Editorial

The cover of this issue relates to an article by Greg Weir and colleagues who describe a chemogenetic strategy to treat experimental neuropathic pain. Chemogenetics refers to the expression of an exogenous receptor, most commonly using a viral vector, which can subsequently be activated by a chemical ligand to trigger a biological action. Weir et al. targeted a mutated glutamate-gated chloride channel from C. elegans, modified to render it insensitive to glutamate, to dorsal root ganglia neurons of mice that had received a peripheral nerve injury to model neuropathic pain. Upon treatment with the anthelmintic drug ivermectin to activate the channel, treated mice exhibited less pain-related hypersensitivity behaviour, as expected from chloride-channel mediated inhibition of nociceptors. In an accompanying Scientific Commentary Allan Basbaum considers some of the challenges to bring such a strategy to the clinic.

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Reconnecting with Joseph and Augusta Dejerine: 100 years on

Bajada et al. mark the centenary of Joseph Dejerine's death by demonstrating the continuing relevance of his research with his long-standing collaborator, Augusta Dejerine-Klumpke, on the white matter pathways of the brain to modern-day connectional anatomy. A first English translation of the original work is provided in the Supplementary Materials.

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Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation

Sir,

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WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Abstract

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

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Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

Abstract

See Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article.Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P < 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4–20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P's < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.

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The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice

Abstract

Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.

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A ventral glomerular deficit in Parkinson’s disease revealed by whole olfactory bulb reconstruction

Abstract

Olfactory dysfunction is common in Parkinson's disease and is an early symptom, but its pathogenesis remains poorly understood. Hindering progress in our mechanistic understanding of olfactory dysfunction in Parkinson's disease is the paucity of literature about the human olfactory bulb, both from normal and Parkinson's disease cases. Qualitatively it is well established that the neat arrangement of the glomerular array seen in the mouse olfactory bulb is missing in humans. But rigorous quantitative approaches to describe and compare the thousands of glomeruli in the human olfactory bulb are not available. Here we report a quantitative approach to describe the glomerular component of the human olfactory bulb, and its application to draw statistical comparisons between olfactory bulbs from normal and Parkinson's disease cases. We subjected horizontal 10 µm sections of olfactory bulbs from six normal and five Parkinson's disease cases to fluorescence immunohistochemistry with antibodies against vesicular glutamate transporter-2 and neural cell adhesion molecule. We scanned the immunostained sections with a fluorescence slide scanner, segmented the glomeruli, and generated 3D reconstructions of whole olfactory bulbs. We document the occurrence of atypical glomerular morphologies and glomerular-like structures deep in the olfactory bulb, both in normal and Parkinson's disease cases. We define a novel and objective parameter: the global glomerular voxel volume, which is the total volume of all voxels that are classified immunohistochemically as glomerular. We find that the global glomerular voxel volume in Parkinson's disease cases is half that of normal cases. The distribution of glomerular voxels along the dorsal-ventral dimension of the olfactory bulb in these series of horizontal sections is significantly altered in Parkinson's disease cases: whereas most glomerular voxels reside within the ventral half of olfactory bulbs from normal cases, glomerular voxels are more evenly spread among the ventral and dorsal halves of olfactory bulbs from Parkinson's disease cases. These quantitative whole-olfactory bulb analyses indicate a predominantly ventral deficit in the glomerular component in Parkinson's disease, consistent with the olfactory vector hypothesis for the pathogenesis of this neurodegenerative disease. The distribution of serine 129-phosphorylated α-synuclein immunoreactive voxels correlates with that of glomerular voxels. The higher the serine 129-phosphorylated α-synuclein load of an olfactory bulb from a Parkinson's disease case, the lower the global glomerular voxel volume. Our rigorous quantitative approach to the whole olfactory bulb will help understand the anatomy and histology of the normal human olfactory bulb and its pathological alterations in Parkinson's disease.

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Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

Abstract

Non-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients.

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Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants

Abstract

Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands—delta-theta (2–8 Hz); alpha (8–12 Hz); beta (12–30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.

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A singular person with multiple interests

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On assessing neurofeedback effects: should double-blind replace neurophysiological mechanisms?

Sir,

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Reply: On assessing neurofeedback effects: should double-blind replace neurophysiological mechanisms?

Sir,

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PRUNE1 : a disease-causing gene for secondary microcephaly

Sir,

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Molecular Tumor Boards: Current Practice and Future Needs

Abstract

Background

due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as Whole Exome- and -Genome Sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.

Methods

based on literature review, a survey amongst hospitals in the Netherlands, and our own experience with the establishment of a nationally operating MTB, this paper evaluates current knowledge and unmet needs, and lays out a strategy for successful MTB implementation.

Results

having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, less than 50% of hospitals and only 5% of non-academic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools and workflow. This may not only lead to variation in quality of care, but also hinders data sharing and thus creation of an effective learning community.

Conclusions

this paper acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice, and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member- and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning, but also improve general interpretation and application of genomics-guided cancer care.

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Crizotinib targets in glioblastoma stem cells

Abstract

Glioblastoma stem cells (GSCs) are believed to be involved in the mechanisms of tumor resistance, therapeutic failures, and recurrences after conventional glioblastoma therapy. Therefore, elimination of GSCs might be a prerequisite for the development of successful therapeutic strategies. ALK, ROS1, and MET are targeted by Crizotinib, a tyrosine kinase inhibitor which has been approved for treatment of ALK-rearranged non–small-cell lung cancer. In this study we investigated ALK, ROS1, and MET status in nine glioblastoma stem cell lines and tumors from which they arise. Fluorescent in situ hybridization (FISH), Sanger's direct sequencing, and immunohistochemistry were used to screen genomic rearrangements (or amplifications), genomic mutations, and protein expression, respectively. The immunohistochemical and FISH studies revealed no significant dysregulation of ROS1 in GSCs and associated tumors. Neither amplification nor polysomy of ALK was observed in GSC, but weak overexpression was detected by IHC in three of nine GSCs. Similarly, no MET amplification was found by FISH but three GSCs presented significant immunohistochemical staining. No ALK or MET mutation was found by Sanger's direct sequencing. In this study, we show no molecular rearrangement of ALK, ROS1, and MET that would lead us not to propose, as a valid strategy, the use of crizotinib to eradicate GSCs. However, MET was overexpressed in all GSCs with mesenchymal subtype and three GSCs presented an overexpression of ALK. Therefore, our study corroborates the idea that MET and ALK may assume a role in the tumorigenicity of GSC.

Tissue and stem cells microarrays from nine glioblastomas samples were used to evaluate expression and chromosomal abnormalities of ALK, ROS1, and MET. No molecular rearrangement of these three important genes was observed but rather an overexpression of ALK and MET in some of the glioblastoma stem cell samples, supporting the role of these two genes in tumorigenicity.

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Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells

Abstract

Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely, ACC-MESO-4, Y-MESO-8A, MSTO-211H, NCI-H28, NCI-H290, and NCI-H2052, and a normal mesothelial cell line MeT-5A. Comparison of IC₅₀ values of the Akt inhibitors showed that afuresertib, an ATP-competitive specific Akt inhibitor, exerted tumor-specific effects on MPM cells. Afuresertib significantly increased caspase-3 and caspase-7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G₁ phase. Western blotting analysis showed that afuresertib increased the expression of p21^WAF1/CIP1 and decreased the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. These results suggest that afuresertib-induced p21 expression promotes G₁ phase arrest by inducing FOXO activity. Furthermore, afuresertib significantly enhanced cisplatin-induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression E2F1 and MYC, which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with MPM.

Novel ATP-competitive Akt inhibitor afuresertib exerts tumor-specific antiproliferative effect on MPM cells. Afuresertib significantly enhanced cisplatin-induced cytotoxicity, suggesting that afuresertib is a useful anticancer drug for treating patients with MPM.

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Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma

Abstract

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Bone marrow involvement by biopsy complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort, bone marrow involvement by PET/CT could not independently predict a shorter PFS and/or OS.

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Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant

Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder.

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Influence of CYP3A and ABCB1 polymorphisms on cyclosporine concentrations in renal transplant recipients

Pharmacogenomics, Ahead of Print.


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Chemical characterization oxidative stability and in vitro antioxidant capacity of sesame oils extracted by supercritical and subcritical techniques and conventional methods: A comparative study using chemometrics

Abstract

In this study, profiles of chemical characterization, oxidative stability and in vitro antioxidant capacity of sesame oils obtained from supercritical and subcritical techniques and conventional methods were studied and compared. The results showed that a large proportion of fatty acid and triacylglycerol were not significantly influenced by the processing technologies (except for LLLn, SOA, C_18:3n-6 and C_22:0). However, significant differences of minor component, oxidation stability and free radical scavenging activity among the test oil samples were observed. Supercritical sesame oils were more excellent than the subcritical sesame oils and oils obtained from the traditional methods, especially in terms of γ-tocopherol, lignan and polyphenol contents and antioxidant capacity, thus indicating that CO₂ fluid technology was a desirable alternative to extract sesame oils with rich nutrition and superb physiological activity. Further, oils obtained from roasted sesame seeds exhibited higher oxidative stability and antioxidant capacity, thus declaring that high temperature roasting was a critical issue that influenced the quality of the final sesame oil product.

Practical applications: This study used two burgeoning technologies, namely supercritical and subcritical techniques for the practical applications of the extraction process of sesame oils from sesame (Sesamum indicum, L.) seeds. Supercritical fluid was an excellent technology to selectively extract bioactive compounds from sesame by using CO₂ as a carrier solvent. The use of CO₂ supercritical fluid in the present study was associated with high efficiency and antioxidant activities of the obtained sesame oils. These results indicate that this technology was an efficient and rapid method for extracting phytochemicals when compared with the conventional methods (hot pressing, cold pressing, solvent extraction and aqueous extraction), thus indicating that it had the potential to work as a satisfactory approach to produce specific sesame oil products for health care and cosmetic use. This method can be easily implemented on an industrial scale.

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Long-term disability progression in primary progressive multiple sclerosis: a 15-year study

Abstract

Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T₁-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R² = 61% versus R² = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone.

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Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients

Abstract

Previous research with aphasic patients has shown that picture naming can be facilitated by concurrent phonemic cueing [e.g. initial phoneme(s) of the word that the patient is trying to retrieve], both as an immediate word retrieval technique, and when practiced repeatedly over time as a long-term anomia treatment. Here, to investigate the neural mechanisms supporting word retrieval, we adopted—for the first time—a functional magnetic resonance imaging task using the same naming procedure as it occurs during the anomia treatment process. Before and directly after a 6-week anomia treatment programme, 18 chronic aphasic stroke patients completed our functional magnetic resonance imaging protocol—a picture naming task aided by three different types of phonemic cues (whole words, initial phonemes, final phonemes) and a noise-control condition. Patients completed a naming task based on the training materials, and a more general comprehensive battery of language tests both before and after the anomia treatment, to determine the effectiveness and specificity of the therapy. Our results demonstrate that the anomia treatment was effective and specific to speech production, significantly improving both patients' naming accuracy and reaction time immediately post-treatment (unstandardized effect size: 29% and 17%, respectively; Cohen's d: 3.45 and 1.83). Longer term gains in naming were maintained 3 months later. Functional imaging results showed that both immediate and long-term facilitation of naming involved a largely overlapping bilateral frontal network including the right anterior insula, inferior frontal and dorsal anterior cingulate cortices, and the left premotor cortex. These areas were associated with a neural priming effect (i.e. reduced blood oxygen level-dependent signal) during both immediate (phonemically-cued versus control-cue conditions), and long-term facilitation of naming (i.e. treated versus untreated items). Of note is that different brain regions were sensitive to different phonemic cue types. Processing of whole word cues was associated with increased activity in the right angular gyrus; whereas partial word cues (initial and final phonemes) recruited the left supplementary motor area, and right anterior insula, inferior frontal cortex, and basal ganglia. The recruitment of multiple and bilateral areas may help explain why phonemic cueing is such a successful behavioural facilitation tool for anomia treatment. Our results have important implications for optimizing current anomia treatment approaches, developing new treatments, and improving speech outcome for aphasic patients.

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Clinical, pathological and functional characterization of riboflavin-responsive neuropathy

Abstract

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

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Divergent neural responses to narrative speech in disorders of consciousness

Abstract

Objective

Clinical assessment of auditory attention in patients with disorders of consciousness is often limited by motor impairment. Here, we employ intersubject correlations among electroencephalography responses to naturalistic speech in order to assay auditory attention among patients and healthy controls.

Methods

Electroencephalographic data were recorded from 20 subjects with disorders of consciousness and 14 healthy controls during of two narrative audio stimuli, presented both forwards and time-reversed. Intersubject correlation of evoked electroencephalography signals were calculated, comparing responses of both groups to those of the healthy control subjects. This analysis was performed blinded and subsequently compared to the diagnostic status of each patient based on the Coma Recovery Scale-Revised.

Results

Subjects with disorders of consciousness exhibit significantly lower intersubject correlation than healthy controls during narrative speech. Additionally, while healthy subjects had higher intersubject correlation values in forwards versus backwards presentation, neural responses did not vary significantly with the direction of playback in subjects with disorders of consciousness. Increased intersubject correlation values in the backward speech condition were noted with improving disorder of consciousness diagnosis, both in cross-sectional analysis and in a subset of patients with longitudinal data.

Interpretation

Intersubject correlation of neural responses to narrative speech audition differentiates healthy controls from patients and appears to index clinical diagnoses in disorders of consciousness.

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CMV and Natural Killer cells: shaping the response to vaccination

Cytomegaloviruses (CMVs) are highly prevalent, persistent human pathogens that not only evade but also shape our immune responses. Natural killer (NK) cells play an important role in the control of CMV and CMVs have in turn developed a plethora of immunoevasion mechanisms targeting NK cells. This complex interplay can leave a long-lasting imprint on the immune system in general and affect responses towards other pathogens and vaccines. This review aims to provide an overview of NK cell biology and development, the manipulation of NK cells by CMVs and the potential impact of these evasion strategies on responses to vaccination.

This article is protected by copyright. All rights reserved

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Autism-relevant traits interact with temporoparietal junction stimulation effects on social cognition: a high-definition transcranial direct current stimulation and electroencephalography study

Abstract

The temporoparietal junction (TPJ) is implicated in mental and emotional state attribution, processes associated with autism-relevant traits. Transcranial direct current stimulation (tDCS) to the TPJ can influence social-cognitive performance. However, associations with electrophysiology and autism-relevant traits remain relatively unexamined. This study had two aims: first, exploring links between Autism-Spectrum Quotient (AQ) scores and social-cognitive performance; second, examining interactions between AQ scores and high-definition-tDCS (HD-tDCS) applied to the right TPJ in terms of mental/emotional state attribution and neurophysiological outcomes. Fifty-three participants completed mental/emotional state attribution tasks before and after HD-tDCS. Pre-stimulation mental state attribution accuracy was reduced in participants with higher AQ Switching scores. Cathodal stimulation was associated with reduced emotion attribution performance in participants with higher AQ Switching and AQ Social scores (the latter at trend-level). Anodal stimulation more frequently interacted with AQ Social scores in terms of neurophysiology, in particular regarding reduced delta power in the left compared to right TPJ, and trend-level positive interactions with P100 and P300 latencies during the emotion recognition task. Elements of attention/switching (AQ Switching) may subserve or underpin elements of social cognition (AQ Social), and cathodal and anodal stimulation may have differing effects depending on trait levels in these domains. This study makes an important and original contribution in terms of increasing understanding of how such trait-level variation might interact with the effects of tDCS and also extending previous studies with regard to understanding potential roles of the rTPJ in both attention and social cognition and how autism-relevant traits might influence TPJ function.

This study examines links between Autism-Spectrum Quotient (AQ) scores and social cognition, and interactions between AQ and rTPJ high-definition-tDCS. Cathodal tDCS reduced emotion attribution performance in participants with higher AQ Switching and AQ Social scores. Anodal tDCS interacted with AQ Social scores, in particular regarding reduced delta power in the lTPJ compared to rTPJ, and trend-level positive interactions with P100 and P300 latencies during emotion attribution. Such trait-level variations interact with tDCS effects on both behaviour and neurophysiology.

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Gene and Cell Therapy in Germany

Human Gene Therapy Oct 2017, Vol. 28, No. 10: 781-781.


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Virotherapy Research in Germany: From Engineering to Translation

Human Gene Therapy Oct 2017, Vol. 28, No. 10: 800-819.


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Wide Awake and Ready to Move: 20 Years of Non-Viral Therapeutic Genome Engineering with the Sleeping Beauty Transposon System

Human Gene Therapy Oct 2017, Vol. 28, No. 10: 842-855.


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Automated Manufacturing of Potent CD20-Directed Chimeric Antigen Receptor T Cells for Clinical Use

Human Gene Therapy Oct 2017, Vol. 28, No. 10: 914-925.


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Teva Announces Reintroduction of Generic Depo-Provera in the United States

JERUSALEM--(BUSINESS WIRE)--Sep. 25, 2017-- Teva Pharmaceutical Industries Ltd., (NYSE: TEVA) today announced the reintroduction of the generic equivalent to Depo-Provera1 Contraceptive Injection (medroxyprogesterone acetate injectable suspension,...

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Functional specialization of intestinal dendritic cell subsets during Th2 helminth infection in mice

Dendritic cells (DCs) are essential in dictating the nature and effectiveness of immune responses. In the intestine DCs can be separated into discrete subsets, defined by expression of CD11b and CD103, each with different developmental requirements and distinct functional potential. Recent evidence has shown that different intestinal DC subsets are involved in the induction of T helper (Th)17 and regulatory T cell responses, but the cells that initiate Th2 immune responses are still incompletely understood. We show that in the Th2 response to an intestinal helminth in mice, only CD11b⁺ and not CD11b⁻ DCs accumulate in the local lymph node, upregulate PDL2 and express markers of alternative activation. An enteric Th1 response instead activated both CD11b⁺ and CD11b⁻ DCs without eliciting alternative activation in either population. Functionally, only CD11b⁺ DCs activated during helminth infection supported Th2 differentiation in naive CD4⁺ T cells. Together our data demonstrate that the ability to prime Th2 cells during intestinal helminth infection, is a selective and inducible characteristic of CD11b⁺ DCs.

This article is protected by copyright. All rights reserved

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Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS colorectal cancers (KRASMUT CRC). Using pooled lentiviral single guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human CRC cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT CRC, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase (NADK) or ketohexokinase (KHK) were growth inhibitory in vivo. Additionally, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors.

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Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies, then examined treatment responses including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed.Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell and CD4+FoxP3-:regulatory T cell ratios in primary renal tumors and increased T cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined-modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone.

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A phase 1, dose escalation study of oral ASP8273 in patients with non-small cell lung cancers with epidermal growth factor receptor mutations

PURPOSE: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M. EXPERIMENTAL DESIGN: In this multi-cohort, phase 1 study (NCT02113813), escalating doses of ASP8273 (25-500mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose-escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating-free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint. RESULTS: A total of 110 patients were treated with ASP8273 across dose-escalation (n=36), response-expansion (n=36), RP2D (300mg; n=19) and food-effect (n=19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n=27/88, 95% CI 19.5-44.5%), and median progression-free survival was 6.8 months (95% CI 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression. CONCLUSIONS: ASP8273 was well-tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy.

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The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma

Purpose. We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynaecological malignancy of poor prognosis. Experimental design. We performed copy number, mutational state and zygosity analysis of 151 genes in SCC arising in MCT (n=25) using next-generation sequencing. The presence of high/intermediate risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome Results. MCT had a low mutation burden with a mean of only 1 mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%) and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8/20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. Conclusions. Ovarian SCC arising in MCT has a high mutational burden with TP53 mutation the most common abnormality. The presence TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs.

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Mutational Analysis of Gene Fusions Predicts Novel MHC Class I-Restricted T cell Epitopes & Immune Signatures in a Subset of Prostate Cancer

Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQs) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico-predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events. Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I-binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration. Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune-cell infiltration within a sub-group of prostate cancer patients.

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A first-in-human Phase 1 study of the anti-cancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors

Purpose: Wnt signaling is implicated in tumor cell de-differentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human Frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental Design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. Objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in 7 dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15 and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related Grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related Grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ~4 days, and had low incidence of anti-drug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients.

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Comparison between the Hypolipidemic Activity of Parsley and Carob in Hypercholesterolemic Male Rats

Hypercholesterolemia is commonly associated with obesity that leads to heart diseases and diabetes. The hepatocardioprotective activity of parsley and carob methanol extract was tested in hypercholesterolemic male rats. Twenty-four male albino rats were divided into four groups (). Group 1 was the negative control group fed with fat rich diet, group 2 (G2) was hypercholesterolemic rats fed with fat rich diet with 2% cholesterol, and group 3 and group 4 (G3 and G4) were hypercholesterolemic rats supplemented with 2% cholesterol and cotreated with 20% w/w parsley seed methanol extract and 20% w/w carob legume methanol extract, respectively. The experiment was conducted for eight weeks. The positive hypercholesterolemic rats showed significant increase in serum levels of total cholesterol, triglycerides, low density lipoprotein (LDL), very low density lipoprotein (VLDL), lactate dehydrogenase (LDH), creatine kinase-mb, liver function enzymes, and decrease in the high density lipoproteins (HDL). Moreover, heart and liver tissues were ameliorated and nearly restored their normal appearance. It could be concluded that both parsley and carob extracts supplementations have a protective effect against hyperlipidemia and improved the histological alteration in heart and liver tissues. The methanol extract of parsley appeared to be more efficient than that of carob in lowering hypercholesterolemia.

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Iterative Schemes to Solve Low-Dimensional Calibration Equations in Parallel MR Image Reconstruction with GRAPPA

GRAPPA (Generalized Autocalibrating Partially Parallel Acquisition) is a widely used parallel MRI reconstruction technique. The processing of data from multichannel receiver coils may increase the storage and computational requirements of GRAPPA reconstruction. Random projection on GRAPPA (RP-GRAPPA) uses random projection (RP) method to overcome the computational overheads of solving large linear equations in the calibration phase of GRAPPA, saving reconstruction time. However, RP-GRAPPA compromises the reconstruction accuracy in case of large reductions in the dimensions of calibration equations. In this paper, we present the implementation of GRAPPA reconstruction method using potential iterative solvers to estimate the reconstruction coefficients from the randomly projected calibration equations. Experimental results show that the proposed methods withstand the reconstruction accuracy (visually and quantitatively) against large reductions in the dimension of linear equations, when compared with RP-GRAPPA reconstruction. Particularly, the proposed method using conjugate gradient for least squares (CGLS) demonstrates more savings in the computational time of GRAPPA, without significant loss in the reconstruction accuracy, when compared with RP-GRAPPA. It is also demonstrated that the proposed method using CGLS complements the channel compression method for reducing the computational complexities associated with higher channel count, thereby resulting in additional memory savings and speedup.

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1H NMR-Based Metabonomic Study of Functional Dyspepsia in Stressed Rats Treated with Chinese Medicine Weikangning

1H NMR-based metabolic profiling combined with multivariate data analysis was used to explore the metabolic phenotype of functional dyspepsia (FD) in stressed rats and evaluate the intervention effects of the Chinese medicine Weikangning (WKN). After a 7-day period of model establishment, a 14-day drug administration schedule was conducted in a WKN-treated group of rats, with the model and normal control groups serving as negative controls. Based on 1H NMR spectra of urine and serum from rats, PCA, PLS-DA, and OPLS-DA were performed to identify changing metabolic profiles. According to the key metabolites determined by OPLS-DA, alterations in energy metabolism, stress-related metabolism, and gut microbiota were found in FD model rats after stress stimulation, and these alterations were restored to normal after WKN administration. This study may provide new insights into the relationship between FD and psychological stress and assist in research into the metabolic mechanisms involved in Chinese medicine.

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Kidney-Replenishing Herb Induces SOCS-3 Expression via ERK/MAPK Pathway and Improves Growth of the First-Trimester Human Trophoblast Cells

Kidney-replenishing herb is a traditional medicine formula in China which has been widely used for clinical treatment of recurrent miscarriage. Our previous study showed that Kidney-replenishing herb could promote proliferation and inhibit apoptosis of the human first-trimester trophoblasts. In the present study, we further explored the potential mechanism and signal pathway of Kidney-replenishing herb on human trophoblast cells. Our research showed that Kidney-replenishing herb stimulated proliferation and reduced apoptosis of human trophoblast cells in vitro, and this appeared to be positive correlation with SOCS-3 transcription, suggesting that Kidney-replenishing herb regulated biological functions of human trophoblast cells by inducing SCOS-3 expression. Furthermore, the Kidney-replenishing herb treatment stimulated the phosphorylation of ERK1/2, and blocking the signaling pathway by mitogen-activated protein MAPK (MEK) inhibitor, U0126, inhibited Kidney-replenishing herb-induced SOCS-3 transcription, depressed proliferation, and promoted apoptosis of human trophoblasts. Kidney-replenishing herbs still induced ERK1/2 phosphorylation after SOCS-3 siRNA silence. Overexpression of SOCS-3 stimulated the proliferation of trophoblast. These findings suggest that SOCS-3 expression is induced by Kidney-replenishing herbs via activation of MAPK pathways, and this may possibly be involved in promoting human trophoblast cells growth which is contributed to embryo development.

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417 Performance of an Automated Severe Sepsis Screening Tool in the Emergency Department

Patients with severe sepsis and septic shock benefit from early recognition and initiation of treatment. Electronic health records (EHRs) now allow for automated screening tools to assist with detection of severe sepsis/septic shock. Our objective was to assess the performance and accuracy of an automated screen for severe sepsis and septic shock in the emergency department (ED).

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Web-based self-management support for people with type 2 diabetes (HeLP-Diabetes): randomised controlled trial in English primary care

Objective

To determine the effectiveness of a web-based self-management programme for people with type 2 diabetes in improving glycaemic control and reducing diabetes-related distress.

Methods and design

Individually randomised two-arm controlled trial.

Setting

21 general practices in England.

Participants

Adults aged 18 or over with a diagnosis of type 2 diabetes registered with participating general practices.

Intervention and comparator

Usual care plus either Healthy Living for People with Diabetes (HeLP-Diabetes), an interactive, theoretically informed, web-based self-management programme or a simple, text-based website containing basic information only.

Outcomes and data collection

Joint primary outcomes were glycated haemoglobin (HbA1c) and diabetes-related distress, measured by the Problem Areas in Diabetes (PAID) scale, collected at 3 and 12 months after randomisation, with 12 months the primary outcome point. Research nurses, blind to allocation collected clinical data; participants completed self-report questionnaires online.

Analysis

The analysis compared groups as randomised (intention to treat) using a linear mixed effects model, adjusted for baseline data with multiple imputation of missing values.

Results

Of the 374 participants randomised between September 2013 and December 2014, 185 were allocated to the intervention and 189 to the control. Final (12 month) follow-up data for HbA1c were available for 318 (85%) and for PAID 337 (90%) of participants. Of these, 291 (78%) and 321 (86%) responses were recorded within the predefined window of 10–14 months. Participants in the intervention group had lower HbA1c than those in the control (mean difference –0.24%; 95% CI –0.44 to –0.049; p=0.014). There was no significant overall difference between groups in the mean PAID score (p=0.21), but prespecified subgroup analysis of participants who had been more recently diagnosed with diabetes showed a beneficial impact of the intervention in this group (p = 0.004). There were no reported harms.

Conclusions

Access to HeLP-Diabetes improved glycaemic control over 12 months.

Trial registration number

ISRCTN02123133.

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Mii-vitaliSe: a pilot randomised controlled trial of a home gaming system (Nintendo Wii) to increase activity levels, vitality and well-being in people with multiple sclerosis

Objectives

While the health and well-being benefits of physical activity are recognised, people with multiple sclerosis (MS) often face greater barriers than the general population. The Nintendo Wii potentially offers a fun, convenient way of overcoming some of these. The aim was to test the feasibility of conducting a definitive trial of the effectiveness and cost-effectiveness of Mii-vitaliSe; a home-based, physiotherapist-supported Nintendo Wii intervention.

Design

A single-centre wait-list randomised controlled study.

Setting

MS service in secondary care.

Participants

Ambulatory, relatively inactive people with clinically confirmed MS.

Intervention

Thirty participants were randomised to receive Mii-vitaliSe either immediately (for 12 months) or after a 6-month wait (for 6 months). Mii-vitaliSe consisted of two supervised Nintendo Wii familiarisation sessions in the hospital followed by home use (Wii Sports, Sports Resort and Fit Plus software) with physiotherapist support and personalised resources.

Outcomes

Included self-reported physical activity levels, quality of life, mood, self-efficacy, fatigue and assessments of balance, gait, mobility and hand dexterity at baseline, 6 and 12 months. Interviews (n=25) explored participants' experiences and, at study end, the two Mii-vitaliSe facilitators' experiences of intervention delivery (main qualitative findings reported separately).

Results

Mean (SD) age was 49.3 (8.7) years, 90% female, with 47% diagnosed with MS <6 years ago and 60% new to active gaming. The recruitment rate was 31% (95% CI 20% to 44%). Outcome data were available for 29 (97%) at 6 months and 28 (93%) at 12 months. No serious adverse events were reported during the study. Qualitative data indicated that Mii-vitaliSe was well-received. Mean Wii use across both groups over the initial 6-month intervention period was twice a week for 27 min/day. Mean cost of delivering Mii-vitaliSe was £684 per person.

Discussion

Mii-vitaliSe appears acceptable and a future trial feasible and warranted. These findings will inform its design.

Trial registration

ISRCTN49286846

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P 25 Reference values for the cross-sectional area of the vagus nerve in healthy subjects – a high-resolution ultrasound study

Examination of peripheral nerves with high-resolution ultrasound (HRUS) now routinely complements electrophysiological studies in various diseases. Prerequisite for nerve HRUS are well-defined reference values. Notably, reference values of the vagus nerve (VN) are varying (Cartwright, 2008; López-Hernández, 2014) and, overall, poorly studied. Aim of this study was to assess reference values for the VN as well as to examine inter-rater and intra-rater reliability and inter-ultrasound system agreement.

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P 23 fMRI-mapping of somatosensory finger representation in complex regional pain syndrome

Somatosensory deficits are often reported in patients with complex regional pain syndrome (CRPS). In particular reduced spatial tactile resolution is a typical clinical finding in CRPS patients. The detailed underlying mechanism for development and preservation of these deficits is not yet fully understood.However, a systematic review of studies on pain representation and cerebral representation showed a smaller representation of the hand in the primary somatosensory cortex (S1) contralateral to the affected upper limb (Di Pietro et al., 2013).

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P 24 Electrophysiological connectivity during oscillatory cycles of alpha activity and the BOLD-signal correlate in major depression

Major depressive disorder (MDD) belongs to the leading causes of disability worldwide. From an electrophysiological point of view, EEG-alpha activity and alpha phase synchronization seem to be possible biomarkers with diagnostic and prognostic value. In parallel, functional magnetic resonance imaging (fMRI) studies suggest altered blood oxygen-level dependent (BOLD) signals in e.g. frontal and prefrontal brain areas (Lemogne et al., 2012). However, the association between electrophysiological alterations and differences of fMRI activity in MDD remains vague.

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Interchageable Use of Proton Pump Inhibitors Based on Relative Potency—Systematic Review and Meta-Analysis

Although proton pump inhibitors (PPIs) are widely used, their relative; potency and ideal dosing regimens are unclear. We used omeprazole equivalency; and the surrogate biomarker, pH4time, to compare PPI effectiveness when given once, twice, or 3 times daily.

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Hair-Collar-and-Tuft-Sign Associated with an Atretic Cephalocele and a Persistent Primitive Falcine Sinus

A male newborn was hospitalized because of an elastic nodule midline in the interparietal scalp (Figure 1, A). The lesion appeared slightly hypertrichotic, about 1 cm in diameter, overlying an erythematous stain. He was neurologically normal; ultrasound (Figure 2, A) and brain magnetic resonance imaging were performed (Figure 2, B). Imaging suggested an atretic cephalocele in the presence of a rare persistent primitive falcine sinus,1,2 associated with focal duplication of the superior sagittal sinus.

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Surgical Interventions in Infants Born Preterm with Congenital Heart Defects: An Analysis of the Kids' Inpatient Database

To evaluate short-term outcomes in infants born preterm with congenital heart defects (CHDs) and the factors associated with surgery, survival, and length of hospitalization in this population.

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Gorham-Stout Disease: Hand Involvement in an 8-Year-Old Child

A right-handed 8-year-old girl with an unremarkable medical history consulted for a painful, swollen left hand, with a large area of edema on the dorsal aspect. There were no signs of erythema, trauma, fever, or an inflammatory syndrome. A radiographic assessment revealed osteolysis of the diaphysis of the fourth metacarpal. Bone scintigraphy showed localized uptake at the fourth metacarpal. Magnetic resonance imaging displayed T1 hypointensity and T2 hyperintensity at the fourth metacarpal and the surrounding soft tissue.

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Statin-associated myopathy in pediatric settings: Myth or fact?

We read with interest the report titled Statin-Associated Myopathy in a Pediatric Preventive Cardiology Practice.1 We have collected data regarding 122 pediatric patients (median age, 12.9 years; range, 6-18) affected by heterozygous familial hypercholesterolemia without other comorbidity receiving statin therapy during a median period of observation of 29 months (range, 12-60). Laboratory values including creatine kinase were obtained at baseline and at follow-up visits (regularly every about 6 months).

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Prognostic implication of NQO1 overexpression in hepatocellular carcinoma

To explore the role of NQO1 overexpression for prognostic implication in HCC, NQO1 mRNA levels were detected in HCC fresh tissue samples of HCC and non tumor tissues, respectively. 156 cases of HCC meeting strict follow-up criteria were selected for immunohistochemical staining of NQO1 protein. Correlations between NQO1 overexpression and clinicopathological features of HCC were evaluated using Chi-square tests, survival rates were calculated using the Kaplan–Meier method, and the relationship between prognostic factors and patient 5-year survival was analyzed using Cox proportional hazard analysis.

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Safety and efficacy of early feeding based on clinical assessment at 4 hours after ERCP: a prospective randomized controlled trial

The optimal timing of refeeding after ERCP is unknown. Some practices keep fasting for 24 hours after ERCP whereas others resume feeding earlier. We aimed to evaluate the risk of post-ERCP pancreatitis (PEP) in patients who initiate early feeding based on their clinical assessment, including serum amylase testing, performed at 4 hours after ERCP.

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Self-expandable metal stent for malignant esophagorespiratory fistula: predictive factors associated with clinical failure

Malignant esophagorespiratory fistula (MERF) has been usually managed by the placement of self-expandable metal stent (SEMS) with conflicting results. This study aimed to identify risk factors associated with clinical failure after SEMS placement for the treatment of MERF.

http://ift.tt/2wXc7Cq

Bone marrow sinusoidal endothelium: damage and potential regeneration following cancer radiotherapy or chemotherapy

Abstract

It is very well known that bone marrow (BM) microvasculature may possess a crucial role in the maintenance of homeostasis of BM due to mutual interactions between BM microvascular system and other physiological functions including haematopoiesis and osteogenesis. Chemotherapy and radiotherapy are known as main approaches for cancer treatment and also are known as the main cause of damage to the BM microvascular system. However, despite the importance of BM microvasculature in orchestrating various biological functions, less attention has been drawn to address the underlying mechanisms for the damage and to explore cellular and molecular mechanisms by which the recovery/regeneration of chemotherapy- and/or radiotherapy-induced BM microvascular system damage can occur. Therefore, in this review we firstly discuss the ultra-/structure and biological characteristics of BM microvascular system (sinusoids). Secondly, potential contribution of BM sinusoids is discussed in pathophysiological circumstances (bone remodelling, haematopoiesis, cancer bone metastasis, and haematological cancers). Thirdly, we address previous preclinical and clinical studies regarding chemotherapy- and irradiation-induced BM microvasculature damage. Finally, potential cellular and molecular mechanisms are discussed for the recovery/regeneration of damaged BM microvascular system, including the potential roles of endothelial progenitor cells, haematopoietic stem/progenitor cells, and stimulation of VEGF/VEGFR and Ang-1/Tie-2 signalling pathways.

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Spotlight on recently published ICVTS articles

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Corrigendum to ‘2017 ESC/EACTS Guidelines for the management of valvular heart disease’ [Eur J Cardiothorac Surg 2017;52:616-664] †

The authors of the European Journal of Cardio-Thoracic Surgery would like to issue the following correction to the 2017 ESC/EACTS Guidelines for the management of valvular heart disease:

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Transatlantic Editorial: thoracic surgeons need recognition of competence in thoracic oncology

Thoracic oncologyEducationCompetence

http://ift.tt/2fzuE5i

2017 ESC/EACTS Guidelines for the management of valvular heart disease

GuidelinesValve diseaseValve surgeryPercutaneous valve interventionAortic regurgitationAortic stenosisMitral regurgitationMitral stenosisTricuspid regurgitationTricuspid stenosisProsthetic heart valves

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Anaortic off-pump versus clampless off-pump using the PAS-Port device versus conventional coronary artery bypass grafting: mid-term results from a matched propensity score analysis of 5422 unselected patients †

Abstract

OBJECTIVES

Meta-analyses from observational and randomized studies have demonstrated benefits of off-pump surgery for hard and surrogate endpoints. In some of them, increased re-revascularization was noted in the off-pump groups, which could impact their long-term survival. Therefore, we analyzed the course of all patients undergoing isolated coronary surgery regarding the major cardiac and cerebrovascular event (MACCE) criteria.

METHODS

A prospective register was taken from a high-volume off-pump center recording all anaortic off-pump (ANA), clampless off-pump (PAS-Port) and conventional (CONV) coronary artery bypass operations between July 2009 and June 2015. Propensity Score Matching was performed based on 28 preoperative risk variables.

RESULTS

We identified 935 triplets (N = 2805). Compared with CONV, in-hospital mortality of both the ANA group (OR for ANA [95% CI] 0.25 [0.06; 0.83], P = 0.021), and the PAS-Port group was lower (OR for PAS-Port [95% CI] 0.50 [0.17; 1.32], P = 0.17). In the mid-term follow-up there were no significant differences between the groups regarding mortality (HR for ANA [95%-CI] 0.83 [0.55–1.26], P = 0.38; HR for PAS-Port [95%-CI] 1.06 [0.70–1.59], P = 0.79), incidence of stroke (HR for ANA 0.81 [0.43–1.53], P = 0.52; HR for PAS-Port 0.78 [0.41–1.50], P = 0.46), myocardial infarction (HR for ANA 0.53 [0.22–1.31], P = 0.17; HR for PAS-Port 0.78 [0.37–1.66], P = 0.52) or re-revascularization rate (HR for ANA 0.99 [0.67–1.44], P = 0.94; HR for PAS-Port 0.95 [0.65–1.38], P = 0.77).

CONCLUSIONS

Both off-pump clampless techniques were associated with lower in-hospital mortality compared with conventional CABG. The mid-term course showed no difference with regard to the MACCE criteria between anaortic off-pump, clampless off-pump using PAS-Port and conventional CABG.

http://ift.tt/2fAANy9

Type 1a endoleak following Zone 1 and Zone 2 thoracic endovascular aortic repair: effect of bird-beak configuration †

Abstract

OBJECTIVES

Type 1a endoleak is one of the most severe complications after thoracic endovascular aortic repair (TEVAR), because it carries the risk of aortic rupture. The association between bird-beak configuration and Type 1a endoleak remains unclear. The purpose of this study was to analyse the predictors of Type 1a endoleak following Zone 1 and Zone 2 TEVAR, with a particular focus on the effect of bird-beak configuration.

METHODS

From April 2008 to July 2015, 105 patients (mean age 68.6 years) who underwent Zone 1 and 2 landing TEVAR were enrolled, with a mean follow-up period of 4.3 years. The patients were categorized into 2 groups, according to the presence (Group B, n = 32) or the absence (Group N, n = 73) of bird-beak configuration on the first postoperative multidetector computed tomography.

RESULTS

The Kaplan–Meier event-free rate curve showed that Type 1a endoleak and bird-beak progression occurred less frequently in Group N than in Group B. Five-year freedom from Type 1a endoleak rates were 79.7% and 100% for Groups B and N, respectively (P = 0.007). Multivariable logistic regression analysis showed that dissecting aortic aneurysm (odds ratio 3.72, 95% confidence interval 1.30–11.0; P = 0.014) and shorter radius of inner curvature (odds ratio 1.09, 95% confidence interval 0.85–0.99; P = 0.025) were significant risk factors for bird-beak configuration. Multivariable Cox proportional hazard regression showed that Z-type stent graft (hazard ratio 2.69, 95% confidence interval 1.11–6.51; P = 0.030) was a significant risk factor for bird-beak progression.

CONCLUSIONS

Appropriate stent grafts need to be chosen carefully to prevent Type 1a endoleak and bird-beak configuration after landing Zone 1 and 2 TEVAR. Patients with bird-beak configuration on early postoperative multidetector computed tomography require closer follow-up to screen for Type 1a endoleak.

http://ift.tt/2wkO3di

Doubly committed ventricular septal defect closure using eccentric occluder via ultraminimal incision

Abstract

OBJECTIVES

This study aimed to investigate the safety, feasibility and availability of doubly committed ventricular septal defect (DCVSD) closure via an ultraminimal intercostal incision under the guidance of transoesophageal echocardiography in children.

METHODS

From August 2014 to August 2016, 35 children with DCVSDs (≤5 mm in diameter) were enrolled in this study. A left parasternal ultraminimal intercostal incision (≤1 cm) and a pericardium hanging technique were employed without sternal incision. DCVSDs were closed through a short delivery sheath assembled with an eccentric occluder device. Transoesophageal echocardiography was used to guide and monitor the entire procedure. All patients were followed up.

RESULTS

All 35 children had complete closures with an operation success rate of 100%. The average size of DCVSDs was 3.50 ± 0.79 (range 2.2–5.0) mm, and the average device size was 5 ± 2 (range 4–9) mm. The average operation duration was 45.42 ± 11.77 (range 25–70) min, and the average hospital stay was 8 ± 2 (range 7–16) days. The median follow-up period was 17 months (range 6 months–2.5 years). Pre-existing aortic regurgitation disappeared after surgery in 1 patient and remained the same in 4 patients. No other complications were found during the operation or during follow-up.

CONCLUSIONS

Under transoesophageal echocardiography guidance, DCVSD closure using an eccentric occluder via an ultraminimal intercostal incision is feasible, safe and effective in children. The use of this approach is recommended.

http://ift.tt/2fz6ibN

Risk factors of myasthenic crisis after thymectomy for thymoma patients with myasthenia gravis †

Abstract

OBJECTIVES

Total thymectomy should be performed on thymoma patients with myasthenia gravis. The aim of the present study was to investigate the risk factors of postoperative myasthenic crisis (POMC) occurrence in these patients.

METHODS

The clinical records of 127 thymoma patients with myasthenia gravis (68 men, 59 women; median age, 50 years) who underwent total thymectomy at our institution from 2005 to 2014 were retrospectively reviewed. The following factors were analysed in relation to POMC: gender, age, duration of symptoms, bulbar symptoms, smoking history, history of myasthenic crisis, comorbidities, perioperative pyridostigmine and prednisolone therapy, spirometric and blood gas parameters, Osserman stage, operation approach, major complications, World Health Organization (WHO) histologic classification, Masaoka stage and use of immunoglobulins or plasmapheresis.

RESULTS

Thirteen patients (10%) experienced POMC and required intubation. All patients were weaned after 2–28 days (median 9 days) and were discharged. Univariate analysis revealed a correlation between POMC and Osserman-stage IIA-IV [odds ratio (OR) = 4.928, 95% confidence interval (CI) = 1.286–18.882, P = 0.01], bulbar symptoms (OR = 3.828, 95% CI = 1.112–13.176, P = 0.04), and forced expiratory volume in one second <70% pred forced expiratory volume in one second (OR = 4.856, 95% CI = 1.380–17.081, P = 0.02). In addition, more frequent POMC occurred in WHO type B2-B3 than in type A-B1 thymomas (OR = 8.118, 95% CI = 1.020–64.590, P = 0.03). Multivariate logistic regression analysis showed that WHO histologic classification B2-B3 (OR = 10.041, 95% CI = 1.228–82.090, P = 0.03) and Osserman-stage IIA-IV (OR = 5.953, 95% CI = 1.506–23.538, P = 0.01) independently predicted POMC.

CONCLUSIONS

Osserman stage (IIA-IV) and WHO type B2-B3 thymomas are independent predictors of POMC in thymoma patients with myasthenia gravis who have undergone total thymectomy. Thus, adequate perioperative care should be provided to these patients.

http://ift.tt/2wWIoOI

Early and late outcomes after surgical repair of congenital supravalvular aortic stenosis: a European Congenital Heart Surgeons Association multicentric study †

Abstract

OBJECTIVES

Our goal was to evaluate the early and late results of the surgical management of congenital supravalvular aortic stenosis (SVAS).

METHODS

We performed a retrospective, multicentre study using data from the European Congenital Heart Surgeons Association. Exclusion criteria were age >18 years, operation before 1990 and redo supravalvular aortic stenosis operations. Multivariate Cox regression analysis was performed to detect independent predictors of adverse events.

RESULTS

Of a total of 301 patients (male/female = 194/107; median age 3.9 years, range 13 days–17.9 years), 17.6% had a prior surgical or interventional procedure. Pulmonary artery stenosis was present in 41.5% and coronary anomalies in 13.6%. The operation consisted of a single patch repair in 36.7%, a pantaloon-shaped patch in 36.7%, a 3-patch technique in 14.3% and other techniques in 11.7%. Postoperative complications occurred in 14.9%, and the early mortality rate was 5%. At a median follow-up of 13 years (interquartile range 3.5–7.8; follow-up completed 79.1%), there were 10 late deaths (4.2%). A surgical reoperation or an interventional cardiology procedure occurred in 12.6% and 7.2%, respectively. No significant differences in outcomes between the techniques were found. Age at repair <12 months and pulmonary artery stenosis were associated with an increased risk of early (P = 0.0001) and overall mortality (P = 0.025), respectively. Having an operation after 2005 and co-existing pulmonary artery stenosis were significant predictors of late reintervention (P = 0.0110 and P = 0.001, respectively).

CONCLUSIONS

Surgical repair of congenital stenosis is an effective procedure with acceptable surgical risk and good late survival, but late morbidity is not negligible, especially in infants and when associated pulmonary artery stenosis is present.

http://ift.tt/2yHwwgN

The aspartate transaminase/alanine transaminase (DeRitis) ratio predicts mid-term mortality and renal and respiratory dysfunction after left ventricular assist device implantation

Abstract

OBJECTIVES

Preoperative liver dysfunction is a well-known risk factor for adverse events after major surgery. However, there is only little data regarding the precise role of the Model of End-Stage Liver Disease (MELD) score and the De Ritis ratio (DRR, alanine transaminase/aspartate aminotransferase) as a predictor for outcome after left ventricular assist device (LVAD) implantation.

METHODS

A retrospective analysis of all patients undergoing LVAD implantation at our institution between January 2012 and August 2014 was performed. The primary outcome was survival at 180 days after surgery.

RESULTS

During the observation period, 63 patients underwent LVAD implantation (mean age 59.9 ± 8.3 years, 50% male). Mean preoperative ejection fraction was 16.3 ± 7.7, 13 patients required preoperative renal replacement therapy and 9 patients were on extracorporeal life support. Mean Interagency Registry for Mechanically Assisted Circulatory Support level was 2.8 ± 1.3, mean preoperative MELD was 12.7 ± 7.2, mean preoperative DRR was 2.01 ± 4.4. Aspartate aminotransferase (102 ± 220.8 vs 57.8 ± 123.4 U/l, P = 0.041), MELD score (16.1 ± 8.8 vs 11.4 ± 6.1, P = 0.017) and DRR (4.2 ± 7.8 vs 1.1 ± 1.1, P = 0.001) were significantly higher in non-survivors than in survivors after 180 days. Using logistic regression analyses, a DRR >1.37 was an independent predictor for 30-day mortality [odds ratio (OR) 4.5] and 180-day mortality (OR 4.1). In addition, the DRR was associated with postoperative acute kidney injury with need for renal replacement therapy (OR 4.2) and prolonged postoperative ventilation time >72 h (OR 3.8). Using receiver operator characteristics analyses, DRR showed a sensitivity of 0.80 and a specificity of 0.81 (area under the curve 0.834, cut-off 1.37) for 180-day mortality.

CONCLUSIONS

The DRR is predictive of early and mid-term mortality as well as relevant morbidities in patients undergoing LVAD implantation. Therefore, the DRR should be considered within the preoperative risk stratification and patient selection for LVAD implantation.

http://ift.tt/2wUE0jw

Pectus excavatum repair after sternotomy: the Chest Wall International Group experience with substernal Nuss bars

Abstract

OBJECTIVES

Patients with pectus excavatum (PE) after prior sternotomy for cardiac surgery present unique challenges for repair of PE. Open repairs have been recommended because of concerns about sternal adhesions and cardiac injury. We report a multi-institutional experience with repair utilizing substernal Nuss bars in this patient population.

METHODS

Surgeons from the Chest Wall International Group were queried for experience and retrospective data on PE repair using sub-sternal Nuss bars in patients with a history of median sternotomy for cardiac surgery (November 2000 to August 2015). A descriptive analysis was performed.

RESULTS

Data for 75 patients were available from 14 centres. The median age at PE repair was 9.5 years (interquartile range 10.9), and the median Haller index was 3.9 (interquartile range 1.43); 56% of the patients were men. The median time to PE repair was 6.4 years (interquartile range 7.886) after prior cardiac surgery. Twelve patients (16%) required resternotomy before support bar placement: 7 pre-emptively and 5 emergently. Sternal elevation before bar placement was used in 34 patients (45%) and thoracoscopy in 67 patients (89%). Standby with cardiopulmonary bypass was available at 9 centres (64%). Inadvertent cardiac injury occurred in 5 cases (7%) without mortality.

CONCLUSIONS

Over a broad range of institutions, substernal Nuss bars were used in PE repair for patients with a history of sternotomy for cardiac surgery. Several technique modifications were reported and may have facilitated repair. Cardiac injury occurred in 7% of cases, and appropriate resources should be available in the event of complications. Prophylactic resternotomy was reported at a minority of centres.

http://ift.tt/2yIHzGH

European prospective multicentre study of hybrid thoracoscopic and transcatheter ablation of persistent atrial fibrillation: the HISTORIC-AF trial †

Abstract

OBJECTIVES

The HISTORIC-AF trial is a prospective, multicentre, single-arm study designed to evaluate the outcomes of a staged endoscopic and transcatheter ablation in patients with stand-alone, persistent or long-standing persistent atrial fibrillation (AF).

METHODS

From 2012 to 2015, 100 consecutive patients were enrolled and underwent thoracoscopic left atrial epicardial isolation ('box lesion') followed by transcatheter ablation in case of AF recurrency. The safety end point was the composite outcome of freedom from major adverse events at 30-days, while efficacy end points were: (i) primary: freedom from AF and stable sinus rhythm following isolated thoracospic ablation >60% and (ii) secondary: freedom from AF and stable sinus rhythm >80% following hybrid ablation (as per HRS criteria).

RESULTS

No death occurred and surgical thoracoscopic procedure was successfully completed in all patients. Survival free from major adverse events at 30 days was 94%: there were 3 permanent pacemaker implants, 2 episodes of stroke and 1 revision for bleeding. At discharge, 87% of patients were in sinus rhythm. A staged transcatheter ablation was carried out in all patients with AF recurrences at the end of 3 months blanking period (17% of patients). At 12-months follow-up, a stable restoration of sinus rhythm was achieved in 75% and 88% of patients following isolated thoracoscopic ablation and hybrid ablation, respectively.

CONCLUSIONS

The HISTORIC-AF trial showed that thoracoscopic isolated surgical ablation reached both the safety and the efficacy end points. Hybrid ablation steadily improved rhythm outcomes and may be considered in the future as the treatment of choice for patients with persistent and long-standing persistent AF.

ClinicalTrials.gov Identifier

NCT01622907.

http://ift.tt/2wWAAg7

MitraClip removal: surgical techniques to preserve native mitral valve leaflets

Abstract

Transcatheter valve procedures are wide-spreading techniques for the treatment of heart valves pathologies. In case of implantation failure, the transcatheter device often needs to be removed. This procedure, which can alter the biological structure integrity, can limit the option available for the subsequent traditional surgery. One of the most popular devices for transcatheter mitral valve repair is the MitraClip system. In this work, we describe 2 different techniques for the surgical removal of MitraClip. These techniques aim to preserve the valve leaflets integrity, to allow for subsequent mitral valve surgical repair.

http://ift.tt/2yIYmt0

Mitral valve repair using a prosthetic ring with chordal sizing system: a modified technique in the presence of myxomatous leaflets

Abstract

A semi-rigid complete ring including a chordal sizing system has been introduced with the aim of standardizing neochordae implantation. Instructions for use of this ring suggest to pass the neochordae through the free margin of mitral leaflets. We introduce a modification of this technique in the presence of myxomatous leaflets.

http://ift.tt/2wVmdbH

Exhaustive preoperative staging increases survival in resected adrenal oligometastatic non-small-cell lung cancer: a multicentre study †

Abstract

OBJECTIVES

Adrenal oligometastatic non-small-cell lung cancer is rare, and surgical management remains controversial.

METHODS

We performed a multicentre, retrospective study from January 2004 to December 2014. The main objective was to evaluate survival in patients who had undergone adrenalectomy after resection of primary lung cancer. Secondary objectives were to determine prognostic, survival and recurrence factors.

RESULTS

Fifty-nine patients were included. Forty-six patients (78%) were men. The median age was 58 years [39–75 years]. Twenty-six cases (44%) showed synchronous presentation, and 33 cases (56%) had a metachronous presentation. The median time to onset of metastasis was 18.3 months [6–105 months]. The 5-year overall survival rate was 59%; the median survival time was 77 months [0.6–123 months]. A recurrence was observed in 70% of the population. Mediastinal lymph node invasion (P = 0.035) is a detrimental prognostic factor of survival.

CONCLUSIONS

After exhaustive staging, patients with adrenal oligometastatic non-small-cell lung cancer benefit from bifocal surgery.

http://ift.tt/2yIYdps

A novel strategy to initiate a peroral endoscopic myotomy program †

Abstract

OBJECTIVES

The standard of care for achalasia remains laparoscopic Heller myotomy with partial fundoplication. Peroral endoscopic myotomy (POEM) has been introduced as an alternative, but safety and long-term comparative efficacy are not yet established. We report our experience in developing a POEM program using a novel hybrid approach.

METHODS

We developed a hybrid approach to POEM with a POEM followed by laparoscopic evaluation, extension of the myotomy, if necessary, and partial fundoplication. We reviewed the results of the programme from April 2012 until May 2015. Starting in 2014, we began offering patients stand-alone POEM. Patient data were collected. Preoperative and postoperative Eckardt scores were compared.

RESULTS

A total of 28 patients underwent POEM or POEM plus laparoscopic evaluation with partial fundoplication. Patient characteristics and perioperative and postoperative data were recorded. The median preoperative Eckardt score was 6 (range 4–11). The mean follow-up period was 136 days (range 41–330) and the median postoperative Eckardt score was 0 (range 0–6) at 6 weeks. Of our initial 10 patients, 6 required laparoscopic extension of the myotomy; 7 subsequent patients did not require an additional myotomy. Three patients who underwent POEM without laparoscopy continued to have dysphagia postoperatively. One patient had an attempted POEM that was aborted secondary to bleeding, and a standard laparoscopic modified Heller myotomy with partial fundoplication was performed.

CONCLUSIONS

The excellent results of laparoscopic myotomy with partial fundoplication are challenging to duplicate during the initial adoption of a POEM approach. We present a program developed to steepen the learning curve and enhance patient safety while implementing this new procedure.

http://ift.tt/2wVkEe1

Pulmonary resection for patients with multidrug-resistant tuberculosis based on survival outcomes: a systematic review and meta-analysis

Summary

We investigated the survival benefit of pulmonary resection for patients with multidrug-resistant tuberculosis. To weigh the survival benefit of pulmonary resection for patients with multidrug-resistant tuberculosis who have undergone surgical treatment combined with medical chemotherapy compared with medical chemotherapy alone, we did a meta-analysis of available studies containing a hazard ratio for pulmonary resection. Among 1726 articles, 6 clinical reports, with a mean sample size of 47 patients per report, met the inclusion criteria. The pooled hazard ratio of 0.68 with a 95% confidence interval of approximately 0.44–1.07 suggested that the survival benefit of surgical pulmonary resection combined with chemotherapy, in a comparison of the groups 'with surgery' and 'without surgery', is not significantly greater than that of chemotherapy alone. Selection bias, due to the absence of rigid predetermined indications for pulmonary resection, limited the validity of this analysis. Due to the heterogeneity of the patient groups, greater attention is required to compute additional hazard ratios in future studies with stratification of factors such as cardiopulmonary functions, disease extent and the presence of a cavity. These additional computations in future studies are necessary to determine the survival benefit and to support the rigid surgical indications.

http://ift.tt/2yHw9D0

Is the frozen elephant trunk procedure superior to the conventional elephant trunk procedure for completion of the second stage? †

Abstract

OBJECTIVES

Our goal was to compare the results and outcomes of second-stage completion in patients who had previously undergone the elephant trunk (ET) or the frozen elephant trunk (FET) procedure for the treatment of complex aortic arch and descending aortic disease.

METHODS

Between August 2001 and December 2014, 53 patients [mean age 61 ± 13 years, 64% (n = 34) male] underwent a second-stage completion procedure. Of these patients, 32% (n = 17) had a previous ET procedure and 68% (n = 36) a previous FET procedure as a first-stage procedure.

RESULTS

The median times to the second-stage procedure were 7 (0–78) months in the ET group and 8 (0–66) months in the FET group. The second-stage procedure included thoracic endovascular aortic repair in 53% (n = 28) of patients and open surgical repair in 47% (n = 25). More endovascular interventions were performed in FET patients (61%, n = 22) than in the ET group (35%, n = 6, P = 0.117). The in-hospital mortality rate was significantly lower in the FET (8%, n = 3) group compared with the ET group (29%, n = 5, P = 0.045). The median follow-up time after the second-stage operation for the entire cohort was 4.6 (0.4–10.4) years. The 5-year survival rate was 76% in the ET patients versus 89% in the FET patients (log-rank: P = 0.11).

CONCLUSIONS

We observed a significantly lower in-hospital mortality rate in the FET group compared to the ET group. This result might be explained by the higher rate of endovascular completion in the FET group. We assume that the FET procedure offers the benefit of a more ideal landing zone, thus facilitating endovascular completion.

http://ift.tt/2wXwUum

Cannabis increased the risk of primary spontaneous pneumothorax in tobacco smokers: a case–control study

Abstract

OBJECTIVES

Previous smaller case series suggested that cannabis smoking may cause spontaneous pneumothorax, but this finding remains controversial. We investigated the possible association between smoking tobacco and cannabis and the risk of having a primary spontaneous pneumothorax in a large, homogeneous cohort of young, healthy individuals.

METHODS

In a case–control study, we prospectively investigated young (≤40 years) patients admitted in Western Denmark from 2009 to 2016 with their first episode of primary spontaneous pneumothorax. Baseline characteristics and smoking habits including both tobacco and cannabis were obtained from questionnaires presented on admittance. We compared our findings with those of a population-based control group matched by age, sex and geographical area. Calculated odds ratios were compared using the Fisher's exact test for small frequencies and the χ² test or the Mann–Whitney test for larger frequencies.

RESULTS

A total of 416 patients participated (male/female ratio = 3.9). We observed a significantly increased risk of primary spontaneous pneumothorax in daily smokers compared with female never smokers (odds ratio = 8.10, 95% confidence interval: 4.61–14.14, P < 0.001) and male never smokers (odds ratio = 4.85, 95% confidence interval: 3.23–7.19, P < 0.001). The combination of smoking both cannabis and tobacco in men increased the risk of spontaneous pneumothorax significantly (odds ratio = 8.74, 95% confidence interval: 4.30–19.51, P < 0.001). In contrast, the cannabis habits of female patients did not differ from those of the Danish population in general.

CONCLUSIONS

Combined smoking of tobacco and cannabis significantly aggravates the risk of having a primary spontaneous pneumothorax in young men compared to both never smokers and daily smokers.

http://ift.tt/2yHwaH4

Reliability of axillary artery cannulation

Aortic arch surgery Axillary cannulation Aberrant right subclavian artery

http://ift.tt/2wVrLTJ

Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

Objectives: To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. Design: Prospective laboratory animal investigation. Setting: Animal research laboratory. Subjects: Newborn and 3 days to 1 week old pigs. Interventions: Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload. Measurements and Main Results: Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor. Conclusions: Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2fSih0S

Diagnostic Accuracy of Point-of-Care Ultrasound Performed by Pulmonary Critical Care Physicians for Right Ventricle Assessment in Patients With Acute Pulmonary Embolism.

Objectives: Risk stratification for acute pulmonary embolism using imaging presence of right ventricular dysfunction is essential for triage; however, comprehensive transthoracic echocardiography has limited availability. We assessed the accuracy and timeliness of Pulmonary Critical Care Medicine Fellow's performance of goal-directed echocardiograms and intensivists' interpretations for evaluating right ventricular dysfunction in acute pulmonary embolism. Design: Prospective observational study and retrospective chart review. Setting: Four hundred fifty bed urban teaching hospital. Patients: Adult in/outpatients diagnosed with acute pulmonary embolism. Interventions: Pulmonary critical care fellows performed and documented their goal-directed echocardiogram as normal or abnormal for right ventricular size and function in patients with acute pulmonary embolism. Gold standard transthoracic echocardiography was performed on schedule unless the goal-directed echocardiogram showed critical findings. Attending intensivists blinded to the clinical scenario reviewed these exams at a later date. Measurements and Main Results: Two hundred eighty-seven consecutive patients were evaluated for acute PE. Pulmonary Critical Care Medicine Fellows performed 154 goal-directed echocardiograms, 110 with complete cardiology-reviewed transthoracic echocardiography within 48 hours for comparison. Pulmonary Critical Care Medicine Fellow's area under the curve for size and function was 0.83 (95% CI, 0.75-0.90) and 0.83 (95% CI, 0.75-0.90), respectively. Intensivists' 1/2 area under the curve for size and function was (1) 0.87 (95% CI, 0.82-0.94), (1) 0.87 (95% CI, 0.80-0.93) and (2) 0.88 (95% CI, 0.82-0.95), (2) 0.88 (95% CI, 0.82-0.95). Median time difference between goal-directed echocardiogram and transthoracic echocardiography was 21 hours 18 minutes. Conclusions: This is the first study to evaluate pulmonary critical care fellows' and intensivists' use of goal-directed echocardiography in diagnosing right ventricular dysfunction in acute pulmonary embolism. Pulmonary Critical Care Medicine Fellows and intensivists made a timely and accurate assessment. Screening for right ventricular dysfunction using goal-directed echocardiography can and should be performed by pulmonary critical care physicians in patients with acute pulmonary embolism. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2xxMOLF