Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains

The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS

Handwriting performance in the absence of visual control in writer's cramp patients: Initial observations

BACKGROUND: The present study was aimed at investigating the writing parameters of writer's cramp patients and control subjects during handwriting of a test sentence in the absence of visual control. METHODS: Eight right-handed patients with writer's cramp and eight healthy volunteers as age-matched control subjects participated in the study. The experimental task consisted in writing a test sentence repeatedly for fifty times on a pressure-sensitive digital board. The subject did not have visual control on his handwriting. The writing performance was stored on a PC and analyzed off-line. RESULTS: During handwriting all patients developed a typical dystonic limb posture and reported an increase in muscular tension along the experimental session. The patients were significantly slower than the controls, with lower mean vertical pressure of the pen tip on the paper and they could not reach the endmost letter of the sentence in the given time window. No other handwriting parameter differences were found between the two groups. CONCLUSION: Our findings indicate that during writing in the absence of visual feedback writer's cramp patients are slower and could not reach the endmost letter of the test sentence, but their level of automatization is not impaired and writer's cramp handwriting parameters are similar to those of the controls except for even lower vertical pressure of the pen tip on the paper, which is probably due to a changed strategy in such experimental conditions

Are movement disorders and sensorimotor injuries pathologic synergies? When normal multi-joint movement synergies become pathologic

The intact nervous system has an exquisite ability to modulate the activity of multiple muscles acting at one or more joints to produce an enormous range of actions. Seemingly simple tasks, such as reaching for an object or walking, in fact rely on very complex spatial and temporal patterns of muscle activations. Neurological disorders such as stroke and focal dystonia affect the ability to coordinate multi-joint movements. This article reviews the state of the art of research of muscle synergies in the intact and damaged nervous system, their implications for recovery and rehabilitation, and proposes avenues for research aimed at restoring the nervous system’s ability to control movement

Köttets öde : En studie av den kristna uppfattningen av kroppen under 100- och 200-talet e.v.t.

This paper studies the perception of the Christian body during the second and third centuries CE. It engages with this question with the aid of early Christian literature from this time period, additionally containing a particular focus on how the Pauline theology of the body influenced later Christian bodily conceptions. By subjecting these works to a close reading and with the aid of an intertextual theory, this thesis attempts to ascertain whether this early Christian perception of the body was fractured in nature, and whether aspects of this division – if evident – can be derived from and ascribed to a Pauline influence. This thesis argues that corporeality was a particularly complex component within the early Christian faith, the fractured nature of which could be derived from the contrasting influences of prior Graeco-Roman and Jewish theologies.Den här uppsatsen studerar den kristna uppfattningen av kroppen under 100- och 200-talet e.v.t. Den behandlar denna fråga med hjälp av tidig kristen litteratur från denna tidsperiod, och inbegriper utöver detta även ett särskilt fokus på hur den Paulinska teologin om kroppen påverkade senare kristna uppfattningar av det kroppsliga. Genom att utsätta dessa verk för en närläsning och med hjälp av en intertextuell teori  så försöker den här uppsatsen därmed att avgöra om denna tidiga kristna uppfattning av kroppen var motsägelsefull i sin natur, och huruvida aspekter av denna splittring – om synlig – kan härstamma från eller tillskrivas Paulinsk influens. Den här uppsatsen argumenterar för att kroppslighet var en särskilt komplex komponent inom den tidiga kristna tron, vars splittrade natur kan härstamma från de kontrasterande influenserna av tidigare grekisk-romerska och judiska teologier

Köttets öde : En studie av den kristna uppfattningen av kroppen under 100- och 200-talet e.v.t.

This paper studies the perception of the Christian body during the second and third centuries CE. It engages with this question with the aid of early Christian literature from this time period, additionally containing a particular focus on how the Pauline theology of the body influenced later Christian bodily conceptions. By subjecting these works to a close reading and with the aid of an intertextual theory, this thesis attempts to ascertain whether this early Christian perception of the body was fractured in nature, and whether aspects of this division – if evident – can be derived from and ascribed to a Pauline influence. This thesis argues that corporeality was a particularly complex component within the early Christian faith, the fractured nature of which could be derived from the contrasting influences of prior Graeco-Roman and Jewish theologies.Den här uppsatsen studerar den kristna uppfattningen av kroppen under 100- och 200-talet e.v.t. Den behandlar denna fråga med hjälp av tidig kristen litteratur från denna tidsperiod, och inbegriper utöver detta även ett särskilt fokus på hur den Paulinska teologin om kroppen påverkade senare kristna uppfattningar av det kroppsliga. Genom att utsätta dessa verk för en närläsning och med hjälp av en intertextuell teori  så försöker den här uppsatsen därmed att avgöra om denna tidiga kristna uppfattning av kroppen var motsägelsefull i sin natur, och huruvida aspekter av denna splittring – om synlig – kan härstamma från eller tillskrivas Paulinsk influens. Den här uppsatsen argumenterar för att kroppslighet var en särskilt komplex komponent inom den tidiga kristna tron, vars splittrade natur kan härstamma från de kontrasterande influenserna av tidigare grekisk-romerska och judiska teologier

Transpupillary thermotherapy and Photodynamic therapy for neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among elderly in industrialized nations, and promises to extract an even greater toll with the imminent demographic shift. Neovascular AMD (wet AMD) often develops quickly and involves the growth of new blood vessels under the retina (choroidal neovascularization, CNV). These new blood vessels tend to be fragile and often leak blood and fluid. The blood and fluid elevates the macula, the central part of the retina, causing rapid visual loss. Without treatment the prognosis is poor with profound impact on an individual s ability to perform daily tasks. Photodynamic therapy (PDT) has been the most common treatment for neovascular AMD. PDT uses a cold laser to seal the leaking blood vessels. This involves injecting a lightsensitive drug that reaches and coats the abnormal blood vessels via the blood stream. The drug is then activated by light leading to a local occlusion of new vessels. Transpupillary thermotherapy (TTT) is technique in which a laser-induced subretinal vascular occlusion can be created through a small temperature elevation but without any photosensitive drugHowever, there has been a controversy about the optimal TTT laser intensity and controlled clinical trails demonstrating efficacy in neovascular AMD have been lacking. The first two studies of the thesis demonstrate that PDT as well as TTT can reduce experimental CNV, without causing damage to the surrounding tissue. A cellular damage in surroundning tissues was however seen at higher dosage. The therapeutic window is thus narrow for both treatments underscoring the importance minimizing treatment doses. We also found that both TTT and PDT induce an immediate thrombosis and cessation of perfusion in CNV areas, but after PDT some areas remained vascularised while after TTT the closure of the abnormal vessels proceeded for at least one week. The third and fourth studies of the thesis were on a prospective clinical study, randomizing 98 patients with neovascular AMD (occult CNV) to either low-dose TTT or PDT. During a follow-up of 12 months, no significant differences between the two groups emerged. The proportion of patients with stabilized visual acuity was approximately 75% in both groups and the two treatments were equally potent at stabilizing patient-reported visual function. Recently intravitreal anti-VEGF has become the first line treatment for neovascular AMD demonstrating superior efficacy for all forms of neovascular AMD. However, anti-VEGF is expensive and requires repeated injections. The use of PDT as an adjuvant to anti-VEGF therapy has been suggested to decrease both the cost and the need for repeated injections. Also this combination may prove beneficial regarding control of lesion growth. The results of this thesis, showing that low dose TTT may be equipotent to PDT, suggests that TTT may be a cost-effective adjuvant to intravitreal anti-VEGF treatment

Studies on pathophysiology and effects of botulinumtoxin in focal dystonia

The pathophysiology of focal dystonia, such as cervical dystonia (CD) and writer's cramp (WR) isfar from determined and the development of effective treatment is thus impeded. The dystonia in WRis often action-specific , and most dystonic patients experience an action-induced worsening of thesymptoms. Patients with CD and WR were studied at rest and during activity by differentneurophysiological methods Intramuscular botulinumtoxin (BTX) injection are increasing1y utilizedin the treament of the focal dystonias. The effects of BTX in CD paients were studied withelectromyography (EMG) and with measurements of clinical efficacy. Bursts of involuntary activity were recorded with EMG in CD patients' sternocleidomastoidmuscles (SCMs), both at rest and during a slight muscle contraction Transcranial magneticstimulation (TMS) induced motor evoked potentials (MEPs) with abnormally short latencies in theSCMs of CD patients. The onset of TMS induced suppression of EMG activity occurred abnormallylate in the CD patients' SCMs. The CD patients' clinical signs were compatible with a unilateralcentral dysfunction, whereas the abnormal results of TMS were seen bilterally both at rest andduring SCM contraction. Studies of precision grip function in patients with WR showed impairedabilities to coordinate grip and lift force trajectories, and to correct erroneously programmed gripforce according to sensory feedback. The WR patients further ha abnormally large grip forceincreases in response to a sudden load increase. The findings in the EMG, TMS and precision gripstudies suggest an impaired motor control in dystonia due to increased motoneuronal excitability anddeficiencies of inhibitory regulation. Dystonic signs increased, and positron emissioon tomographyshowed increased regional cerebral blood flow (rCBF) in the left primary sensory-motor and premotorcortical areas, the left thalamus and the right cerebellum, as WR paients wrote for longer periodsThese rCBF increases suggest an increased activation of a cerebro.cerebellar motor circuit indystonia. The WR patients concurrently prosgressively decreased the rCBF in the left supramarginaland angular gyri. Control subjects had no progressive changes of rCBF during prolonged writing, buttheir rCBF changes during writing(compared to during drawing) resembled the WR patients' patternof progressive rCBF changes during prolonged writing. The normal cerebral processes during writinseem thus to be exaggerated in WR, wich may contribute to the task-specific dysfunction. Data from CD status scales according to Tsui and to Fahn correlated well with pathient'ratingof the BTX treament effect. BTX injections improved but failed to nomalize CD patients' qualityof life. EMG of single motor units in SCMs repeatedly injected with BTX indicated persitentreduction of the number of size of functional muscle fibres, but otherwise restored functionalneuromuscular organization when CD symptoms had relapsed. Keyword: Dystonia, cervical dystonia, writer's cramp, pathophysiology, botulinumtoxin electromyography, transcranial magnetic stimulation, precision grip, motor control, positron emission tomography, regional cerebral blood flow, quality of life