Receptive Field Remodeling Induced by Skin Stimulation in Cerebellar Neurons in vivo.

The receptive field of a neuron reflects its function. For example, for parallel fiber (PF) inputs in C3 zone the cerebellar cortex, the excitatory and inhibitory receptive fields of a Purkinje cell (PC) have different locations, and each location has a specific relationship to the location of the climbing fiber (CF) receptive field of the PC. Previous studies have shown that this pattern of input connectivity to the PC and its afferent inhibitory interneurons can be fundamentally disrupted by applying direct electrical stimulation to the PFs, paired or unpaired with CF activation, with protocols that induce plasticity in these synapses. However, afferent fiber stimulation, which is typically used in experimental studies of plasticity, set up highly artificial input patterns at the level of the recipient cells, raising the issue that these forms of plasticity potentially may not occur under more natural input patterns. Here we used skin stimulation to set up spatiotemporally more realistic afferent input patterns in the PFs to investigate whether these input patterns are also capable of inducing synaptic plasticity using similar protocols that have previously been described for direct PF stimulation. We find that receptive field components can be added to and removed from PCs and interneurons following brief periods of skin stimulation. Following these protocols, the receptive fields of mossy fibers were unchanged. These findings confirm that previously described plasticity protocols may have a functional role also for more normal patterns of afferent input

Likhet inför lagen? - En studie av tingsrätternas bevisvärdering i mål om grov kvinnofridskränkning 2016

Gross violation of a woman’s integrity is a crime which penalizes a series of criminal acts committed by a man against a woman whom he is, or has been, married to or with whom he is or has been cohabiting under circumstances comparable to marriage. The purpose of the introduction of this criminal act was to upgrade the penal value of such acts and to take into account the woman’s entire situation when she has been subject to a series of relatively minor criminal acts. The equality between men and women should increase by introducing the new law in the Swedish Penal code. However, since the criminal acts occur behind closed doors without witnessess is domestic violence hard to prove. The main purpose of this thesis is to examine the evaluation of evidence in cases concerning the criminal act in Chapter 4, section 4 a of the Swedish Penal code which prescribes liability for gross violation of a womans’s integrity. In order to examine the evaluation of evidence in cases concerning gross violation of a woman’s integrity, 295 judgements from the Swedish district courts have been subject to examination. The empirical study initially demonstrated great variations in how the courts reported the grounds for the decision. In order to provide more uniform judgements, a law should be enacted which states how the grounds for the decisions should be reported. The empirical study also showed multiple differences in the courts evaluation of evidence and what evidence the courts required for the evidentiary requirement to be met. In 58 % of the evaluated judgements, the district court required corroborating evidence for each and every criminal act, which stated the gross violation of a woman’s integrity. These dictrict courts widely dismissed the action. The court did not require corroborating evidence for each and every criminal act, in the rest of the evaluated judgements. In these cases, the injured persons testimony resulted in a conviction without corroborating evidence for each and every criminal act. These district courts widely announced convictions for gross violation of a woman’s integrity. Thus, the empirical study demonstrated that in some cases decisions were made with a requirement of corroborating evidence for each and every criminal act, and in other cases such evidence was not required. Two conclusions can be drawn from the foregoing: one, that the inconsistency of the evaluation of evidence is not compatible with the principles of equal treatment, and two, that the defendants possibility to predict the verdict deteriorates. Thus, the inconsistency of the evaluation of evidence in cases concerning gross violation of a woman’s integrity is not compatible with the principle of legal security. In order to provide equal treatment and predictability, a method for the evaluation of evidence is needed. However, such method for the evaluation of evidence would make it difficult to announce convictions, which would affect the public trust in the judiciary.Brottet grov kvinnofridskränkning straffbelägger mäns systematiska kränkningar av närstående kvinnor. Som skäl för införandet av brottet anfördes att mäns våld mot kvinnor har sin grund i strukturer i samhället som innebär att kvinnan anses vara underordnad mannen. Genom att införa brottet grov kvinnofridskränkning skulle systematiska kränkningar av en närstående kvinna bestraffas strängare, vilket skulle bidra till ökad jämställdhet mellan könen. Vid prövningen av straffansvar för brottet ställs emellertid domstolarna inför svårigheter vid bevisvärderingen, eftersom det i mål om våld i nära relationer ofta saknas bevisning till stöd för målsägandens berättelse om övergreppen. I framställningen granskas domstolarnas bevisvärdering i mål om grov kvinnofridskränkning i förhållande till den bevisproblematik som ofta råder i mål om grov kvinnofridskränkning. Härvid undersöks särskilt vilka krav som ställs på bevisningen för att beviskravet ska anses vara uppfyllt i mål om grov kvinnofridskränkning. För att granska domstolarnas bevisvärdering i mål om grov kvinnofridskränkning genomfördes en empirisk studie av 295 tingsrättsavgöranden som meddelats under 2016. Den empiriska studien visade inledningsvis att det förekommer stora variationer i hur bevisvärderingen genomförs samt hur domstolarna redovisar bevisvärderingen i domskälen. De stora variationerna i domstolarnas bevisvärdering och redovisningen av bevisvärderingen i domskälen medför att det ur ett rättssäkerhetsperspektiv är önskvärt att införa en lagreglering som stadgar hur domstolens bevisvärdering ska redovisas i domskälen. Rättsfallsstudien visade även att tingsrätterna uppställer olika krav på bevisningen för att beviskravet ska anses vara uppfyllt i mål om grov kvinnofridskränkning. I 58 % av de granskade avgörandena krävde domstolarna att bevisning till stöd för målsägandens utsaga skulle föreligga på varje enskild åtalspunkt, vilket medförde att bevissvårigheterna kvarstod vid prövningen av ansvar för grov kvinnofridskränkning. Denna rättstillämpning resulterade i stor utsträckning i att åtalet för grov kvinnofridskränkning ogillades. I resterande domar krävde domstolen inte att bevisning till stöd för målsägandens utsaga skulle föreligga på varje enskild åtalspunkt. Istället undersökte domstolen på ett generellt plan vilken bevisning som fanns till stöd för målsägandens utsaga, för att sedan konstatera huruvida målsägandens utsaga kunde ligga till grund för en fällande dom på samtliga åtalspunkter. Denna rättstillämpning resulterade i att fällande domar för grov kvinnofridskränkning meddelades i större utsträckning jämfört med när domstolen uppställde krav på stödbevisning på varje enskild åtalspunkt. Den icke enhetliga rättstillämpningen beträffande vilka krav som ställs på bevisningen för att en fällande dom ska kunna meddelas medför en risk för att enskilda inte tillförsäkras likhet inför lagen, samtidigt som denna osäkerhet medför en svårighet att förutse domstolarnas rättstillämpning. Den empiriska studiens resultat visade således att brottet grov kvinnofridskränkning inte tillämpas på ett enhetligt sätt, vilket är problematiskt ur ett rättssäkerhetsperspektiv. För att åstadkomma en förbättrad rättssäkerhet finns det skäl att undersöka huruvida avsteg från den fria bevisprövningens princip ska genomföras genom en metod för bevisvärderingen. En sådan metod skulle emellertid kunna medföra en försämrad möjlighet för domstolarna att utöva rättsligt tvång i brottmål, vilket skulle inverka negativt på allmänhetens förtroende för rättsväsendet

Probabilistic identification of cerebellar cortical neurones across species.

Despite our fine-grain anatomical knowledge of the cerebellar cortex, electrophysiological studies of circuit information processing over the last fifty years have been hampered by the difficulty of reliably assigning signals to identified cell types. We approached this problem by assessing the spontaneous activity signatures of identified cerebellar cortical neurones. A range of statistics describing firing frequency and irregularity were then used, individually and in combination, to build Gaussian Process Classifiers (GPC) leading to a probabilistic classification of each neurone type and the computation of equi-probable decision boundaries between cell classes. Firing frequency statistics were useful for separating Purkinje cells from granular layer units, whilst firing irregularity measures proved most useful for distinguishing cells within granular layer cell classes. Considered as single statistics, we achieved classification accuracies of 72.5% and 92.7% for granular layer and molecular layer units respectively. Combining statistics to form twin-variate GPC models substantially improved classification accuracies with the combination of mean spike frequency and log-interval entropy offering classification accuracies of 92.7% and 99.2% for our molecular and granular layer models, respectively. A cross-species comparison was performed, using data drawn from anaesthetised mice and decerebrate cats, where our models offered 80% and 100% classification accuracy. We then used our models to assess non-identified data from awake monkeys and rabbits in order to highlight subsets of neurones with the greatest degree of similarity to identified cell classes. In this way, our GPC-based approach for tentatively identifying neurones from their spontaneous activity signatures, in the absence of an established ground-truth, nonetheless affords the experimenter a statistically robust means of grouping cells with properties matching known cell classes. Our approach therefore may have broad application to a variety of future cerebellar cortical investigations, particularly in awake animals where opportunities for definitive cell identification are limited

What are we measuring? A critique of range of motion methods currently in use for Dupuytren's disease and recommendations for practice

Background: Range of motion is the most frequently reported measure used in practice to evaluate outcomes. A goniometer is the most reliable tool to assess range of motion yet, the lack of consistency in reporting prevents comparison between studies. The aim of this study is to identify how range of motion is currently assessed and reported in Dupuytren’s disease literature. Following analysis recommendations for practice will be made to enable consistency in future studies for comparability. This paper highlights the variation in range of motion reporting in Dupuytren’s disease. Methods: A Participants, Intervention, Comparison, Outcomes and Study design format was used for the search strategy and search terms. Surgery, needle fasciotomy or collagenase injection for primary or recurrent Dupuytren’s disease in adults were included if outcomes were monitored using range of motion to record change. A literature search was performed in May 2013 using subject heading and free-text terms to also capture electronic publications ahead of print. In total 638 publications were identified and following screening 90 articles met the inclusion criteria. Data was extracted and entered onto a spreadsheet for analysis. A thematic analysis was carried out to establish any duplication, resulting in the final range of motion measures identified. Results: Range of motion measurement lacked clarity, with goniometry reportedly used in only 43 of the 90 studies, 16 stated the use of a range of motion protocol. A total of 24 different descriptors were identified describing range of motion in the 90 studies. While some studies reported active range of motion, others reported passive or were unclear. Eight of the 24 categories were identified through thematic analysis as possibly describing the same measure, ‘lack of joint extension’ and accounted for the most frequently used. Conclusions: Published studies lacked clarity in reporting range of motion, preventing data comparison and meta-analysis. Percentage change lacks context and without access to raw data, does not allow direct comparison of baseline characteristics. A clear description of what is being measured within each study was required. It is recommended that range of motion measuring and reporting for Dupuytren’s disease requires consistency to address issues that fall into 3 main categories:- Definition of terms Protocol statement Outcome reportin

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes

The regulation of oncogenic Ras/ERK signalling by dual-specificitymitogen activated protein kinase phosphatases (MKPs)

AbstractDual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent work based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer

Cerebellar Zones: A Personal History

Cerebellar zones were there, of course, before anyone noticed them. Their history is that of young people, unhindered by preconceived ideas, who followed up their observations with available or new techniques. In the 1960s of the last century, the circumstances were fortunate because three groups, in Leiden, Lund, and Bristol, using different approaches, stumbled on the same zonal pattern in the cerebellum of the cat. In Leiden, the Häggqvist myelin stain divulged the compartments in the cerebellar white matter that channel the afferent and efferent connections of the zones. In Lund, the spino-olivocerebellar pathways activated from individual spinal funiculi revealed the zonal pattern. In Bristol, charting the axon reflex of olivocerebellar climbing fibers on the surface of the cerebellum resulted in a very similar zonal map. The history of the zones is one of accidents and purposeful pursuit. The technicians, librarians, animal caretakers, students, secretaries, and medical illustrators who made it possible remain unnamed, but their contributions certainly should be acknowledged

Phospholipase Cbeta4 and protein kinase Calpha and/or protein kinase CbetaI are involved in the induction of long term depression in cerebellar Purkinje cells.

Activation of the type-1 metabotropic glutamate receptor (mGluR1) signaling pathway in the cerebellum involves activation of phospholipase C (PLC) and protein kinase C (PKC) for the induction of cerebellar long term depression (LTD). The PLC and PKC isoforms that are involved in LTD remain unclear, however. One previous study found no change in LTD in PKCgamma-deficient mice, thus, in the present study, we examined cerebellar LTD in PLCbeta4-deficient mice. Immunohistochemical and Western blot analyses of cerebellum from wild-type mice revealed that PLCbeta1 was expressed weakly and uniformly, PLCbeta2 was not detected, PLCbeta3 was expressed predominantly in caudal cerebellum (lobes 7-10), and PLCbeta4 was expressed uniformly throughout. In PLCbeta4-deficient mice, expression of total PLCbeta, the mGluR1-mediated Ca(2+) response, and LTD induction were greatly reduced in rostral cerebellum (lobes 1-6). Furthermore, we used immunohistochemistry to localize PKCalpha, -betaI, -betaII, and -gamma in mouse cerebellar Purkinje cells during LTD induction. Both PKCalpha and PKCbetaI were found to be translocated to the plasmamembrane under these conditions. Taken together, these results suggest that mGluR1-mediated activation of PLCbeta4 in rostral cerebellar Purkinje cells induced LTD via PKCalpha and/or PKCbetaI