Lumbar dynamic pedicle-based stabilization versus fusion in degenerative disease: a multicenter, double-blind, prospective, randomized controlled trial.

OBJECTIVE: Fusion is the standard of treatment for degenerative lumbar symptomatic instabilities. Dynamic stabilization is a potential alternative, with the aim of reducing pathological motion. Potential advantages are a reduction of surgical complexity and morbidity. The aim of this study was to assess whether dynamic stabilization is associated with a higher degree of functional improvement while reducing surgical complexity and thereby surgical duration and perioperative complications in comparison with lumbar fusion. METHODS: This was a multicenter, double-blind, prospective, randomized, 2-arm superiority trial. Patients with symptomatic mono- or bisegmental lumbar degenerative disease with or without stenosis and instability were randomized 1:1 to instrumented fusion or pedicle-based dynamic stabilization. Patients underwent either rigid internal fixation and interbody fusion or pedicle-based dynamic stabilization. The primary endpoint was the Oswestry Disability Index (ODI) score, and secondary endpoints were pain, health-related quality of life, and patient satisfaction at 24 months. RESULTS: Of 293 patients randomized to fusion or dynamic stabilization, 269 were available for analysis. The duration of surgery was significantly shorter for dynamic stabilization versus fusion, and the blood loss was significantly less for dynamic stabilization (380 ml vs 506 ml). Assessment of primary and secondary outcome parameters revealed no significant differences between groups. There were no differences in the incidence of adverse events. CONCLUSIONS: Dynamic pedicle-based stabilization can achieve similar clinical outcome as fusion in the treatment of lumbar degenerative instabilities. Secondary failures are not different between groups. However, dynamic stabilization is less complex than fusion and is a feasible alternative.

Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.

The neuroprotective role of microglial cells against amyloid beta-mediated toxicity in organotypic hippocampal slice cultures.

During Alzheimer's disease (AD) progression, microglial cells play complex roles and have potentially detrimental as well as beneficial effects. The use of appropriate model systems is essential for characterizing and understanding the roles of microglia in AD pathology. Here, we used organotypic hippocampal slice cultures (OHSCs) to investigate the impact of microglia on amyloid beta (Aß)-mediated toxicity. Neurons in OHSCs containing microglia were not vulnerable to cell death after 7 days of repeated treatment with Aß1-42 oligomer-enriched preparations. However, when clodronate was used to remove microglia, treatment with Aß1-42 resulted in significant neuronal death. Further investigations indicated signs of endoplasmic reticulum stress and caspase activation after Aß1-42 challenge only when microglia were absent. Interestingly, microglia provided protection without displaying any classic signs of activation, such as an amoeboid morphology or the release of pro-inflammatory mediators (e.g., IL-6, TNF-α, NO). Furthermore, depleting microglia or inhibiting microglial uptake mechanisms resulted in significant more Aß deposition compared to that observed in OHSCs containing functional microglia, suggesting that microglia efficiently cleared Aß. Because inhibiting microglial uptake increased neuronal cell death, the ability of microglia to engulf Aß is thought to contribute to its protective properties. Our study argues for a beneficial role of functional ramified microglia whereby they act against the accumulation of neurotoxic forms of Aß and support neuronal resilience in an in situ model of AD pathology.

Encoding the Sequence of Specific Autoantibodies Against beta-Amyloid and alpha-Synuclein in Neurodegenerative Diseases.

There is no effective disease-modifying therapy for Alzheimer's or Parkinson's disease. As pathological hallmarks, the specific peptide amyloid-ß and the specific protein α-Synuclein aggregate and deposit in and destabilize neurons, which lead to their degeneration. Within the context of a potential immunization strategy for these diseases, naturally occurring autoantibodies could play a crucial role in treatment due to their ability to inhibit peptide/protein aggregation and mediate their phagocytosis. We developed a procedure to extract the genetic information of such amyloid-ß- and α-Synuclein- specific naturally occurring autoantibodies for future passive immunization strategies. We performed FACS-based single-cell sorting on whole blood donated from healthy individuals and performed single-cell RT-PCR analysis to amplify the coding sequences of antigen-binding regions of each antibody-secreting B1 cell. Sequences were further analyzed to determine CDR sequences and germline expression. Therefore, only low percentages of B1 cells obtained were amyloid-ß+/α-Synuclein+. After cell sorting, the variable regions of full IgGs were sequenced, demonstrating preferred usage of IGVH3 and IGKV1. The study we present herein describes an approaching for extracting and amplifying the sequence information of autoantibodies based on single-cell analysis of donated blood and producing a recombinant antibody pool for potential passive immunization against neurodegenerative diseases. We sorted a small pool of CD20+ CD27+ CD43+ CD69- IgG+ and Aß+/α-Syn+ B cells.

Health outcome of older hospitalized patients in internal medicine environments evaluated by Identification of Seniors at Risk (ISAR) screening and geriatric assessment.

BACKGROUND: Hospitals are in need of valid and economic screening and assessment tools that help identifying older patients at risk for complications which require intensified support during their hospital stay. METHODS: Five hundred forty-seven internal medicine in-patients (mean age 78.14 ± 5.96 years; 54.7% males) prospectively received Identification of Seniors at Risk (ISAR) screening. If screening results were positive (ISAR score ≥ 2), a comprehensive geriatric assessment (CGA) was performed. We explored sensitivity and specificity of different ISAR and CGA cutoffs. Further, we analyzed the risk of falls and how patients got discharged from hospital. RESULTS: ISAR+/CGA abnormal patients spent more days in hospital (16.1 ± 14.5), received more nursing hours per day (3.0 ± 2.3), more hours of physiotherapy during their hospital stay (2.2 ± 3.2), and had more falls (10.1%) compared to ISAR+/CGA normal (10.9 ± 12.3, 2.0 ± 1.2, 1.2 ± 4.3, and 2.8%, respectively, all p ≤ 0.016) and ISAR- (9.6 ± 11.5, 2.3 ± 4.5, 0.7 ± 2.0, and 2.2%, respectively, all p ≤ 0.002) patients. ISAR+/CGA abnormal patients terminated their treatment regularly with being discharged back home less often (59.6%) compared to ISAR+/CGA normal (78.5%, p = 0.002) and ISAR- (78.2%, p = 0.056) patients. ISAR cutoff≥2 and CGA defined as abnormal in case of impairment of ADL plus another CGA domain achieved best sensitivity/specificity. CONCLUSIONS: Abnormal geriatric risk screening and assessment are associated with longer hospital stay and higher amount of nursing and physiotherapy during hospital stay, greater risk of falling, and a lower percentage of successfully terminated treatment in older in-patients.

Treatment of Odontoid Type II Fractures in Octogenarians: Balancing Two Different Treatment Strategies.

OBJECTIVE: Demographic changes have led to a higher incidence of C-2 fractures, especially in elderly patients. For patients with type II fractures, treatment remains controversial, as discussed by Anderson and D'Alonzo, due to the rising morbidity and mortality rates for any treatment. The aim of this study was to compare conservative and surgical management in patients with type II C-2 fractures regarding outcomes, complications, and the mortality rate. METHODS: A retrospective analysis was performed of the medical records, X-rays, and/or computed tomography scans of patients ≥80 years of age with type II fractures who were admitted to our Department of Neurosurgery between January 1990 and December 2017. The success of treatment was evaluated 3 months after surgery. RESULTS: In total, 125 patients were included, of whom 98 were treated surgically and 27 were treated conservatively. Surgical treatment was successful in 90.8% of cases, while conservative treatment was successful in 70.0%. The in-hospital mortality was 14.29% and the 3-month mortality was 27.8% in the surgical group, compared to 3.7% and 20% in the conservatively treated group. The in-hospital complication rate was 22.4% in the surgically treated patients and 7.4% in the conservatively treated patients. CONCLUSION: Surgical treatment of type II fractures seemed to be associated with higher success and complication rates than conservative treatment. Nevertheless, 3-month mortality was comparable in both groups. Therefore, we conclude that surgical treatment for type II fractures in elderly patients is superior to conservative management, although conservative treatment remains a valuable option in elderly patients with severe comorbidities.

Effect of naturally occurring α-synuclein-antibodies on toxic α-synuclein-fragments.

Alpha-synuclein (α-Syn) is a soluble protein primarily expressed in presynaptic terminals in the central nervous system (CNS). Aggregates of fibrillated α-Syn are the major component of Lewy bodies (LB), a pathologic hallmark of idiopathic Parkinson's disease (PD). Recently, naturally occurring autoantibodies against human α-Syn (nAbs α-Syn) were detected in the peripheral blood of PD patients and controls. Here, we investigated the inhibitory effects of nAbs α-Syn on distinct α-Syn fragments, as well as inflammatory responses and cytotoxicity evoked by nAbs α-Syn in primary microglia. All α-Syn fragments induced the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) from microglia in primary culture. Cotreatment with nAbs α-Syn alleviated the release of pro-inflammatory cytokines induced by α-Syn fragments α-Syn 1-95, α-Syn 61-140, α-Syn 96-140 and α-Syn 112. Treatment with the α-Syn fragments α-Syn 1-95, α-Syn 61-140 and α-Syn 112 impaired the viability of primary microglia. This effect could not be counteracted by cotreatment with nAbs α-Syn. Data suggest an important role of nAbs α-Syn in the α-Syn-induced inflammation cascade, and indicate the potential importance of nAbs in the pathogenesis of PD. This could provide an experimental therapeutic target for patients with PD.

Improve hip fracture outcome in the elderly patient (iHOPE): a study protocol for a pragmatic, multicentre randomised controlled trial to test the efficacy of spinal versus general anaesthesia.

INTRODUCTION: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse. METHODS AND ANALYSIS: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60. ETHICS AND DISSEMINATION: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals. TRIAL REGISTRATION NUMBER: DRKS00013644; Pre-results.

[Inclusion Body Myopathy, Paget's Disease, and Fronto-temporal Dementia: a VCP-related Multi-systemic Proteinopathy]. / Einschlusskörpermyopathie, Paget-Krankheit und frontotemporale Demenz: eine VCP-bedingte, multisystemische Proteinopathie.

Mutations of the human VCP gene, which encodes the V: alosin C: ontaining P: rotein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively. Based on the clinical findings, a genetic analysis was performed which revealed a heterozygous c.277C>T (p.Arg93Cys) mutation of the VCP gene, thus confirming the diagnosis of IBMPFD (I: nclusion B: ody M: yopathie with P: aget Disease of the Bones and F: ronto-temporal D: ementia).

Is treatment of geriatric hip fracture patients cost-covering? Results of a prospective study conducted at a German University Hospital.

INTRODUCTION: Hip fractures have increased medical and socio-economic importance due to demographic transition. Information concerning direct treatment costs and their reimbursement in Germany is lacking. MATERIALS AND METHODS: Four hundred two hip fracture patients older than 60 years of age were observed prospectively at a German University Hospital. Treatment costs were determined with up to 196 cost factors and compared to the reimbursement. Finally, statistical analysis was performed to identify clinical parameters influencing the cost-reimbursement relation. RESULTS: Treatment costs were 8853 € (95% CI 8297-9410 €), while reimbursement was 8196 € (95% CI 7707-8772 €), resulting in a deficit of 657 € (95% CI 143-1117 €). Bivariate analysis showed that the cost-reimbursement relation was negatively influenced mainly by higher age, higher ASA score, readmission to the intensive care unit (ICU) and red blood cell transfusion. Adjusted for other parameters, readmission to the ICU was a significant negative predictor (- 2669 €; 95% CI - 4070 to - 1268 €; p < 0.001), while age of 60-75 years was a positive predictor for the cost-reimbursement relation (1373 €; 95% CI 265-2480 €; p = 0.015). CONCLUSIONS: Treatment of geriatric hip fracture patients in a university hospital in Germany does not seem to be cost-covering. Adjustment of the reimbursement for treatment of complex hip fracture patients should be considered.

Synthesis of a biological active ß-hairpin peptide by addition of two structural motifs.

The idea of privileged scaffolds - that there seem to be more bioactive compounds found around some structures than others - is well established for small drug molecules, but has little significance for standalone peptide secondary structures whose adaptable shapes escape the definition of a 3D motif in the absence of a protein scaffold. Here, we joined two independent biological functions in a single highly restricted peptide to support the hypothesis that the ß-hairpin shape is the common basis of two otherwise unrelated biological recognition processes. To achieve this, the hydrophobic cluster HWX4LV from the decapeptide cyclic hairpin model peptide C1-C10cyclo-CHWEGNKLVC was included in the bicyclic peptide 2. The designed ß-hairpin peptide C4-C17, C8-C13bicyclo-KHQCHWECTZGRCRLVCGRSGS (2, Z=citrulline), serves, on the one hand, as a specific epitope for rheumatoid autoantibodies and, on the other hand, shows a not negligible antibiotic effect against the bacterial strain E. coli AS19.

Factors influencing the progress of mobilization in hip fracture patients during the early postsurgical period?-A prospective observational study.

OBJECTIVE: The aim of the present study was to determine the independent factors influencing mobilization progress after geriatric hip fractures. PATIENTS AND METHODS: 392 Hip fracture patients older than 60 years were included in this prospective, observational, cohort study. The progress of mobilization was measured with walking ability 4 days post-surgery, ability to climb stairs until discharge and the Tinetti test at discharge. Factors correlated with the progress of mobilization were determined using multivariate analyses. RESULTS: The independent factors influencing walking ability 4 days post-surgery were the pre-fracture Charlson Comorbidity Index (OR=0.834, p=0.005), the American Society of Anesthesiologists Score (OR=0.550, p=0.013), pre-fracture Barthel Index ([BI], OR=1.019, p=0.012) and risk for depression, as measured by the Geriatric Depression Scale, (OR=0.896, p=0.013). The probability of climbing stairs until discharge was influenced by the patient's age (OR=0.840, p<0.001), pre-fracture BI (OR=1.047, p=0.042), cognitive impairment, as measured by the mini mental state examination (OR=1.182 p=0.008), pre surgical hemoglobin (OR=1.026, p=0.044), time until surgery (OR=0.961, p=0.023), duration of surgery (OR=0.982, p=0.014), and surgery type (prosthesis, OR=4.545, p=0.001). Similar variables influenced the Tinetti test ad discharge. CONCLUSION: While pre-fracture co-morbidities and function cannot be changed, the treatment of patients with cognitive impairment and depressive symptoms should be optimized. Efforts should be undertaken to ensure early surgery for all hip fractures.

The endogenous α7 nicotinic acetylcholine receptor antagonist kynurenic acid modulates amyloid-ß-induced inflammation in BV-2 microglial cells.

Amyloid-ß has been shown to interact with the α7 nicotinic acetylcholine receptor on neuronal cells. Not much is known on the effect on microglial cells and whether this effect can be modulated by the endogenous α7 nicotinic acetylcholine receptor antagonist kynurenic acid. Our aim was to investigate the effect of kynurenic acid on amyloid-ß-treated BV-2 microglial cells with respect to α7 nicotinic acetylcholine receptor expression, cell viability, cytokine production and phagocytotic abilities. Therefore BV-2 cells were treated with oligomeric or fibrillar forms of amyloid-ß(1-40) and co-treated with kynurenic acid. α7 nicotinic acetylcholine receptor quantity was investigated using Western blotting. Cell viability was assessed by staining cells with fluorescein diacetate and propidium iodide. Pro-inflammatory cytokines were measured in cell culture supernatants of treated cells with ELISAs; NO with Griess reagents and amyloid-ß uptake were investigated with fluorescence-activated cell sorting and verified by Western blotting. Amyloid-ß nor kynurenic acid did have an effect on the protein level of the α7 nicotinic acetylcholine receptor. Amyloid-Beta induced cell mortality was unchanged after addition of kynurenic acid. However, kynurenic acid co-treatment reduced the pro-inflammatory cytokines tumour necrosis factor-α and IL-6 and amyloid-ß phagocytosis. We provide evidence for an immunomodulating effect of the endogenous α7 nicotinic acetylcholine receptor antagonist kynurenic acid. Our findings indicate a role for kynurenic acid in amyloid-ß associated neuroinflammation in Alzheimer disease.

The role of choroid plexus in IVIG-induced beta-amyloid clearance.

We have shown that intravenous immunoglobulin (IVIG) contains anti-Aß autoantibodies and IVIG could induce beta amyloid (Aß) efflux from cerebrospinal fluid (CSF) to blood in both Multiple Sclerosis (MS) and Alzheimer disease (AD) patients. However, the molecular mechanism underlying IVIG-induced Aß efflux remains unclear. In this study, we used amyloid precursor protein (AßPP) transgenic mice to investigate if the IVIG could induce efflux of Aß from the brain and whether low-density lipoprotein receptor-related protein-1 (LRP1), a hypothetic Aß transporter in blood-CSF barrier (BCB); could mediate this clearance process. We currently provide strong evidence to demonstrate that IVIG could reduce brain Aß levels by pulling Aß into the blood system in AßPP transgenic mice. In the mechanistic study, IVIG could induce Aß efflux through the in vitro BCB membrane formed by cultured BCB epithelial cells. Both receptor-associated protein (RAP; a functional inhibitor of LRP1), and LRP1 siRNA were able to significantly inhibit the Aß efflux. Should Aß prove to be the underlying cause of AD, our results strongly suggest that IVIG could be beneficial in the therapy for AD by inducing efflux of Aß from the brain through the LRP1 in the BCB.

Prion peptide uptake in microglial cells--the effect of naturally occurring autoantibodies against prion protein.

In prion disease, a profound microglial activation that precedes neurodegeneration has been observed in the CNS. It is still not fully elucidated whether microglial activation has beneficial effects in terms of prion clearance or whether microglial cells have a mainly detrimental function through the release of pro-inflammatory cytokines. To date, no disease-modifying therapy exists. Several immunization attempts have been performed as one therapeutic approach. Recently, naturally occurring autoantibodies against the prion protein (nAbs-PrP) have been detected. These autoantibodies are able to break down fibrils of the most commonly used mutant prion variant PrP106-126 A117V and prevent PrP106-126 A117V-induced toxicity in primary neurons. In this study, we examined the phagocytosis of the prion peptide PrP106-126 A117V by primary microglial cells and the effect of nAbs-PrP on microglia. nAbs-PrP considerably enhanced the uptake of PrP106-126 A117V without inducing an inflammatory response in microglial cells. PrP106-126 A117V uptake was at least partially mediated through scavenger receptors. Phagocytosis of PrP106-126 A117V with nAbs-PrP was inhibited by wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, indicating a separate uptake mechanism for nAbs-PrP mediated phagocytosis. These data suggest the possible mechanisms of action of nAbs-PrP in prion disease.

Re-admission to Level 2 unit after hip-fracture surgery - Risk factors, reasons and outcome.

INTRODUCTION: Hip fractures are common geriatric fractures with increasing incidence. Treatment of these fractures is still associated with high rates of complications and poor outcome. Data concerning unexpected re-admission to a Level 2 unit after an initial inconspicuous postoperative course are limited. We aimed to identify causes and associated risk factors for admission as well as impact of re-admission on acute care and short-term outcome. PATIENTS AND METHODS: Patients over 60 years of age with hip fractures were included in this prospective single-centre observational study. Patients with polytrauma or malignancy-associated fractures were excluded. Age, gender, fracture type, pre-fracture residential, physical and cognitive status, recording to the American Society of Anesthesiologists (ASA) score, Barthel Index (BI) and Mini-Mental State Examination (MMSE) were recorded on admission. Date, type of surgery and operation time were evaluated. Postoperatively, the prevalence of and reasons for unexpected re-admission to the Level 2 unit and patients' outcome were measured. Parameters were hospital mortality, BI at discharge, length of stay in hospital and type of discharge. Univariate and multivariate analyses were performed to identify risk factors for admission to the Level 2 unit and influence on patients' outcome. RESULTS: Out of 402 included patients, 48 (12%) were re-admitted to the Level 2 unit. The most frequent reasons were non-surgical (n=38), such as respiratory failure (n=12), cardiovascular diseases (n=8) and acute renal failure (n=5). Ten patients were re-admitted due to a revision surgery of the hip. We identified two independent risk factors for readmission: male gender (odds ratio (OR)=2.38, confidence interval (95% CI)=1.10-5.15, p=0.027) and type of fracture, especially femoral neck fracture (OR=7.40, 95% CI=2.39-23.26, p=0.001). Patients who were re-admitted to the Level 2 unit had a higher mortality (ß=2.09, OR=8.07, 95% CI=2.44-26.75, p=0.001), an increase in hospital stay (ß=7.0, 95% CI 5.2-8.7, p<0.001) and a lower functional outcome (BI, ß=-17, 95% CI=-23 to -10, p<0.001). CONCLUSION: Unexpected admission to the Level 2 unit in the post-surgical period is a frequent phenomenon in geriatric hip-fracture patients. Males and femoral neck fracture patients seem to be especially endangered. Although the majority of reasons for admissions were not immediately life-threatening illnesses, they had a substantial negative impact on patients' outcome. This emphasises the importance of careful handling of this frail patient population.

Cost-effectiveness of deep brain stimulation in patients with Parkinson's disease.

In addition to medical treatment, deep brain stimulation has become an alternative therapeutic option in advanced Parkinson's disease. High initial costs of surgery have to be weighted against long-term gains in health-related quality of life. The objective of this study was to assess the cost-effectiveness of deep brain stimulation compared with long-term medical treatment. We performed a cost-utility analysis using a lifetime Markov model for Parkinson's disease. Health utilities were evaluated using the EQ-5D generic health status measure. Data on effectiveness and adverse events were obtained from clinical studies, published reports, or meta-analyses. Costs were assessed from the German health care provider perspective. Both were discounted at 3% per year. Key assumptions affecting costs and health status were investigated using one-way and two-way sensitivity analyses. The lifetime incremental cost-utility ratio for deep brain stimulation was €6700 per quality-adjusted life year (QALY) and €9800 and €2500 per United Parkinson's Disease Rating Scale part II (motor experiences of daily living) and part III (motor examination) score point gained, respectively. Deep brain stimulation costs were mainly driven by the cost of surgery and of battery exchange. Health status was improved and motor complications were reduced by DBS. Sensitivity analysis revealed that battery life time was the most influential parameter, with the incremental cost-utility ratio ranging from €20,000 per QALY to deep brain stimulation dominating medical treatment. Deep brain stimulation can be considered cost-effective, offering a value-for-money profile comparable to other well accepted health care technologies. Our data support adopting and reimbursing deep brain stimulation within the German health care system.

Activation of KCNN3/SK3/K(Ca)2.3 channels attenuates enhanced calcium influx and inflammatory cytokine production in activated microglia.

In neurons, small-conductance calcium-activated potassium (KCNN/SK/K(Ca)2) channels maintain calcium homeostasis after N-methyl-D-aspartate (NMDA) receptor activation, thereby preventing excitotoxic neuronal death. So far, little is known about the function of KCNN/SK/K(Ca)2 channels in non-neuronal cells, such as microglial cells. In this study, we addressed the question whether KCNN/SK/K(Ca)2 channels activation affected inflammatory responses of primary mouse microglial cells upon lipopolysaccharide (LPS) stimulation. We found that N-cyclohexyl-N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine (CyPPA), a positive pharmacological activator of KCNN/SK/K(Ca)2 channels, significantly reduced LPS-stimulated activation of microglia in a concentration-dependent manner. The general KCNN/SK/K(Ca)2 channel blocker apamin reverted these effects of CyPPA on microglial proliferation. Since calcium plays a central role in microglial activation, we further addressed whether KCNN/SK/K(Ca)2 channel activation affected the changes of intracellular calcium levels, [Ca(2+)](i), in microglial cells. Our data show that LPS-induced elevation of [Ca(2+)](i) was attenuated following activation of KCNN2/3/K(Ca)2.2/K(Ca)2.3 channels by CyPPA. Furthermore, CyPPA reduced downstream events including tumor necrosis factor alpha and interleukin 6 cytokine production and nitric oxide release in activated microglia. Further, we applied specific peptide inhibitors of the KCNN/SK/K(Ca)2 channel subtypes to identify which particular channel subtype mediated the observed anti-inflammatory effects. Only inhibitory peptides targeting KCNN3/SK3/K(Ca)2.3 channels, but not KCNN2/SK2/K(Ca)2.2 channel inhibition, reversed the CyPPA-effects on LPS-induced microglial proliferation. These findings revealed that KCNN3/SK3/K(Ca)2.3 channels can modulate the LPS-induced inflammatory responses in microglial cells. Thus, KCNN3/SK3/K(Ca)2.3 channels may serve as a therapeutic target for reducing microglial activity and related inflammatory responses in the central nervous system.

Pathogenic and physiological autoantibodies in the central nervous system.

In this article, we review the current knowledge on pathological and physiological autoantibodies directed toward structures in the central nervous system (CNS) with an emphasis on their regulation and origin. Pathological autoantibodies in the CNS that are associated with autoimmunity often lead to severe neurological deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a marker for diagnostic purposes without contributing to the pathological process and/or disease progression. The existence of naturally occurring physiological autoantibodies has been known for a long time, and their role in maintaining homeostasis is well established. Within the brain, naturally occurring autoantibodies targeting aggregated proteins have been detected and might be promising candidates for new therapeutic approaches for neurodegenerative disorders. Further evidence has demonstrated the existence of naturally occurring antibodies targeting antigens on neurons and oligodendrocytes that promote axonal outgrowth and remyelination. The numerous actions of physiological autoantibodies as well as their regulation and origin are summarized in this review.