Impact of dietary polyphenols on neuroinflammation-associated disorders

Neurological Sciences - Neurodegenerative disorders like Alzheimer’s, Parkinson’s, and associated dementia typically originate with altered protein folding and aggregation of their...     

Development of an inhalation unit risk factor for hexavalent chromium

A unit risk factor (URF) was developed for hexavalent chromium (CrVI). The URF is based on excess lung cancer mortality in two key epidemiological studies of chromate production workers. The Crump et al. (2003) study concerns the Painesville, OH worker cohort, while Gibb et al. (2000) regards the Baltimore, MD cohort. A supporting assessment was also performed for a cohort from four low-dose chromate plants (Leverkusen and Uerdingen, Germany, Corpus Christi, TX, Castle Hayne, NC). For the Crump et al. (2003) study, grouped observed and expected number of lung cancer mortalities along with cumulative CrVI exposures were used to obtain the maximum likelihood estimate and asymptotic variance of the slope (β) for the linear multiplicative relative risk model using Poisson regression modeling. For the Gibb et al. (2000) study, Cox proportional hazards modeling was performed with optimal exposure lag and adjusting for the effect of covariates (e.g., smoking) to estimate β values. Life-table analyses were used to develop URFs for each of the two key studies, as well as for supporting and related studies. The two key study URFs were combined using weighting factors relevant to confidence to derive the final URF for CrVI of 2.3E-03 per μg CrVI/m³.     

Ferumoxytol Is Not Retained in Kidney Allografts in Patients Undergoing Acute Rejection

Purpose

To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients.

Procedures

The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10–26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05.

Results

At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20–24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25–97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44).

Conclusion

After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts.

     

Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality

Objectives Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality.Methods By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32 415 adults with a cancer diagnosis at Vanderbilt and 79 258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index.Results Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR.Conclusions EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.     

A study of interobserver reproducibility of morphologic lesions of focal segmental glomerulosclerosis

The morphology of focal segmental glomerulosclerosis (FSGS) includes collapsing, cellular, and sclerosing forms. The Columbia Working Classification of FSGS divides these into collapsing (COLL), cellular (CELL), tip lesion (TIP), perihilar (PH), and not otherwise specified (NOS) morphologic forms. This study examined the ability of renal pathologists to classify FSGS using single light microscopic images of glomeruli as a uniform data set. Sixty-one digital images of individual glomeruli with FSGS, stained by periodic acid-Schiff or Jones methenamine silver methods, were classified independently by six specialist renal pathologists. Diagnostic consistency was quantified using the kappa statistic for nominal categories. Agreement for 366 diagnoses by six observers was 75.2 % with a kappa value of 0.676. Six of six observers agreed in 31 of 61 cases (50.8 %) and four or more in 53 cases (86.9 %). Respective kappa values ranged from moderate to good: COLL 0.77, CELL 0.53, TIP 0.76, PH 0.84, and NOS 0.60. Capillary retraction with lobular expansion, hypercellularity, and sclerosis in the same glomerular segments, and the location of segmental lesions were sources of diagnostic inconsistency. The morphologic forms of FSGS defined by the Columbia system are reproducible between observers and have a low probability of confusion between forms. Individual glomeruli may have overlapping features of more than one form of FSGS.     

Ophthalmic manifestations in the COVID-19 clinical spectrum

Purpose:The aim of this study was to determine the frequency and various types of ophthalmic manifestation of patients with COVID-19.Methods:This is a prospective observational study conducted on patients with SARS-Co-V-2 infection, at a dedicated tertiary COVID-19 hospital in South India from April 1 to July 31, 2020. At the time of their admission to the COVID hospital, demographic data such as name, age, sex was recorded. A thorough history regarding the onset, duration, progression, nature of symptoms and its associated factors, medication history, treatment history were elicited and documented. Ocular examination was performed under torchlight by an ophthalmologist posted for COVID duty. Further investigations including imaging were sought for, depending on clinical indications. Serial follow-up examinations of all patients were carried out every 72 hours or when patients complained of any ocular symptoms whichever earlier, until discharge. All relevant data were compiled and statistically analyzed.Results:A total of 2742 patients were examined. Of them, 1461 (53.28%) were males and 1281 (46.72%) were females. The mean age (±SD) was 39.46 ± 17.63 years. None of the patients in our study had any ocular symptoms or signs as the presenting complaint at the time of their admission. On subsequent follow-up, only 20 (0.72%) developed ocular manifestations, of which 19 (95%) had features suggestive of Bilateral viral conjunctivitis. However, 1 (5%) patient had orbital cellulitis secondary to pansinusitis.Conclusion:Ophthalmic manifestations in the clinical spectrum of COVID-19 infection are uncommon and unlikely to be the presenting clinical impression. However, it has broadened our view to a wider spectrum of COVID-19 presentations enhancing our clinical acumen for staunch detection of COVID-19 suspects in our daily practice, augmenting early diagnosis and management and also break the chain of transmission for the greater good of humanity.     

Diversity Assessment Among Alternaria solani Isolates Causing Early Blight of Tomato in India

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Early blight (EB), caused by the fungus, Alternaria solani, is one of the most destructive diseases of...     

CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut

The chemokine receptor CCR9 and its only known ligand CCL25 play an important role in gut inflammation and autoimmune colitis. The function of CCR9-CCL25 in the migration of immune cells is well characterized. However, its role in the immune cell differentiation is mostly not known. Using dextran sodium sulfate (DSS)-induced gut inflammation model, we showed that CCR9⁺ dendritic cells (DCs) specifically CD11b⁻CD103⁺ DCs were significantly increased in the gut-associated lymphoid tissues (GALT) compared to control mice. These CCR9⁺ DCs express lower MHC II and CD86 molecules and had regulatory surface markers (FasL and latency-associated peptide, LAP) in the GALT. In the presence of CCL25, CCR9⁺ DCs promoted in vitro differentiation of Foxp3⁺ regulatory CD4⁺ T cells (Tregs). CCL25-induced differentiation of Tregs was due to intrinsic signaling in the DCs but not through CD4⁺ T cells, which was driven by the production of thymic stromal lymphopoietin (TSLP) and not IL-10. Furthermore, adoptive transfer of CCR9⁺ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the OVA-specific gut-allergic response. Our results suggest CCR9⁺ DCs have a regulatory function and may provide a new cellular therapeutic strategy to control gut inflammation and allergic immune reaction.     

Multinucleated epithelial giant cells in colorectal polyps: a potential mimic of viropathic and/or dysplastic changes

Multinucleated epithelial giant cells (MEG) simulating viral cytopathic effect and/or dysplasia have been reported in the esophagus in association with inflammation, but the occurrence of similar cells in the colon has not been documented. Twenty-three colon specimens (22 biopsies and 1 partial colectomy) featuring MEG from 21 patients were evaluated for a variety of histologic features and correlated with clinical, endoscopic, and follow-up data. Patients included 9 males and 12 females (mean age, 64.9 years; range, 45-86 years). Eleven cases were obtained from 10 asymptomatic patients undergoing surveillance biopsies. Presenting symptoms in the remaining patients were dyspepsia, anemia, abdominal pain, and hematochezia. Over half (13 of 23) of the specimens were from descending and rectosigmoid colon, and almost all were visualized as polyps on endoscopy. Microscopically, all but 1 of the cases featured multiple MEG (range, 6 to >50 cells per biopsy) in the base and mid crypt zones of inflamed polyps with serrated architecture. Immunohistochemical stains for CMV, HSV, adenovirus, EBV, and polyoma virus were negative and no viral particles were identified on ultrastructural examination. Nuclear staining for hMLH1 and hMSH2, markers of microsatellite instability, was similar in distribution to adjacent serrated crypts, but reduced staining intensity was noted in occasional multinucleated cells. Expression of Ki-67 and cleaved caspase 3 was consistent with a quiescent or low proliferative state. Clinical follow-up was available for 9 patients (mean duration, 22.7 months). One patient died of heart failure; all others were well at last follow-up. Bizarre MEG may occasionally be seen within the crypts of inflamed polyps with serrated architecture, raising concern for dysplasia or viral infection. Immunohistochemical and ultrastructural studies fail to establish a viral etiology, and follow-up does not indicate clinically aggressive disease. These changes appear to represent a nonspecific, possibly degenerative response to inflammation and injury, and should be distinguished from dysplasia.