Increased C4d and Bb immunoreactivity and decreased MBL immunoreactivity characterise first-time pathologic first-trimester miscarriage: a case-control study.

The role of the complement system in first-time pathologic first-trimester miscarriage was investigated. In this case-control study, tissue samples of 126 women with pathologic miscarriage and termination of normal pregnancies were assessed. The pathologic pregnancy group consisted of 40 women with missed miscarriage, 13 women with incomplete miscarriage and 10 women with a blighted ovum. The control group consisted of 63 normal-appearing pregnancies. Immunoreactivity for C4d, Bb and MBL was evaluated in the deciduas and villous trophoblasts separately using a semi-quantitative histological scoring system (H-score). C4d and Bb H-scores were higher and MBL H-score was reduced in the deciduas and villous tissues from pathologic miscarriage compared to termination of pregnancies (p = .003 and p = .001; p = .011 and p < .001; p < .001 and p < .001, respectively). C4d and Bb activities were increased and MBL activity was decreased in human first-time pathologic first-trimester miscarriage. We suggest that three complement pathways may play a role in human first-time pathologic first-trimester miscarriage. Impact statement Previous studies focussed on complement proteins related to a single complement pathway in cases often associated with antiphospholipid syndrome (APS) or recurrent miscarriage. In APS-related cases, the classical pathway is activated. In antibody-dependent and in antibody-independent mouse models of foetal loss, classical and alternative pathways are activated, respectively. Lectin pathway deficiency has been reported in some recurrent miscarriage. The complement pathway or pathways, which have a role in human pathologic miscarriage was the starting point of this study. There has been no study done till now reporting the role of the three complement pathways in human pathologic miscarriage. In this study, we found increased classical and alternative complement pathway activities and decreased lectin pathway activity in tissues from first-time pathologic human miscarriage.

Retrospective Evaluation of Children with Congenital Pulmonary Airway Malformation: A Single Center Experience of 20 Years.

OBJECTIVES: Congenital pulmonary airway malformation (CPAM) is an uncommon congenital abnormality of the lungs that generally presents during prenatal period or early childhood. In this study, we aimed to evaluate clinical and pathologic findings of the children with CPAMs who were referred to our center between 1992 and 2011. MATERIAL AND METHODS: We reviewed 19 children with CPAM, who were diagnosed and treated at the Izmir Dr. Behçet Uz Children's Hospital between 1992 and 2011. All of them are alive and have been still followed up by our center. RESULTS: The study population consisted of 9 boys (47.4%) and 10 girls (52.6%) with a mean age of 3.26 (1 month - 13 years). Most newborns had respiratory distress, while recurrent pulmonary infections were detected in older children. Surgical treatment was performed on patients with subtypes I (n = 4; 21.1%), II (n = 8; 42.1%), III (n = 5; 26.3%), and IV (n = 2; 10.5%). In 13 cases (63.4%), lesions were located in the right lung and in almost all cases lesions were confined to one lobe. A one-month- old child with type I CPAM had multiple lesions involving two lobes and in only a newborn with type II CPAM, lesions were located bilaterally. There was no type 0 cases in this series. All cases were treated with lobectomy without any complication. CONCLUSION: In the present study, a realistic comprehensive picture of CPAM in a central children's hospital has been provided. In addition, we want to emphasize that complications and unnecessary medical treatment could be reduced with early surgery.

Pediatric langerhans cell histiocytosis: single center experience over a 17-year period.

This study aimed to analyze children with the diagnosis of Langerhans cell histiocytosis (LCH) who were diagnosed and treated between 1998-2015. Medical records were evaluated retrospectively for clinical and laboratory features, treatment details, and outcome. There were 20 patients, the median age of diagnosis was 37 months, M/F ratio: 1.5. Nine had single system (SS), 11 had multisystem (MS) LCH. Spontaneous regression occurred in three infants with skin limited LCH. Eight patients had risk organ involvement in MS-LCH group. The curettage alone was performed in only one case. Patients received LCH-II/ LCH-III based chemotherapy schema. Radiotherapy was performed to vertebral disease and residual craniofacial bone disease in four cases. The regression and relapse rates were 100% and 33% for SS-LCH. The regression and relapse rates were 73%, and 18% for MS-LCH. Two infants with MS-LCH died despite chemotherapy. Pulmonary and liver involvements affected outcome adversely in MS-LCH. Multidisciplinary treatment approaches are needed.

Investigation of iron's neurotoxicity during cerebral maturation in the neonatal rat model of haemolysis.

INTRODUCTION: Haemolytic disease of newborns due to rhesus and AB0 incompatibility is encountered frequently in neonatal clinics and may lead to severe haemolysis. In this study, it is suggested that important amounts of iron released with haemolysis may have a toxic effect on the brain parenchymal tissue, and the severity of the toxic effect can be correlated with the maturation of the brain barrier systems. To demonstrate the accumulation and the neuro-toxic effects of free iron (Fe) in the brain an experimental haemolysis model with various maturation phases was performed. MATERIAL AND METHODS: The study was composed of 48 Wistar rats with the following ages: five days old (Group A), 10 days old (Group B), and 19 days old (Group C). Each group was divided into three experimental subgroups and three control groups. Experimental groups were treated with intraperitoneal 75 mg/kg/day phenyl hydrazine hydrochloride for haemolysis. RESULTS: We demonstrated that the blood brain barrier (BBB) is permeable in five-day-old newborn rats and is mature in 10- and 19-day-old rats. Iron staining and neuronal damage were detected in group A and group B rats. No damage was detected in the brain tissue of group C animals. The presence of iron staining and neuronal damage in group B with mature BBB may suggest the existence of other incomplete barrier systems different from BBB that lead to iron accumulation in the brain. CONCLUSIONS: Blood brain barrier has a partial role in Fe transport, and the alternative barrier systems may also be involved. It could be supposed that after maturation of all barrier systems, excessive Fe penetration to the brain cannot occur. Our findings showed that the toxic amounts of iron may penetrate into the brain parenchyma of newborns despite the BBB preservation and cause neuronal damage in newborns, but the mature brain is not affected by the same magnitude blood levels.

A case of rectal carcinoma with skin and bone marrow metastasis with concurrent extensive visceral involvement; unusual and dismal co-incidence.

Novel systemic therapies and modern surgical and ablative approaches have improved the survival rates for the patients with metastatic colorectal cancer. However, there are still patients with poor prognosis and underlying mechanisms that could not be defined clearly. Metastatic colorectal cancer patients with skin metastasis have a poor prognosis. A 45-year-old man, who presented with large bowel obstruction, was diagnosed with metastatic rectal adenocarcinoma. Unresectable liver metastases were found at diagnosis. FOLFOX plus bevacizumab treatment was started, but the patient developed bowel obstruction after the third cycle. Therefore, ileostomy was performed. Multiple skin, lung, liver and bone metastases appeared during that time. Bone marrow biopsy demonstrated diffuse infiltration by adenocarcinoma cells. Even though partial remission was achieved after 4 cycles of FOLFIRI-cetuximab, the disease progressed after the 8th cycle. The patient lost his life due to disease progression 8 months after the diagnosis. Bone marrow and skin are unusual sites of metastasis for colorectal carcinoma. Metastases in bone marrow and skin develop at later stages of metastatic disease. This patient lived only 4 months after the development of skin and bone marrow metastases. Skin and bone marrow metastases may be the harbingers of short survival. Biopsy of metastatic sites is crucial for diagnosis and detailed molecular analysis. Molecular pathway alterations underlying worse disease course may be found, and hence probable targets for drug improvement may be indicated.

The effect of hypothermia on adnexal torsion/detorsion injury in a rat ovary model.

PURPOSE: Much attention has been given to hypothermia as it is effective in inhibiting inflammatory responses and also ischemia/reperfusion injury. Therefore, the aim of this study was to evaluate the effect of hypothermia on torsion/detorsion injury in rats. METHODS: Twenty-eight rats were randomly divided into four groups of sham-operated (SG), adnexal torsion/detorsion group (TG), adnexal torsion/detorsion+hypothermia group (THG) and hypothermia group (HG). In the SG group, right ovaries were excised after 3-h fixation to abdominal wall. In the TG, right adnexal underwent 720° torsion in a counterclockwise direction for 3h and then excised after 3-h detorsion period. In the THG, after 3-h torsion period, ovaries were immediately subjected to hypothermia (4°C) for 30-min and they were excised after 3-h detorsioned period. In the HG, the right ovaries were subjected to hypothermia for 30-min and excised after 3-h fixation period. One half of each ovary was immediately stored for antioxidant enzyme activity and tissue lipid peroxidation. The remainder was fixed for histopathological examination. RESULTS: Adnexal torsion and detorsion significantly increased the tissue level of Malondialdehyde, Superoxide dismutase and Reduced glutathione. On the other hand, hypothermia significantly reduced these oxidative stress parameters. The histopathological changes were less in the THG group; these changes were not statistically different from the other groups. CONCLUSION: The results of this study suggested that hypothermia inhibited the production of oxidative stress in the ovaries subjected to torsion/detorsion injury.

The relationship of melanocytic differentiation with prognostic markers in medullary thyroid carcinomas.

INTRODUCTION: Medullary thyroid carcinoma (MTC) makes up 5-10% of thyroid malignancies. Small cell, squamous, giant cell or melanocytic differentiation can rarely be seen in MTCs. It is important to determine those with the potential to act aggressively such as cases with melanocytic differentiation at the time of diagnosis. MATERIALS AND METHOD: A total of 46 MTC cases diagnosed at four different centers between 2002 and 2013 were included in the study. Immunohistochemical (IHC) staining with Melan-A and HMB-45 was performed in all cases. RESULTS: Six of the 46 MTC cases were medullary microcarcinomas and three were multicentric medullary carcinomas. There were 34 females and 12 males with a mean age at onset of 51.4 years and mean tumor diameter of 23.2mm. Lymph node metastasis (LNM) was found in 13 of the 38 cases that had data regarding the lymph nodes. Immunohistochemically, Melan A staining was seen in four cases. HMB45 staining was seen in four cases. A statistically significant relationship was found between LNM and diameter, Melan A expression (p=0.02, p=0.03 respectively) but there was no significant relationship with HMB45 expression (p=0.07). General survival data were present for 35 of the 46 cases. All cases without lymph node metastasis survived (21/21) while 8 of 11 cases with lymph node metastasis survived among cases with survival data; one case that was diffuse-strong positive for both HMB45 and Melan A was lost due to distant organ metastasis six months after the diagnosis. DISCUSSION: Should the possibility of melanocytic differentiation be evaluated in cases where melanocytic differentiation is not reflected in the morphology (lack of pigment) in MTCs? We did not come across a study on the subject in the English literature. The effect of melanocytic differentiation on the prognosis in MTCs should be investigated in larger series.

Unclassified diffuse ductal cholangiocarcinoma; report of a case.

Cholangiocarcinoma (CCA) is the second most common malignant tumor of the liver. It is simply classified as intrahepatic and extrahepatic CCA (including perihilar and distal extra hepatic CCA) according to the anatomic localization. Various classification systems were described for staging cholangiocarcinoma. We represent an interesting case of cholangiocarcinoma which is in the shadow area of classification by involving intrahepatic, hilar, and distal extra hepatic bile ducts. To our knowledge, this is the first case in the literature with diffuse bile duct involvement.

Regulatory T cells and their prognostic value in hepatopancreatobiliary tumours.

BACKGROUND/AIMS: The aim of this study was to determine the prognostic values of Foxp3+ Treg cells, CD4+ Tcells and CD8+ T cells in cancer cases of gallbladder, pancreas and liver. METHODOLOGY: This study included 20 patients with gallbladder cancer, 25 patients with pancreatic cancer and 8 patients with liver cancer. Foxp3, CD4 and CD8 were immunohistochemically evaluated and compared with histopathological and clinical prognostic parameters. RESULTS: Foxp3, CD4 and CD8 expression levels were significantly higher in peritumoral areas than in intratumoral areas in patients with gallbladder, pancreas, liver cancers (p<0,05). Positivity of Foxp3, CD4 and CD8 was correlated with advanced stage (p<0,05), poor differentiation, lymphovascular invasion, perineural invasion, advanced age. Patients with high positivity of Foxp3 had a shorter disease free survival (p<0,05). CONCLUSION: Our results indicate that the ratio of Tregs/T helper cells (Foxp3+/CD4+) cells was higher in intratumoral area in hepatopancreatobiliary tumors. We conclude that intratumoral inlamatory cells might work for cancer cells, besides peritumoral cells work against cancer cells.

Investigation of the direct hepatic effects of intramuscular interleukin-8 injection in an experimental rabbit model.

BACKGROUND: The aim of this study was to investigate the effects of intramuscular IL-8 injection on hepatic tissues using an in vivo histopathological animal model. MATERIAL AND METHODS: Twelve New Zealand white rabbits were used for this randomized, controlled, single-blinded interventional study. For 6 days, 1 gluteus maximus muscle was injected daily with 1 mcg/kg of IL-8 in 6 rabbits (Group A). The remaining 6 rabbits (to determine to normal porto-hepatic morphology of the rabbit genus) were in the sham group (Group B). At the end of the 7th day, all rabbits were killed and livers were meticulously harvested. Microscopically, regional tissues were scored according to portal inflammation, focal necrosis, piecemeal necrosis, and total impact. RESULTS: Total impact score, portal inflammation, focal necrosis, and piecemeal necrosis were the histopathologic changes present in a higher incidence in the IL-8 group compared with the control group. The differences were significant when the groups were compared according to total impact score, portal inflammation, focal necrosis, and piecemeal necrosis according to Pearson's correlation (p<0.05). The most significant differences were detected at the total impact scores (p=0.002) and the portal inflammation scores (p=0.008). CONCLUSIONS: Our results showed that IL-8 may damage hepatocytes. This can be the determined target for new therapeutic strategies. Further trials should be designed to obtain definitive results.

Tissue expression of MLH1, PMS2, MSH2, and MSH6 proteins and prognostic value of microsatellite instability in Wilms tumor: experience of 45 cases.

BACKGROUND: Although the importance of microsatellite instability (MSI) and mismatch repair genes (MMR) is strongly established in colorectal cancer seen in the Lynch syndrome, its significance has not been fully established in Wilms tumor (WT). The aim of this study was to determine the prognostic value of MSI and MMR proteins in WT. METHODS: This study included 45 pediatric cases with nephroblastoma. Protein expression was analyzed by immunohistochemistry of archival tissue sections. Real-time PCR melting analysis and fluorescence capillary electrophoresis (FCE) were performed to evaluate the MSI markers BAT25, BAT26, NR21, NR24, MONO27, penta D, and penta C in DNA extracted from tumor and normal tissues. RESULTS: Lower levels of MSI were observed in six cases (13.3%). There were no statistically significant correlations between MSI and some clinical prognostic factors such as stage of the tumors, and survival rates. Nineteen tumors (42.2%) showed loss of protein expression of MLH1, PMS2, MSH2, or MSH6. MMR protein defects were correlated with size (P = .021), and stage (P = .019) of the tumor, and survival rates (P < .01).Similarly MSI was also correlated with the size of the tumor (P = .046). CONCLUSIONS: This study showed that a small proportion of WT might be associated with the presence of MSI, as is the case with defects of DNA mismatch repair genes in the pathogenesis of WT. However, there was no concordance with the frequency of tissue expression of MMR proteins and MSI. These findings suggest that MMR genes may play an important role in the development of WT via different pathways.

Effects of resveratrol on incisional wound healing in rats.

PURPOSE: The objective of this study was to investigate the effect of resveratrol on the healing process after midline laparotomy in rats. METHODS: The study was performed on adult female Wistar-Albino rats. The study group was orally administered 0.5 mg/kg resveratrol once a day for 7 days before the operation until 12 h before surgery and then the treatment was maintained throughout the study. Each rat was anesthetized, and a 4-cm midline laparotomy was performed. Ten animals in each group were sacrificed on postoperative days 7, and 14. A tensile strength analysis was performed, hydroxyproline levels were measured, and the abdominal incision wounds were examined histologically. RESULTS: Resveratrol administration significantly increased the tensile strength of the abdominal fascia, and increased the hydroxyproline levels on postoperative day 14. The acute inflammation scores, collagen deposition scores and the neovascularization scores on postoperative days 7 and 14 were found to be significantly higher in the resveratrol treatment group compared to the control group. The amount of granulation tissue and the fibroblast maturation scores were found to be significantly higher only on postoperative day 14 in the treatment group compared to the control group. CONCLUSION: Our findings show that resveratrol may have a beneficial effect on incisional wound healing.

Inflammatory myofibroblastic tumor of the gallblader.

BACKGROUND: Inflammatory myofibroblastic tumors are rare benign tumors that can mimic malignancy. Their precise aetiology is unknown. They are seen more frequently in childhood and the most common involvement is seen in the lungs. Primary inflammatory myofibroblastic tumors of the gallbladder are rather infrequent. The present knowledge is based on case reports. CASE REPORT: A 66 year-old male patient presented to the hospital with complaints of abdominal pain, nausea and vomiting. Upon physical examination, a clinical picture of abdominal tenderness on the right upper quadrant of the abdomen was identified. Laboratory examinations revealed leukocytosis and hypochromic microcytic anaemia with an increased erythrocyte sedimentation rates and C-reactive protein levels. A mass almost completely filling the gallbladder was detected by imaging studies. The patient was operated on with a malignant preoperative diagnosis and underwent a liver resection of segments 4 and 5, which included a cholecystectomy. The histopathological examination of the surgical specimen revealed an inflammatory myofibroblastic tumor including many histiocytes stained positively with CD 68. CONCLUSION: Inflammatory myofibroblastic tumors can be localised in the gallbladder mimicking gallbladder cancer.

A regional panorama of dysferlinopathies.

OBJECTIVE: We describe the characteristic features of 11 patients (6 men and 5 women) with dysferlinopathies confirmed by muscle biopsies. In addition, we aimed to provide a realistic comprehensive picture of the severe muscle diseases in the Aegean Region of Turkey. MATERIAL AND METHOD: We retrospectively reviewed 90 patients who underwent muscle biopsy examinations between 2008 and 2011 in the pathology laboratory of Izmir Dr.Behcet Uz Children's Hospital. Biopsy specimens of all patients clinically diagnosed as muscular dystrophy referred from 4 different centers of neurological disorders were collected. RESULTS: Dystrophinopathy was the most (n=45) and gammasarcoglycanopathy was the second common (n=13) muscular dystrophy in this series. The mean age of all 90 patients was 8.8 years (3 months- 64 years). Only 14 cases (15.5%) were older than 14, and 23 cases were younger than two years. Dysferlinopathy was the most common dystrophy in the older age group. There were statistical significant differences between the types of dystrophy and inflammation (0.021), creatine kinase levels (p= 0.001), age (p=0.001), and gender (p < 0.001) of the patients. CONCLUSION: The present study revealed that dysferlinopathies is not an uncommon form of muscular dystrophies in western Turkey. We have concluded that if avoidance from unnecessary therapeutic interventions is desired, we must be aware of the relative frequencies of dysferlinopathies.

[Angiomyxoma: always myxoid, sometimes aggressive]. / Anjiomiksom: Her Zaman Miksoid, Bazen Agresif.

Angiomyxoma is a distinct soft tissue tumor characterized by the presence of prominent myxoid matrix and numerous thin-walled blood vessels. This tumor has a predilection for the trunk, head and neck, extremities, and genitalia. It is a benign tumor and total excision is curative. Recurrence is rare except for aggressive angiomyxomas. A 12-year-old girl with a 10-year history of a subcutaneous mass on the left gluteus measuring 4.5x4x3 cm had been referred. The tumor was encapsulated and was located in the reticular dermis and subcutaneous tissue, composed of stellate cells with mucinous stroma. Thin-walled blood vessels were prominent. Immunohistochemically, tumor cells were immunoreactive for vimentin. No immunoreactivity was present for estrogen receptor, CD34, smooth muscle actin, S-100 protein and desmin. The purpose of this report is to present a classical example of an isolated superficial angiomyxoma and discuss the differential diagnosis, because of its relatively infrequent occurence.

Simvastatin improves incisional wound healing in a rat model: an experimental study.

UNLABELLED:  This study investigated the effect of simvastatin on the heal- ing process of abdominal wall wounds in rats. METHODS: The study was performed with adult female Wistar-Albino rats. Control group (n = 20) rats were fed standard laboratory diet until 12 hours before sur- gery. Study group (n = 20) rats received oral simvastatin therapy with an orogastric tube (10 mg/kg once a day) for 7 days until 12 hours before surgery. Each rat was anesthetized, and a 4 cm-long midline laparotomy was performed. Ten animals from each group were killed at postoperative days (PODs) 7 and 14. Breaking strength analysis was measured, and the abdominal incision wounds were examined histolog- ically. RESULTS: Hydroxyproline levels and tensile strength of abdominal fascia were significantly higher in the study group on PODs 7 and 14 compared to the control group. The granulation tissue fibroblast matu- ration scores on POD 7, and both collagen deposition scores and neo- vascularization scores on PODs 7 and 14, were found to be statistically significantly higher in the simvastatin treatment group compared to the control group, based on the results of the histologic tissue examina- tions. CONCLUSION: Simvastatin can be used as a supporting therapy in wound healing. .

Telomerase reverse transcriptase catalytic subunit expression and proliferation index in Wilms tumor.

Telomerase activity provides telomere maintenance in chromosomes. It prevents cells from entering senescence. Telomerase activity is one of the crucial steps in various cancers. Wilms tumor (nephroblastoma) is one of the most common solid tumors of childhood. Hitherto, telomerase reverse transcriptase (TERT) catalytic subunit expression in Wilms tumor has not been investigated widely. The aim of this study was to explore the expression level of human TERT in Wilms tumor and to correlate with some clinical prognosis factors such as tumor weight, stage, histology, and Ki67 expression. This study included 41 nephroblastoma cases of childhood. The telomerase catalytic subunit expression and proliferation index was determined using an immunohistochemical method on archival paraffin-embedded tissue sections. Statistical analysis was done on SPSS 9.05 by Mann-Whitney U test and Spearman's correlation analysis. TERT expression was negative in 11 cases (26.8%), weakly positive in 14 cases (34.1%), and strongly positive in 16 cases (39%). The proliferation index was found to be 20 to 90 (mean 58.9 ± 26.8). Using Spearman correlation analysis, both the TERT expression (p=0.032) and Ki67 index (p=0.048) were found to be correlated with survival rate. Similarly, both the telomerase expression (p=0.011) and the Ki67 index (0.040) were correlated with the weight and dimension of the tumor. But there was no relationship between telomerase expression and Ki67 index (p=0.429). The mean survival time for telomerase negative cases was 56.6 ± 27.3 months, while it was 34.67 ± 28.36 months for positive cases. The Mann-Whitney U test revealed that levels of telomerase (p=0.040) significantly affected the survival rate. In the present study, we showed that the presence of TERT expression correlated with both tumor size and survival time. These findings suggest that senescence may play an important role in WT evolution, and determination of telomere maintenance will be useful to predict survival and follow-up of patients with Wilms tumor.

Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation.

Centronuclear myopathies (CNM) describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM) is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM). Autosomal recessive centronuclear myopathy (ARCNM) is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.