Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.

Mechanical Thrombectomy Versus Best Medical Treatment in the Late Time Window in Non-DEFUSE-Non-DAWN Patients: A Multicenter Cohort Study.

BACKGROUND: We assessed the efficacy and safety of mechanical thrombectomy (MT) in adult stroke patients with anterior circulation large vessel occlusion presenting in the late time window not fulfilling the DEFUSE-3 (Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging trial) and DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct trial) inclusion criteria. METHODS: Cohort study of adults with anterior circulation large vessel occlusion admitted between 6 and 24 hours after last-seen-well at 5 participating Swiss stroke centers between 2014 and 2021. Mismatch was assessed by computer tomography or magnetic resonance imaging perfusion with automated software (RAPID or OLEA). We excluded patients meeting DEFUSE-3 and DAWN inclusion criteria and compared those who underwent MT with those receiving best medical treatment alone by inverse probability of treatment weighting using the propensity score. The primary efficacy end point was a favorable functional outcome at 90 days, defined as a modified Rankin Scale score shift toward lower categories. The primary safety end point was symptomatic intracranial hemorrhage within 7 days of stroke onset; the secondary was all-cause mortality within 90 days. RESULTS: Among 278 patients with anterior circulation large vessel occlusion presenting in the late time window, 190 (68%) did not meet the DEFUSE-3 and DAWN inclusion criteria and thus were included in the analyses. Of those, 102 (54%) received MT. In the inverse probability of treatment weighting analysis, patients in the MT group had higher odds of favorable outcomes compared with the best medical treatment alone group (modified Rankin Scale shift: acOR, 1.46 [1.02-2.10]; P=0.04) and lower odds of all-cause mortality within 90 days (aOR, 0.59 [0.37-0.93]; P=0.02). There were no significant differences in symptomatic intracranial hemorrhage (MT versus best medical treatment alone: 5% versus 2%, P=0.63). CONCLUSIONS: Two out of 3 patients with anterior circulation large vessel occlusion presenting in the late time window did not meet the DEFUSE-3 and DAWN inclusion criteria. In these patients, MT was associated with higher odds of favorable functional outcomes without increased rates of symptomatic intracranial hemorrhage. These findings support the enrollment of patients into ongoing randomized trials on MT in the late window with more permissive inclusion criteria.

Magnetic Resonance Imaging or Computed Tomography for Suspected Acute Stroke: Association of Admission Image Modality with Acute Recanalization Therapies, Workflow Metrics, and Outcomes.

OBJECTIVE: To examine rates of intravenous thrombolysis (IVT), mechanical thrombectomy (MT), door-to-needle (DTN) time, door-to-puncture (DTP) time, and functional outcome between patients with admission magnetic resonance imaging (MRI) versus computed tomography (CT). METHODS: An observational cohort study of consecutive patients using a target trial design within the nationwide Swiss-Stroke-Registry from January 2014 to August 2020 was carried out. Exclusion criteria included MRI contraindications, transferred patients, and unstable or frail patients. Multilevel mixed-effects logistic regression with multiple imputation was used to calculate adjusted odds ratios with 95% confidence intervals for IVT, MT, DTN, DTP, and good functional outcome (mRS 0-2) at 90 days. RESULTS: Of the 11,049 patients included (mean [SD] age, 71 [15] years; 4,811 [44%] women; 69% ischemic stroke, 16% transient ischemic attack, 8% stroke mimics, 6% intracranial hemorrhage), 3,741 (34%) received MRI and 7,308 (66%) CT. Patients undergoing MRI had lower National Institutes of Health Stroke Scale (median [interquartile range] 2 [0-6] vs 4 [1-11]), and presented later after symptom onset (150 vs 123 min, p < 0.001). Admission MRI was associated with: lower adjusted odds of IVT (aOR 0.83, 0.73-0.96), but not with MT (aOR 1.11, 0.93-1.34); longer adjusted DTN (+22 min [13-30]), but not with longer DTP times; and higher adjusted odds of favorable outcome (aOR 1.54, 1.30-1.81). INTERPRETATION: We found an association of MRI with lower rates of IVT and a significant delay in DTN, but not in DTP and rates of MT. Given the delays in workflow metrics, prospective trials are required to show that tissue-based benefits of baseline MRI compensate for the temporal benefits of CT. ANN NEUROL 2022;92:184-194.

[Mild behavioral impairment checklist : English-German translation and feasibility study assessing its use in clinical practice]. / "Mild-behavioral-impairment"-Checkliste : Englisch-deutsche Übersetzung und Beurteilung der Anwendbarkeit in klinischer Praxis.

BACKGROUND: The mild behavioral impairment (MBI) syndrome is defined by the emergence in later life of persistent neuropsychiatric symptoms. The MBI checklist (MBI-C) can be used for systematic detection and documentation of such symptoms. OBJECTIVE: Development of a German version of the MBI­C and assessment of its application in a clinical setting. MATERIAL AND METHODS: The MBI­C was translated from English into German in collaboration with the main author of the original version, and its practical application was then tested on a study population (n = 21) in a gerontopsychiatric inpatient clinic. Patient compliance, understanding of questions, time effort, evaluation procedure and possible discrepancy between patient and family member evaluations were assessed. RESULTS: The German translation of the original MBI­C obtained certification as an official version and can be downloaded at https://mbitest.org . All 34 questions were fully completed by the study population, the level of understanding of questions was good, with the mean time effort being 16 min. In some cases, significant differences between patients' and family members' responses were found. DISCUSSION: The presence of MBI may indicate the development of an otherwise presymptomatic neurodegenerative dementia syndrome. Hence, the MBI­C could aid in the early detection of neurodegenerative dementia. By means of the translated version of the MBI­C presented in this study, this hypothesis can now be tested in German-speaking countries.

Endemic influences of political regimes, healthcare systems, and preferences on the frequencies and incidences of nephropathies in eastern Saxony, Germany
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INTRODUCTION: The possible confounding influence of investigator-related preferences, available histological techniques, and healthcare systems on the frequencies and incidences of primary and secondary nephropathies was evaluated in this long-term observation. MATERIALS AND METHODS: The observation time from 1983 to 2010 was divided in regard to the political regimes: a) prior to and after German reunification: German Democratic Republic (GDR, period 1 from 1983 to 1990)/Federal Republic of Germany (FRG, period 2 from 1990 to 2010); and the two heads of the division of nephrology, b) conductor 1 (1983 - 2006) and conductor 2 (2006 - 2010). 467 kidney biopsies at the University Hospital of Leipzig were included in our analysis. RESULTS: In period 1, due to the unavailability of immunofluorescence methods, mesangioproliferative glomerulonephritis (MesP) was the most dominating nephropathy. In period 2, IgA nephropathy (IgAN) was the most common nephropathy (17%). IgAN was followed by crescentic glomerulonephritis (13%), hypertensive nephropathy (10%), minimal-change disease, and membranous glomerulonephritis (each 9%). From period 1 to period 2, MesP/IgAN (62% to 16%), membranoproliferative glomerulonephritis and postinfectious glomerulonephritis decreased significantly (p < 0.05). IgAN decreased significantly (p < 0.05) from conductor 1 to conductor 2 (21% to 6%), while diabetic nephropathy significantly increased. Focal-segmental glomerulosclerosis (FSGS) had the highest incidence rate with 1.0, followed by IgAN with 0.8 (per 100,000 per year). CONCLUSION: In a nearly ethnically identical cohort, we have demonstrated that confounding factors, e.g., healthcare systems and preferences of conductors, have a strong influence - more than 10-fold variance - on frequency and incidence on the spectrum of nephropathies.
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Modern peptide biomarkers and echocardiography in cardiac healthy haemodialysis patients.

BACKGROUND: In this prospective study, we aimed to assess the haemodynamic changes before and after haemodialysis (HD) in cardiac healthy subjects on chronic HD by imaging methods and endocrine markers of fluid balance. METHODS: Mid-regional pro-atrial natriuretic peptide (MR-proANP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), vasopressin (AVP) and copeptin (CT-proAVP), metanephrines and normetanephrines, renin and aldosterone, standard transthoracic echocardiography and diameter of vena cava inferior (VCID) were performed in 20 patients with end stage renal disease (CKD5D) before and after HD and were stratified in residual excretion (RE, less or more 0.5 l) and ultrafiltration rate (UF, less or more 2 l). RESULTS: Copeptin was significantly higher in patients before HD. Copeptin was inversely correlated with haemodialysis treatment adequacy (KT/v), RE and UF, but was not significantly influenced by age, gender and body mass index (BMI). MR-proANP was significantly reduced by haemodialysis by 27% and was inversely correlated with KT/v, but there was a significant influence by UF, RE, age, gender and BMI. NT-proBNP was significantly higher in patients before HD and was not influenced by RE and UF. Renin, aldosterone, metanephrines and normetanephrines did not demonstrate significant differences. Echocardiographic parameters and VCID were significantly correlated with RE, UF and copeptin. CONCLUSION: Modern biomarkers will provide cardiovascular risk assessment, but elimination (UF), RE and other factors may influence the serum concentrations, e.g. in patients with renal impairment. The interpretation will be limited by altered reference ranges, and will be restricted to individual courses combined with clinical and echocardiographic data.

Lipoprotein(a) as a blood marker for large artery atherosclerosis stroke etiology: validation in a prospective cohort from a swiss stroke center.

BACKGROUND: Lipoprotein (a) [Lp(a)] serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort. METHODS: This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients [NCT00878813]), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers. RESULTS: Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10and#xA0;Lp(a) with LAA stroke aetiology (aOR 1.47 [95% CI 1.03and#x2013;2.09], p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes. CONCLUSIONS: In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov. REGISTRATION NUMBER: NCT00878813.

Effectiveness of an Individualized Exergame-Based Motor-Cognitive Training Concept Targeted to Improve Cognitive Functioning in Older Adults With Mild Neurocognitive Disorder: Study Protocol for a Randomized Controlled Trial.

BACKGROUND: Simultaneous motor-cognitive training is considered promising for preventing the decline in cognitive functioning in older adults with mild neurocognitive disorder (mNCD) and can be highly motivating when applied in the form of exergaming. The literature points to opportunities for improvement in the application of exergames in individuals with mNCD by developing novel exergames and exergame-based training concepts that are specifically tailored to patients with mNCD and ensuring the implementation of effective training components. OBJECTIVE: This study systematically explores the effectiveness of a newly developed exergame-based motor-cognitive training concept (called "Brain-IT") targeted to improve cognitive functioning in older adults with mNCD. METHODS: A 2-arm, parallel-group, single-blinded randomized controlled trial with a 1:1 allocation ratio (ie, intervention: control), including 34 to 40 older adults with mNCD will be conducted between May 2022 and December 2023. The control group will proceed with the usual care provided by the (memory) clinics where the patients are recruited. The intervention group will perform a 12-week training intervention according to the "Brain-IT" training concept, in addition to usual care. Global cognitive functioning will be assessed as the primary outcome. As secondary outcomes, domain-specific cognitive functioning, brain structure and function, spatiotemporal parameters of gait, instrumental activities of daily living, psychosocial factors, and resting cardiac vagal modulation will be assessed. Pre- and postintervention measurements will take place within 2 weeks before starting and after completing the intervention. A 2-way analysis of covariance or the Quade nonparametric analysis of covariance will be computed for all primary and secondary outcomes, with the premeasurement value as a covariate for the predicting group factor and the postmeasurement value as the outcome variable. To determine whether the effects are substantive, partial eta-squared (η2p) effect sizes will be calculated for all primary and secondary outcomes. RESULTS: Upon the initial submission of this study protocol, 13 patients were contacted by the study team. Four patients were included in the study, 2 were excluded because they were not eligible, and 7 were being informed about the study in detail. Of the 4 included patients, 2 already completed all premeasurements and were in week 2 of the intervention period. Data collection is expected to be completed by December 2023. A manuscript of the results will be submitted for publication in a peer-reviewed open-access journal in 2024. CONCLUSIONS: This study contributes to the evidence base in the highly relevant area of preventing disability because of cognitive impairment, which has been declared a public health priority by the World Health Organization. TRIAL REGISTRATION: ClinicalTrials.gov NCT05387057; https://clinicaltrials.gov/ct2/show/NCT05387057. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41173.

Clinical Course and Recurrence in Transient Global Amnesia: A Study From the TEMPiS Telestroke Network.

BACKGROUND AND PURPOSE: While the clinical hallmarks of transient global amnesia (TGA) are well defined, its pathophysiological causes are poorly understood. Specifically, risk factors for recurrences are yet to be determined. METHODS: This retrospective study analyzed TGA cases diagnosed and treated within the TEMPiS telestroke network and a university stroke center in Germany. Demographic and clinical data were assessed and characteristics of TGA episodes were recorded, such as season of occurrence, trigger factors, duration, and concomitant symptoms. Follow-up of the potential recurrence of TGA was performed using a standardized questionnaire. RESULTS: Overall 109 patients were included (age 64±8 years [mean±SD], 59.6% female). The most common vascular risk factor was arterial hypertension (60.6%), and other concomitant conditions included migraine (11.9%), hypothyroidism (22.9%), and atrial fibrillation (4.6%). The most frequent concomitant clinical feature accompanying the TGA episode at admission was elevated blood pressure (48.6%). Nineteen patients experienced at least one recurrent TGA episode. Migraine and hypothyroidism were only observed in subjects with a single TGA episode without recurrence (migraine: 14.4% without recurrence vs. none in the recurrence group, p=0.02; hypothyroidism: 27.8% without recurrence vs. none in the recurrence group, p=0.009). In contrast, atrial fibrillation was more common in subjects with TGA recurrence (p<0.001). CONCLUSIONS: Arterial hypertension is prevalent in TGA patients, with elevated blood pressure being the most-frequent concomitant condition. In our cohort, recurrence of TGA occurred in approximately one-fifth of patients. Concomitant conditions such as migraine, hypothyroidism, and atrial fibrillation occurred at different frequencies in the two groups.

Mechanical thrombectomy for large vessel occlusion between 6 and 24 h: outcome comparison of DEFUSE-3/DAWN eligible versus non-eligible patients.

BACKGROUND: The DEFUSE-3 and DAWN trials showed that mechanical thrombectomy (MT) improves the outcome of selected patients with anterior circulation large vessel occlusions (LVO) up to 24 h after stroke onset. However, it is unknown whether only those patients fulfilling the trial inclusion criteria benefit, or whether benefit is seen in a broader range of patients presenting between 6 and 24 h. AIMS: We determined whether fulfilling the DEFUSE-3 and DAWN selection criteria affects outcomes in MT patients in clinical practice. METHODS: We reviewed adult patients with LVO treated with MT between 6 and 24 h after stroke onset at five Swiss stroke centers between 2014 and 2021. We compared two groups: (1) patients who satisfied neither DEFUSE-3 nor DAWN criteria (NDND) and (2) those who satisfied DEFUSE-3 or DAWN criteria (DOD). We used logistic regression to examine the impact of trial eligibility on two safety outcomes (symptomatic intracranial hemorrhage [sICH] and all-cause mortality at 3 months) and two efficacy outcomes (modified Rankin Score [mRS] shift toward lower categories and mRS of 0-2 at 3 months). RESULTS: Of 174 patients who received MT, 102 (59%) belonged to the NDND group. Rates of sICH were similar between the NDND group and the DOD group (3% vs. 4%, p = 1.00). Multivariable regression revealed no differences in 3-month all-cause mortality (aOR 2.07, 95% CI 0.64-6.84, p = 0.23) or functional outcomes (mRS shift: acOR 0.81, 95% CI 0.37-1.79, p = 0.60; mRS 0-2: aOR 0.91, 95% CI 0.31-2.57, p = 0.85). CONCLUSION: Among adult patients with LVO treated with MT between 6 and 24 h, safety and efficacy outcomes were similar between DEFUSE-3/DAWN eligible and ineligible patients. Our data provide a compelling rationale for randomized trials with broader inclusion criteria for MT.

Urokinase-type plasminogen activator regulates neurodegeneration and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus.

Expression of urokinase-type plasminogen activator (uPA) is increased after brain injury, suggesting that, like in cancer tissue, uPA plays roles in brain remodeling. Here we injured brain with intrahippocampal kainic acid (KA) injection in adult Wt and uPA-/- mice. At 20 days post-injury, uPA-/- mice had more severe loss of contralateral pyramidal (p<0.05) and hilar neurons (p<0.05) than Wt mice. The number of doublecortin (DCX)-positive newly born neurons was also reduced in uPA-/- mice as compared to Wt (p<0.01). No difference was observed in granule cell dispersion or distribution of DCX-positive neurons in the dentate gyrus. uPA deficiency did not affect the total length of hippocampal blood vessels or vessel density. No differences were observed in the severity of status epilepticus or consequent epilepsy between the genotypes. These data indicate that uPA deficiency can unfavorably modulate both delayed neurodegeneration and neurogenesis but has little effect on post-injury neuronal migration and vascular density. Our results favor the idea that elevated uPA during the post-injury phase is neuroprotective.

Dual RAAS Blockade with Aliskiren in Patients with Severely Impaired Chronic Kidney Disease.

Dual renin-angiotensin-aldosterone blockade (dRAASb) is purposed in the prevention of the cardiorenal syndrome (CRS). However, all attempts with dRAASb even in patients with moderate impaired chronic kidney disease (CKD) were terminated due to the typical severe adverse events (SAE), e. g., hyperkalemia and rise of serum creatinine. The aim of our study with the direct renin inhibitor aliskiren was to evaluate the effect of dRAASb with a washout phase in patients with severely advanced CKD. We have studied 45 patients (G3b to 4, A2 and >A3; median glomerular filtration rate (GFR) CKD-EPI 31 (23-40) ml/min per 1.73 m² BSA (body surface area), albumin-creatinine-ratio in urine (UACR) (0.413 (0.164 to 1.39) g/g) and proteinuria (0.5 (0.2 to 0.9) g/l) before, with and without aliskiren (150 respectively 300 mg per day) added to an angiotensin-converting enzyme inhibitor (ACEi) or an AT1-receptor blocker (ARB) over 4 ½ years. The dRAASb with aliskiren showed a significant decrease of proteinuria (0.5 to 0.38 g/l), especially in patients with an UACR≥350 mg/g and in the subgroup analysis e. g., in patients with diabetes, but proteinuria increased in the washout phase again. The blood pressure (130/80 mm Hg), serum potassium (4.9 to 5.0 mmol/l) and GFR remained nearly constant (31 to 29.5 ml/min per 1.73 m2 BSA). A more than 30% increase in serum creatinine was associated with an UACR>300 mg/g. The dRAASb has beneficial effects on proteinuria and is safe in patients with severely advanced CKD. However, in patients with high UACR (>300 mg/g) raise of creatinine and potassium have to be controlled.

The Pituitary-Thyroid Axis and Prolactin Secretion in Hemodialysis Patients in Two Endemic Regions of Eastern Germany.

INTRODUCTION: Endocrine disorders of the pituitary axes are frequent in patients with hemodialysis (CKD5D). The aim of this multicenter study (Leipzig (L), Quedlinburg and Blankenburg in the Harz region (Hz)) in CKD5D patients was to evaluate influences of CKD5D related factors, morphological and biochemical parameters, and serum iodine and prolactin concentrations on the pituitary-thyroid axis. PATIENTS AND METHODS: 170 patients (L n=58; Hz n=112) were included in this prospective, non-interventional, cross-sectional study. Mann-Whitney-U-test and bivariate correlation analyses with Spearman-Rho test (r correlation coefficient) were used in statistical analysis. RESULTS: TSH was higher in patients with prolactin concentrations>370 mIU/l (p=0.013), in patients with high flux membranes (p=0.0013) and in patients with longer dialysis vintage (p=0.04). Median iodine serum concentrations were slightly elevated in the Leipzig cohort (p=0.001) and correlated with fT4 (p<0.001, r=0.43) and albumin (p=0.001, r=0.245) but not with morphological signs. Albumin was correlated with fT3 (p<0.001, r=0.339) and fT4 (p<0.001, r=0.421). Prolactin was correlated with residual excretion rate (p=0.001, r=- 0.303) and thyroid volume (p=0.027, r=0.217). CONCLUSIONS: In the assessment of the thyroid status in CKD5D patients, the synopsis of the clinical and nutritional status, comorbidities, ultrasound of the thyroid gland and laboratory results is necessary for further intervention with hormone replacement. Standardized reference values of the pituitary-thyroid axis should be critically evaluated and are still lacking in CKD5D.

Influence of Erythropoiesis-Stimulating Agents on HbA1c and Fructosamine in Patients with Haemodialysis.

HbA1c is the most accepted laboratory parameter for the long term observation of glucose control. There is still much of a debate about the use of HbA1c as a metabolic indicator in diabetic patients (DM) on haemodialysis (HD) and erythropoiesis-stimulating agent (ESA) therapy because of the altered erythrocyte turn over in patients with chronic kidney disease and haemodialysis (CKD5D). In 102 CKD5 patients with and without diabetes mellitus, we examined the dose dependent variability in HbA1c and fructosamine levels under haemodialysis and treated with epoetin α (n=48) and a new generation agent with continuous stimulation of methoxy polyethylene glycol epoetin beta (C.E.R.A.; n=54). HbA1c levels were affected by therapy with ESA treatments. ESA dose was inversely correlated with HbA1c and an escalation of 10.000 IU per week induced an estimated decrease of HbA1c of 0.6 percent. In addition, the increase of reticulocyte number as a marker for erythropoiesis was significantly inversely correlated with the increase of ΔHbA1c. ESA treatments had no such effect on the alternative metabolic parameter fructosamine. When compared, both therapeutic agents had comparable success in attaining haemoglobin (Hb) target values. C.E.R.A. showed better correlation and was more effective over a longer dose interval. Our results show that HbA1c levels in patients should be carefully interpreted based on interfering factors. Nevertheless, HbA1c is currently the most consistent parameter for use ascertaining metabolic status of patients suffering from diabetes mellitus.

Calretinin and parvalbumin immunoreactive interneurons in the retrosplenial cortex of the rat brain: Qualitative and quantitative analyses.

The retrosplenial cortex (RSC) is a mesocortical region broadly involved with memory and navigation. It shares many characteristics with the perirhinal cortex (PRC), both of which appear to be significantly involved in the spreading of epileptic activity. We hypothesized that RSC possesses an interneuronal composition similar to that of PRC. To prove the hypothesis we studied the general pattern of calretinin (CR) and parvalbumin (PV) immunoreactivity in the RSC of the rat brain, its optical density as well as the morphological features and density of CR- and PV-immunoreactive (CR+ and PV+) interneurons. We also analyzed the overall neuronal density on Nissl-stained sections in RSC. Finally, we compared our results with our earlier analysis of PRC (Barinka et al., 2012). Compared to PRC, RSC was observed to have a higher intensity of PV staining and lower intensity of CR staining of neuropil. Vertically-oriented bipolar neurons were the most common morphological type among CR+ neurons. The staining pattern did not allow for a similarly detailed analysis of somatodendritic morphology of PV+ neurons. RSC possessed lower absolute (i.e., neurons/mm(3)) and relative (i.e., percentage of the overall neuronal population) densities of CR+ neurons and similar absolute and lower relative densities of PV+ neurons relative to PRC. CR: PV neuronal ratio in RSC (1:2 in area 29 and 1:2.2 in area 30) differed from PRC (1:1.2 in area 35 and 1:1.7 in area 36). In conclusion, RSC, although similar in many aspects to PRC, differs strikingly in the interneuronal composition relative to PRC.

Calretinin immunoreactivity in the claustrum of the rat.

The claustrum is a telencephalic structure which consists of dorsal segment adjoining the insular cortex and a ventral segment termed also endopiriform nucleus (END). The dorsal segment (claustrum) is divided into a dorsal and ventral zone, while the END is parcellated into dorsal, ventral and intermediate END. The claustrum and the END consist of glutamatergic projection neurons and GABAergic local interneurons coexpressing calcium binding proteins. Among neurons expressing calcium binding proteins the calretinin (CR)-immunoreactive interneurons exert specific functions in neuronal circuits, including disinhibition of excitatory neurons. Previous anatomical data indicate extensive and reciprocally organized claustral projections with cerebral cortex. We asked if the distribution of cells immunoreactive for CR delineates anatomical or functional subdivisions in the claustrum and in the END. Both segments of the claustrum and all subdivisions of the END contained CR immunoreactive neurons with varying distribution. The ventral zone of the claustrum exhibited weak labeling with isolated cell bodies and thin fibers and is devoid of immunoreactive puncta. Within the medial margin of the intermediate END we noted a group of strongly positive neurons. Cells immunoreactive for CR in all subdivisions of the claustrum and END were bipolar, multipolar and oval with smooth, beaded aspiny dendrites. Small number of CR-immunoreactive neurons displayed thin dendrites which enter to adjoining structures. Penetration of dendrites was reciprocal. These results show an inhomogenity over the claustrum and the END in distribution and types of CR immunoreactive neurons. The distribution of the CR-immunoreactive neurons respects the anatomical but not functional zones of the claustral complex.

Calretinin, parvalbumin and calbindin immunoreactive interneurons in perirhinal cortex and temporal area Te3V of the rat brain: qualitative and quantitative analyses.

The perirhinal cortex (PRC) composed of areas 35 and 36 forms an important route for activity transfer between the hippocampus-entorhinal cortex and neocortex. Its function in memory formation and consolidation as well as in the initiation and spreading of epileptic activity was already partially elucidated. We studied the general pattern of calretinin (CR), parvalbumin (PV) and calbindin (CB) immunoreactivity and its corrected relative optical density (cROD) as well as morphological features and density of CR and PV immunoreactive (CR+, PV+) interneurons in the rat PRC. Neighboring neocortical association area Te3V was analyzed as well. The PRC differed from the Te3V in higher CR and lower PV overall immunoreactivity level. On CR immunostained sections, the difference between high cROD value in area 35 and low cROD value in area Te3V reached statistical significance (p<0.05). The pattern of CB immunoreactivity was similar to that of the neocortex. Vertically oriented bipolar neurons were the most common morphological type of CR+ neurons, multipolar neuronal morphology was typical among PV+ neurons and vertically oriented bipolar neurons and multipolar neurons were approximately equally frequent among CB+ neurons. The density of CR+ and PV+ neurons was stereologically measured. While the density of PV+ neurons was not significantly different in PRC when compared to Te3V, density of CR+ neurons in area 35 was significantly higher by comparison with Te3V (p<0.05). Further, the overall neuronal density was measured on Nissl stained sections and the proportion of CR+ and PV+ interneurons was expressed as a percentage of the total neurons counts. The percentage of CR+ interneurons was higher in area 35 by comparison with area Te3 (p<0.05), while the percentage of PV+ interneurons did not significantly differ among the examined areas. In conclusion, the PRC possesses specific interneuronal equipment with unusually high proportion of CR+ interneurons, what might be of importance for the presumed gating function of PRC in normal and diseased states.

Calretinin immunoreactivity in focal cortical dysplasias and in non-malformed epileptic cortex.

Focal cortical dysplasias (FCDs) represent a prominent cause of pharmacologically intractable epilepsy. In FCD, the decrease of parvalbumin immunoreactive (PV+) inhibitory interneurons has been repeatedly documented. Here, we wanted to show whether another interneuronal population, the calretinin immunoreactive (CR+) neurons, exhibits any change in human FCD. We also investigated samples of morphologically normal temporal neocortex resected together with sclerotic hippocampus (nHSTN), where decrease of PV+ interneurons was previously documented as well. Brain tissue from 24 patients surgically treated for pharmacoresistant epilepsy was examined. Calretinin immunoreactivity was qualitatively evaluated and the density of CR+ neuronal profiles was quantified. As a control, post-mortem acquired neocortical samples of nine patients without any brain affecting disease were used. CR+ neurons were located predominantly in superficial cortical layers both in controls and pathological samples. Similarly, the morphology of CR+ neurons was unaffected in pathological samples. The overall density of CR+ neurons was significantly decreased in FCD type I (to approximately 70% of control values) and even more in FCD type II (to approximately 50% of controls). In nHSTN, no change compared to controls was found in CR+ neuronal density. Our results may contribute to the better understanding of the role of individual interneuronal populations in epileptogenesis.