Spatial characterization of interictal high frequency oscillations in epileptic neocortex

Interictal high frequency oscillations (HFOs), in particular those with frequency components in excess of 200 Hz, have been proposed as important biomarkers of epileptic cortex as well as the genesis of seizures. We investigated the spatial extent, classification and distribution of HFOs using a dense 4 × 4 mm2 two dimensional microelectrode array implanted in the neocortex of four patients undergoing epilepsy surgery. The majority (97%) of oscillations detected included fast ripples and were concentrated in relatively few recording sites. While most HFOs were limited to single channels, ∼10% occurred on a larger spatial scale with simultaneous but morphologically distinct detections in multiple channels. Eighty per cent of these large-scale events were associated with interictal epileptiform discharges. We propose that large-scale HFOs, rather than the more frequent highly focal events, are the substrates of the HFOs detected by clinical depth electrodes. This feature was prominent in three patients but rarely seen in only one patient recorded outside epileptogenic cortex. Additionally, we found that HFOs were commonly associated with widespread interictal epileptiform discharges but not with locally generated ‘microdischarges’. Our observations raise the possibility that, rather than being initiators of epileptiform activity, fast ripples may be markers of a secondary local response

Placenta increta causing hemoperitoneum in the 26th week of pregnancy: a case report

Abstract Introduction Placenta increta is a serious complication of pregnancy. We describe a case leading to uterine rupture associated with massive intra-abdominal hemorrhage. Case presentation A 34-year-old Caucasian Albanian woman, gravida 2, para 1, was admitted to the emergency department of our hospital for acute abdominal pain associated with profound secondary anemia. An anatomopathological diagnosis of placenta increta destruens was made. An urgent hysterectomy was performed after resuscitation procedures, applied due to the severe anemia and the abdominal drama accompanying the case. Intra-operatively, a uterus-saving procedure was found to be impossible, and hysterectomy remained the only surgical option. The uterine structures were sent for further microscopic evaluation. On histological examination, deep trophoblastic infiltration of the uterine wall was observed, justifying the surgeon's decision. Our patient received blood transfusions and antibiotics. Her sutures were removed on the eighth postoperative day and she was discharged the following day in a stable condition. Conclusion This case, describing a patient with uterine rupture and massive hemorrhage, illustrates a serious and potentially fatal complication of placenta previa. In such cases, surgery is essential, and hysterectomy may be the only viable option.</p

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Tracking and coordinating an international curation effort for the CCDS Project

The Consensus Coding Sequence (CCDS) collaboration involves curators at multiple centers with a goal of producing a conservative set of high quality, protein-coding region annotations for the human and mouse reference genome assemblies. The CCDS data set reflects a ‘gold standard’ definition of best supported protein annotations, and corresponding genes, which pass a standard series of quality assurance checks and are supported by manual curation. This data set supports use of genome annotation information by human and mouse researchers for effective experimental design, analysis and interpretation. The CCDS project consists of analysis of automated whole-genome annotation builds to identify identical CDS annotations, quality assurance testing and manual curation support. Identical CDS annotations are tracked with a CCDS identifier (ID) and any future change to the annotated CDS structure must be agreed upon by the collaborating members. CCDS curation guidelines were developed to address some aspects of curation in order to improve initial annotation consistency and to reduce time spent in discussing proposed annotation updates. Here, we present the current status of the CCDS database and details on our procedures to track and coordinate our efforts. We also present the relevant background and reasoning behind the curation standards that we have developed for CCDS database treatment of transcripts that are nonsense-mediated decay (NMD) candidates, for transcripts containing upstream open reading frames, for identifying the most likely translation start codons and for the annotation of readthrough transcripts. Examples are provided to illustrate the application of these guidelines

Genotype and Cardiovascular Phenotype Correlations With TBX1 in 1,022 Velo-Cardio-Facial/Digeorge/22q11.2 Deletion Syndrome Patients

Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype-enrichment groups. Nine common SNPs (minor allele frequency, MAF \u3e 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome

Reach and grasp by people with tetraplegia using a neurally controlled robotic arm

Paralysis following spinal cord injury (SCI), brainstem stroke, amyotrophic lateral sclerosis (ALS) and other disorders can disconnect the brain from the body, eliminating the ability to carry out volitional movements. A neural interface system (NIS)1–5 could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with longstanding tetraplegia can use an NIS to move and click a computer cursor and to control physical devices6–8. Able-bodied monkeys have used an NIS to control a robotic arm9, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here, we demonstrate the ability of two people with long-standing tetraplegia to use NIS-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor five years earlier, also used a robotic arm to drink coffee from a bottle. While robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after CNS injury, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals

The Consensus Coding Sequence (Ccds) Project: Identifying a Common Protein-Coding Gene Set for the Human and Mouse Genomes

Effective use of the human and mouse genomes requires reliable identification of genes and their products. Although multiple public resources provide annotation, different methods are used that can result in similar but not identical representation of genes, transcripts, and proteins. The collaborative consensus coding sequence (CCDS) project tracks identical protein annotations on the reference mouse and human genomes with a stable identifier (CCDS ID), and ensures that they are consistently represented on the NCBI, Ensembl, and UCSC Genome Browsers. Importantly, the project coordinates on manually reviewing inconsistent protein annotations between sites, as well as annotations for which new evidence suggests a revision is needed, to progressively converge on a complete protein-coding set for the human and mouse reference genomes, while maintaining a high standard of reliability and biological accuracy. To date, the project has identified 20,159 human and 17,707 mouse consensus coding regions from 17,052 human and 16,893 mouse genes. Three evaluation methods indicate that the entries in the CCDS set are highly likely to represent real proteins, more so than annotations from contributing groups not included in CCDS. The CCDS database thus centralizes the function of identifying well-supported, identically-annotated, protein-coding regions.National Human Genome Research Institute (U.S.) (Grant number 1U54HG004555-01)Wellcome Trust (London, England) (Grant number WT062023)Wellcome Trust (London, England) (Grant number WT077198

Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (gt;99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMOdependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness

Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously