type 3. No OPTN inclusions were detected in FTLD-tau and alpha-synucleinopathy. We conclude that OPTN inclusions are relatively rare and largely restricted to a minority of TDP-43 positive ALS and FTLD-TDP cases. Our results do not support the proposition that OPTN inclusions play a central role in the pathogenesis of ALS, FTLD or any other neurodegenerative disorder.

Unilateral isometric muscle contractions increase motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation not only in the contracting muscle but also in the resting contralateral homologous muscle. Corticospinal excitability in the M1 contralateral to the contracting muscle changes depending on the type of muscle contraction. Here, we investigated the possibility that corticospinal excitability in M1 ipsilateral to the contracting muscle is modulated in a contraction-type-dependent manner. To this end, we evaluated MEPs in the resting left flexor carpi radialis (FCR) during unilateral shortening, lengthening, and isometric muscle contractions of the right wrist flexors at 10, 20, and 30% of maximal isometric contraction force. To compare the effects of different unilateral contractions on MEPs between the contracting and resting sides, MEPs in the right FCR were recorded on two separate days. In a separate experiment, we investigated the contraction specificity of the crossed effect at the spinal level by recording H-reflexes from the resting left FCR during contraction of the right wrist flexors. The results showed that MEPs in the contracting right FCR were the smallest during lengthening contraction. By contrast, MEPs in the resting left FCR were the largest during lengthening contraction, whereas the H-reflex was similar in the resting left FCR during the three types of muscle contraction. These results suggest that different types of unilateral muscle contraction asymmetrically modulate MEP size in the resting contralateral homologous muscle and in the contracting muscle and that this regulation occurs at the supraspinal level.

Germinomas represent the most frequent tumour type in the pineal region and the synchronous involvement of the suprasellar region, frequently termed bifocal disease, is increasingly recognised. The incidence, pathogenesis, histomorphological, radiological, clinical features, and management strategies are discussed.A 6-year-old girl presented with clinical features of hypothalamic-pituitary axis dysfunction. MRI showed two distinct lesions in the pineal and suprasellar regions. Tumour markers for germ cell tumours from blood and cerebrospinal fluid were within the normal range. The suprasellar lesion was biopsied and the histology revealed a germinoma. She received a radical course of radiotherapy covering the entire craniospinal axis (24 Gy/15#) followed by focal boost to the sites of primary disease (16 Gy/10#). Three months after the completion of treatment, the patient achieved a complete clinical and radiological response, which was maintained during the 13-month follow-up period.The optimum management of primary intracranial pineal and suprasellar (bifocal) germinomas still remains controversial. The definition as either localised or disseminated disease has major implications on required treatment and its associated late morbidity. Prospective studies with large cooperative groups worldwide and consensus meetings may reduce uncertainties regarding available management options.

Age alters the control of voluntary movement. A widely observed age-related adaptation is the heightened activation of the antagonist muscles during voluntary movements. We examined the possibility that age also modifies cortical reciprocal inhibition. In young (age 27, n = 6) and old (age 73, n = 6) adults a mild conditioning electrical stimulus was delivered to the median nerve at the elbow. The test stimulus, delivered by transcranial magnetic stimulation (TMS) at 1-ms increments between 11 and 24 ms after the electrical conditioning stimulus, evoked motor potentials (MEP) in the extensor carpi radialis (ECR) and flexor carpi radialis (FCR). The absolute TMS intensity, expressed as the percent of stimulator output, used to produce 1-mV control MEPs in the ECR was similar in young (mean 58.5, standard deviation +/-12.8%) and old adults (60.3+/-20.3%, P = 0.855). The size of the control MEP in the ECR was also similar in young (0.98+/-0.10 mV) and old subjects (0.90+/-0.14 mV, P = 0.686). The age by conditioning interval interaction (P = 0.001) showed that the MEPs in the ECR were significantly depressed at 14, 15, 16, 17, 18, and 19 ms (range 55.5--65.9% of control, all P0.05) compared with control value of 100% and with old adults who showed no depression. The MEPs remained at control level in the FCR and were also unaffected in the first dorsal interosseus. These data confirm the existence of cortical reciprocal inhibition reported previously in young humans and show that age reduces this inhibition similarly to the previously reported reduction of spinal reciprocal inhibition reported in old adults. Activation of agonist and antagonist muscle pairs are most likely organized around a dual system of cortically and spinally mediated reciprocal inhibition that is altered by age. The data also indicate the need to use age-matched control subjects when comparing individuals with abnormalities resulting from disorders that occur at an old age.

The purpose of this study was to determine the effects of short-term exercise cessation on lipid and lipoprotein profile and insulin sensitivity in highly trained runners (n = 12; mean age 19.9 years) and power athletes (n = 12; mean age 24.4 years). Following 14 days of exercise cessation, running time to exhaustion and maximal oxygen uptake decreased by 9.2% and 4.8% (P0.05) in the runners, while in the power athletes one repetition maximum squat and bench press did not change (P0.05). No changes occurred in body composition. Data from a 2-h oral glucose tolerance test revealed an impairment of the glycemic state in all athletes (P0.05). In contrast, exercise cessation did not significantly (P0.05) alter plasma levels of cholesterol, triglycerides, and low density (LDL) and high density lipoprotein (HDL). No changes were observed in HDL2, HDL2b, and HDL3 subfractions, LDL diameter, and qualitative LDL pattern (P0.05). These data thus suggest that despite a decrease in insulin sensitivity, short-term exercise cessation, independent of exercise mode, was insufficient to alter plasma lipid and lipoprotein profiles in well-trained athletes.

Page 1724, column 2, section 2.4, paragraph 2, lines 25–31: The following sentence, which previously read: To verify the effectiveness of BT on a balance outcome measures, we computed the within-subject standardized mean difference [SMDws = ([mean pre-value − mean post-value]/SD pre-value)] and the between-subject standardized mean difference [SMDbs = ([mean post-value intervention group − mean post-value control group]/pooled variance)]. Should read: To verify the effectiveness of BT on balance outcome measures, we computed the within-subject standardized mean difference (SMDws = [mean pre-value − mean post-value]/standard deviation pre-value) and the between-subject standardized mean difference (SMDbs = [mean post-value intervention group − mean post-value control group]/pooled standard deviation).

Page 1630, column 2, section 2.3, paragraph 2, lines 15–20: The following sentence, which previously read: To determine the effectiveness of an exercise intervention in relation to gait speed, we computed between-subject effect size (ES) using the implemented formula in Review Manager version 5.3 (Hedges’ adjusted g) as (ES = ±[(mean post-value intervention group) − (mean post-value control group)]/pooled variance) [91]. Should read: To determine the effectiveness of an exercise intervention in relation to gait speed, we computed between-subject effect size (ES) using the implemented formula in Review Manager version 5.3 (Hedges’ adjusted g) as (ES = [(mean post-value intervention group) − (mean post-value control group)]/pooled standard deviation) [91].

Page 559, column 2, section 2.4, paragraph 2, lines 47–52: The following sentence, which previously read: Within-subject ESdw (ESdw = ± [mean pre-value − mean post-value]/SD pre-value) and between-subject ESdb (ESdb = ± [mean post-value intervention group − mean post-value control group]/pooled variance) were computed according to Cohen [15] (where SD is standard deviation). Should read: Within-subject ESdw (ESdw = [mean pre-value − mean post-value]/SD pre-value) and between-subject ESdb (ESdb = [mean post-value intervention group − mean post-value control group]/pooled SD) were computed according to Cohen [15] (where SD is standard deviation).

The aim of this study was to examine the effect of aminoguanidine (AG), which is thought to be an inducible nitric oxide synthase (iNOS) inhibitor, on lesion volume induced by cold injury in the parietal cortex of the rat. Cold lesion was induced by applying a precooled (-78 degrees C) copper cylinder (diameter: 3 mm) for 6 s to the intact dura. Lesion volume was determined using the triphenyltetrazolium-chloride method after 24 h. Pretreatment (1 h) and posttreatment (7.5 h) with AG [10 or 100 mg/kg body mass (BM)] reduced the lesion volume by 15 and 27%, respectively. However, posttreatment alone with AG (10 and 100 mg/kg BM) caused less of a reduction in lesion volume, by 8 and 20%, respectively. Pre- and posttreatment with AG also reduced the plasma nitrate/nitrite concentration compared with lesioned, saline-treated rats. Only a double therapy with AG (100 mg/kg BM) resulted in a significant reduction (48%) compared to saline alone, which was even larger (55%) compared to the sham group. The tissue nitrate/ nitrite concentration was significantly attenuated by pre- and posttreatment with AG (100 mg/kg BM) not only in the ipsilateral but also in the contralateral hemisphere. There was no difference regarding the parameter between shams and lesioned, saline-treated rats. Since combined pre- and posttreatment with AG reduced the lesion volume more than posttreatment alone and the plasma and tissue nitrate/nitrite concentrations were diminished during AG therapy compared to shams, we hypothesize that AG inhibits not only iNOS but also other enzymes, such as nNOS, diamine oxidase, and advanced glycation endproducts synthase.