Characteristics,evolution, and outcome of patients with non-infectious uveitis referred for rheumatologic assessment and management: an Egyptian multicenter retrospective study

Clinical Rheumatology - To investigate the characteristics, evolution, and visual outcome of non-infectious uveitis. Records of 201 patients with non-infectious uveitis (136 (67.7%) males and 84...     

Rift Valley fever surveillance in mobile sheep flocks in the Nile Delta

Rift Valley fever (RVF) surveillance was carried out in the Nile Delta by monitoring mobile and stationary sheep flocks for antibodies to RVF virus. Sheep are known to be susceptible to RVF virus infection and experienced severe morbidity in 1977 and 1978 when RVF was epidemic in Egypt. Four hundred six sheep in 32 flocks were surveyed during 1984. Twenty-four sheep from 7 flocks had antibodies to RVF virus detected by hemagglutination inhibition and plaque reduction neutralization tests. Antibodies were found primarily in sheep greater than 3 years of age, although 1- and 2-year-old sheep were included in the sample. No seroconversion was observed among 177 seronegative sheep that were bled successively for a period of 10 months. These results indicate that epizootic RVF was probably not present in the Nile Delta during 1984.     

An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (M^pro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with M^pro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4, together with three known compounds, ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, was isolated from peach fruits.     

Epithelial NAIPs protect against colonic tumorigenesis

NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6^Δ/Δ), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6^Δ/Δ mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6^Δ/Δ mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6^Δ/Δ mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6^Δ/Δ mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial-intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis.Inflammatory bowel disease (IBD) is an important risk factor that favors the development and progression of colitis-associated cancer (CAC; Eaden et al., 2001; Terzić et al., 2010; Rubin et al., 2013). Even in the absence of overt inflammatory disease in colorectal cancer (CRC), loss of barrier function in the tumor epithelium enables translocation of microbial products into tumor tissue. This triggers the activation of lamina propria immunocytes and colonic epithelial cells via pattern-recognition receptors (PRRs) to produce cytokines and chemokines. Those factors then promote tumor growth and mediate recruitment of further immune cells (Grivennikov et al., 2012; Mueller, 2012). Alternatively, epithelial innate immune components could be subverted during tumorigenesis and influence tumor growth independently. Although cytokine/chemokine-mediated modulation of tumor growth has been described, the role of epithelial-intrinsic, innate immune components still remains elusive.Several Nod-like receptors (NLRs) have previously been implicated in colon inflammation and tumorigenesis, mostly in protective roles (Allen et al., 2010; Hu et al., 2010; Chen et al., 2011; Elinav et al., 2011; Zaki et al., 2011; Carvalho et al., 2012). In some cases, this has been attributed to reduced inflammasome-mediated release of IL-18, which is protective for the colonic epithelium (Allen et al., 2010; Dupaul-Chicoine et al., 2010). In other cases, noninflammasome-mediated factors were found to protect mice against CAC development. For example, NLRP12 was protective against colonic inflammation and tumorigenesis by dampening NF-κB and ERK activation in macrophages (Zaki et al., 2011). However, several discrepancies also exist, as illustrated by Caspase-1–deficient mice, which display increased colon tumorigenesis. In one study, this was dependent on NLRC4 and was epithelial intrinsic rather than inflammation mediated (Hu et al., 2010), whereas, in another study, increased tumorigenesis involved NLRP3 and was inflammation and hematopoietic cell–dependent (Allen et al., 2010). Such discrepancies are suggested to arise from differences in microbiota between facilities or use of WT mice from external sources (Ubeda et al., 2012), but could also arise from opposing functions of inflammasome components in different tissues, which has been demonstrated in a skin tumorigenesis model (Drexler et al., 2012).The physiological function of the NLR protein NAIP (NLR family apoptosis inhibitory protein, previously known as neuronal apoptosis inhibitory protein) is not fully characterized, mainly because mice have several possibly redundant Naip paralogs (e.g., 4 functional and 2 noncoding Naip genes in the C57BL/6 genome; Yaraghi et al., 1998; Endrizzi et al., 2000; Growney and Dietrich, 2000). Humans also have several NAIP genes, only one of which is full length (Schmutz et al., 2004; Romanish et al., 2009). NAIPs are intracellular, cytosolic proteins with a tripartite structure; three N-terminal baculovirus inhibitor of apoptosis (IAP) protein repeat (BIR) domains, a central NACHT domain and C-terminal leucine rich-repeat (LRR) domains. The latter two domains group NAIPs to the NLR family of proteins. Indeed, NAIPs are best characterized for their inflammasome function. Mouse and human NAIPs are involved in the detection of intracellular pathogens, such as Salmonella, and activation of the NLRC4 inflammasome, inducing pyroptosis and caspase-1–mediated cleavage of IL-1β and IL-18 (Kofoed and Vance, 2011; Zhao et al., 2011; Rayamajhi et al., 2013; Yang et al., 2013). In mice, NAIP paralogs provide specificity to different bacterial components (Kofoed and Vance, 2011; Zhao et al., 2011). In vivo, the NAIP5-NLRC4 inflammasome was required for sepsis-induced mortality by an Escherichia coli pathobiont or by systemic delivery of intracellular-targeted flagellin, although partial redundancy to other Naip paralogs was apparent (Ayres et al., 2012; von Moltke et al., 2012).NAIPs also belong to the IAP family due to three N-terminal BIR domains; but whether they actually function as inhibitors of apoptosis is controversial. Some studies show direct binding and inhibition of caspase-3 and -9 (Maier et al., 2002; Davoodi et al., 2004, 2010), but others do not (Roy et al., 1997). Also, NAIPs lack certain caspase-interaction residues within the BIR domains that would be necessary for direct inhibition of caspases, raising concern about whether NAIP can inhibit caspases in physiological settings (Scott et al., 2005; Eckelman and Salvesen, 2006; Eckelman et al., 2006). Additionally, NAIPs mediate inflammasome-induced caspase-1 activation and induction of pyroptosis via NLRC4, which is contrary to the suggested inhibitor of apoptosis function (Kofoed and Vance, 2012). BIR domains, however, can mediate a broad range of protein–protein interactions and therefore could be implicated in diverse cellular functions in addition to inhibition of caspases. In NAIPs, the BIR domains appeared to be necessary for NLRC4 inflammasome formation and activation of caspase-1 (Kofoed and Vance, 2011).A mouse model lacking all Naip paralogs has not been available, preventing definitive analysis of NAIPs physiological function. In this study, we describe the first complete Naip1-6 knockout mice and demonstrate a crucial role for NAIPs in preventing colonic tumor initiation and progression.     

Platelet-albumin-bilirubin score-a predictor of outcome of acute variceal bleeding in patients with cirrhosis

BACKGROUND The albumin-bilirubin(ALBI) score was validated as a prognostic indicator in patients with liver disease and hepatocellular carcinoma. Incorporating platelet count in the platelet-albumin-bilirubin(PALBI) score improved validity in predicting outcome of patients undergoing resection and ablation.AIM To evaluate the PALBI score in predicting outcome of acute variceal bleeding in patients with cirrhosis.METHODS The data of 1517 patients with cirrhosis presenting with variceal bleeding were analyzed. Child Turcotte Pugh(CTP) class, Model of End-stage Liver Disease(MELD), ALBI and PALBI scores were calculated on admission, and were correlated to the outcome of variceal bleeding. Areas under the receivingoperator characteristic curve(AUROC) were calculated for survival and rebleeding.RESULTS Mean age was 52.6 years; 1176 were male(77.5%), 69 CTP-A(4.5%), 434 CTP-B(29.2%), 1014 CTP-C(66.8%); 306 PALBI-1(20.2%), 285 PALBI-2(18.8%), and 926 PALBI-3(61.1%). Three hundred and thirty-two patients died during hospitalization(21.9%). Bleeding-related mortality occurred in 11% of CTP-B,28% of CTP-C, in 21.8% of PALBI-2 and 34.4% of PALBI-3 patients. The AUROC for predicting survival of acute variceal bleeding was 0.668, 0.689, 0.803 and 0.871 for CTP, MELD, ALBI and PALBI scores, respectively. For predicting rebleeding the AUROC was 0.681, 0.74, 0.766 and 0.794 for CTP, MELD, ALBI and PALBI scores, respectively.CONCLUSION PALBI score on admission is a good prognostic indicator for patients with acute variceal bleeding and predicts early mortality and rebleeding.