Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a ...transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and “toxic” gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
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•Most Foxp3+ Treg cells in the inflamed CNS express Blimp1•Blimp1 inhibits Dnmt3a and prevents methylation of the Foxp3 locus•IL-6 contributes to methylation of the Foxp3 locus in a Dnmt3a-dependent manner•Blimp1 counteracts the IL-6-driven destabilization of Treg cells
An inflammatory environment threatens the stability of Foxp3+ Treg cells. Garg et al. show that by expressing the transcriptional regulator Blimp1, Treg cells resist the IL-6-driven loss of Foxp3 in inflamed tissues. Blimp1 prevents the methylation and reduced expression of Foxp3 through inhibition of the methyltransferase Dnmt3a.
Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an ...experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6
, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.
Uterine angioleiomyoma is an extremely rare and unique variant of leiomyoma. It usually occurs in middle-aged women, who commonly present with menorrhagia, abdominal pain, or abdominal mass. The ...lesions are either single or multiple and manifest as submucosal, intramural, or subserosal whorled nodules. Microscopy of the individual nodule shows interlacing fascicles of spindle cells swirling around thick-walled blood vessels. Angioleiomyoma usually lacks mitotic figures, pleomorphism, or necrosis, although cases with marked nuclear atypia and multinucleated giant cells have been reported. The tumor cells are immunoreactive for smooth muscle actin, desmin, h-caldesmon, and progesterone receptor, with a low Ki-67 labeling index. Because these lesions are vascular, they may undergo spontaneous rupture and pose a life-threatening emergency, especially in pregnancy. There are no specific imaging findings; therefore, a preoperative diagnosis is extremely difficult. It is important to recognize this entity and differentiate it from a malignancy, particularly when angioleiomyoma shows significant cytologic atypia or raised cancer antigen 125 levels by thorough sampling. When required, a proper immunohistochemical panel should be used to arrive at a correct diagnosis. In this review, we discuss the current knowledge on uterine angioleiomyoma and its clinical relevance.
Background: The disease severity, ranging from being asymptomatic to having acute illness, and associated inflammatory responses has suggested that alterations in the gut microbiota may play a ...crucial role in the development of chronic disorders due to COVID-19 infection. This study describes gut microbiota dysbiosis in COVID-19 patients and its implications relating to the disease. Design: A cross sectional prospective study was performed on thirty RT-PCR-confirmed COVID-19 patients admitted to the All India Institute of Medical Sciences, Bhopal, India, between September 10 and 20, 2020. Ten healthy volunteers were recruited as the control group. IFN, TNF, and IL-21 profiling was conducted using plasma samples, and gut bacterial analysis was performed after obtaining the metagenomics data of stool samples. Results: Patients with a variable COVID-19 severity showed distinct gut microflora and peripheral interleukin-21 levels. A low Firmicute/Bacteroidetes ratio, caused by the depletion of the fibre-utilizing bacteria, F. prausnitzii, B. Plebius, and Prevotella, and an increase in Bacteroidetes has associated gut microbiota dysbiosis with COVID-19 disease severity. Conclusions: The loss of the functional attributes of signature commensals in the gut, due to dysbiosis, is a predisposing factor of COVID-19 pathophysiology.
Subpulmonary membrane is a rare cause of right ventricular outflow tract (RVOT) obstruction, and only a few case reports exist with or without associated ventricular septal defect. We report a series ...of three cases with subpulmonary membrane causing RVOT obstruction. Two of these have been operated (the first case operated after unsuccessful attempt at balloon dilatation), and the third case is on follow-up at present.
The transplacental route of vertical transmission of Hepatitis B Virus (HBV) has been known for over a decade. Here we present evidence which suggest HBV can replicate in placenta. Forty-one HBsAg ...positive and 10 control pregnant women were enrolled in the study after obtaining informed consent. HBV positives were further divided in the High Viral Load (HVL) Group and Low Viral Load (LVL) Group according to INASL guidelines 2018. The Presence of the HBV DNA and expression of NTCP in the placenta was analyzed by qPCR/RT-qPCR and/or immunohistochemistry (IHC). The presence of cccDNA was assessed using Digital Droplet PCR while the presence of pre-genomic (pg) RNA was assessed through qRT-PCR and sequencing. The presence of HBeAg and HBcAg in the placenta was assessed by IHC. Immunostaining of NTCP, HBeAg and HBcAg on trophoblasts along with the presence of total HBV DNA, cccDNA and pgRNA indicated, that these cells are not only susceptible to HBV infection but may also support viral replication. This is further supported by the finding that trophoblasts of the several HBeAg seronegative samples harbored the HBeAg. Although, we did not find any correlation in NTCP expression and viral markers with viral load indicates placental replication may not aping hepatocytes. The presence of the HBV receptor, NTCP along with the presence of cccDNA, pgRNA, and HBeAg in placenta of HBV infected females without circulating HBeAg suggest that placenta act as a replication host.
This study aimed to determine whether ultrasound-guided transversus abdominis plane (TAP) block is more effective in reducing postoperative pain and analgesic consumption than local anesthetic ...infiltration (LAI) at the port site for elective laparoscopic gynecological surgeries.
Eighty patients with the American Society of Anesthesiologists status I/II undergoing laparoscopic gynecology surgery were enrolled for this randomized control trial. After general anesthesia was administered, patients in group C received LAI at each port site, and patients in group T received bilateral ultrasound-guided TAP. Postoperative pain was assessed at time intervals of 1/2, 2, 4, 6, 8, and 24 h using the numeric pain scale (NPS). Clinical metrics such as postoperative analgesic diclofenac consumption, need for rescue fentanyl, nausea-vomiting scores, and antiemetic requirements were also recorded.
Seventy-four patients were included in the final analysis. Postoperatively, patients in group T had significantly lower NPS than those in group C (P < 0.05). The highest difference in the postoperative NPS was observed at 2 h (median 1Q, 3Q; group C = 3 2, 4; group T = 1 0, 2; P < 0.001). A statistically significant difference was observed in the frequency of diclofenac (75 mg intravenous) requirement between the groups (P = 0.010). No significant difference was observed between the groups in need of rescue fentanyl or antiemetic and the nausea-vomiting scores.
In patients undergoing laparoscopic gynecological surgery, ultrasound-guided TAP block provided greater postoperative analgesic benefits in terms of lower NPS and reduced analgesic requirements than port site LAI.
This cross-sectional study was performed with the aim of determining the prevalence of hepatitis E virus (HEV) infection among acute hepatitis patients attending a tertiary care teaching hospital in ...a developing country and to determine the relative performance of prevalent diagnostic assays in establishing its diagnosis.
A total of 46 adult patients were included in this study, all of whom presented with jaundice of <4 weeks' duration and elevation of AST and ALT above 500 U/L. The prevalence of HEV among patients with acute hepatitis was calculated on the basis of the proportion of recruited patients reacting positively in serum anti-HEV immunoglobulin M (IgM) and real-time polymerase chain reaction (RT-PCR) assays.
Among the recruited patients, 11 (23.91%) and 15 (32.6%) patients were positive for anti-HEV IgM and RT-PCR, respectively. The two tests demonstrated poor inter-test agreement, thereby implying the necessity of performing both tests for reliable diagnosis of acute HEV virus infection. We also observed a significant difference in the duration of illness between RT-PCR positive and negative patients (P = 0.008). The mean (±SD) duration of illness in the two groups was 8.6 (±3.50) and 11.66 (± 5.15) days, respectively. Combining the results of IgM ELISA and RT-PCR, we observed that 23 out of 46 patients (50%) had evidence of acute HEV virus infection among our patients.
Our study suggests that HEV is the commonest cause of acute hepatitis in adult patients attending a tertiary care teaching hospital and that the diagnostic algorithm for its confirmation should include both IgM ELISA and RT-PCR assays.
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