Measles pneumonitis, an important cause to recognize in the era of COVID-19: a case report.

Measles is an acute febrile viral illness with a characteristic rash. It is usually present in children. Due to the vaccine's development and wide use, serious complications are quite infrequent in vaccine-covered areas. Case Presentation: A 36-year-old immunocompetent woman presented with a fever and a macular rash affecting the face and upper trunk. She was found to have transaminitis and later developed bilateral pulmonary infiltrates with decreased oxygen saturation. After extensive work, the measles PCR returned positive results. The patient was treated conservatively until she recovered. Discussion: Measles pneumonitis is a rare complication that usually occurs in immunosuppressed patients. Due to the coronavirus disease pandemic, diagnosis can be difficult, especially if the presentation is not classic. Conclusion: We report this case to emphasize the importance of correct diagnosis and proper management.

Challenges and promise of targeting miRNA in rheumatic diseases: a computational approach to identify miRNA association with cell types, cytokines, and disease mechanisms.

MicroRNAs (miRNAs) are small non-coding RNAs that alter the expression of target genes at the post-transcriptional level, influencing diverse outcomes in metabolism, cell differentiation, proliferation, cell survival, and cell death. Dysregulated miRNA expression is implicated in various rheumatic conditions, including ankylosing spondylitis (AS), gout, juvenile idiopathic arthritis (JIA), osteoarthritis (OA), psoriatic arthritis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE) and systemic sclerosis. For this review, we used an open-source programming language- PowerShell, to scan the massive number of existing primary research publications on PubMed on miRNAs in these nine diseases to identify and count unique co-occurrences of individual miRNAs and the disease name. These counts were used to rank the top seven most relevant immuno-miRs based on their research volume in each rheumatic disease. Individual miRNAs were also screened for publication with the names of immune cells, cytokines, and pathological processes involved in rheumatic diseases. These occurrences were tabulated into matrices to identify hotspots for research relevance. Based on this information, we summarize the basic and clinical findings for the top three miRNAs - miR-146, miR-155, and miR-21 - whose relevance spans across multiple rheumatic diseases. Furthermore, we highlight some unique miRNAs for each disease and why some rheumatic conditions lack research in this emerging epigenetics field. With the overwhelming number of publications on miRNAs in rheumatic diseases, this review serves as a 'relevance finder' to guide researchers in selecting miRNAs based on the compiled existing knowledge of their involvement in disease pathogenesis. This approach applies to other disease contexts with the end goal of developing miRNA-based therapeutics.

Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts.

Extracellular sulfatase-2 (Sulf-2) influences receptor-ligand binding and subsequent signaling by chemokines and growth factors, yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis (RA). In the present study, we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts (RASFs). Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice. RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated ~2500 genes compared to scrambled siRNA. Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA. Western blot, ELISA, and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1, VCAM1, CAD11, PDPN, CCL5, CX3CL1, CXCL10, and CXCL11. Signaling studies identified the protein kinase C-delta (PKCδ) and c-Jun N-terminal kinase (JNK) pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion. Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation. Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδ and JNK, thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs. Interestingly, Sulf-2 expression positively correlated with the expression of TNF receptor 1, and coimmunoprecipitation assays demonstrated the binding of these two proteins, suggesting they exhibit crosstalk in TNF-α signaling. This study identified a novel role of Sulf-2 in TNF-α signaling and the activation of RA synoviocytes, providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway.

TGF ß-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1ß-induced TAK1 phosphorylation-a prerequisite for and indicator of its functional potential-by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs.

Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance.

Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

Giant right atrium in a foetus.

Giant right atrium is a rarely reported condition, especially in intrauterine life. It may be mistaken with pericardial effusion and Ebstein's anomaly, which are more common causes of right atrial enlargement. We present a case of prenatal diagnosis of giant right atrium detected at 29 weeks of gestation by fetal echocardiography.

Hydrophilic polymers as release modifiers for primaquine phosphate: Effect of polymeric dispersion

Primaquine (PQ), a synthetic compound with potent antimalarial activity is characterized by low plasma half life, requiring frequent administration leading to several undesired side effects, patient incompliance. The objective of the present study was to design an extended release formulation incorporating PQ in hydrophillic matrix composed of HPMC,Sodium CMC, Sodium alginate. Effects of polymeric dispersions of ethyl cellulose (EC) and polyvinylpyrrolidone (PVP) was also studied. Tablets were prepared by wet granulation method. The results of angle of repose (<30) and compressiblity index (upto 15%) indicate good flow properties. Tablets were subjected to weight variation, hardness, friability and drug content tests. The swelling and drug release profile were investigated under dissolution condition. The result showed that the swelling index & release retarding capacity follows HPMC>Sodium CMC>Sodium alginate, which was further sustained by polymeric dispersions of EC and PVP. The kinetics of drugs showed extended release of up to 20 hrs (F3) following non fickian diffusion (0.45

La primaquina (PQ), un compuesto sintético con actividad antimalaria fuerte, se caracteriza por tener una vida media de plasma baja, lo que requiere una administración frecuente y provoca varios efectos colaterales no deseados, con inconformidad del paciente. El objetivo del estudio actual fue diseñar una formulación de liberación prolongada que incorpora PQ en una matriz hidrofílica compuesta de HPMC, CMC de sodio y alginato de sodio. Se estudiaron también los efectos de las dispersiones poliméricas de etilcelulosa (EC) y polivinilpirrolidona (PVP). Los comprimidos se prepararon según el método de granulación húmeda. Los resultados de la respuesta de ángulo (<30) y el índice de compresibilidad (hasta el 15%) mostraron propiedades de flujo buenas. Los comprimidos se sometieron a pruebas de variación de peso, dureza, friabilidad y contenido de fármaco. La hinchazón y el perfil de liberación del fármaco se investigaron bajo condiciones de disolución. Los resultados mostraron que el índice de inflamación y la capacidad retardada de liberación son mayores con HPMC que con CMC de sodio, y que estos a su vez son mayores que con alginato de sodio, los cuales fueron más sostenidos por dispersiones poliméricas de EC y PVC. La cinética de los fármacos mostró una liberación prolongada de hasta 20 horas (F3) siguiendo una difusión no de Fick (0,45

Portability of tag SNPs across isolated population groups: an example from India.

Isolated population groups are useful in conducting association studies of complex diseases to avoid various pitfalls, including those arising from population stratification. Since DNA resequencing is expensive, it is recommended that genotyping be carried out at tagSNP (tSNP) loci. For this, tSNPs identified in one isolated population need to be used in another. Unless tSNPs are highly portable across populations this strategy may result in loss of information in association studies. We examined the issue of tSNP portability by sampling individuals from 10 isolated ethnic groups from India. We generated DNA resequencing data pertaining to 3 genomic regions and identified tSNPs in each population. We defined an index of tSNP portability and showed that portability is low across isolated Indian ethnic groups. The extent of portability did not significantly correlate with genetic similarity among the populations studied here. We also analyzed our data with sequence data from individuals of African and European descent. Our results indicated that it may be necessary to carry out resequencing in a small number of individuals to discover SNPs and identify tSNPs in the specific isolated population in which a disease association study is to be conducted.

DNA sequence variation and haplotype structure of the ICAM1 and TNF genes in 12 ethnic groups of India reveal patterns of importance in designing association studies.

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies.

Inhibition of platelet aggregation by rat trophoblasts.

OBJECTIVE: To determine the effect of rat trophoblast cell suspensions on adenosine diphosphate (ADP)-induced platelet aggregation. MATERIALS AND METHODS: The trophoblasts were isolated from ectoplacental cones (a preplacental tissue very rich in trophoblasts) developed in rat embryos on day 12 of pregnancy (normal period of gestation: 22-23 days). Platelet-rich plasma (PRP) was obtained from adult male rats. The trophoblasts were preincubated (37 degrees C, 30 min), suspended in the medium, and then re-incubated with PRP for 3-5 min. RESULTS: 5 x 10(4) and 7 x 10(4) trophoblasts inhibited ADP-induced platelet aggregation by 10 and 18%, respectively. When the trophoblast cell concentration was increased to 1-2 x 10(5) cells, a proaggregatory phenomenon was observed, even in the absence of ADP. However, there was no inhibition of aggregation or promotion of aggregation when fixed trophoblasts or live endometrial stromal cells were incubated with PRP. CONCLUSION: The results indicate that the aggregation inhibition response was cell specific and concentration dependent. A 68-kD protein was detected in the medium when it was conditioned with 5-7 x 10(4) but not with 1-2 x 10(5) trophoblasts. However, the inhibitory or stimulatory effect does not seem to be dependent on the presence of this protein.

Ontogeny of adenosine deaminase in developing trophoblast and decidual cells of rat and hamster.

The enzyme adenosine deaminase (ADA) is expressed at high level in the tissue of foeto-maternal interface during early pregnancy. As the main constituents of this interface are trophoblast (TR) and decidual cells (DC), the enzyme was estimated in isolated TR and DC to determine the extent of contribution by the respective cells. The enzyme level was estimated in cytosolic fraction, cell lysate and in conditioned media of these cells in rat and hamster. In both species the concentration of ADA was found to be markedly high in cytosolic fraction over to the cell lysate and the conditioned media in both TR and DC. Species-wise, it was higher in hamster. Cell-wise, the enzyme activity was significantly higher in TR than DC in rat but equal in hamster. In the conditioned medium, also, the enzyme activity was higher in TR in both species. The inference drawn from the results are: 1) the maximum enzyme activity in cytosolic fraction of TR and DC of both species clearly indicates equal involvement of the cells that constitute foeto-maternal unit, 2) the enhanced level of enzyme in TR and DC of hamster over to those of rat is possibly due to the higher proliferative activity in the cells of this species because of shorter gestation (16-17 days in hamster and 22-23 days in rats).

Effect of inhibitors of enzymes involved in polyamine biosynthesis pathway on pregnancy in mouse and hamster.

The syntheses of polyamines, which play a definitive role in cell proliferation and tissue growth during early embryogenesis, are believed to be principally regulated by two enzymes: ornithine decarboxylase (ODC) and polyamine oxidase (PAO). However, when the level of enzyme ODC goes down, another enzyme known as S-adenosyl methyl decarboxylase (SAMDC) is believed to up-regulate the biosynthetic pathway. In the present study, the effects of inhibitors of enzymes SAMDC and PAO were determined in mated hamster and mouse in peri-and immediate postimplantation stages of pregnancy. It was noticed that, whereas the SAMDC inhibitor (MDL-73815) failed to arrest the pregnancy in the hamster in spite of raising the dose to 100 mg/kg, the PAO inhibitor (MDL-72527DA) was found to be 100% effective at 75 mg/kg in both species. The results confirmed the role of enzyme PAO in promoting early development of the embryo.