Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations ...of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.
This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of ...autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting.
To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy.
Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses.
Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited.
Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of ...CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A 34-year-old white woman who was 30 weeks’ pregnant initially presented to her primary care physician with a cough for which she was given antibiotics, but she had persistent symptoms. These were ...followed by chest pain, as a result of which she was referred to our department. She had a past medical history of hypertension, and currently was in her sixth pregnancy, with no reported complications in the previous pregnancies. Review of systems was otherwise negative. She had a three-pack-year smoking history, but denied smoking during her current pregnancy.
Water permeable porosities and thermal conductivity of ceramic construction materials have been experimentally determined in this work. The samples were selected so as to obtain a wide variation in ...their apparent porosity. To study the influence of porosity on thermal conductivity, thermal conductivities of all the samples were measured in oven dried and water saturated conditions. A model relating porosity with thermal conductivity of these materials is proposed. In the model, two types of pores are hypothesized, namely; enclosed pores and enclosing pores. The three-dimensional steady-state heat transfer through unit cells containing each of the two types of pores, is solved to evaluate their effective thermal conductivity. By using the law of mixture for the random distribution of the type of pores, an equation combining the conductivities of the two cells is framed to get overall effective thermal conductivity of the material, in both dry and saturated states. The experimentally determined values of thermal conductivities reported in literature for some bricks are then compared with those predicted through this model.
Celotno besedilo
Dostopno za:
DOBA, FGGLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objectives: Use of off-label tissue graft materials, such as acellular dermal matrix (ADM), for in utero repair of severe spina bifida (SB), where primary skin layer closure is not possible, is ...associated with poor neurological outcomes. The cryopreserved human umbilical cord (HUC) patch has regenerative, anti-inflammatory, and anti-scarring properties, and provides watertight SB repair. We tested the hypothesis that the HUC is a superior skin patch to ADM for reducing inflammation at the repair site and preserving spinal cord function. Methods: In timed-pregnant ewes with twins, on gestational day (GD) 75, spina bifida was created without a myelotomy (functional model). On GD 95, repair was performed using HUC vs. ADM patches (randomly assigned) by suturing them to the skin edges. Additionally, full thickness skin closure as a primary skin closure (PSC) served as a positive control. Delivery was performed on GD 140, followed by blinded to treatment neurological assessments of the lambs using the Texas Spinal Cord Injury Scale (TSCIS) for gait, proprioception, and nociception. Lambs without spina bifida were used as controls (CTL). Ex vivo magnetic resonance imaging of spines at the repair site were performed, followed by quantitative pathological assessments. Histological assessments (blinded) included Masson’s trichrome, and immunofluorescence for myeloperoxidase (MPO; neutrophils) and for reactive astrocytes (inflammation) by co-staining vimentin and GFAP. Results: The combined hind limbs’ TSCIS was significantly higher in the HUC group than in ADM and PSC groups, p = 0.007. Both ADM and PSC groups exhibited loss of proprioception and mild to moderate ataxia compared to controls. MRI showed increased pathological findings in the PSC group when compared to the HUC group, p = 0.045. Histologically, the meningeal layer was thickened (inflammation) by 2–3 fold in ADM and PSC groups when compared to HUC and CTL groups, p = 0.01. There was lower MPO positive cells in the HUC group than in the ADM group, p = 0.018. Posterior column astrocyte activation was increased in ADM and PSC lambs compared to HUC lambs, p = 0.03. Conclusion: The HUC as a skin patch for in utero spina bifida repair preserves spinal cord function by reducing underlying inflammation when compared to ADM.
A model is presented in this work through which variation of hydraulic diffusivity of concrete with relative water content can be obtained from pore size distribution as an input. The specific water ...capacity and hydraulic conductivity of concrete are expressed in terms of pore size characteristics, considering laminar flow due to capillary suction through tortuous elliptic tubes, oriented equally in three orthogonal directions. Hydraulic diffusivity being the ratio of hydraulic conductivity and specific water capacity is thus expressed in terms of pore size characteristics. The input pore size distributions have been determined experimentally for normal strength concrete mixes through mercury intrusion porosimetry. Using the model the variation of hydraulic diffusivity with relative water content is determined for three cases viz. 1) ideal continuous wetting, 2) ideal continuous drying and 3) random access of pores by water. These results are then compared with an experimentally obtained variation.
This paper presents an overlay architecture where service providers deploy a set of service nodes (called MSNs) in the network to efficiently implement media-streaming applications. These MSNs are ...organized into an overlay and act as application-layer multicast forwarding entities for a set of clients. We present a decentralized scheme that organizes the MSNs into an appropriate overlay structure that is particularly beneficial for real-time applications. We formulate our optimization criterion as a "degree-constrained minimum average-latency problem" which is known to be NP-hard. A key feature of this formulation is that it gives a dynamic priority to different MSNs based on the size of its service set. Our proposed approach iteratively modifies the overlay tree using localized transformations to adapt with changing distribution of MSNs, clients, as well as network conditions. We show that a centralized greedy approach to this problem does not perform quite as well, while our distributed iterative scheme efficiently converges to near-optimal solutions.
We introduce and analyze a scalable rekeying scheme for implementing secure group communications Internet protocol multicast. We show that our scheme incurs constant processing, message, and storage ...overhead for a rekey operation when a single member joins or leaves the group, and logarithmic overhead for bulk simultaneous changes to the group membership. These bounds hold even when group dynamics are not known a priori. Our rekeying algorithm requires a particular clustering of the members of the secure multicast group. We describe a protocol to achieve such clustering and show that it is feasible to efficiently cluster members over realistic Internet-like topologies. We evaluate the overhead of our own rekeying scheme and also of previously published schemes via simulation over an Internet topology map containing over 280 000 routers. Through analysis and detailed simulations, we show that this rekeying scheme performs better than previous schemes for a single change to group membership. Further, for bulk group changes, our algorithm outperforms all previously known schemes by several orders of magnitude in terms of actual bandwidth usage, processing costs, and storage requirements.
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