Pregnancy and inflammatory bowel diseases: Current perspectives,risks and patient management

Inflammatory bowel diseases(IBD) are chronic idiopathic inflammatory conditions characterized by relapsing and remitting episodes of inflammation which can affect several different regions of the gastrointestinal tract, but also shows extra-intestinal manifestations. IBD is most frequently diagnosed during peak female reproductive years, with 25% of women with IBD conceiving after their diagnosis. While IBD therapy has improved dramatically with enhanced surveillance and more abundant and powerful treatment options, IBD disease can have important effects on pregnancy and presents several challenges for maintaining optimal outcomes for mothers with IBD and the developing fetus/neonate. Women with IBD, the medical team treating them(both gastroenterologists and obstetricians/gynecologists) must often make highly complicated choices regarding conception, pregnancy, and post-natal care(particularly breastfeeding) related to their choice of treatment options at different phases of pregnancy as well as post-partum. This current review discusses current concerns and recommendations for pregnancy duringIBD and is intended for gastroenterologists, general practitioners and IBD patients intending to become,(or already) pregnant, and their families. We have addressed patterns of IBD inheritance, effects of IBD on fertility and conception(in both men and women), the effects of IBD disease activity on maintenance of pregnancy and outcomes, risks of diagnostic procedures during pregnancy and potential risks and complications associated with different classes of IBD therapeutics. We also have evaluated the clinical experience using "top-down" care with biologics, which is currently the standard care at our institution. Post-partum care and breastfeeding recommendations are also addressed.     

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 μM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration-dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 μM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 μM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF.     

Changes in phosphorylation of CREB, ERK, and c-fos induction in rat ventral tegmental area, hippocampus and prefrontal cortex after conditioned place preference induced by chemical stimulation of lateral hypothalamus

Experimental evidence indicates that chemical stimulation of lateral hypothalamus (LH) by carbachol can produce conditioned place preference (CPP) in rats. Several lines of evidence have shown that cAMP-response element binding protein (CREB), extracellular signal-regulated kinase (ERK), and c-fos have pivotal role in CPP induced by drugs of abuse, such as morphine, cocaine, nicotine, and alcohol. Therefore, in the present study, we investigated the changes in phosphorylated-CREB (p-CREB) and -ERK (p-ERK), and c-fos induction within ventral tegmental area (VTA), hippocampus and prefrontal cortex (PFC) after the acquisition of CPP induced by intra-LH administration of carbachol. Animals were unilaterally implanted by cannula into LH. For chemical stimulation of LH, carbachol (250 nmol/0.5 μl saline) was microinjected once each day, during 3-day conditioning phase (acquisition period) of CPP paradigm. After the acquisition period, the brains were removed, and p-CREB and p-ERK, and c-fos induction in the ipsilateral VTA, hippocampus and PFC were measured by Western blot analysis. The results indicated a significant increase in level of phosphorylated CREB (P<0.01) in VTA, and PFC (P<0.05), during LH stimulation-induced CPP, while its level decreased in hippocampus (P<0.05). Also, in aforementioned regions, an increase in c-fos level was observed, but this enhancement in PFC was not significant. Moreover, p-ERK changed in these areas, but not significantly. Our findings suggest that studying the intracellular signals and their changes, such as phosphorylated-CREB, can elucidate a functional relationship between LH and other brain structures involved in reward processing in rats.     

Proinflammatory Cytokine Gene Polymorphisms in Irritable Bowel Syndrome

Introduction

Irritable bowel syndrome (IBS) is a multifactorial functional gastrointestinal disorder, characterized by recurrent abdominal pain and altered bowel habits. Proinflammatory cytokines can play an important role in intestinal inflammation, while their production is under genetic control.

Methods

This study was performed in a group of patients with IBS to analyze the genotype frequencies of a number polymorphic genes coding for proinflammatory cytokine (interleukin-6 (IL), tumor necrosis factor-alpha (TNF-α), and IL-1 group). Using polymerase chain reaction with sequence-specific primers method, the cytokine genes were amplified, and alleles and genotypes of 71 patients with IBS were detected on gel electrophoresis, and the results were compared with healthy control subjects.

Results

Results of the analyzed data showed that the frequencies IL-1R C allele at position Pst-I 1970 (P?=?0.017), IL-6 G allele at position ?174 (P?=?0.002), and TNF-α G allele at position ?238 (P?<?0.001) in the patient group were significantly higher than the control group. IL-6 GG genotype (?174) and TNF-α GG genotype (?238) in the patient group were also significantly overrepresented (P?<?0.001), while IL-6 CG genotype (?174) and TNF-α GA genotype (?238) were significantly decreased in the patients with IBS (P?<?0.001). The frequencies of IL-6 (?174, nt565) GG haplotype and TNF-α (?308, ?238) GG haplotype were also significantly higher in the patient group (P?<?0.001), whereas the frequencies of the haplotypes IL-6 CG and TNF-α GA were significantly decreased in the patients with IBS (P?<?0.001).

Conclusion

IL-6 and TNF-alpha proinflammatory cytokine gene polymorphisms could change individual susceptibility to IBS and might have a role in pathophysiology of disease.     

T-Helper 1, T-Helper 2, and T-Regulatory Cytokines Gene Polymorphisms in Irritable Bowel Syndrome

Inflammation and mucosal immune system activation have an important role in irritable bowel syndrome (IBS), whereas genetic factors can control some immunological mediators. In this study, a number of polymorphic genes coding for T-helper 1, T-helper 2, and T-regulatory cytokines were genotyped in 71 patients with IBS, and the results were compared with controls. IL-4 CC genotype at position −590, IL-4 TT genotype at position −33, and IL-10 GA genotype at position −1082 were significantly overrepresented in the patients with IBS in comparison with controls (P < 0.001). The frequencies of the following haplotypes in the patient group were significantly higher than in the control group: IL-2 (−330, +160) GT haplotype (P = 0.002), IL-4 (−1098, −590, −33) TCC haplotype (P < 0.001), and TCT haplotype (P < 0.001). While production of cytokines could be affected by genetic polymorphisms within coding and promoter regions of cytokine genes, IL-4 and IL-10 gene polymorphisms could affect individual susceptibility to IBS.     

Pathologic significance of the "dural tail sign"

Objective

The exact nature of the “dural tail sign” (thickening of the dura adjacent to the tumour in contrast enhanced T1-MRI imaging) is still not clearly established. In this study we tried to verify the histological appearance of the “dural tail sign” and probable correlation between different MRI findings and dural tail histology.

Material and methods

In this study, 129 patients with intracranial lesions underwent MRI imaging with 1.5 T scanner. The “dural tail sign” was defined using Goldsher et al. criteria. Size and pattern of enhancement of the tumour and adjacent dura was noted in MRI and in the pathologic samples, dural tail and the dura beneath the tumour was assessed.

Results

In 30 cases, “dural tail sign” was evident on MRI, dural tail noted in 17 of these cases in histological samples (12 meningiomas, 3 pituitary adenomas and 2 schwannomas). All of them had vessel dilatation, 6 showed tumoural invasion, 4 demonstrated intravascular growth of the lesion and 1 showed inflammation of the dura.

Conclusion

In our study MRI findings failed to predict tumoural invasion of the dural tail in histologic samples and because of frequent presence of tumour nests in it, the dura matter should be resected as widely as possible.     

Decades of Genetic Research on Soybean mosaic virus Resistance in Soybean

This review summarizes the history and current state of the known genetic basis for soybean resistance to Soybean mosaic virus (SMV), and examines how the integration of molecular markers has been utilized in breeding for crop improvement. SVM causes yield loss and seed quality reduction in soybean based on the SMV strain and the host genotype. Understanding the molecular underpinnings of SMV–soybean interactions and the genes conferring resistance to SMV has been a focus of intense research interest for decades. Soybean reactions are classified into three main responses: resistant, necrotic, or susceptible. Significant progress has been achieved that has greatly increased the understanding of soybean germplasm diversity, differential reactions to SMV strains, genotype–strain interactions, genes/alleles conferring specific reactions, and interactions among resistance genes and alleles. Many studies that aimed to uncover the physical position of resistance genes have been published in recent decades, collectively proposing different candidate genes. The studies on SMV resistance loci revealed that the resistance genes are mainly distributed on three chromosomes. Resistance has been pyramided in various combinations for durable resistance to SMV strains. The causative genes are still elusive despite early successes in identifying resistance alleles in soybean; however, a gene at the Rsv4 locus has been well validated.     

Functional polyamine metabolic enzymes and pathways encoded by the virosphere

Viruses produce more viruses by manipulating the metabolic and replication systems of their host cells. Many have acquired metabolic genes from ancestral hosts and use the encoded enzymes to subvert host metabolism. The polyamine spermidine is required for bacteriophage and eukaryotic virus replication, and herein, we have identified and functionally characterized diverse phage- and virus-encoded polyamine metabolic enzymes and pathways. These include pyridoxal 5′-phosphate (PLP)-dependent ornithine decarboxylase (ODC), pyruvoyl-dependent ODC and arginine decarboxylase (ADC), arginase, S-adenosylmethionine decarboxylase (AdoMetDC/speD), spermidine synthase, homospermidine synthase, spermidine N-acetyltransferase, and N-acetylspermidine amidohydrolase. We identified homologs of the spermidine-modified translation factor eIF5a encoded by giant viruses of the Imitervirales. Although AdoMetDC/speD is prevalent among marine phages, some homologs have lost AdoMetDC activity and have evolved into pyruvoyl-dependent ADC or ODC. The pelagiphages that encode the pyruvoyl-dependent ADCs infect the abundant ocean bacterium Candidatus Pelagibacter ubique, which we have found encodes a PLP-dependent ODC homolog that has evolved into an ADC, indicating that infected cells would contain both PLP- and pyruvoyl-dependent ADCs. Complete or partial spermidine or homospermidine biosynthetic pathways are found encoded in the giant viruses of the Algavirales and Imitervirales, and in addition, some viruses of the Imitervirales can release spermidine from the inactive N-acetylspermidine. In contrast, diverse phages encode spermidine N-acetyltransferase that can sequester spermidine into its inactive N-acetyl form. Together, the virome-encoded enzymes and pathways for biosynthesis and release or biochemical sequestration of spermidine or its structural analog homospermidine consolidate and expand evidence supporting an important and global role of spermidine in virus biology.

The polyamine spermidine (Fig. 1) is a metabolically primordial polycation found throughout bacteria, archaea, and eukaryotes (1). It is a fundamental molecule of life that was likely present in the last universal common ancestor (2). In Escherichia coli, 90% of spermidine is noncovalently bound to RNA (3) and is required for efficient translational elongation by the ribosome (4). Spermidine increases global messenger RNA (mRNA) translation in E. coli by facilitating the queuosine modification of specific tRNA anticodon wobble bases (4). Consistent with these findings, in strains of E. coli deleted for genes that modify the anticodon wobble position in transfer RNAs (tRNAs), spermidine becomes absolutely essential for growth (5), which may be due to spermidine-mediated stabilization of the tRNA interaction with the translating ribosome. Spermidine is not only important for growth of bacteria; over 40 y ago, it was shown that T4 and T7 bacteriophages replicated more slowly in a spermidine-deficient mutant of E. coli (6). Replication of JG004 and N4-like phages in Pseudomonas aeruginosa PAO1 is absolutely dependent on spermidine (7, 8).Open in a separate windowFig. 1.Polyamine metabolic pathways. Pathways biochemically characterized herein are indicated by blue arrows and blue enzyme names.In eukaryotic cells, spermidine is universally required for growth and cell proliferation. An aminobutyl moiety of spermidine (Fig. 1) is transferred by deoxyhypusine synthase (DHS) to a single lysine of the translation factor eIF5A to eventually form the essential hypusine posttranslational modification (9). Hypusinated eIF5a is needed for translation of mRNAs encoding proline-rich motifs and for translation termination (10). Replication of eukaryotic RNA viruses is highly dependent on host spermidine (11), and spermidine-derived hypusination of host eIF5a is required for Ebola virus replication and is considered a potential target to inhibit viral replication (12).Viruses reprogram the metabolism of host cells to make more virions by redirecting expression and activity of host-encoded enzymes and by expressing virus-encoded enzymes. Using homology-based approaches, nucleocytoplasmic large DNA viruses have been found to encode homologs of enzymes involved in nitrogen metabolism, glycolysis, and the tricarboxylic acid cycle (13). Bacteriophages have been found to encode homologs of enzymes involved in inorganic sulfur metabolism (14) and nucleotide metabolism (15). The eukaryotic chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1) encodes an entire functional biosynthetic pathway for production of homospermidine (Fig. 1), a structural analog of spermidine, consisting of L-arginine decarboxylase (ADC), agmatine deiminase/iminohydrolase (AIH), N-carbamoylputrescine amidohydrolase (NCPAH), and homospermidine synthase (HSS) (16–18). In addition, PBCV-1 encodes a polyamine N-acetyltransferase (19). A biochemically functional HSS enzyme is encoded by Ralstonia phage ϕRSL1 (20). Considering the importance of polyamines to phage and virus replication, we sought to systematically identify and functionally characterize polyamine metabolic enzymes and pathways encoded in phage and virus genomes. Some of the taxonomic affiliations of giant viruses included in our study are based on a recently published hierarchical taxonomy for the Nucleocytoviricota (21).