Although current literature has addressed gastrointestinal presentations including nausea, vomiting, diarrhea, abnormal liver chemistries, and hyperlipasemia as possible coronavirus disease 2019 ...(COVID-19) manifestations, the risk and type of gastrointestinal bleeding (GIB) in this population is not well characterized.
This is a matched case-control (1:2) study with 41 cases of GIB (31 upper and 10 lower) in patients with COVID-19 and 82 matched controls of patients with COVID-19 without GIB. The primary objective was to characterize bleeding etiologies, and our secondary aim was to discuss outcomes and therapeutic approaches.
There was no difference in the presenting symptoms of the cases and controls, and no difference in severity of COVID-19 manifestations (P > 0.05) was observed. Ten (32%) patients with upper GIB underwent esophagogastroduodenoscopy and 5 (50%) patients with lower GIBs underwent flexible sigmoidoscopy or colonoscopy. The most common upper and lower GIB etiologies were gastric or duodenal ulcers (80%) and rectal ulcers related to rectal tubes (60%), respectively. Four of the esophagogastroduodenoscopies resulted in therapeutic interventions, and the 3 patients with rectal ulcers were referred to colorectal surgery for rectal packing. Successful hemostasis was achieved in all 7 cases that required interventions. Transfusion requirements between patients who underwent endoscopic therapy and those who were conservatively managed were not significantly different. Anticoagulation and rectal tube usage trended toward being a risk factor for GIB, although it did not reach statistical significance.
In COVID-19 patients with GIB, compared with matched controls of COVID-19 patients without GIB, there seemed to be no difference in initial presenting symptoms. Of those with upper and lower GIB, the most common etiology was peptic ulcer disease and rectal ulcers from rectal tubes, respectively. Conservative management seems to be a reasonable initial approach in managing these complex cases, but larger studies are needed to guide management.
Abstract
Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as surrogate markers for ...therapy response. N-glycanase 1 (NGLY1) deficiency is an ultra-rare autosomal recessive disorder characterized by developmental delay, peripheral neuropathy, elevated liver transaminases, hyperkinetic movement disorder and (hypo)-alacrima. We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls. GNA accumulation is directly linked to the absence of functional NGLY1, presenting strong potential for its use as a biomarker. In agreement, a quantitative liquid chromatography with tandem mass spectrometry assay, developed to assess GNA from 3 to 3000 ng/ml, showed that it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and patients (plasma and urine). Elevated GNA levels differentiate patients from controls, are stable over time and correlate with changes in NGLY1 activity. GNA as a biomarker has the potential to identify and validate patients with NGLY1 deficiency, act as a direct pharmacodynamic marker and serve as a potential surrogate endpoint in clinical trials.
Graphical Abstract
Graphical Abstract
Campylobacter jejuni is a major cause of bacterial diarrhea worldwide and associated with numerous sequela, including Guillain-Barré Syndrome, inflammatory bowel disease, reactive arthritis, and ...irritable bowel syndrome. C. jejuni is unusual for an intestinal pathogen in its ability to coat its surface with a polysaccharide capsule (CPS). The genes responsible for the biosynthesis of the phase variable CPS is located in the hypervariable region of C. jejuni genome which has been used to develop multiplex PCR to classify CPS types based on the Penner serotypes. However, there still are non-typable CPS C. jejuni by the current multiplex PCR scheme. The application of the next generation sequencing and whole genome analysis software were used for the identification of novel capsule biosynthesis of C. jejuni isolates. Unique PCR primers were designed to identify these new capsule biosynthesis loci. The designed primers sets were combined in a new multiplex mix called epsilon. The unique sequences provide an additional information of the biosynthesis loci responsible for some of the common CPS sugars/residues such as heptose, deoxtyheptose and MeOPN among C. jejuni in this new group of CPS multiplex assay. This new primer complements the current C. jejuni multiplex capsule typing system and will help in identifying previously untypeable capsule locus of C. jejuni isolates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the ...accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing “psychosine hypothesis.” We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients.We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized L-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.
Infectious diarrhea is a World Health Organization public health priority area due to the lack of effective vaccines and an accelerating global antimicrobial resistance crisis. New strategies are ...urgently needed such as immunoprophylactic for prevention of diarrheal diseases. Hyperimmune bovine colostrum (HBC) is an established and effective prophylactic for infectious diarrhea. The commercial HBC product, Travelan® (Immuron Ltd, Australia) targets multiple strains of enterotoxigenic Escherichia coli (ETEC) is highly effective in preventing diarrhea in human clinical studies. Although Travelan® targets ETEC, preliminary studies suggested cross-reactivity with other Gram-negative enteric pathogens including Shigella and Salmonella species. For this study we selected an invasive diarrheal/dysentery-causing enteric pathogen, Shigella, to evaluate the effectiveness of Travelan®, both in vitro and in vivo. Here we demonstrate broad cross-reactivity of Travelan® with all four Shigella spp. (S. flexneri, S. sonnei, S. dysenteriae and S. boydii) and important virulence factor Shigella antigens. Naïve juvenile rhesus macaques (NJRM) were randomized, 8 dosed with Travelan® and 4 with a placebo intragastrically twice daily over 6 days. All NJRM were challenged with S. flexneri 2a strain 2457T on the 4th day of treatment and monitored for diarrheal symptoms. All placebo-treated NJRM displayed acute dysentery symptoms within 24-36 hours of challenge. Two Travelan®-treated NJRM displayed dysentery symptoms and six animals remained healthy and symptom-free post challenge; resulting in 75% efficacy of prevention of shigellosis (p = 0.014). These results strongly indicate that Travelan® is functionally cross-reactive and an effective prophylactic for shigellosis. This has positive implications for the prophylactic use of Travelan® for protection against both ETEC and Shigella spp. diarrheal infections. Future refinement and expansion of pathogens recognized by HBC including Travelan® could revolutionize current management of gastrointestinal infections and outbreaks in travelers' including military, peacekeepers, humanitarian workers and in populations living in endemic regions of the world.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sanfilippo syndrome type B (Sanfilippo B; Mucopolysaccharidosis type IIIB) occurs due to genetic deficiency of lysosomal alpha-N-acetylglucosaminidase (NAGLU) and subsequent lysosomal accumulation of ...heparan sulfate (HS), which coincides with devastating neurodegenerative disease. Because NAGLU expressed in Chinese hamster ovary cells is not mannose-6-phosphorylated, we developed an insulin-like growth factor 2 (IGF2)-tagged NAGLU molecule (BMN 250; tralesinidase alfa) that binds avidly to the IGF2 / cation-independent mannose 6-phosphate receptor (CI-MPR) for glycosylation independent lysosomal targeting. BMN 250 is currently being developed as an investigational enzyme replacement therapy for Sanfilippo B. Here we distinguish two cellular uptake mechanisms by which BMN 250 is targeted to lysosomes. In normal rodent-derived neurons and astrocytes, the majority of BMN250 uptake over 24 hours reaches saturation, which can be competitively inhibited with IGF2, suggestive of CI-MPR-mediated uptake. Kuptake, defined as the concentration of enzyme at half-maximal uptake, is 5 nM and 3 nM in neurons and astrocytes, with a maximal uptake capacity (Vmax) corresponding to 764 nmol/hr/mg and 5380 nmol/hr/mg, respectively. Similar to neurons and astrocytes, BMN 250 uptake in Sanfilippo B patient fibroblasts is predominantly CI-MPR-mediated, resulting in augmentation of NAGLU activity with doses of enzyme that fall well below the Kuptake (5 nM), which are sufficient to prevent HS accumulation. In contrast, uptake of the untagged recombinant human NAGLU (rhNAGLU) enzyme in neurons, astrocytes and fibroblasts is negligible at the same doses tested. In microglia, receptor-independent uptake, defined as enzyme uptake resistant to competition with excess IGF2, results in appreciable lysosomal delivery of BMN 250 and rhNAGLU (Vmax = 12,336 nmol/hr/mg and 5469 nmol/hr/mg, respectively). These results suggest that while receptor-independent mechanisms exist for lysosomal targeting of rhNAGLU in microglia, BMN 250, by its IGF2 tag moiety, confers increased CI-MPR-mediated lysosomal targeting to neurons and astrocytes, two additional critical cell types of Sanfilippo B disease pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A considerable need exists for improved biomarkers for differential diagnosis, prognosis and monitoring of therapeutic interventions for mucopolysaccharidoses (MPS), inherited metabolic disorders ...that involve lysosomal storage of glycosaminoglycans. Here we report a simple, reliable method based on the detection of abundant nonreducing ends of the glycosaminoglycans that accumulate in cells, blood and urine of individuals with MPS. In this method, glycosaminoglycans are enzymatically depolymerized, releasing unique mono-, di- or trisaccharides from the nonreducing ends of the chains. The composition of the released mono- and oligosaccharides depends on the nature of the lysosomal enzyme deficiency, and therefore they serve as diagnostic biomarkers. Analysis by LC/MS allowed qualitative and quantitative assessment of the biomarkers in biological samples. We provide a simple conceptual scheme for diagnosing MPS in uncharacterized samples and a method to monitor efficacy of enzyme replacement therapy or other forms of treatment.
β-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing β-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as ...Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by β-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute‐on‐chronic liver failure (ACLF) carries high short‐term mortality. The North American Consortium for the Study of End‐Stage Liver Disease (NACSELD)–ACLF score, positive if ≥2 organ failures are ...present, is a bedside tool that predicts short‐term mortality in patients with cirrhosis. However, it was created using major liver referral centers, where a minority of patients with cirrhosis are hospitalized. Therefore, this study used the Nationwide Inpatient Sample, a nationally representative database, from 2005 to 2014 to externally validate the NACSELD‐ACLF score in a cohort of patients with decompensated cirrhosis who were identified by a validated algorithm. Organ failures were identified using diagnosis codes. The primary objective was to evaluate the association between the NACSELD‐ACLF score and inpatient mortality, whereas secondary objectives compared outcomes depending on presence of infection or hospitalization at a transplant center. Multivariate logistic regression was used to compare outcomes, and area under the curve was calculated. There were 1,523,478 discharges that were included with 106,634 (7.0%) having a positive NACSELD‐ACLF score. Patients were a mean 58 years old, and a majority were white men. Infection was present in 33.7% of the sample. Inpatient survival decreased with each organ failure and if infection was present. Patients with the NACSELD‐ACLF score had significantly lower inpatient survival on crude (94% versus 48%; P < 0.001) and multivariate analysis (odds ratio OR, 0.08; 95% confidence interval CI, 0.07‐0.08) and area under the receiver operating characteristic curve 0.77 (95% CI, 0.77‐0.78). Liver transplant centers had clinically similar but significantly better survival at each organ failure, in patients with the NACSELD‐ACLF score, and on multivariate analysis (OR, 1.17; 95% CI, 1.13‐1.22). Using a national cohort, our study validated the NACSELD‐ACLF score as an excellent, simple bedside tool to predict short‐term survival in patients with decompensated cirrhosis.
Background and Aims
Kidney dysfunction is associated with increased mortality among patients with cirrhosis. We investigated whether kidney dysfunction types e.g., acute kidney injury (AKI), chronic ...kidney disease (CKD), and AKI on CKD were differentially associated with inpatient mortality.
Methods
We utilized the nationwide inpatient sample, a nationally representative database, from 2007 to 2014. We included all hospitalizations with previously validated codes for cirrhosis or associated decompensated cirrhosis diagnoses. We defined kidney dysfunction types also from previously validated codes, and we grouped hospitalizations into the following diagnoses: normal, AKI, CKD, and AKI on CKD. Our primary outcome was inpatient morta
l
ity.
Results
There were 1,293,779 hospitalizations with cirrhosis sampled in this study. Of these hospitalizations, 849,193 (66%) had normal kidney function, 176,418 (14%) had AKI, 157,600 (12%) had CKD, and 110,568 (9%) had AKI on CKD. We found that the proportion of hospitalizations with AKI, CKD, and AKI on CKD increased significantly throughout the study period (
p
< 0.001, test for trend for all). Kidney dysfunction type was differentially associated with inpatient mortality, even after adjustment: as compared to those with CKD, normal kidney function: OR 0.75 95 CI 0.73–0.78, AKI: OR 2.40 95 CI 2.32–2.48, and AKI on CKD: OR 1.66 95 CI 1.60–1.72.
Discussion
Using a nationally representative cohort of all hospitalizations with cirrhosis, our study highlights that the burden of kidney dysfunction, especially AKI, among hospitalizations with cirrhosis is rising, and the inclusion of kidney dysfunction type may be an opportunity to improve prognostication.
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