PatientMatcher: A customizable Python-based open-source tool for matching undiagnosed rare disease patients via the Matchmaker Exchange network.

The amount of data available from genomic medicine has revolutionized the approach to identify the determinants underlying many rare diseases. The task of confirming a genotype-phenotype causality for a patient affected with a rare genetic disease is often challenging. In this context, the establishment of the Matchmaker Exchange (MME) network has assumed a pivotal role in bridging heterogeneous patient information stored on different medical and research servers. MME has made it possible to solve rare disease cases by "matching" the genotypic and phenotypic characteristics of a patient of interest with patient data available at other clinical facilities participating in the network. Here, we present PatientMatcher (https://github.com/Clinical-Genomics/patientMatcher), an open-source Python and MongoDB-based software solution developed by Clinical Genomics facility at the Science for Life Laboratory in Stockholm. PatientMatcher is designed as a standalone MME server, but can easily communicate via REST API with external applications managing genetic analyses and patient data. The MME node is being implemented in clinical routine in collaboration with the Genomic Medicine Center Karolinska at the Karolinska University Hospital. PatientMatcher is written to implement the MME API and provides several customizable settings, including a custom-fit similarity score algorithm and adjustable matching results notifications.

Vision-Based Tracking of Surgical Motion During Live Open-Heart Surgery.

BACKGROUND: Motion tracking during live surgeries may be used to assess surgeons' intra-operative performance, provide feedback, and predict outcome. Current assessment protocols rely on human observations, controlled laboratory settings, or tracking technologies not suitable for live operating theatres. In this study, a novel method for motion tracking of live open-heart surgery was developed, and evaluated. MATERIALS AND METHODS: Three-D-printed 'tracking die' with miniature markers were fitted to DeBakey forceps. The surgical field was recorded with a video camera mounted above the operating table. Software was developed for tracking the die from the recordings. The system was tested on five open-heart procedures. Surgeons were asked to report subjective system related concerns during live surgery and assess the weight of the die on blind test. The accuracy of the system was evaluated against ground truth generated by a robot. RESULTS: The 3D-printed die weighed 6 g and tolerated sterilization with hydrogen peroxide, which added approximately 13% to the mass of the forceps. Surgeons sensed a shift in the balance of the instrument but could on blind test not correctly verify changes in weight. When two or more markers were detected, the 3D position estimate was on average within 2-3 mm, and 1.1-2.6 degrees from ground truth. Computational time was 30-50 ms per frame on a standard laptop. CONCLUSIONS: The vision-based motion tracking system was applicable for live surgeries with negligible inconvenience to the surgeons. Motion data was extracted with acceptable accuracy and speed at low computational cost.

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

Loqusdb: added value of an observations database of local genomic variation.

BACKGROUND: Exome and genome sequencing is becoming the method of choice for rare disease diagnostics. One of the key challenges remaining is distinguishing the disease causing variants from the benign background variation. After analysis and annotation of the sequencing data there are typically thousands of candidate variants requiring further investigation. One of the most effective and least biased ways to reduce this number is to assess the rarity of a variant in any population. Currently, there are a number of reliable sources of information for major population frequencies when considering single nucleotide variants (SNVs) and small insertion and deletions (INDELs), with gnomAD as the most prominent public resource available. However, local variation or frequencies in sub-populations may be underrepresented in these public resources. In contrast, for structural variation (SV), the background frequency in the general population is more or less unknown mostly due to challenges in calling SVs in a consistent way. Keeping track of local variation is one way to overcome these problems and significantly reduce the number of potential disease causing variants retained for manual inspection, both for SNVs and SVs. RESULTS: Here, we present loqusdb, a tool to solve the challenge of keeping track of any type of variant observations from genome sequencing data. Loqusdb was designed to handle a large flow of samples and unlike other solutions, samples can be added continuously to the database without rebuilding it, facilitating improvements and additions. We assessed the added value of a local observations database using 98 samples annotated with information from a background of 888 unrelated individuals. CONCLUSIONS: We show both how powerful SV analysis can be when filtering for population frequencies and how the number of apparently rare SNVs/INDELs can be reduced by adding local population information even after annotating the data with other large frequency databases, such as gnomAD. In conclusion, we show that a local frequency database is an attractive, and a necessary addition to the publicly available databases that facilitate the analysis of exome and genome data in a clinical setting.

Positron emission tomography visualized stimulation of the vestibular organ is localized in Heschl's gyrus.

The existence of a human primary vestibular cortex is still debated. Current knowledge mainly derives from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) acquisitions during artificial vestibular stimulation. This may be problematic as artificial vestibular stimulation entails coactivation of other sensory receptors. The use of fMRI is challenging as the strong magnetic field and loud noise during MRI may both stimulate the vestibular organ. This study aimed to characterize the cortical activity during natural stimulation of the human vestibular organ. Two fluorodeoxyglucose (FDG)-PET scans were obtained after natural vestibular stimulation in a self-propelled chair. Two types of stimuli were applied: (a) rotation (horizontal semicircular canal) and (b) linear sideways movement (utriculus). A comparable baseline FDG-PET scan was obtained after sitting motion-less in the chair. In both stimulation paradigms, significantly increased FDG uptake was measured bilaterally in the medial part of Heschl's gyrus, with some overlap into the posterior insula. This is the first neuroimaging study to visualize cortical processing of natural vestibular stimuli. FDG uptake was demonstrated in the medial-most part of Heschl's gyrus, normally associated with the primary auditory cortex. This anatomical localization seems plausible, considering that the labyrinth contains both the vestibular organ and the cochlea.

Exploring the effects of deep brain stimulation and vision on tremor in Parkinson's disease - benefits from objective methods.

BACKGROUND: Tremor is a cardinal symptom of Parkinson's disease (PD) that may cause severe disability. As such, objective methods to determine the exact characteristics of the tremor may improve the evaluation of therapy. This methodology study aims to validate the utility of two objective technical methods of recording Parkinsonian tremor and evaluate their ability to determine the effects of Deep Brain Stimulation (DBS) of the subthalamic nucleus and of vision. METHODS: We studied 10 patients with idiopathic PD, who were responsive to L-Dopa and had more than 1 year use of bilateral subthalamic nucleus stimulation. The patients did not have to display visible tremor to be included in the study. Tremor was recorded with two objective methods, a force platform and a 3 dimensional (3D) motion capture system that tracked movements in four key proximal sections of the body (knee, hip, shoulder and head). They were assessed after an overnight withdrawal of anti-PD medications with DBS ON and OFF and with eyes open and closed during unperturbed and perturbed stance with randomized calf vibration, using a randomized test order design. RESULTS: Tremor was detected with the Unified Parkinson's Disease Rating Scale (UPDRS) in 6 of 10 patients but only distally (hands and feet) with DBS OFF. With the force platform and the 3D motion capture system, tremor was detected in 6 of 10 and 7 of 10 patients respectively, mostly in DBS OFF but also with DBS ON in some patients. The 3D motion capture system revealed that more than one body section was usually affected by tremor and that the tremor amplitude was non-uniform, but the frequency almost identical, across sites. DBS reduced tremor amplitude non-uniformly across the body. Visual input mostly reduced tremor amplitude with DBS ON. CONCLUSIONS: Technical recording methods offer objective and sensitive detection of tremor that provide detailed characteristics such as peak amplitude, frequency and distribution pattern, and thus, provide information that can guide the optimization of treatments. Both methods detected the effects of DBS and visual input but the 3D motion system was more versatile in that it could detail the presence and properties of tremor at individual body sections.

Different Visual Weighting due to Fast or Slow Vestibular Deafferentation: Before and after Schwannoma Surgery.

Background: Feedback postural control depends upon information from somatosensation, vision, and the vestibular system that are weighted depending on their relative importance within the central nervous system. Following loss of any sensory component, the weighting changes, e.g., when suffering a vestibular loss, the most common notion is that patients become more dependent on visual cues for maintaining postural control. Dizziness and disequilibrium are common after surgery in schwannoma patients, which could be due to interpretation of the remaining sensory systems involved in feedback-dependent postural control and spatial orientation. Objective: To compare visual dependency in spatial orientation and postural control in patients suffering from unilateral vestibular loss within different time frames. Methods: Patients scheduled for schwannoma surgery: group 1 (n = 27) with no vestibular function prior to surgery (lost through years), group 2 (n = 12) with remaining vestibular function at the time of surgery (fast deafferentation), and group 3 (n = 18) with remaining function that was lost through gentamicin installations in the middle ear (slow deafferentation). All patients performed vibratory posturography and rod and frame investigation before surgery and 6 months after surgery. Results: Postural control improved after surgery in patients that suffered a slow deafferentation (groups 1 and 3) (p < 0.001). Patients that suffered fast loss of remaining vestibular function (group 2) became less visual field dependent after surgery (p ≤ 0.035) and were less able to maintain stability compared with group 1 (p = 0.010) and group 3 (p = 0.010). Conclusions: The nature and time course of vestibular deafferentation influence the weighting of remaining sensory systems in order to maintain postural control and spatial orientation.

Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development.

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.

MultiQC: summarize analysis results for multiple tools and samples in a single report.

MOTIVATION: Fast and accurate quality control is essential for studies involving next-generation sequencing data. Whilst numerous tools exist to quantify QC metrics, there is no common approach to flexibly integrate these across tools and large sample sets. Assessing analysis results across an entire project can be time consuming and error prone; batch effects and outlier samples can easily be missed in the early stages of analysis. RESULTS: We present MultiQC, a tool to create a single report visualising output from multiple tools across many samples, enabling global trends and biases to be quickly identified. MultiQC can plot data from many common bioinformatics tools and is built to allow easy extension and customization. AVAILABILITY AND IMPLEMENTATION: MultiQC is available with an GNU GPLv3 license on GitHub, the Python Package Index and Bioconda. Documentation and example reports are available at http://multiqc.info CONTACT: phil.ewels@scilifelab.se.

Hearing and Vestibular Function After Preoperative Intratympanic Gentamicin Therapy for Vestibular Schwanomma as Part of Vestibular Prehab.

OBJECTIVE: To evaluate auditory and vestibular function after presurgical treatment with gentamicin in schwannoma patients. BACKGROUND: The vestibular PREHAB protocol aims at diminishing the remaining vestibular function before vestibular schwannoma surgery, to ensure less acute symptoms from surgery, and initiate a more efficient vestibular rehabilitation already before surgery. However, the potential cochleotoxicity of gentamicin is a concern, since modern schwannoma surgery strives to preserve hearing. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Seventeen patients diagnosed with vestibular schwannoma between 2004 and 2011, and took part in vestibular PREHAB program. The patients were of age 21 to 66 years (mean 48.8), 9 females and 8 males. INTERVENTION: Intratympanic gentamicin installations before surgery as part of the vestibular PREHAB. MAIN OUTCOME MEASURES: Hearing thresholds, word recognition score, caloric response, subjective visual vertical and horizontal, cVEMP, and vestibular impulse tests. RESULTS: Combined analysis of frequency and hearing threshold showed a significant decrease after gentamicin therapy (p < 0.001). Pure-tone average decreased with 7.1 ± 8.5 dB (p = 0.004), and speech recognition with 10%. The treatment resulted in unilateral vestibular deafferentation with no notable reaction to bithermal caloric irrigation (reduction 64%, p < 0.001), loss of the vestibulo-ocular response measured by the head-impulse test, and deviation of subjective horizontal/vertical to the side of the lesion (+2.2 degrees, p = 0.010). CONCLUSIONS: Intratympanic installations of gentamicin, as part of the vestibular PREHAB, result in unilateral vestibular deafferentation, but constitute a definite risk for high-frequency hearing loss. The hearing results are in line with those reported upon when treating Menière's disease.

Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid.

BACKGROUND: Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing. METHODS: We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatography-mass spectrometry approach to measure coenzyme Q in patient samples. RESULTS: We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts. CONCLUSION: We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.

Vestibular Rehabilitation Affects Vestibular Asymmetry among Patients with Fall-Related Wrist Fractures - A Randomized Controlled Trial.

BACKGROUND: Fall-related fractures are an increasing problem for society. Dizziness is identified as a risk factor for falls and vestibular asymmetry is often found among patients with fall-related fractures. An option to prevent fall-related fractures may be to identify patients with vestibular asymmetry and to improve their balance and asymmetry by exercise. OBJECTIVE: To examine whether vestibular rehabilitation improves vestibular function, balance and self-rated health among patients with fall-related wrist fractures. METHODS: Sixty-eight persons (65 women) with fall-related wrist fractures, mean age 72 years (54-89) participated in this randomized controlled trial. The following tests and measurements were performed: head shake test to evaluate vestibular asymmetry as primary outcome measure, five clinical balance measures, a force plate to measure postural sway, a tuning fork to measure vibration and the EQ5D questionnaire to measure self-rated health. The intervention comprised group-based vestibular rehabilitation sessions conducted twice a week for 9 weeks. RESULTS: Nystagmus occurred in the head shake test in 65% (44 of 68) of the patients, indicating vestibular asymmetry. More patients in the intervention group (6 of 21) than in the control group (0 of 23) changed from having nystagmus in the head shake test at baseline (indicating vestibular asymmetry) to not having nystagmus at follow-up, and more patients in the control group (3 of 9) than in the intervention group (0 of 3) changed from not having nystagmus at baseline to have nystagmus at follow-up (p < 0.00). No other changes occurred between the two groups between baseline and follow-up. At baseline, patients with vestibular asymmetry had more balance deficits and increased postural sway compared to patients without (p = 0.00-0.05). CONCLUSION: Group sessions with vestibular rehabilitation twice a week for 9 weeks affected the occurrence of vestibular asymmetry positively among patients having vestibular asymmetry. Patients with vestibular asymmetry had more balance deficits and increased postural sway than patients without vestibular asymmetry. Vestibular assessment is important, and, in patients with diagnosed vestibular asymmetry, vestibular rehabilitation may prove beneficial on balance and possibly reduce the risk of future falls.

The incidence of acute gastrointestinal illness in Sweden.

AIMS: The aim of this study was to estimate the self-reported domestic incidence of acute gastrointestinal illness in the Swedish population irrespective of route of transmission or type of pathogen causing the disease. Previous studies in Sweden have primarily focused on incidence of acute gastrointestinal illness related to consumption of contaminated food and drinking water. METHODS: In May 2009, we sent a questionnaire to 4000 randomly selected persons aged 0-85 years, asking about the number of episodes of stomach disease during the last 12 months. To validate the data on symptoms, we compared the study results with anonymous queries submitted to a Swedish medical website. RESULTS: The response rate was 64%. We estimated that a total number of 2744,778 acute gastrointestinal illness episodes (95% confidence intervals 2475,641-3013,915) occurred between 1 May 2008 and 30 April 2009. Comparing the number of reported episodes with web queries indicated that the low number of episodes during the first 6 months was an effect of seasonality rather than recall bias. Further, the result of the recall bias analysis suggested that the survey captured approximately 65% of the true number of episodes among the respondents. CONCLUSIONS: The estimated number of Swedish acute gastrointestinal illness cases in this study is about five times higher than previous estimates this study provides valuable information on the incidence of gastrointestinal symptoms in Sweden, irrespective of route of transmission, indicating a high burden of acute gastrointestinal illness, especially among children, and large societal costs, primarily due to production losses.

Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism.

BACKGROUND: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine. RESULTS: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome. CONCLUSIONS: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.

Long-term linguistic outcome in adults with congenital cytomegalovirus infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common prenatal infection and the main infectious cause of neurodevelopmental abnormalities in developed countries. Long-term neuropsychological outcome of cCMV infection is still not well understood. This is the first study that presents linguistic follow-up data performed on adults who were infected in utero. METHOD: All individuals from a universal newborn CMV screening study in Sweden sampled from 1977 to 1985 were invited to participate in a follow-up study. 34/71 persons (48%) with cCMV and 22/46 controls (48%) were enrolled. Participants were between 34 and 43 years. Linguistic ability was evaluated with two-word fluency tasks (FAS letter fluency and verb fluency), and a qualitative analysis of the participants' word retrieval strategies was conducted. RESULTS: No statistically significant group differences were found in the total number of retrieved words. When related to Swedish norm data, 43% of participants with cCMV infection, all asymptomatic at birth, had adequate results on both FAS and verb fluency tasks, compared to 86% of the controls. Education level was the most important factor for word fluency ability in both groups. Adults with cCMV infection and higher education levels used less effective retrieval strategies on FAS letter fluency than controls. CONCLUSION: This study suggests that adults with cCMV infection may have deficits in the word retrieval process, even in the absence of known neurodevelopmental disorders. Long-term effects of cCMV infection may exist even in those with asymptomatic infection at birth.

Expression of insulin signalling components in the sensory epithelium of the human saccule.

Several studies have demonstrated a link between diabetes and the dysfunction of the inner ear. Few studies, however, have reported the signalling mechanisms involved in metabolic control in human inner ear cells. Knowledge of the expression and role of the insulin receptor and downstream signalling components in the inner ear is sparce. Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. Thus, the insulin receptor, insulin signalling components and selected cAMP signalling components are expressed in the human saccule. In addition to well-known mechanisms of diabetes complications, such as neuropathy and vascular lesions, the expression of these proteins in the saccule could have a role in the observed link between diabetes and balance/hearing disorders.

Vestibular asymmetry predicts falls among elderly patients with multi-sensory dizziness.

BACKGROUND: Dizziness is the most common symptom in elderly patients and has been identified as a risk factor for falls. While BPPV is the most common cause of dizziness among elderly, multisensory deficits is the second, with visual, vestibular and proprioceptive reduced function. Asymmetric vestibular function is overrepresented in elderly persons with hip fractures and wrist fractures and can be accessed for screening. METHODS: In this prospective study with one year observation period, 55 patients (41 women, 14 men), 65 to 90 years old (median 80, interquartile range 11) with multisensory dizziness were included. RESULTS: Headshake test were pathologic in 24 patients, which substantially increased the risk of falls (OR 3.4). Thirteen of the 21 patients who had fallen (p = 0.03), and all 6 patients who sustained three falls or more (p = 0.04), had vestibular asymmetry. No other measure could predict the risk of falls (OR 0.55-1.71). CONCLUSION: Signs of vestibular asymmetry among elderly with multisensory dizziness could predict falls. Hence, it seems important to address fall-prevention programs to such a group of patients. Simple bedside tests of vestibular asymmetry might be a possibility to screen for one risk factor for falls among elderly.

Experimentally induced deep cervical muscle pain distorts head on trunk orientation.

PURPOSE: We wanted to explore the specific proprioceptive effect of cervical pain on sensorimotor control. Sensorimotor control comprises proprioceptive feedback, central integration and subsequent muscular response. Pain might be one cause of previously reported disturbances in joint kinematics, head on trunk orientation and postural control. However, the causal relationship between the impact of cervical pain on proprioception and thus on sensorimotor control has to be established. METHODS: Eleven healthy subjects were examined in their ability to reproduce two different head on trunk targets, neutral head position (NHP) and 30° target position, with a 3D motion analyser before, directly after and 15 min after experimentally induced neck pain. Pain was induced by hypertonic saline infusion at C2/3 level in the splenius capitis muscle on one side (referred to as "injected side"). RESULTS: All subjects experienced temporary pain and the head repositioning error increased significantly during head repositioning to the 30° target to the injected side (p = 0.011). A post hoc analysis showed that pain interfered with proprioception to the injected side during acute pain (p < 0.001), but also when the pain had waned (p = 0.002). Accuracy decreased immediately after pain induction for the 30° target position to the side where pain was induced (3.3 â†’ 5.3°, p = 0.033), but not to the contralateral side (4.9 â†’ 4.1°, p = 0.657). There was no significant impact of pain on accuracy for NHP. A sensory mismatch appeared in some subjects, who experienced dizziness. CONCLUSIONS: Acute cervical pain distorts sensorimotor control with side-specific changes, but also has more complex effects that appear when pain has waned.

Subthalamic deep brain stimulation improves smooth pursuit and saccade performance in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) in the subthalamic nucleus (STN) significantly reduces symptoms of Parkinson's disease (PD) such as bradykinesia, tremor and rigidity. It also reduces the need for anti-PD medication, and thereby potential side-effects of L-Dopa. Although DBS in the STN is a highly effective therapeutic intervention in PD, its mechanism and effects on oculomotor eye movement control and particularly smooth pursuit eye movements have to date rarely been investigated. Furthermore, previous reports provide conflicting information. The aim was to investigate how DBS in STN affected oculomotor performance in persons with PD using novel analysis techniques. METHODS: Twenty-five patients were eligible (22 males, 3 females) according to the clinical inclusion criteria: idiopathic PD responsive to L-Dopa and having had bilateral STN stimulation for at least one year to ensure stable DBS treatment. Fifteen patients were excluded due to the strict inclusion criteria applied to avoid interacting and confounding factors when determining the effects of DBS applied alone without PD medication. One patient declined participation. Nine PD patients (median age 63, range 59-69 years) were assessed after having their PD medications withdrawn overnight. They were examined with DBS ON and OFF, with the ON/OFF order individually randomized. RESULTS: DBS ON increased smooth pursuit velocity accuracy (p < 0.001) and smooth pursuit gain (p = 0.005), especially for faster smooth pursuits (p = 0.034). DBS ON generally increased saccade amplitude accuracy (p = 0.007) and tended to increase peak saccade velocity also (p = 0.087), specifically both saccade velocity and amplitude accuracy for the 20 and 40 degree saccades (p < 0.05). Smooth pursuit latency tended to be longer (p = 0.090) approaching normal with DBS ON. Saccade latency was unaffected. CONCLUSIONS: STN stimulation from DBS alone significantly improved both smooth pursuit and saccade performance in patients with PD. The STN stimulation enhancement found for oculomotor performance suggests clear positive implications for patients' ability to perform tasks that rely on visual motor control and visual feedback. The new oculomotor analysis methods provide a sensitive vehicle to detect subtle pathological modifications from PD and the functional enhancements produced by STN stimulation from DBS alone.

Betahistine prevents development of endolymphatic hydrops in a mouse model of insulin resistance and diabetes.

BACKGROUND: Diabetes is associated with inner ear dysfunction. Furthermore, C57BL/6J mice fed high fat diet (HFD), a model for insulin resistance and diabetes, develop endolymphatic hydrops (EH). AIM: Evaluate if betahistine, spironolactone (aldosterone antagonist) and empagliflozin (sodium -glucose cotransporter2 inhibitor) can prevent EH induced by HFD and explore potential mechanisms. METHODS: C57BL/6J mice fed HFD were treated with respective drug. The size of the endolymphatic fluid compartment was measured using contrast enhanced MRI. Secondarily, mice treated with cilostamide, a phosphodiesterase3 inhibitor, to induce EH and HEI-OC1 auditory cells were used to study potential cellular mechanisms of betahistine. RESULTS: HFD-induced EH was prevented by betahistine but not by spironolactone and empagliflozin. Betahistine induced phosphorylation of protein kinaseA substrates but did not prevent cilostamide-induced EH. CONCLUSIONS: Betahistine prevents the development of EH in mice fed HFD, most likely not involving pathways downstream of phosphodiesterase3, an enzyme with implications for dysfunction in diabetes. The finding that spironolactone did not prevent HFD-induced EH suggests different mechanisms for EH induction/treatment since spironolactone prevents EH induced by vasopressin, as previously observed. SIGNIFICANCE: This further demonstrates that independent mechanisms can cause hydropic inner ear diseases which suggests different therapeutic approaches and emphazises the need for personalized medicine.