Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis.

BACKGROUND: Acute cerebellitis (AC) in children and adolescents is an inflammatory disease of the cerebellum due to viral or bacterial infections but also autoimmune-mediated processes. OBJECTIVE: To investigate the frequency of autoantibodies in serum and CSF as well as the neuroradiological features in children with AC. MATERIAL AND METHODS: Children presenting with symptoms suggestive of AC defined as acute/subacute onset of cerebellar symptoms and MRI evidence of cerebellar inflammation or additional CSF pleocytosis, positive oligoclonal bands (OCBs), and/or presence of autoantibodies in case of negative cerebellar MRI. Children fulfilling the above-mentioned criteria and a complete data set including clinical presentation, CSF studies, testing for neuronal/cerebellar and MOG antibodies as well as MRI scans performed at disease onset were eligible for this retrospective multicenter study. RESULTS: 36 patients fulfilled the inclusion criteria for AC (f:m = 14:22, median age 5.5 years). Ataxia was the most common cerebellar symptom present in 30/36 (83 %) in addition to dysmetria (15/36) or dysarthria (13/36). A substantial number of children (21/36) also had signs of encephalitis such as somnolence or seizures. In 10/36 (28 %) children the following autoantibodies (abs) were found: MOG-abs (n = 5) in serum, GFAPα-abs (n = 1) in CSF, GlyR-abs (n = 1) in CSF, mGluR1-abs (n = 1) in CSF and serum. In two further children, antibodies were detected only in serum (GlyR-abs, n = 1; GFAPα-abs, n = 1). MRI signal alterations in cerebellum were found in 30/36 children (83 %). Additional supra- and/or infratentorial lesions were present in 12/36 children, including all five children with MOG-abs. Outcome after a median follow-up of 3 months (range: 1 a 75) was favorable with an mRS ≤2 in 24/36 (67 %) after therapy. Antibody (ab)-positive children were significantly more likely to have a better outcome than ab-negative children (p = .022). CONCLUSION: In nearly 30 % of children in our study with AC, a range of abs was found, underscoring that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected AC. The detection of MOG-abs in AC does expand the MOGAD spectrum.

High-alert medications for hospitalised paediatric patients - a two-step survey among paediatric clinical expert pharmacists in Germany.

Paediatric patients are more vulnerable to be harmed by medication errors compared to adults due to pharmacokinetic and pharmacodynamic changes in their development, individual dosing calculations, and manipulation of ready to-use products intended for adult patients. According to the Institute of Safe Medication Practices, there are some "drugs that bear a heightened risk of causing significant patient harm when they are used in error"; these drugs are called high-alert medications (HAM). The two-step survey among paediatric clinical expert pharmacists presented here aimed to compile a nation-wide HAM list. To provide detailed guidance, this survey followed a drugbased approach, resulting in specific potential drug related problems (DRPs) and associated recommendations for prevention. In contrast to this approach, in the first round of the survey two drug classes were included that both were rated as HAM (i.e.chemotherapy and parenteral nutrition). Twenty single drugs were identified as HAM, 65% of which were cardiovascular or neurological drugs. The paediatric expert pharmacists mentioned in total 216 potential DRPs; in particular, they identified potential administration-related problems (28% of all DRPs), dosing-related problems (26%), and drug-choice-related problems (18%, e.g.drug confusion and drug monitoring). Moreover, they suggested 275 potential interventions to address these DRPs. Two thirds of all interventions dealt with the preparation by the hospital pharmacy, standardisation of processes (e.g.labelling), and education or training. In conclusion, this survey provided a German paediatric high-alert medication list from a paediatric pharmacist point of view. Moreover, the experts mentioned for the first time specific potential DRPs and associated interventions to guide a local multidisciplinary approach for preventing medication-related harm in children.

Reconciling livestock production and wild herbivore conservation: challenges and opportunities.

Increasing food security and preventing further loss of biodiversity are two of humanity's most pressing challenges. Yet, efforts to address these challenges often lead to situations of conflict between the interests of agricultural production and those of biodiversity conservation. Here, we focus on conflicts between livestock production and the conservation of wild herbivores, which have received little attention in the scientific literature. We identify four key socio-ecological challenges underlying such conflicts, which we illustrate using a range of case studies. We argue that addressing these challenges will require the implementation of co-management approaches that promote the participation of relevant stakeholders in processes of ecological monitoring, impact assessment, decision-making, and active knowledge sharing.

Transportation capacity for patients with highly infectious diseases in Europe: a survey in 16 nations.

Highly infectious diseases (HIDs) are defined as being transmissible from person to person, causing life-threatening illnesses and presenting a serious public health hazard. In most European Union member states specialized isolation facilities are responsible for the management of such cases. Ground ambulances are often affiliated with those facilities because rapid relocation of patients is most desirable. To date, no pooled data on the accessibility, technical specifications and operational procedures for such transport capacities are available. During 2009, the 'European Network for HIDs' conducted a cross-sectional analysis of hospitals responsible for HID patients in Europe including an assessment of (a) legal aspects; (b) technical and infrastructure aspects; and (c) operational procedures for ground ambulances used for HID transport. Overall, 48 isolation facilities in 16 European countries were evaluated and feedback rates ranged from 78% to 100% (n = 37 to n = 48 centres). Only 46.8% (22/47) of all centres have both national and local guidelines regulating HID patient transport. If recommended, specific equipment is found in 90% of centres (9/10), but standard ambulances in only 6/13 centres (46%). Exclusive entrances (32/45; 71%) and pathways (30/44; 68.2%) for patient admission, as well as protocols for disinfection of ambulances (34/47; 72.3%) and equipment (30/43; 69.8%) exist in most centres. In conclusion, the availability and technical specifications of ambulances broadly differ, reflecting different preparedness levels within the European Union. Hence, regulations for technical specifications and operational procedures should be harmonized to promote patient and healthcare worker safety.

Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability?

PURPOSE: Symptom progression in Huntington disease (HD) is associated with cognitive decline which may interfere with the self-report of symptoms. Unfortunately, data to support or refute the psychometric reliability of patient-reported outcomes (PROs) as HD progresses are limited. This is problematic given that PROs are increasingly recognized as important measures of efficacy for new treatments. METHODS: We examined PRO data from the HDQLIFE Measurement System (Speech Difficulties; Swallowing Difficulties; Chorea) in 509 individuals with premanifest, early-stage, or late-stage HD. Clinician-administered assessments of motor functioning (items from the UHDRS) and standardized objective assessments of cognition (Stroop, Symbol Digit Modalities) were also collected. We examined item bias using differential item functioning (DIF) across HD stage (premanifest, early-, late-) and relative to cognitive performance. We also examined the correlations between self-report and clinician ratings. Regression models that considered total cognitive ability were utilized to determine psychometric reliability of the PROs. RESULTS: Most PRO items were free from DIF for both staging and cognition. There were modest correlations between PROs and clinician report (ranged from - 0.40 to - 0.60). Modeling analyses indicated that psychometric reliability breaks down with poorer cognition and more progressed disease stage; split-half reliability was compromised (i.e., split-half reliability < 0.80) when scores were < 136 for Chorea, < 109 for Speech Difficulties, and < 179 for Swallowing Difficulties. CONCLUSIONS: Results indicate that the psychometric reliability of PROs can be compromised as HD symptoms progress and cognition declines. Clinicians should consider PROs in conjunction with other types of assessments when total cognition scores exceed critical thresholds.

[Two synchronous malignancies in a single nephrectomy specimen]. / Zwei synchrone Malignome in einem Nephrektomiepräparat.

We report a case of a 65-year-old man examined for hematuria and neurologic symptoms. Radiologically a tumour of the kidney was suspected, with metastatic involvement of the brain and both lungs. The urologists then performed a cytoreductive nephrectomy.In histopathological examination of the nephrectomy specimen a clear cell renal cell carcinoma (clear cell RCC) was found. However, an additional focus of a high-grade adenocarcinoma was discovered that turned out to be a metastasis of a poor differentiated lung adenocarcinoma. This diagnosis was supported by positive TTF1 and napsin-A as well as good clinical correlations.The article summarizes the differential diagnostic considerations of poor differentiated adenocarcinoma of the kidney, aimed at gross and microscopic morphology, immunohistochemistry and clinical-pathological correlation. A review of literature about a tumour-in-tumour metastasis is included.

A new measure for end of life planning, preparation, and preferences in Huntington disease: HDQLIFE end of life planning.

BACKGROUND: Huntington disease is a fatal inherited neurodegenerative disease. Because the end result of Huntington disease is death due to Huntington disease-related causes, there is a need for better understanding and caring for individuals at their end of life. AIM: The purpose of this study was to develop a new measure to evaluate end of life planning. DESIGN: We conducted qualitative focus groups, solicited expert input, and completed a literature review to develop a 16-item measure to evaluate important aspects of end of life planning for Huntington disease. Item response theory and differential item functioning analyses were utilized to examine the psychometric properties of items; exploratory factor analysis was used to establish meaningful subscales. PARTICIPANTS: Participants included 508 individuals with pre-manifest or manifest Huntington disease. RESULTS: Item response theory supported the retention of all 16 items on the huntington disease quality of life ("HDQLIFE") end of life planning measure. Exploratory factor analysis supported a four-factor structure: legal planning, financial planning, preferences for hospice care, and preferences for conditions (locations, surroundings, etc.) at the time of death. Although a handful of items exhibited some evidence of differential item functioning, these items were retained due to their relevant clinical content. The final 16-item scale includes an overall total score and four subscale scores that reflect the different end of life planning constructs. CONCLUSIONS: The 16-item HDQLIFE end of life planning measure demonstrates adequate psychometric properties; it may be a useful tool for clinicians to clarify patients' preferences about end of life care.

Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, ß- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aß production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aß production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.

[A 10-year evaluation of geriatric rehabilitation in Rhineland-Palatinate]. / 10 Jahre Evaluation der geriatrischen Rehabilitation in Rheinland-Pfalz.

BACKGROUND: An evaluation of geriatric rehabilitation has been carried out in Rhineland-Palatinate for over 10 years by collecting data of patients absolving an inpatient geriatric rehabilitation program. The aim of the project was to improve the transparency of outcome quality. The procedure is equally supported by geriatric rehabilitation clinics, health insurance companies and the Medical Service of Health Insurance (MDK). MATERIAL AND METHODS: Consented information about the rehabilitation process has been collected from every geriatric rehabilitation clinic in Rhineland-Palatinate. The data were pseudonymized and sent to the MDK in Rhineland-Palatinate for statistical analysis. The dataset included age, diagnosis, life circumstances before rehabilitation, duration of the rehabilitation, therapy implemented and need for support (with or without personal assistance) in eight activities of daily living at the beginning and at the end of rehabilitation. RESULTS: The results of 45,751 participants who underwent rehabilitation between 2005 and 2014 are presented. There was a slight tendency towards an increase in the number of very old geriatric patients undergoing rehabilitation. The average duration of rehabilitation decreased slightly during the observation period, while the frequency of therapy increased. The reduction in the need for assistance during rehabilitation remained constant over the observation period. CONCLUSION: Systematic evaluation improves the transparency of the rehabilitation process.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PURPOSE: Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD. METHODS: An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items. RESULTS: EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying. CONCLUSION: The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

The development of a new computer adaptive test to evaluate chorea in Huntington disease: HDQLIFE Chorea.

PURPOSE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with motor, behavioral, and cognitive deficits. The hallmark symptom of HD, chorea, is often the focus of HD clinical trials. Unfortunately, there are no self-reported measures of chorea. To address this shortcoming, we developed a new measure of chorea for use in HD, HDQLIFE Chorea. METHODS: Qualitative data and literature reviews were conducted to develop an initial item pool of 141 chorea items. An iterative process, including cognitive interviews, expert review, translatability review, and literacy review, was used to refine this item pool to 64 items. These 64 items were field tested in 507 individuals with prodromal and/or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to identify a unidimensional set of items. Then, an item response theory graded response model (GRM) and differential item functioning analyses were conducted to select the final items for inclusion in this measure. RESULTS: EFA and CFA supported the retention of 34 chorea items. GRM and DIF supported the retention of all of these items in the final measure. GRM calibration data were used to inform the selection of a 6-item, static short form and to program the HDQLIFE Chorea computer adaptive test (CAT). CAT simulation analyses indicated a 0.99 correlation between the CAT scores and the full item bank. CONCLUSIONS: The new HDQLIFE Chorea CAT and corresponding 6-item short form were developed using established rigorous measurement development standards; this is the first self-reported measure developed to evaluate the impact of chorea on HRQOL in HD. This development work indicates that these measures have strong psychometric properties; future work is needed to establish test-retest reliability and responsiveness to change.

HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties.

PURPOSE: Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD. METHODS: Five hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures. RESULTS: EFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank. CONCLUSIONS: CATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent.

[New strategies for exercise training in osteoporosis]. / Innovatives Bewegungstraining bei Osteoporose.

In the prevention and treatment of osteoporosis, movement with muscle strengthening and proprioceptive training plays a major role. This was taken into consideration in the guidelines by the governing body on osteoporosis (Dachverband Osteoporose, DVO) from 2014 on prophylaxis, diagnosis and treatment of osteoporosis and in the DVO guidelines from 2008 on physiotherapy and exercise therapy for osteoporosis. Increases in lumbar bone density of between 0.5 % and 2.5 % can be achieved in women by strengthening exercises with high resistance. With this combination and strengthening of the quadriceps muscle a reduction of falls and hence the fracture risk could also be achieved. In traumatology, training for muscle strengthening is not always possible, especially for elderly patients. Practically relevant alternatives are regular walking and aquatraining, which may also lead to a significant increase in bone mineral density. Furthermore, large effects can be achieved with alternating side whole-body vibration (WBV) training with whole body vibration plates with only 3 days of training per week and with short training periods (15-20 min). Rates of increase in leg strength between 20 % and almost 40 % and in bone density between 0.5 % and 4 % in 6 months have been described. Whether and with what intensity whole body vibration therapy could be used for e.g. more rapid healing of fractures, is currently unclear. Initial positive results have been described in animal models.

[Identification, diagnostics and guideline conform therapy of osteoporosis (DVO) in trauma patients : a treatment algorithm]. / Identifikation, Diagnostik und leitliniengerechte Osteoporosetherapie (DVO) unfallchirurgischer Patienten : Ein Behandlungsalgorithmus.

Osteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.

Expression, purification and initial characterization of human meprin ß from Pichia pastoris.

Human meprin ß (h-meprin ß), a single-zinc metalloendoprotease of the astacin family, is potentially involved in disorders such as fibrosis and Alzheimer's disease. Here, we describe the expression of the enzyme in the yeast Pichia pastoris. The N-terminal signal sequence was replaced by the α-leader of Saccharomyces, enabling efficient secretion of the mature enzyme, harboring either an N-terminal or C-terminal His-tag. The purification by affinity and hydrophobic interaction chromatography resulted in isolation of 58.4 mg/l of homogenous human pro-meprin ß from fermentation broth. The activated enzyme isolated from yeast (yh-meprin ß) displayed virtually identical enzymatic activity as h-meprin from a mammalian cell line. Furthermore, the yh-meprin ß was N-glycosylated and secreted as a dimer with a molecular mass of 148 kDa. Endoglycosidase H treatment generated a protein with a molecular mass of 133 kDa, but essentially unchanged kinetic parameters. Thus, our data suggest that human meprin ß expressed in P. pastoris displays virtually identical parameters as meprin from other sources. The high yield of protein expression, the ease of purification and the deglycosylation in its native state appear to favor further studies aiming at inhibitor screening and structure-based inhibitor refinement.

An empirical inferential method of estimating nitrogen deposition to Mediterranean-type ecosystems: the San Bernardino Mountains case study.

The empirical inferential method (EIM) allows for spatially and temporally-dense estimates of atmospheric nitrogen (N) deposition to Mediterranean ecosystems. This method, set within a GIS platform, is based on ambient concentrations of NH3, NO, NO2 and HNO3; surface conductance of NH4(+) and NO3(-); stomatal conductance of NH3, NO, NO2 and HNO3; and satellite-derived LAI. Estimated deposition is based on data collected during 2002-2006 in the San Bernardino Mountains (SBM) of southern California. Approximately 2/3 of dry N deposition was to plant surfaces and 1/3 as stomatal uptake. Summer-season N deposition ranged from <3 kg ha(-1) in the eastern SBM to ∼ 60 kg ha(-1) in the western SBM near the Los Angeles Basin and compared well with the throughfall and big-leaf micrometeorological inferential methods. Extrapolating summertime N deposition estimates to annual values showed large areas of the SBM exceeding critical loads for nutrient N in chaparral and mixed conifer forests.

Atmospheric deposition of nitrogen, sulfur and base cations in jack pine stands in the Athabasca Oil Sands Region, Alberta, Canada.

Atmospheric deposition in the Athabasca Oil Sands Region decreased exponentially with distance from the industrial center. Throughfall deposition (kg ha(-1) yr(-1)) of NH(4)-N (.8-14.7) was double that of NO(3)-N (.3-6.7), while SO(4)-S ranged from 2.5 to 23.7. Gaseous pollutants (NO(2), HNO(3), NH(3), SO(2)) are important drivers of atmospheric deposition but weak correlations between gaseous pollutants and deposition suggest that particulate deposition is also important. The deposition (eq ha(-1)) of base cations (Ca + Mg + Na) across the sampling network was highly similar to N + S deposition, suggesting that acidic deposition is neutralized by base cation deposition and that eutrophication impacts from excess N may be of greater concern than acidification. Emissions from a large forest fire in summer 2011 were most prominently reflected in increased concentrations of HNO(3) and throughfall deposition of SO4-S at some sites. Deposition of NO(3)-N also increased as did NH(4)-N deposition to a lesser degree.

Disrupted cross-laminar cortical processing in ß amyloid pathology precedes cell death.

Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological ß-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical ß-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aß are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.