309 research outputs found
COVID-19-Associated Bifacial Weakness with Paresthesia Subtype of Guillain-Barré Syndrome
We report a case of bifacial weakness with paresthesia, a recognized Guillain-Barré syndrome subtype characterized by rapidly progressive facial weakness and paresthesia without ataxia or other cranial neuropathies, which was temporally associated with antecedent coronavirus 2019 (COVID-19). This case highlights a potentially novel but critically important neurologic association of the COVID-19 disease process. Herein, we detail the clinicoradiologic work-up and diagnosis, clinical course, and multidisciplinary medical management of this patient with COVID-19. This case is illustrative of the increasingly recognized but potentially underreported neurologic manifestations of COVID-19, which must be considered and further investigated in this pandemic disease
Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling
Fibrin is the major extracellular component of blood clots and a proteinaceous hydrogel used as a versatile biomaterial. Fibrin forms branched networks built of laterally associated double-stranded protofibrils. This multiscale hierarchical structure is crucial for the extraordinary mechanical resilience of blood clots, yet the structural basis of clot mechanical properties remains largely unclear due, in part, to the unresolved molecular packing of fibrin fibers. Here the packing structure of fibrin fibers is quantitatively assessed by combining Small Angle X-ray Scattering (SAXS) measurements of fibrin reconstituted under a wide range of conditions with computational molecular modeling of fibrin protofibrils. The number, positions, and intensities of the Bragg peaks observed in the SAXS experiments were reproduced computationally based on the all-atom molecular structure of reconstructed fibrin protofibrils. Specifically, the model correctly predicts the intensities of the reflections of the 22.5 nm axial repeat, corresponding to the half-staggered longitudinal arrangement of fibrin molecules. In addition, the SAXS measurements showed that protofibrils within fibrin fibers have a partially ordered lateral arrangement with a characteristic transverse repeat distance of 13 nm, irrespective of the fiber thickness. These findings provide fundamental insights into the molecular structure of fibrin clots that underlies their biological and physical properties. This journal i
Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.
OBJECTIVE: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN: We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1ÎČ and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION: Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1ÎČ-targeting therapies upstream of IL-23
Clonal transitions and phenotypic evolution in Barrett esophagus
BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE
Determining Risk for Severe Leptospirosis by Molecular Analysis of Environmental Surface Waters for Pathogenic Leptospira
BACKGROUND: Although previous data indicate that the overall incidence of human leptospirosis in the Peruvian Amazon is similar in urban and rural sites, severe leptospirosis has been observed only in the urban context. As a potential explanation for this epidemiological observation, we tested the hypothesis that concentrations of more virulent Leptospira would be higher in urban than in rural environmental surface waters. METHODS AND FINDINGS: A quantitative real-time PCR assay was used to compare levels of Leptospira in urban and rural environmental surface waters in sites in the Peruvian Amazon region of Iquitos. Molecular taxonomic analysis of a 1,200-bp segment of the leptospiral 16S ribosomal RNA gene was used to identify Leptospira to the species level. Pathogenic Leptospira species were found only in urban slum water sources (Fisher's exact test; p = 0.013). The concentration of pathogen-related Leptospira was higher in urban than rural water sources (~10(3) leptospires/ml versus 0.5 Ă 10(2) leptospires/ml; F = 8.406, p < 0.05). Identical 16S rRNA gene sequences from Leptospira interrogans serovar Icterohaemorrhagiae were found in urban slum market area gutter water and in human isolates, suggesting a specific mode of transmission from rats to humans. In a prospective, population-based study of patients presenting with acute febrile illness, isolation of L. interrogans-related leptospires from humans was significantly associated with urban acquisition (75% of urban isolates); human isolates of other leptospiral species were associated with rural acquisition (78% of rural isolates) (chi-square analysis; p < 0.01). This distribution of human leptospiral isolates mirrored the distribution of leptospiral 16S ribosomal gene sequences in urban and rural water sources. CONCLUSIONS: Our findings data support the hypothesis that urban severe leptospirosis in the Peruvian Amazon is associated with higher concentrations of more pathogenic leptospires at sites of exposure and transmission. This combined quantitative and molecular taxonomical risk assessment of environmental surface waters is globally applicable for assessing risk for leptospiral infection and severe disease in leptospirosis-endemic regions
Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115
BACKGROUND & AIMS: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model.METHODS AND RESULTS: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity.CONCLUSIONS: Our data suggest that the hyperchole-sterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.</p
PEARLS: Low Stellar Density Galaxies in the El Gordo Cluster Observed with JWST
A full understanding of how unusually large "Ultra Diffuse Galaxies" (UDGs)
fit into our conventional understanding of dwarf galaxies remains elusive,
despite the large number of objects identified locally. A natural extension of
UDG research is the study of similar galaxies at higher redshift to establish
how their properties may evolve over time. However, this has been a challenging
task given how severely systematic effects and cosmological surface brightness
dimming inhibit our ability to study low-surface brightness galaxies at
high-. Here, we present an identification of low stellar surface density
galaxies (LDGs), likely the progenitors of local UDGs, at moderate redshift
with deep near-IR observations of the El Gordo cluster at with JWST.
By stacking 8 NIRCAM filters, we are able to achieve an apparent surface
brightness sensitivity of mag arcsec, faint enough to be
complete to the bright end of the LDG population. Our analysis identifies
significant differences between this population and local UDGs, such as their
color and size distributions, which suggest that UDG progenitors are bluer and
more extended at high- than at . This suggests that multiple
mechanisms are responsible for UDG formation and that prolonged transformation
of cluster dwarfs is not a primary UDG formation mechanism at high-.
Furthermore, we find a slight overabundance of LDGs in El Gordo, and, in
contrast to findings in local clusters, our analysis does not show a deficit of
LDGs in the center of El Gordo, implying that tidal destruction of LDGs is
significant between and .Comment: Resubmitted to ApJ after minor revision
Effective peer-to-peer support for young people with end-stage renal disease: a mixed methods evaluation of Camp COOL
__Abstract__
__Background__ The Camp COOL programme aims to help young Dutch people with end-stage renal disease
(ESRD) develop self-management skills. Fellow patients already treated in adult care
(hereafter referred to as âbuddiesâ) organise the day-to-day program, run the camp, counsel
the attendees, and also participate in the activities. The attendees are young people who still
have to transfer to adult care. This study aimed to explore the effects of this specific form of
peer-to-peer support on the self-management of young people (16â25 years) with ESRD who
participated in Camp COOL (CC) (hereafter referred to as âparticipantsâ).
__Methods__ A mixed methods research design was employed. Semi-structured interviews (n = 19) with
initiators/staff, participants, and healthcare professionals were conducted. These were
combined with retrospective and pre-post surveys among participants (n = 62), and
observations during two camp weeks.
__Results__ Self-reported effects of participants were: increased self-confidence, more disease-related
knowledge, feeling capable of being more responsible and open towards others, and daring to
stand up for yourself. According to participants, being a buddy or having one positively
affected them. Self-efficacy of attendees and independence of buddies increased, while
attendeesâ sense of social inclusion decreased (measured as domains of health-related quality
of life). The buddy role was a pro-active combination of being supervisor, advisor, and
leader.
__Conclusions__ Camp COOL allowed young people to support each other in adjusting to everyday life with
ESRD. Participating in the camp positively influenced self-management in this group. Peerto-
peer support through buddies was much appreciated. Support from young adults was not
only beneficial for adolescent attendees, but also for young adult buddies. Paediatric
nephrologists are encouraged to refer patients to CC and to facilitate such initiatives.
Together with nephrologists in adult care, they could take on a role in selecting buddies
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