Comparison of indapamide and low-dose hydrochlorothiazide monotherapy in black patients with mild to moderate hypertension

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Relationships between plasma amino acid concentrations and blood pressure in South Africans of African descent

Oral supplementation with the amino acid arginine, the precursor of the vasodilator nitric oxide (NO), is associated with a reduction in blood pressure (BP). However, it is uncertain whether a decreased plasma arginine concentration predicts increases in BP. We assessed the relationship between fasting plasma arginine or other amino acid concentrations and 24 hour ambulatory BP in 75 nevertreated participants recruited from the Johannesburg area, 55 of whom were male. Plasma amino acid concentrations were measured with high performance liquid chromatography-mass-spectrometry. Plasma arginine concentrations were not inversely correlated with ambulatory BP. However, plasma arginine concentrations were increased in 36 participants with a mean daytime systolic BP >140 mm Hg (61 ± 17 μmol/L) as compared to the remaining participants (54 ± 15 μmol/L, p‹0.05). Moreover, plasma arginine concentrations were positively correlated with 24-hour diastolic BP (r=0.26, p‹0.05). In males with a BMI‹30kg/m2, plasma arginine concentrations were positively correlated with both night diastolic (r=0.46, p‹0.005) and systolic (r=0.42, p‹0.005) BP. In a multivariate model with adjustments for age gender, body mass index, and other amino acid concentrations, plasma arginine concentrations were independently and positively associated with night diastolic BP (p‹0.05). In conclusion plasma arginine concentrations are positively associated with ambulatory BP in a group of participants of African descent in South Africa. These data do not support the notion that deficiencies of arginine, the amino acid substrate for NO, are related to increases in BP in groups of African ancestry living in South Africa. However, as with other ethnic groups, the positive relationship between plasma arginine concentrations and BP suggests a reduced capacity to utilise the amino acid substrate for NO synthesis

Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology

In hepatic schistosomiasis, pathology arises when schistosome eggs become lodged in the host liver, evoking an interleukin 4 (IL-4)- and IL-13-mediated dominant CD4+ Th2 immune response. This response leads to the development of granulomas and fibrosis, with eosinophils, neutrophils, macrophages, hepatic stellate cells, and lymphocytes all identified as major cellular contributors to these events. This review outlines the cellular and molecular mechanisms of hepatic schistosomiasis, with an emphasis on the major cellular components and their release of chemokines. The differences between Schistosoma mansoni- and Schistosoma japonicum-induced hepatic granuloma are also discussed. This comprehensive overview of the processes associated with hepatic schistosomiasis may provide new insights into improved treatment for both schistosomiasis and other granulofibrotic diseases

Transient expression of Interleukin-21 in the second hit of acute pancreatitis may potentiate immune paresis in severe acute pancreatitis

OBJECTIVES : Interleukin-21 (IL-21) is a cytokine associated with tissue inflammation, autoimmune and infectious diseases. Organ dysfunction and death can occur in patients with acute pancreatitis (AP) in two distinct clinical phases. Initially, a systemic inflammatory response syndrome may be followed by systemic sepsis from infected pancreatic necrosis, known as the “second hit.” The expression and possible role of IL-21 in AP has not been established. METHODS : Thirty-six patients with mild, moderate, and severe AP (SAP) were enrolled. Peripheral blood samples of patients were drawn on days 7, 9, 11, and 13. Reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assay were performed to determine the expression and concentration of IL-21. RESULTS : Interleukin-21 mRNA levels increased significantly at day 9 in severe (P = 0.002) pancreatitis compared with both the mild and control patient groups. At the protein level, IL-21 was elevated in SAP patients compared with those with mild pancreatitis, although this was not significant. Furthermore, day 9 IL-21 was elevated in septic SAP patients and patients with pancreatic necrosis. CONCLUSIONS : Interleukin-21 is transiently elevated in SAP compared with the mild/moderate group, and hence IL-21 may contribute to the immune imbalance that occurs in AP.Grants from SAGES (Abbott Research Award), Discovery Foundation, Wits Donald Gordon Medical Centre, and The University of the Witwatersrand Individual Research Grant (001283844110151211055142) and Seed Funding Grant (001251844110151211050000000000000000 4550).http://www.pancreasjournal.com2020-01-01hj2019Surger

Transcriptional profiling of the oesophageal gland region of male worms of Schistosoma mansoni

The intestinal tract of schistosomes opens at the mouth and leads into the foregut or oesophageal region that is lined with syncytium continuous with the apical cytoplasm of the tegument. The oesophagus is surrounded by a specialised gland, the oesophageal gland. This gland releases materials into the lumen of the oesophagus and the region is thought to initiate the lysis of erythrocytes and neutralisation of immune effectors of the host. The oesophageal region is present in the early invasive schistosomulum, a stage potentially targetable by anti-schistosome vaccines. We used a 44k oligonucleotide microarray to identify highly up-regulated genes in microdissected frozen sections of the oesophageal gland of male worms of S. mansoni. We show that 122 genes were up-regulated 2-fold or higher in the oesophageal gland compared with a whole male worm tissue control. The enriched genes included several associated with lipid metabolism and transmembrane transport as well as some micro-exon genes. Since the oesophageal gland is important in the initiation of digestion and the fact that it develops early after invasion of the mammalian host, further study of selected highly up-regulated functionally important genes in this tissue may reveal new anti-schistosome intervention targets for schistosomiasis control. (C) 2014 Elsevier B.V. All rights reserved

Defining a proinflammatory neutrophil phenotype in response to Schistosome eggs

Neutrophils contribute to the pathological processes of a number of inflammatory disorders, including rheumatoid arthritis, sepsis and cystic fibrosis. Neutrophils also play prominent roles in schistosomiasis japonica liver fibrosis, being central mediators of inflammation following granuloma formation. In this study, we investigated the interaction between Schistosoma japonicum eggs and neutrophils, and the effect of eggs on the inflammatory phenotype of neutrophils. Our results showed significant upregulated expression of pro-inflammatory cytokines (IL-1α, IL-1β and IL-8) and chemokines (CCL3, CCL4 and CXCL2) in neutrophils after 4 h in vitro stimulation with S. japonicum eggs. Furthermore, mitochondrial DNA was released by stimulated neutrophils, and induced the production of matrix metalloproteinase 9 (MMP-9), a protease involved in inflammation and associated tissue destruction. We also found that intact live eggs and isolated soluble egg antigen (SEA) triggered the release of neutrophil extracellular traps (NETs), but, unlike those reported in bacterial or fungal infection, NETs did not kill schistosome eggs in vitro. Together these show that S. japonicum eggs can induce the inflammatory phenotype of neutrophils, and further our understanding of the host-parasite interplay that takes place within the in vivo microenvironment of schistosome-induced granuloma. These findings represent novel findings in a metazoan parasite, and confirm characteristics of NETs that have until now, only been observed in response to protozoan pathogens

Transcriptional profiling of chronic clinical hepatic schistosomiasis japonica indicates reduced metabolism and immune responses

SUMMARYSchistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and was the most upregulated gene in schistosomiasis only patients, all of which presented with hepatomegaly. The unique features of gene expression, in conjunction with previous reports in the murine model of the cellular composition of granulomas, granuloma formation and recovery, provide an increased understanding of the molecular immunopathology and general physiological processes underlying hepatic schistosomiasis.</jats:p

Characterising granuloma regression and liver recovery in a murine model of schistosomiasis japonica

For hepatic schistosomiasis the egg-induced granulomatous response and the development of extensive fibrosis are the main pathologies. We used a Schistosoma japonicum-infected mouse model to characterise the multi-cellular pathways associated with the recovery from hepatic fibrosis following clearance of the infection with the anti-schistosomal drug, praziquantel. In the recovering liver splenomegaly, granuloma density and liver fibrosis were all reduced. Inflammatory cell infiltration into the liver was evident, and the numbers of neutrophils, eosinophils and macrophages were significantly decreased. Transcriptomic analysis revealed the up-regulation of fatty acid metabolism genes and the identification of Peroxisome proliferator activated receptor alpha as the upstream regulator of liver recovery. The aryl hydrocarbon receptor signalling pathway which regulates xenobiotic metabolism was also differentially up-regulated. These findings provide a better understanding of the mechanisms associated with the regression of hepatic schistosomiasis. (C) 2016 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved