The specific dermatoses of pregnancy are rare and consist of pemphigoid gestationis (PG), intrahepatic cholestasis of pregnancy (ICP), polymorphic eruption of pregnancy and atopic eruption of pregnancy. The dermatoses are characterized by pruritus, and they are important to recognize since PG and ICP increase the risk of prematurity, fetal distress and stillbirth. Diagnosis is based on medical history, morphology, blood sample and biopsy. The dermatoses are treated with respectively ursodeoxycholic acid (in case of ICP) and steroids. Breast-feeding is recommended and induction of labour is not normally indicated.
In Islam, the month of Ramadan is a period of fasting lasting 29 or 30 days. Epidemiological studies among Muslims in Denmark have not been conducted, but studies show, that fasting among pregnant Muslim women is common. Fasting does not increase the risk of growth restriction or preterm delivery, but there are reports of decreased foetal movements. Furthermore, the fasting may have long-term health consequences for the offspring, especially when they reach their middle age. According to Islam and the interpretation, pregnant and breast-feeding women are allowed to postpone the fasting of the month of Ramadan to a later period.
Dentin matrix protein 1 (DMP1) is a noncollagenous protein important for the mineralization of bones and teeth. Examination of the transcription factor binding sites within the 6.24?kb upstream sequence of rat DMP1 promoter by Matinspector software revealed that TCF11 had the highest number (six) of binding sites with 100% matrix similarity. Four of these sites are conserved in the mouse DMP1 promoter. TCF11 is a member of the Cap-n-Collar (cnc) family of basic leucine zipper transcription factors. Results from this study showed that TCF11 can bind specifically to the DMP1 promoter and activate its transcription in odontoblasts and osteoblasts. This could be attributed to both direct and indirect effects of TCF11. Electrophoretic mobility shift (EMSA) assay showed differential interaction between TCF11 and its binding sites on the DMP1 promoter. 21?bp oligos spanning the TCF11 matrix were used as probes in EMSA, and the results showed that the binding was specific to the sequence of the TCF11 matrix as well as the flanking sequences and this is typical of a heterodimer binding site. Results also showed changes in the binding pattern when cells were differentiated in osteogenic medium for 2?d. Thus, TCF11 may play an important role in the transcriptional regulation of DMP1 gene.
The blood-brain barrier (BBB) is structurally unique and regulates what is transported into and out of the brain, thereby maintaining brain homeostasis. In inflammatory settings the BBB becomes leaky, regulation of transport is lost and neuronal function goes awry. It is caused by a number of mediators such as complement activation products, processes and networks going haywire, the exact cellular and molecular mechanisms of which remain an enigma. Complement activation byproduct, C5a signaling through its G-protein coupled receptor C5aR1/CD88 increased BBB permeability in neuroinflammatory disease settings in vivo. Studies in brain endothelial cells in vitro demonstrated that the C5a/C5aR1 signaling occurred through the NF-?B pathway and altered miRNA in these cells. Inhibition or deletion of C5aR1 was protective in brain, both in vivo and in vitro revealing their potential as possible effective therapeutic targets. Although, this is a field where progress has been made, yet a lot remains to be done due to a number of limitations. This review will deal with the advances in the experimental models, technology and the underlying mechanisms causing the BBB pathology, with an emphasis on the complement proteins and their downstream mechanisms.
Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings.
The thalamus is increasingly gaining importance in psychiatric disorders. There are case reports in the literature of neuropsychiatric symptoms associated with thalamic infarcts. The present report elucidates the complexities of linking neuropsychiatric symptoms to a benign thalamic brain lesion, and its impact on management.
Ground-glass hepatocytes are seen in chronic hepatitis B virus (HBV) infection and are known to harbor pre-S mutants, which are implicated in the pathogenesis of hepatocellular carcinoma (HCC). However, the association between ground-glass hepatocytes and HCC has yet to be clearly elucidated. The aim in the present study was to investigate the association of ground-glass hepatocytes with (1) the histologic characteristics of HBV-related HCC and (2) the grade of inflammation, stage of fibrosis, serologic markers of HBV infection, HBV viral load, and ?-fetoprotein levels. We evaluated 45 hepatectomy specimens from chronic HBV-infected patients: 25 with HCC and 20 without. In comparison with those without HCC, cases with HCC had a significantly higher prevalence of type II ground-glass hepatocytes (84% versus 55%, P = .0488), demonstrating a geographically clustered pattern (84% versus 45%, P = .0102) and exceeding type I in the individual samples (84% versus 35%, P = .0005). Type II ground-glass hepatocytes also had a statistically significant association with higher stages of fibrosis, being present in 21 cases (66%) with Ishak fibrosis stages 3 to 6 as compared with only 4 cases (31%) without type II ground-glass hepatocytes (P = .0176). In conclusion, type II ground-glass hepatocytes are more likely to be present in cases of HCC, growing in a clustered pattern, and are also associated with advanced fibrosis in chronic HBV infection. Our data suggest that a growth advantage or clonal proliferation of hepatocytes with mutant hepatitis B surface antigen may play a role in the pathogenesis of HBV-related HCC with clinical relevance.
Complement factor H (Cfh) is a key regulator of the complement cascade and protects C57BL/6 mice from immune complex-mediated complement-dependent glomerulonephritis. In chronic serum sickness (CSS) there are increased deposits of immune complexes in the glomeruli with inflammation and a scarring phenotype. As cucurmin is an effective anti-inflammatory agent and reduces complement activation, we hypothesized that it should alleviate renal disease in this setting. To determine the effectiveness of curcumin, an apoferritin-induced CSS model in Cfh-deficient (Cfh(-/-)) mice was used. Curcumin treatment (30 mg/kg) given every day in parallel with apoferritin reduced glomerulonephritis and enhanced kidney function (blood urea nitrogen, 45·4 ± 7·5 versus 35·6 ± 5·1; albuminuria, 50·1 ± 7·1 versus 15·7 ± 7·1; glomerulonephritis, 2·62 + 0·25 versus 2 + 0·3, P < 0·05). In line with reduced IgG deposits in mice with CSS given curcumin, C9 deposits were reduced indicating reduced complement activation. Mice treated with curcumin had a significant reduction in the number of splenic CD19(+) B cells and the ratio of CD19 : CD3 cells (P < 0·05) with no change in the T-cell population. Myeloperoxidase assay showed reduced macrophages in the kidney. However, a significant reduction in the M2 subset of splenic macrophages by apoferritin was prevented by curcumin, suggesting a protective function. Curcumin treatment reduced mRNA expression of inflammatory proteins monocyte chemoattractant protein-1 and transforming growth factor-? and matrix proteins, fibronectin, laminin and collagen. Our results clearly illustrate that curcumin reduces glomerulosclerosis, improves kidney function and could serve as a therapeutic agent during serum sickness.
Hepatocellular carcinoma (HCC) is a major complication of cirrhosis and has been increasing in incidence in recent years. Fatty liver disease is an increasingly common cause of chronic liver disease, and there have been several case reports of HCC in patients with non-cirrhotic fatty liver disease. However, there is limited data from systematic studies with histological confirmation of the presence of both the HCC and the non-cirrhotic fatty liver disease.
Inflammation is a key factor in a number of neurodegenerative diseases including systemic lupus erythematosus. The complement system is an important mechanism in initiating and amplifying inflammation. Our recent studies demonstrate that C5a, a protein fragment generated during complement activation could alter the blood-brain barrier integrity, and thereby disturb the brain microenvironment. To understand the mechanism by which this occurs, we examined the effects of C5a on apoptosis, translocation of nuclear factor-?B (NF-?b) and the expression of I?b?, MAPK, CREB and TJ protein, zona occludens (ZO-1) in mouse brain endothelial cells. Apoptosis was examined by DNA laddering and caspase 3 activity and the distribution of the ZO-1 and the p65 subunit of NF-?B were determined by immunofluorescence. Inhibition of CD88 reduced translocation of NF-?b into the nucleus, altered ZO-1 at the interfaces of neighboring cells, decreased caspase 3 activity and prevented apoptosis in these cells. Our results indicate that signaling through CD88 regulates the blood-brain barrier in a NF-?b-dependent manner. These studies suggest that the C5a receptor, CD88 is a promising therapeutic target that will reduce NF-?b-signaling cascades in inflammatory settings.
The incidence of Clostridium difficile infection (CDI) has increased since 2000, with greater numbers of severe cases reported, in part due to the emergence of a hypervirulent strain. Initial therapy with metronidazole is still recommended for mild to moderate CDI, but vancomycin is recommended for first-line therapy of severe CDI. Colectomy could be life-saving for some patients with severe disease that does not respond to maximal medical therapy. Recurrent CDI is a challenge to treat; no single effective therapy currently exists. Treatments include antibiotics, adjunct probiotics, fecal microbiota transplant and immune approaches. This Review discusses the various therapeutic approaches used for the treatment of refractory and recurrent CDI.
Septic encephalopathy is a frequent complication of the sepsis syndrome, with no therapies available that can prevent the associated neurological dysfunction in humans. It is caused by a number of processes and networks going awry, the exact cellular and molecular mechanisms of which remain an enigma. Several mediators of inflammation have been assigned a key role in sepsis, including cytokines, chemokines and complement cascade. With the observations that brain dysfunction in a sepsis setting can be alleviated by regulation of the cytokines and complement proteins in various species of animals, optimism is building for a possible therapy of sepsis-damaged brain. This article reviewed the advances in the understanding of the underlying mechanisms causing pathology in SE, with an emphasis on the inflammatory and excitatory mediators such as the cytokines, complement proteins and neurotransmitters, investigating their potential as possible therapeutic targets.
Respiratory syncytial virus (RSV) is a common cause of bronchiolitis in infants. Although antiinflammatory in nature, glucocorticoids have been shown to be ineffective in the treatment of RSV-induced bronchiolitis and wheezing. In addition, the effectiveness of glucocorticoids at inhibiting RSV-induced proinflammatory cytokine production in cell culture has been questioned. In this study, we have investigated the effect of RSV infection on glucocorticoid-induced gene activation in lung epithelium-derived cells. We show that RSV infection inhibits dexamethasone induction of three glucocorticoid receptor (GR)-regulated genes (glucocorticoid-inducible leucine zipper, FK506 binding protein, and MAPK phosphatase 1) in A549, BEAS-2B cells, and primary small airway epithelial cells. UV irradiation of the virus prevents this repression, suggesting that viral replication is required. RSV is known to activate the nuclear factor ?B (NF?B) pathway, which is mutually antagonistic towards the GR pathway. However, specific inhibition of NF?B had no effect on the repression of GR-induced genes by RSV infection, indicating that RSV repression of GR is independent of NF?B. RSV infection of A549 cells does not alter GR protein levels or GR nuclear translocation but does reduce GR binding to the promoters of the glucocorticoid responsive genes analyzed in this study. Repression of GR by RSV infection may account for the apparent clinical ineffectiveness of glucocorticoids in RSV bronchiolitis therapy. In addition, this data adds to our previously published data suggesting that GR may be a general target for infectious agents. Identifying the mechanisms through which this suppression occurs may lead to the development of novel therapeutics.
Complement receptor 1 (CR1) on human erythrocytes (Es) and complement factor H (CFH) on rodent platelets perform immune adherence, which is a function that allows the processing of immune complexes (ICs) bearing C3 by the mononuclear phagocyte system. Similar immune adherence occurs in the glomerular podocyte by CR1 in humans and CFH in rodents. As a model for human IC processing, we studied transgenic mice lacking CFH systemically but with human CR1 on Es. These CR1(hu)Tg/CFH(-/-) mice spontaneously developed proliferative glomerulonephritis, which was accelerated in a chronic serum sickness model by active immunization with heterologous apoferritin. ICs containing Ag, IgG and C3 bound to Es in CR1(hu)Tg/CFH(-/-) mice. In this setting, there was increased IC deposition in glomeruli, attributable to the presence of CR1 on Es, together with the absence of CFH on platelets and podocytes. In the absence of plasma CFH, the accumulated ICs activated complement, which led to spontaneous and chronic serum sickness-induced proliferative glomerulonephritis. These findings illustrate the complexities of complement-dependent IC processing by blood cells and in the glomerulus, and the importance of CFH as a plasma complement regulator.
To investigate the role of C5a generated on complement activation in brain, the lupus model, MRL/lpr mice were treated with C5a receptor(R) antagonist (ant). Neutrophil infiltration, ICAM, TNF-alpha and iNOS mRNA expression, neuronal apoptosis and the expression of p-JNK, pSTAT1 and p-Erk were reduced and p-Akt increased on C5aR inhibition in MRL/lpr brains. MRL/lpr serum caused increased apoptosis in neurons showing that lupus had a direct effect on these cells. C5aRant pretreatment prevented the lupus serum induced loss of neuronal cells. Our findings demonstrate for the first time that C5a/C5aR signaling plays an important role in the pathogenesis of CNS lupus.
The blood-brain barrier (BBB) is a crucial anatomic location in the brain. Its dysfunction complicates many neurodegenerative diseases, from acute conditions, such as sepsis, to chronic diseases, such as systemic lupus erythematosus (SLE). Several studies suggest an altered BBB in lupus, but the underlying mechanism remains unknown. In the current study, we observed a definite loss of BBB integrity in MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) lupus mice by IgG infiltration into brain parenchyma. In line with this result, we examined the role of complement activation, a key event in this setting, in maintenance of BBB integrity. Complement activation generates C5a, a molecule with multiple functions. Because the expression of the C5a receptor (C5aR) is significantly increased in brain endothelial cells treated with lupus serum, the study focused on the role of C5a signaling through its G-protein-coupled receptor C5aR in brain endothelial cells, in a lupus setting. Reactive oxygen species production increased significantly in endothelial cells, in both primary cells and the bEnd3 cell line treated with lupus serum from MRL/lpr mice, compared with those treated with control serum from MRL(+/+) mice. In addition, increased permeability monitored by changes in transendothelial electrical resistance, cytoskeletal remodeling caused by actin fiber rearrangement, and increased iNOS mRNA expression were observed in bEnd3 cells. These disruptive effects were alleviated by pretreating cells with a C5a receptor antagonist (C5aRant) or a C5a antibody. Furthermore, the structural integrity of the vasculature in MRL/lpr brain was maintained by C5aR inhibition. These results demonstrate the regulation of BBB integrity by the complement system in a neuroinflammatory setting. For the first time, a novel role of C5a in the maintenance of BBB integrity is identified and the potential of C5a/C5aR blockade highlighted as a promising therapeutic strategy in SLE and other neurodegenerative diseases.
The synthesis, structural, and spectral characterization as well as a theoretical study of a family of alkaline-earth-metal acetylides provides insights into synthetic access and the structural and bonding characteristics of this group of highly reactive compounds. Based on our earlier communication that reported unusual geometry for a family of triphenylsilyl-substituted alkaline-earth-metal acetylides, we herein present our studies on an expanded family of target derivatives, providing experimental and theoretical data to offer new insights into the intensively debated theme of structural chemistry in heavy alkaline-earth-metal chemistry.
Health services often manage agitated or violent people, and for emergency psychiatric services such behaviour is particularly prevalent (10%). The drugs used in this situation should ensure that the person swiftly and safely regains composure.
To clarify the obstetric consequences in a second pregnancy after a first singleton pregnancy complicated by spontaneous preterm delivery or preeclampsia and stratified by the variation in fetal growth.
In populations of northern European descent, the p.C282Y mutation in the HFE gene is highly prevalent, and HFE-associated hereditary hemochromatosis is the most common type of inherited iron overload disorder. Inappropriate low secretion of hepcidin, which negatively regulates iron absorption, is postulated to be the mechanism for iron overload in this condition. The characteristic biochemical abnormalities are elevated serum transferrin-iron saturation and serum ferritin. Typical clinical manifestations include cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated serum aminotransferase levels, diabetes mellitus, restrictive cardiomyopathy and arthropathy of the second and third metacarpophalangeal joints. Most patients are now diagnosed before the development of these clinical features. Molecular genetic tests are currently available for genotypic diagnosis. In selected individuals, diagnosis might require liver biopsy or quantitative phlebotomy. Iron depletion by phlebotomy is the mainstay of treatment and is highly effective in preventing the complications of iron overload if instituted before the development of cirrhosis. Genetic testing is currently not recommended for population screening because of low yield as the majority of the healthy, asymptomatic p.C282Y homozygotes do not develop clinically significant iron overload. HFE gene testing remains an excellent tool for the screening of first-degree relatives of affected probands who are p.C282Y homozygotes.
To examine differences in speed of improvement and remission in people with mania undergoing bilateral, brief-pulse, twice-weekly electroconvulsive therapy (ECT) at stimulus intensities administered just above and 2.5 times their individually titrated seizure threshold.
Glucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity.
Neuroendocrine tumors (NETs) occur in virtually all sites of the body. As NETs arising in different organs share similar morphologic features, distinguishing metastatic from primary NETs on the basis of morphologic grounds alone is difficult. Pancreatic duodenal homeobox 1 (PDX-1) is a Hox-type transcription factor that is essential for both exocrine and endocrine pancreatic differentiation and maintenance of ?-cell function. We investigated PDX-1 as an immunohistochemical (IHC) marker in primary pancreatic NETs. Eighty primary NETs [25 pancreatic, 29 bronchopulmonary, and 26 in the gastrointestinal (GI) tract] and 13 metastatic NETs in the liver were studied. Clinical and radiologic data were reviewed to confirm the stated primary sites. IHC analysis for PDX-1, CDX-2, thyroid transcription factor-1 (TTF-1), keratin 7 (CK7), and keratin 20 (CK20) was performed, and the results were based on review blinded to the primary sites. PDX-1 was seen in 18 of 25 (72%) pancreatic NETs; in contrast, only 3 of 29 (10%) bronchopulmonary NETs and 1 of 26 (4%) GI NETs were positive. PDX-1 was therefore 93% specific and 72% sensitive for pancreatic NETs. TTF-1 was expressed only in bronchopulmonary NETs; all other NETs were negative for TTF-1. CK7 was also very specific (92%) and moderately sensitive (66%) for bronchopulmonary NETs. CDX-2 was seen in 22 of 26 (85%) cases of GI NETs and in only 1 of 51 (2%) cases of extra-GI NETs. Thus, CDX-2 was 98% specific and 85% sensitive for GI NETs. In terms of metastatic NETs found in the liver, PDX-1 was positive in 5 of 5 cases of metastatic pancreatic NETs and 2 of 2 cases of metastatic duodenal NETs. PDX-1 is highly specific, with very good overall diagnostic accuracy for pancreatic NETs. An IHC panel including PDX-1, CDX-2, TTF-1, CK7, and CK20 may be useful in distinguishing NETs of pancreatic origin from other primaries.
The role of Foxp3-positive regulatory T cells (Foxp3 Tregs) in suppression of antitumoral immune response is well documented in patients with cancer. However, it is not known whether Foxp3 Tregs are associated with specific clinicopathologic characteristics of hepatocellular carcinoma (HCC). The aims of the present study were: (1) to investigate the relationship between Foxp3 Tregs and histologic differentiation, Edmondson-Steiner (ES) nuclear grade, vascular invasion, and pathologic stage of HCC in patients undergoing surgery for their disease; and (2) to evaluate any Foxp3 Treg-defined difference in the risk for tumor recurrence or death. The study sample included 131 histologic sections of HCC. The number of tumor-infiltrating CD3, CD8, and Foxp3 lymphocytes was assessed by immunohistochemistry. An increased Foxp3:CD3 ratio was associated with more poorly differentiated HCC (P=0.0016) and higher ES nuclear grade (P=0.0407). An increased Foxp3:CD8 ratio was also associated with poorer differentiation (P=0.0044), higher ES nuclear grade (P=0.0179), recurrence (P=0.0183), decreased overall survival (hazard ratio=1.153; 95% confidence interval, 1.019-1.304; P=0.0235), and decreased disease-free survival (hazard ratio=1.138; 95% confidence interval, 1.016-1.273; P=0.0249). Tumor size and type of surgery (surgical resection) were associated with decreased disease-free survival on univariate analysis but not on multivariate analysis. In conclusion, a higher concentration of tumor-infiltrating Foxp3 Tregs in HCC is associated with higher grade and poorly differentiated tumors and signifies an unfavorable prognosis.
Acute cellular rejections of higher grades of histologic severity are associated with increased risk of graft failure and death after liver transplantation. Plasma cell-rich infiltrates are associated with adverse clinical outcomes in acute renal allograft rejection and in liver allografts without rejection, but there are limited data on plasma cell-rich infiltrates in acute liver allograft rejection. In this study, 59 biopsies of acute liver allograft rejection were confirmed histologically and clinically, independently graded, and the percentage of plasma cells in portal inflammatory infiltrate was objectively assessed using a standardized protocol. Plasma cell infiltrates were observed in 32 (54%) of the specimens, the mean percentage of plasma cells in the infiltrates being 2.97%. Infiltrates with any plasma cells were significantly more common in groups with higher histologic severity of rejection (75% and 100% versus 31% and 48%, P = .006). The mean percentage of plasma cells in the portal infiltrate was also significantly higher in groups with higher histologic severity of rejection (4.95% and 17.82% versus 0.37 and 0.82%, P = .0002). All the biopsies with more than 30% plasma cells in the infiltrate were found to have severe rejection, whereas all with more than 10% plasma cells had either moderate or severe rejection. The association of plasma cell-rich infiltrates with histologic severity of rejection suggests that plasma cell-rich infiltrates could potentially be useful as a marker of severe rejection.
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