Expression of DC-SIGN and DC-SIGNRs in placentas of HIV-positive patients

Background. Human dendritic cell-specific intracellular adhesion molecule-3 (ICAM3)-grabbing non-integrin (DC-SIGN) is a mannose-binding lectin that initiates interaction between dendritic cells and resting T-lymphocytes. DC-SIGN is highly expressed in placental tissue on dendritic cells and Hofbauer cells, and it is suggested that HIV may become adsorbed to DC-SIGN on Hofbauer cells as part of the mechanism of mother-to-child HIV transmission. A possible mechanism of transfer of the virus from the Hofbauer cells to the fetus is the subsequent adsorption to DC-SIGN-related molecules (DC-SIGNRs), present on immediately adjacent capillary vascular endothelium. However, data on DC-SIGN and DC-SIGNR expression in the placenta are few. Methods. Forty term placentas from HIV-positive mothers and 21 term placentas from HIV-negative mothers underwent immunohistochemistry staining for DC-SIGN and DC-SIGNR expression. Five random sets of 10 villi were assessed, and the average number of positive cells were counted in each case. In addition, where possible, maternal and cord blood viral loads and maternal CD4+ counts were performed in the HIV-positive group only. Results. The median maternal CD4+ count was 377 cells/µl and 27% of participants had undetectable viral loads; the median detectable viral load was 3.72 log. Most (97%) of the cord bloods tested in infants from HIV-positive mothers had lower than detectable viral loads. HIV-positive cases had significantly greater expression of both DC-SIGNRs (median values in HIV-positive cases, 14.5 positive cells/10 villi (pc/10villi), compared with 11 pc/10villi in HIV-negative cases, p=0.020) and DC-SIGN (median value in HIV-positive cases, 26.5 pc/10villi, compared with 23 pc/10villi in HIV-negative cases, p=0.037). DC-SIGNR expression was also noted in Hofbauer cells and decidual macrophages in addition to endothelium (reported currently). There was no difference in expression of DC-SIGN and DC-SIGNRs in patients with or without chorioamnionitis, but there was an inverse relationship between DC-SIGN and DC-SIGNR expression and maternal CD4+ counts in HIV-positive cases.  Conclusion. Both DC-SIGN and DC-SIGNR expression were higher in placentas from HIV-positive mothers compared with HIV-negative cases. These lectins may be potential new therapeutic targets for preventing vertical transmission of HIV

Beware of 'normal' creatine kinase levels in HIV-associated polmyositis

Generalised weakness may be a common complaint of persons infected with HIV, but the development of significant proximal weakness requires specific attention. Polymyositis may occur in HIV infection and is readily treatable with prednisone. Elevated creatine kinase (CK) levels have been regarded as an important criterion for diagnosing polymyositis. A study of HIV-associated polymyositis reported similarly elevated CK levels to those observed in non-HIV settings.1 However, muscle inflammation can be associated with normal or near-normal CK levels. We report 4 cases of HIV-associated polymyositis in which the diagnosis was almost missed owing to the absence of raised CK levels

Disseminated mucormycosis and necrotizing fasciitis in immune-compromised patients: Two case reports

We present two case reports of disseminated mucormycosis and necrotizing fasciitis in an immunecompromised patient. First, a 3-month-old with untreated HIV infection presented in septic shock with abdominal wall-necrotizing fasciitis. Laparotomy  revealed extensive abdominal wall necrosis, bowel, liver, kidney and subsequent retroperitoneal, posterior diaphragm and inferior vena cava involvement. Second, a  3-year-old on chemotherapy for Burkitt’s lymphoma presented with pancytopenia, sepsis, abdominal wall-necrotizing fasciitis and left lower limb ischaemia. At surgery, there was necrosis of the abdominal wall, the large bowel and the ureter and thrombosis of the iliac vessels. Histology in both cases showed necrosis with fungal invasion consistent with mucormycosis. Both patients suffered mortality. We discuss  mucormycosis and review the literature regarding mucormycosis in immune-compromised paediatric patients.Keywords: child, immune-compromised, mucormycosis, necrotizing fasciitis, paediatri

Case report : a toddler with anasarca caused by congenital nephrotic syndrome

Congenital nephrotic syndrome is a rare inherited disorder arising from defects in the proteins of the cells in the glomerular basement membrane and develops either in utero or at birth. The clinical presentation is the result of massive protein loss in the urine with associated compensatory mechanisms. Here we present a clinical case of a female toddler with a history of anasarca (severe generalised edema) from birth and who presents with the classical biochemical laboratory findings of nephrotic syndrome, together with the more pronounced features that arise from protein loss including abnormal thyroid function testing and a marked hypercholesterolaemia. Renal biopsy indicated congenital nephrotic syndrome of the Finnish type. This clinical-diagnostic case report represents an example of the broad spectrum of pathophysiological findings of a severe congenital nephrotic syndrome.http://www.ifcc.org/ifcc-communications-publications-division-cpd/ifcc-publications/ejifcc-journalam2018Chemical Patholog

Biofilms associated with bowel necrosis: A newly recognised phenomenon in infants

Background. A biofilm is defined as a collection of organisms attached to a surface and surrounded by a matrix.Objective. To present three cases in which bowel necrosis coexisted with biofilm.Methods. The medical records, bacteriological findings and tissue biopsies from three infants with bowel necrosis who subsequently died from sepsis were analysed. Tissue sent for histological evaluation was prepared for light microscopy. Haematoxylin and eosin (H&E), Sandiford and Alcian blue/periodic acid Schiff (ABPAS) stains were performed. Tissue samples were ex-waxed for electron microscopy in one case.Results. The three patients described all had necrotic bowel at laparotomy, all cultured Klebsiella pneumoniae from peritoneal pus swabs, and all died despite appropriate antibiotics. All specimens showed varying degrees of bowel necrosis and an organising acute peritoneal reaction. In addition, all showed colonies of Gram-negative bacteria within a mucopolysaccharide matrix.Conclusions. The identification of biofilms in necrotic bowel has raised questions regarding their clinical implications. Further studies are needed to evaluate all resected necrotic bowel for biofilms and the clinical implications of this finding.

Epigenetic changes as a common trigger of muscle weakness in congenital myopathies

Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorder

Predictive Value of Tumor Ki-67 Expression in Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studie

A Study to investigate the role of p27 and Cyclin E immunoexpression as a prognostic factor in early breast carcinoma

<p>Abstract</p> <p>Background</p> <p>Cyclin E and p27 expression is easy to assess in human tissues by standard immunohistochemical techniques. Immunohistochemistry is cost effective, relatively easy to perform and will play more of a role in the future management of cancer. The aim of this study was to investigate the role of p27 and cyclin E immunoexpression as a prognostic factor in early breast carcinoma.</p> <p>Methods</p> <p>Cyclin E and p27 immunohistochemistry was performed on sixty six cases of breast carcinoma submitted over a five year period to the Division of Anatomical Pathology, Groote Schuur hospital; Whittaker and Associates; and PathCare. All tumours included in this study were less than 5 cm in diameter (pT1 and pT2 stage) and all the patients had wide local excisions performed. Follow up information was obtained from patient folders in the Department of Radiation Oncology.</p> <p>Results</p> <p>There was no significant association of cyclin E and p27 expression with distant metastasis free survival (MFS) for all invasive carcinomas in contrast to grade, lymph node spread and vascular invasion. However, there was a statistically significant direct association of cyclin E with distant metastases in all invasive carcinomas, in the subgroup of infiltrating duct carcinomas (IDC) and in the node negative group when cyclin E was stratified as negative and positive (low/high). In this study of early breast carcinoma, only 9/66 cases showed cyclin E expression. Of these, four patients had distant metastases, one patient had a local recurrence and four patients were alive at last follow-up. Furthermore, cyclin E expression was significantly associated with grade, lymph node spread, oestrogen receptor status and histological type. None of the lobular carcinomas showed cyclin E positivity and only one case of lobular carcinoma presented with distant metastases.</p> <p>59/66 cases were positive (low/high) for p27 while seven cases were negative, 22 cases showed low expression and 37 cases demonstrated high p27 expression.</p> <p>p27 was significantly associated with oestrogen receptor status only for all invasive carcinomas and in the IDC group. There was no statistical relationship between p27 and cyclin E, but 50 (76%) tumours with positive p27 expression were negative for cyclin E. There were similar results for the invasive ductal carcinoma subgroup.</p> <p>Conclusion</p> <p>This study shows that p27 and cyclin E are not good independent prognostic markers for early breast carcinoma in contrast to grade, lymph node spread and vascular invasion for all invasive carcinomas. However, cyclin E provides some prognostic value as there is a direct statistical association with the development of distant metastases. Many previous studies have correlated overexpression of cyclin E with an aggressive course. The inverse relationship between p27 and cyclin E expression which has been reported in the literature has been highlighted, but this was not statistically significant. Most cases showed positive p27 expression and negative Cyclin E expression. This may be due to the early stage of the disease.</p

A study to investigate the role of P27 and Cyclin E immunoexpression as a prognostic factor in early breast carcinoma

Includes bibliographical references (leaves 64-71).Cyclin E and p27 expression is easy to assess in human tissues by standard immunohistochemical techniques. Immunohistochemistry is cost effective, relatively easy to perform and will play more of a role in the future management of cancer. To investigate the role of p27 and cyclin E immunoexpression as a prognostic factor in early breast carcinoma. Cyclin E and p27 immunohistochemistry was performed on sixty six cases of breast carcinoma submtted over a five year period to the Division of Anatomical Pathology, Groote Schuur hospital; Whittaker and Associates; and PathCare. All tumours included in this study were less than 5cm in diameter (pT1 and pT2 stage) and all the patients had wide local excisions peformed. Follow up information was obtained from patient folders in the Department of Radiation Oncology

Expression of DC-SIGN and DC-SIGNRs in placentas of HIV-positive patients

Background. Human dendritic cell-specific intracellular adhesion molecule-3 (ICAM3)-grabbing non-integrin (DC-SIGN) is a mannose-binding lectin that initiates interaction between dendritic cells and resting T-lymphocytes. DC-SIGN is highly expressed in placental tissue on dendritic cells and Hofbauer cells, and it is suggested that HIV may become adsorbed to DC-SIGN on Hofbauer cells as part of the mechanism of mother-to-child HIV transmission. A possible mechanism of transfer of the virus from the Hofbauer cells to the fetus is the subsequent adsorption to DC-SIGN-related molecules (DC-SIGNRs), present on immediately adjacent capillary vascular endothelium. However, data on DC-SIGN and DC-SIGNR expression in the placenta are few. Methods. Forty term placentas from HIV-positive mothers and 21 term placentas from HIV-negative mothers underwent immunohistochemistry staining for DC-SIGN and DC-SIGNR expression. Five random sets of 10 villi were assessed, and the average number of positive cells were counted in each case. In addition, where possible, maternal and cord blood viral loads and maternal CD4+ counts were performed in the HIV-positive group only. Results. The median maternal CD4+ count was 377 cells/µl and 27% of participants had undetectable viral loads; the median detectable viral load was 3.72 log. Most (97%) of the cord bloods tested in infants from HIV-positive mothers had lower than detectable viral loads. HIV-positive cases had significantly greater expression of both DC-SIGNRs (median values in HIV-positive cases, 14.5 positive cells/10 villi (pc/10villi), compared with 11 pc/10villi in HIV-negative cases, p=0.020) and DC-SIGN (median value in HIV-positive cases, 26.5 pc/10villi, compared with 23 pc/10villi in HIV-negative cases, p=0.037). DC-SIGNR expression was also noted in Hofbauer cells and decidual macrophages in addition to endothelium (reported currently). There was no difference in expression of DC-SIGN and DC-SIGNRs in patients with or without chorioamnionitis, but there was an inverse relationship between DC-SIGN and DC-SIGNR expression and maternal CD4+ counts in HIV-positive cases.  Conclusion. Both DC-SIGN and DC-SIGNR expression were higher in placentas from HIV-positive mothers compared with HIV-negative cases. These lectins may be potential new therapeutic targets for preventing vertical transmission of HIV