[Creutzfeldt-Jakob Disease Versus Anti-NMDA Receptor Encephalitis A Case Report]. / Creutzfeldt-Jakob Erkrankung versus Anti-NMDA-Rezeptor-Enzephalitis ­ eine Kasuistik.

Clinically differentiating between autoimmune and neurodegenerative disorders can often pose a diagnostic challenge. The differential diagnosis of rapidly progressing neurological and cognitive symptoms includes central nervous system tumours, cerebral vasculitis, and inflammatory, autoimmune, or paraneoplastic encephalopathies. Rarer neurodegenerative diseases such as Creutzfeldt-Jakob disease should also be considered. Detection of treatable causes, such as autoimmune disorders, remains important when potentially occurring in conjunction with Creutzfeldt-Jakob disease. The following report describes a rare case in which autoimmune encephalopathy and prion disease were considered as possible comorbidities.

A bistable, multiport valve enables microformulators creating microclinical analyzers that reveal aberrant glutamate metabolism in astrocytes derived from a tuberous sclerosis patient.

There is a need for valves and pumps that operate at the microscale with precision and accuracy, are versatile in their application, and are easily fabricated. To that end, we developed a new rotary planar multiport valve to faithfully select solutions (contamination = 5.22 ± 0.06 ppb) and a rotary planar peristaltic pump to precisely control fluid delivery (flow rate = 2.4 ± 1.7 to 890 ± 77 µL/min). Both the valve and pump were implemented in a planar format amenable to single-layer soft lithographic fabrication. These planar microfluidics were actuated by a rotary motor controlled remotely by custom software. Together, these two devices constitute an innovative microformulator that was used to prepare precise, high-fidelity mixtures of up to five solutions (deviation from prescribed mixture = ±|0.02 ± 0.02| %). This system weighed less than a kilogram, occupied around 500 cm3, and generated pressures of 255 ± 47 kPa. This microformulator was then combined with an electrochemical sensor creating a microclinical analyzer (µCA) for detecting glutamate in real time. Using the chamber of the µCA as an in-line bioreactor, we compared glutamate homeostasis in human astrocytes differentiated from human-induced pluripotent stem cells (hiPSCs) from a control subject (CC-3) and a Tuberous Sclerosis Complex (TSC) patient carrying a pathogenic TSC2 mutation. When challenged with glutamate, TSC astrocytes took up less glutamate than control cells. These data validate the analytical power of the µCA and the utility of the microformulator by leveraging it to assess disease-related alterations in cellular homeostasis.

[Risk factors for hypertensive and cerebral amyloid angiopathy associated intracerebral hemorrhage: a retrospective comparison]. / Risikofaktoren für hypertensive und zerebrale Amyloidangiopathie-assoziierte intracerebrale Blutungen: ein retrospektiver Vergleich.

INTRODUCTION: The aim of this study was to compare possible risk factors for the most common forms of spontaneous intracerebral hemorrhage (ICH), namely hypertensive and cerebral amyloid angiopathy (CAA) associated ICH. METHODS: Retrospectively, different parameters and factors were compared in patients with hypertensive ICH (n = 141) and patients with a CAAassociated ICH (n = 95). These included age, INR value and blood pressure at admission, cardiovascular risk factors as well as pre-medication. The Chi-square test with the Yates' continuity correction and the t-test were used as test methods. RESULTS: Patients of the group with CAA-associated ICH were significantly older than patients with a hypertensive ICH (p = 0.001). In addition, there was a significantly higher incidence of acetylsalicylic acid prior treatment (p = 0.042) and a previous stroke (p = 0.048) in the CAA patients. Patients of both groups had a high proportion of arterial hypertension as pre-diagnosis, which was significantly more common in patients with hypertensive ICH (p < 0,001). Patients with a hypertensive ICH also had significantly higher systolic and diastolic blood pressure values (p < 0.001) and higher INR values (p = 0.005) at admission. A subgroup analysis of all patients without anticoagulation (ZAA group: n = 78, hypertensive ICB group: n = 99) showed similar results. However, there was no significant difference (p = 0.037) for a previous stroke, but there was a significant difference in premedication with a statin (p = 0.032). DISCUSSION: Arterial hypertension is a relevant risk factor in both forms of intracerebral hemorrhage and should therefore receive adequate prophylaxis. For a more detailed classification of the other risk factors, further studies with larger cases are necessary.

Endovascular stroke treatment now and then-procedural and clinical effectiveness and safety of different mechanical thrombectomy techniques over time.

BACKGROUND: The most essential development in endovascular stroke treatment (EST) was the shift from intra-arterial thrombolysis to endovascular thrombectomy with dedicated thrombectomy devices, most notably the introduction of stent-retrievers. We evaluated procedural and clinical effectiveness and safety of different EST techniques over time. METHODS: We retrospectively analyzed EST cases that were treated by the same interventionalist before (n=36) and after (n=50) stent-retrievers were established as the treatment device of first choice. EST techniques in the first cohort comprised intra-arterial thrombolysis (n=24), manual thrombus aspiration (n=15), the use of the Penumbra thrombectomy system (n=13) and the Phenox clot retriever (n=3), intracranial stenting (n=10), and EST with stent-retrievers as a salvage procedure (n=11). In the second cohort, EST with stent-retrievers was the treatment option of first choice (n=47). Intra-arterial thrombolysis (n=15) and stenting of the occluded vessel (n=1) were performed, whenever EST with stent-retrievers failed. RESULTS: In both cohorts, revascularization rates (TICI ≥2b) were high (91.7% and 86.0%, respectively). A significantly lower number of interventional techniques per case were required in the second cohort (mean ± SD, 1.4±0.5 vs. 2.1±0.9, P<0.001). Recanalization was achieved almost twice as fast in the second cohort (85 vs. 163 minutes on average, P<0.001). The rate of patients achieving good functional outcome (mRS ≤2) was higher in the second cohort (40.0% vs. 22.2%, P=0.083). CONCLUSIONS: Our findings imply that when stent-retrievers were established as first-line the treatment device a significantly lower number of interventional techniques per case were required and recanalization was achieved almost twice as fast.

Cerebral Amyloid Angiopathy in Stroke Medicine.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a degenerative vasculopathy that is classically associated with lobar intracerebral or sulcal hemorrhage. Its prevalence is estimated at 30% in the seventh decade and 50% in the eighth and ninth decades. In this review, we summarize the risks linked to CAA with respect to the treatment and prevention of stroke. METHODS: This review is based on pertinent publications retrieved by a selective search employing the terms "amyloid cerebral angiopathy," "stroke," "intra - cerebral bleeding," and "acute stroke therapy." RESULTS: Among patients given systemic lytic treatment for stroke, those who have microhemorrhages tend to have a higher risk of treatment-associated brain hemorrhage. In a meta-analysis, 70% of patients who sustained a hemorrhage after thrombolytic therapy were found to have CAA, compared to only 22% in a control population. Patients with cerebral hemorrhages have microhemorrhages more commonly than patients with transient ischemic attacks (TIA) or infarcts. This was observed among persons under treatment with vitamin K antagonists (odds ratio, 2.7) or platelet aggregation inhibitors (odds ratio, 1.7). Moreover, the apolipoprotein E2 allele is associated with a higher incidence of intracerebral hemorrhage (ICH) under oral anticoagulation. Strict treatment of arterial hypertension can lower the risk of ICH in persons with probable CAA by 77%. On the other hand, the use of statins after a lobar ICH increases the risk for a clinically manifest recurrent hemorrhage from 14% to 22%. CONCLUSION: In patients with CAA, arterial hypertension should be tightly controlled. On the other hand, caution should be exercised in prescribing oral anticoagulants or platelet aggregation inhibitors for patients with CAA, or statins for patients who have already sustained a lobar ICH.

Engineering challenges for instrumenting and controlling integrated organ-on-chip systems.

The sophistication and success of recently reported microfabricated organs-on-chips and human organ constructs have made it possible to design scaled and interconnected organ systems that may significantly augment the current drug development pipeline and lead to advances in systems biology. Physiologically realistic live microHuman (µHu) and milliHuman (mHu) systems operating for weeks to months present exciting and important engineering challenges such as determining the appropriate size for each organ to ensure appropriate relative organ functional activity, achieving appropriate cell density, providing the requisite universal perfusion media, sensing the breadth of physiological responses, and maintaining stable control of the entire system, while maintaining fluid scaling that consists of ~5 mL for the mHu and ~5 µL for the µHu. We believe that successful mHu and µHu systems for drug development and systems biology will require low-volume microdevices that support chemical signaling, microfabricated pumps, valves and microformulators, automated optical microscopy, electrochemical sensors for rapid metabolic assessment, ion mobility-mass spectrometry for real-time molecular analysis, advanced bioinformatics, and machine learning algorithms for automated model inference and integrated electronic control. Toward this goal, we are building functional prototype components and are working toward top-down system integration.

Neurovascular unit on a chip: implications for translational applications.

The blood-brain barrier (BBB) dynamically controls exchange between the brain and the body, but this interaction cannot be studied directly in the intact human brain or sufficiently represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and do not adequately predict drug efficacy and toxicity. Under the National Institutes of Health Microtissue Initiative, we are developing a three-dimensional, multicompartment, organotypic microphysiological system representative of a neurovascular unit of the brain. The neurovascular unit system will serve as a model to study interactions between the central nervous system neurons and the cerebral spinal fluid (CSF) compartment, all coupled to a realistic blood-surrogate supply and venous return system that also incorporates circulating immune cells and the choroid plexus. Hence all three critical brain barriers will be recapitulated: blood-brain, brain-CSF, and blood-CSF. Primary and stem cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions. Cytomegalovirus, a common herpesvirus, will be used as an initial model of infections regulated by the BBB. This novel technological platform, which combines innovative microfluidics, cell culture, analytical instruments, bioinformatics, control theory, neuroscience, and drug discovery, will replicate chemical communication, molecular trafficking, and inflammation in the brain. The platform will enable targeted and clinically relevant nutritional and pharmacologic interventions for or prevention of such chronic diseases as obesity and acute injury such as stroke, and will uncover potential adverse effects of drugs. If successful, this project will produce clinically useful technologies and reveal new insights into how the brain receives, modifies, and is affected by drugs, other neurotropic agents, and diseases.

Why we do not have--and will not have--the integrated and "smart" alarm systems that technology would allow us to have today.

BACKGROUND: Many authors have been advocating "smart alarm systems" for more than 30 years, and technology for such systems has been described in the literature for more than 20 years. Such systems do not exist today. GOALS: Incoming data would be analyzed to reject artifact. Multiple inputs would be used to determine alarm conditions. Information would be passed to the best person to address the problem. If the primary person failed to respond, a backup person would be notified. THE PROBLEM: One might show a statistical improvement in patient outcome with a new system, but there would always be patients who would have had an alarm under the old system, and who did not have an alarm with the new system. Only if Congress would exempt the alarm integrators from liability, as the vaccine makers are protected, could such a system be built.

Nanofiber size-dependent sensitivity of fibroblast directionality to the methodology for scaffold alignment.

The sensitivity of fibroblast guidance on directional cues provided by aligned nanofibers is studied for scaffolds of successively smaller fiber sizes (740±280, 245±85, 140±40, and 80±10 nm) fabricated using mandrel and electrical alignment methodologies for electrospun nanofibers (∼10° angular deviation (AD)), as well as nanoimprint methodologies for perfectly aligned fibers (0° AD). On aligned scaffolds of large fibers (∼740 nm) cell directionality closely follows the underlying fibers, irrespective of the alignment method. However, on mandrel aligned scaffolds of successively smaller fibers the cell directionality exhibits greater deviations from the underlying fiber alignment due to the higher likelihood of interaction of cell lamellipodia with multiple, rather than single, nanofibers. Using electrically aligned scaffolds, fibroblast directionality deviations can be maintained in the range of nanofiber alignment deviation for fiber sizes down to ∼100 nm. This improvement in cell guidance is attributed to molecular scale directional adhesion cues for cell receptors, which occur within electrically aligned scaffolds due to fiber polarization parallel to the geometric alignment axis of the nanofiber under the modified electric field during electrospinning. While fibroblast directionality is similar on electrically aligned vs. nanoimprinted scaffolds for fiber sizes >100 nm, cell directionality is influenced more strongly by the perfect alignment cues of the latter on ∼100 nm fiber scaffolds. The scaffold alignment methodology is hence highly significant, especially for tissue engineering applications requiring sub-100 nm aligned fibers.

Transcranial Doppler monitoring in Parkinson's disease: cerebrovascular compensation of orthostatic hypotension.

Despite of precipitous blood pressure falls in Parkinson's Disease (PD) patients, they may not experience syncope or postural complaints. Can cerebral blood flow regulation explain why orthostatic hypotension (OH) has often no accompanying symptoms? In patients with PD and OH (18 asymptomatic; 8 symptomatic), arterial blood pressure (ABP) as well as Doppler-detected cerebral blood flow velocity (CBFV) in middle and posterior cerebral arteries (MCA and PCA) were monitored during head-up tilt and compared with 25 controls and eight non-PD-OH patients. Analysis included the transfer function between slow spontaneous pressure and flow-oscillations. ABP and CBFV were maintained at significantly higher levels in asymptomatic than symptomatic PD-OH (ABP: 85.7 ± 10.5 vs. 66.9 ± 12.5%; MCA-FV: 83.3 ± 9.3 vs. 66.1 ± 6.8%; PCA-FV: 84.4 ± 12.2 vs. 65.9 ± 9.3% of supine). When orthostatic complaints occurred, CBFV depended directly on ABP changes (MCA r(2) = 0.64; PCA r(2) = 0.62; both p < 0.05). Despite of a tilt-induced blood pressure instability in PD-OH, the transfer function parameters did not differ from normal [phase: MCA: 46.6 ± 20.5°; PCA 39.2 ± 28.8°, gain: MCA 2.0 ± 0.7; PCA 2.9 ± 1.6)]. Results showed a normal autoregulatory response to downward blood pressure shifts in PD. Moreover, orthostatic blood pressure instability is compensated equally sufficient in anterior and posterior parts of cerebral circulation. Whether in PD patients, OH becomes symptomatic rather seems to depend on blood pressure falling below the autoregulated range.

Transdermal dopaminergic stimulation with rotigotine in Parkinsonian akinetic crisis.

Akinetic crisis (AC) is a much-feared complication of Parkinson's disease (PD) which may appear upon abrupt cessation or malabsorption of dopaminergic medication due to gastrointestinal tract disorders or acute surgery. Intravenous infusion of amantadine sulphate or subcutaneous administration of apomorphine are established treatment strategies for AC. We speculate whether the use of a non-invasive transdermal application form (patch) of a dopaminergic drug (rotigotine) may represent a useful alternative treatment option. We describe the successful treatment of severe AC using rotigotine in a PD patient with gastro-oesophageal ulcers which precluded administration of any oral medication. This case demonstrates that a rotigotine patch might be effective in the treatment of AC. We suggest that rotigotine may represent a useful treatment option due to its favourable receptor profile and unique application form. In particular, it may be helpful in situations that might provoke AC, such as acute surgery. However, experience of the use of the rotigotine patch in this clinical setting is rather sparse and the patch is currently not approved for this indication.

Eyeblink conditioning is impaired in subjects with essential tremor.

Several lines of evidence point to an involvement of the olivo-cerebellar system in the pathogenesis of essential tremor (ET), with clinical signs of cerebellar dysfunction being present in some subjects in the advanced stage. Besides motor coordination, the cerebellum is critically involved in motor learning. Evidence of motor learning deficits would strengthen the hypothesis of olivo-cerebellar involvement in ET. Conditioning of the eyeblink reflex is a well-established paradigm to assess motor learning. Twenty-three ET subjects (13 males, 10 females; mean age 44.3 +/- 22.3 years, mean disease duration 17.4 +/- 17.3 years) and 23 age-matched healthy controls were studied on two consecutive days using a standard delay eyeblink conditioning protocol. Six ET subjects exhibited accompanying clinical signs of cerebellar dysfunction. Care was taken to examine subjects without medication affecting central nervous functioning. Seven ET subjects and three controls on low-dose beta-blocker treatments, which had no effect on eyeblink conditioning in animal studies, were allowed into the study. The ability to acquire conditioned eyeblink responses was significantly reduced in ET subjects compared with controls. Impairment of eyeblink conditioning was not due to low-dose beta-blocker medication. Additionally, acquisition of conditioned eyeblink response was reduced in ET subjects regardless of the presence of cerebellar signs in clinical examination. There were no differences in timing or extinction of conditioned responses between groups and conditioning deficits did not correlate with the degree of tremor or ataxia as rated by clinical scores. The findings of disordered eyeblink conditioning support the hypothesis that ET is caused by a functional disturbance of olivo-cerebellar circuits which may cause cerebellar dysfunction. In particular, results point to an involvement of the olivo-cerebellar system in early stages of ET.