Based on previous studies showing abnormalities in the intestinal pathophysiology characterized by disruption in the gut barrier functions, and alteration in the intestinal microbial load and ...composition, we set out in the study to examine the expression of genes that might be involved in mediating these changes in Townes sickle cell disease (SCD) mice at 6 months old compared to non-SCD control mice. Using qPCR on total RNA isolated from the intestine, we found downregulation of the TJ genes
JAM-A
,
Occludin
, and
ZO-1
in both the small intestine and colon.
E-Cadherin
and
MUC2
were also downregulated. In contrast, gene encoding claudin-2 that mediates increase permeability to water and ions was upregulated in the small intestine.
Claudin-2
upregulation is usually also associated with ongoing inflammation. Intestinal epithelium also includes Paneth cells that produce antimicrobial peptides (AMPs) that regulate intestinal microbial community. We also found that the expression of the genes encoding the AMPs defensin-α4 was reduced in the small intestine and colon and defensin-α1 in the colon in the SCD mice. Our findings are novel and provide direction for further studies into the characteristics and mechanisms of the intestinal pathophysiologic changes observed in SCD.
The reliability of single antigen bead (SAB) assays and their use in predicting a negative cell based cross match (CBXM) is essential in the era of expanded organ sharing. A wide range of accuracy ...(80–95%) in predicting negative CBXM has been reported. We hypothesized that in SAB assays an antibody against an HLA eplet that was common among a number of different HLA alleles would be distributed among all of the shared eplet positive SABs. This would reduce binding to the donor specific SAB resulting in an under-estimate of antibody strength. We tested this proposal in adsorption studies using, instead of lymphocytes, a novel reagent, single-SAB (sSAB). Properties of SAB assays were examined that provided a basis for conducting adsorption – elution experiments with the sSABs. We found that incubation of sera with sA*02:01 or sB*42:01 not only depleted reactivity to these alleles but also depleted reactivity to beads that shared the reactive eplet. Anti-eplet strength from SAB data (sum of the MFI of eplet positive SABs (MFI-s) was compared with CBXM out comes in two case studies and with 99 proficiency testing sera. In these validation studies, an MFI-s above 11,000 was associated with a positive FCXM. This approach was placed into clinical practice for listing unacceptable antigens that shared a common eplet. CDCXMs (n = 3261) and FCXMs (n = 1012) were performed on patients listed in UNOS for deceased donor kidneys. All CDCXMs were negative and all FCXMs except one were negative. We conclude that summation of eplet strength provides a highly reliable method of predicting prospective negative CBXMs resulting in substantial savings of time and effort. Based on shared eplet summation data, CMS/NYSDOH has accepted our bead based XM (BBXM) method (aka, virtual XM) performed prior to transplant as fulfilling the regulation that XM results be available before kidney transplantation.
Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not ...all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age. On the other hand, the dilemma facing the patients and families is how acceptable HSCT that carries some mortality risks to them. We have analyzed the chronic conditions due to SCD in 449 patients to determine whether SCD-related multiple chronic conditions (MCC) can be risk-stratified to identify the group of patients predicted to not only have shortened lifespans but also functional limitation and poor quality of life so that these at-risk patients can be offered HSCT early and before MCC develops. We identified that the age of onset of the first SCD-related chronic conditions strongly predicted for the risks for disease-related MCC. SCD patients who suffered their first disease-related chronic condition before age 30 years developed MCC at a rate of 19.1 times faster than those at a later age. These patients are therefore high-risk patients and should be offered HSCT early in the course of their disease before multiple organ damage intervenes, even if matched-related donors are not available. This patient selection and timing approach provides a forum for an easy-to-understand and real-time discussion, including the choice of donor type, with SCD patients and families when considering HSCT.
Background The segment of the vein mobilized for arterial anastomosis in the creation of an arteriovenous fistula (AVF) is the swing segment. This segment may experience turbulent flow and altered ...shear mechanical stress that result in stenosis. We sought to determine the frequency of stenotic lesions in the swing segment. Study Design Case series. Settings & Participants From January 31, 2003, to June 30, 2005, records of all patients referred to an outpatient hemodialysis vascular access center for AVF dysfunction were reviewed (n = 484). Of these, 278 patients had angiographically documented stenosis (any degree of luminal narrowing) on their first visit. Outcomes & Measurements Distribution of stenoses in different segments of the AVF. Swing-segment stenoses were classified as proximal (outflow into axillary vein system), distal or juxta-anastomotic (adjacent to the anastomosis), and the cephalic arch. Results Overall prevalence of angiographically documented swing segment stenosis (proximal, distal or juxta-anastomotic, and cephalic arch) was 45.7% (127 of 278 patients), whereas the remaining stenoses (151 of 278 patients) were distributed among the puncture zone, arterial, arterial anastomosis, and central veins. The most frequent location of the swing-segment stenosis was juxta-anatomosis (63%; 80 of 127 patients), followed by cephalic arch (19%; 24 of 127 patients) and proximal swing segment (18%; 23 of 127 patients). The distribution of swing-segment stenosis (n = 127) was equivalent among the various fistulas (brachial-cephalic, 35.4%; radial-cephalic, 33.9%; and brachial-basilic, 30.7%). Eighty-three percent of swing-segment stenoses were significant (>50% luminal narrowing) and underwent percutaneous transluminal angioplasty, with a 93% success rate. Limitations Retrospective nature of the study and potential selection bias. Conclusion In our population, swing-segment stenosis is the most common lesion in dysfunctional AVFs; juxta-anastomotic stenosis is the predominant lesion independent of fistula type. Whether the occurrence of swing-segment stenosis is caused by mobilization of the vein during surgery is not clear.
The F11 Receptor (F11R), AKA Junctional Adhesion Molecule-A (JAM-A) (F11R/JAM-A), is an adhesion protein constitutively expressed on the membrane surface of circulating platelets and the luminal ...surface of inflamed endothelial cells (EC).
Platelet adhesion to an inflamed endothelium is one of the early steps of atherosclerotic plaque formation. Our previous studies, conducted with cultured EC in vitro, have demonstrated the expression of F11R/JAM-A on the luminal surface of inflamed EC, platelet adhesion to inflamed EC through F11R/JAM-A interactions, and inhibition of this interaction by the presence of F11R/JAM-A antagonistic peptide (F11Rpeptide 4D). In the present study, we examined in vivo the overall health-benefits and cardiovascular effects of long-term treatment of animals prone to atherosclerosis, ApoE−/− mice, with F11R-peptide 4D.
Twenty ApoE−/− mice were assigned to daily treatment with peptide 4D and compared to their counterparts control untreated mice. Mice were observed for wellness and survival. Plaque size in the aorta and heart was measured using histological analysis. Effects of peptide 4D (or scramble control) on platelet adhesion to inflamed endothelium were measured using intravital microscopy.
Significant reductions in atherosclerotic plaques number and size, an overall robust health with longer survival were found in the peptide 4D treated group of ApoE−/− mice. Intravital microscopic studies conducted in exposed vessels of ApoE−/− mice demonstrated significant inhibition by peptide 4D of platelet adhesion to the cytokine-inflamed endothelium.
Our results demonstrate that peptide 4D significantly reduces atherosclerotic plaque formation in ApoE−/− mice and inhibits platelet adhesion to the inflamed arterial endothelium.
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•We examined effects of F11R derived peptide 4D (P4D) on cardiovascular health and atherosclerotic plaque of ApoE-/- mice.•The F11R peptide 4D reduced plaque formation and prolonged survival with overall better health in ApoE-/- mice.•P4D inhibited adhesion of platelets to cytokine-inflamed aortic endothelium in ApoE-/- mice shown by intravital microscopy.•P4D represents a potential drug for the prevention and treatment of thrombosis and atherosclerosis triggered by inflammation.
An increased incidence of thrombotic complications in patients with coronavirus disease 2019 (COVID-19) has been reported. Severe acute kidney injury (AKI) is one of the major clinical manifestations ...of COVID-19 with the need for renal replacement therapy. It was observed that hemodialysis (HD) accesses tended to thrombose more often in the COVID-19 population than in non-COVID-19 patients. We hypothesize that the hypercoagulable state of COVID-19 is associated with higher incidence of access clotting.
In this retrospective single-centered study at Kings County Hospital in New York City, 1,075 patients with COVID-19 were screened, and 174 patients who received HD from January 3, 2021 to May 15, 2020 were enrolled to examine the risk factors of dialysis access clotting in patients with COVID-19.
Of the 174 patients, 109 (63%) were COVID-19 positive. 39 (22.6%) patients had dialysis access clotting at least once during their hospitalization, and they had significantly higher body mass index (BMI) (p = 0.001), higher rates of COVID-19 (p = 0.015), AKI (p < 0.001), higher platelet counts (p = 0.029), higher lactate dehydrogenase levels (p = 0.009), and lower albumin levels (p = 0.001) than those without access malfunctions. Low albumin levels (p = 0.008), AKI (p = 0.008), and high BMI (p = 0.018) were risk factors associated with HD access clotting among COVID-19 patients.
Patients with COVID-19 who receive HD for AKI with high BMI are at a higher risk of clotting their HD access.
The F11R/JAM-A cell adhesion protein was examined as the therapeutic target in triple negative breast cancer (TNBC) with the use of the peptide antagonist to F11R/JAM-A, that previously inhibited the ...early stages of breast cancer metastasis in vitro.
The online in silico analysis was performed by TNMPlot, UALCAN, and KM plotter. The in vitro experiments were performed to verify the effect of peptide 4D (P4D) on human endothelial cell lines EA.hy926 and HMEC-1 as well as on human TNBC cell line MDA-MB-231. The cell morphology upon P4D treatment was verified by light microscopy, while the cell functions were assessed by colony forming assay, MTT cell viability assay, BrdU cell proliferation assay, and Transepithelial/Endothelial Electrical Resistance measurements. The in vivo experiments on 4T1 murine breast cancer model were followed by histopathological analysis and a series of quantitative analyses of murine tissues.
By in silico analysis we have found the elevated gene expression in breast cancer with particular emphasis on TNBC. The elevated F11R expression in TNBC was related with poorer survival prognosis. Peptide 4D has altered the morphology and increased the permeability of endothelial monolayers. The colony formation, viability, and proliferation of MDA-MB-231 cells were decreased. P4D inhibited the metastasis in 4T1 breast cancer murine model in a statistically significant manner that was demonstrated by the resampling bootstrap technique.
The P4D peptide antagonist to F11R/JAM-A is able to hinder the metastasis in TNBC. This assumption needs to be confirmed by additional 4T1 mouse model study performed on larger group size, before making the decision on human clinical trials.
There is an increase in older-adult renal transplant recipients in United States. The objective of this study was to assess the association between physical function (PF) and patient survival in ...renal transplant recipients who are aged 65 years or older. Using United Network for Organ Sharing (UNOS) data from 2007 to 2016, renal transplant recipients aged 65 years or older were included. Multivariable Cox regression was used to assess associations between survival and functional status adjusted for age, sex, race, donor quality, diabetes, and dialysis vintage. The study identified 26,721 patients. Patient survival was significantly higher in recipients who needed no assistance and lowest in patients in need of total assistance (P < .0001). In deceased donor (DD) transplants, the relative risk for mortality was 2.06 (1.74-2.43) for total assistance and 1.17 (1.08-1.28) for moderate assistance compared to no assistance (P < .0001). In living donor (LD) transplants, the relative risk of mortality was 1.38 (0.78-2.42) for patients needing total assistance and 1.37 (1.14-1.65) for patients needing moderate assistance compared to patients who did not need assistance (0.003). PF is an independent predictor of post-transplant mortality. Assessment of older potential renal transplant recipients should include assessment and standardization of functional status to counsel about post-transplant survival.
•There is an increase in older renal transplant recipients in the United States.•Poor physical function has an adverse association with both patient and graft survival independent of age and other adjusters such as diabetes and dialysis at listing.•This impact is seen both in recipients of deceased and living donor kidneys, although the impact is greater among the recipients of deceased donor kidneys.•Physical dysfunction should be considered a component of evaluation and counseling.
Over the past 20 years, the advancement of artificial intelligence (AI) and deep learning (DL) has allowed for fast sorting and analysis of large sets of data. In the field of gastroenterology, ...colorectal screening procedures produces an abundance of data through video and imaging. With AI and DL, this information can be used to create systems where automatic polyp detection and characterization is possible. Convoluted Neural Networks (CNNs) have proven to be an effective way to increase polyp detection and ultimately adenoma detection rates. Different methods of polyp characterization of being hyperplastic vs. adenomatous or non-neoplastic vs. neoplastic has also been investigated showing promising results.
The rate of missed polyps on colonoscopy can be as high as 25%. At the beginning of the 2000s, hand-crafted machine learning (ML) algorithms were created and trained retrospectively on colonoscopy images and videos, achieving high sensitivity, specificity, and accuracy of over 90% in many of the studies. Over time, the advancement of DL and CNNs has allowed algorithms to be trained on non-medical images and applied retrospectively to colonoscopy videos and images with similar results. Within the past few years, these algorithms have been applied in real-time colonoscopies and has shown mixed results, one showing no difference while others showing increased polyp detection.Various methods of polyp characterization have also been investigated. Through AI, DL, and CNNs polyps can be identified has hyperplastic/adenomatous or non-neoplastic/neoplastic with high sensitivity, specificity, and accuracy. One of the research areas in polyp characterization is how to capture the polyp image. This paper looks at different modalities of characterizing polyps such as magnifying narrow band imaging (NBI), endocytoscopy, laser-induced florescent spectroscopy, auto-florescent endoscopy, and white-light endoscopy.
Overall, much progress has been made in automatic detection and characterization of polyps in real time. Barring ethical or mass adoption setbacks, it is inevitable that AI will be involved in the field of GI, especially in colorectal polyp detection and identification.
Obesity and diabetes mellitus are prevalent among the African-American/Black population. They result in multiple chronic conditions that impact the quality and lifespan of the patients. Their ...occurrence in patients with sickle cell disease (SCD) will increase the risks for multimorbidity in these patients. We have carried out a chart survey of a cohort of 449 patients with SCD to determine the prevalence rates of obesity and diabetes mellitus in these patients. SCD patients were less likely to develop obesity and diabetes mellitus, compared to their peers of the same race/ethnicity. The lower prevalence rates were observed in those over the age of 6 years, irrespective of the gender of the patients. Their life-time probabilities for obesity and diabetes mellitus were also low. Within this group of SCD patients, obesity was associated with significantly higher prevalence of diabetes mellitus. The underlying reasons for our observed results of low prevalence rate of obesity in SCD remain speculative but may be related to reduced calorie intake, increased calorie use due to hypermetabolism, reduced intestinal absorption, or intestinal dysbiosis.
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