Hepatotoxicity of vanadyl sulfate in nondiabetic and streptozotocin-induced diabetic rats.

This study examined the effects of vanadyl sulfate (VOSO4) on the livers of nondiabetic and streptozotocin-induced diabetic rats. Rats were divided into 6 groups. Groups 1, 2, and 3 consisted of nondiabetic rats that were, respectively, control animals or those receiving an intraperitoneal (i.p.) injection of either 5 or 10 mg·kg-1 (i.p.) VOSO4 for 30 days. Groups 4, 5, and 6 consisted of diabetic animals that were, respectively, control animals or those treated with 5 or 10 mg·kg-1 (i.p.) VOSO4 for 30 days. Results showed that VOSO4 reduced body mass in nondiabetic rats, whereas it increased body mass in diabetic groups. Plasma transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, and alkaline phosphatase activities and malondialdehyde levels were increased, while liver catalase and superoxide dismutase activities were profoundly decreased in diabetic animals in comparison with enzyme activities in the nondiabetic group. Rats in the diabetic group also showed notable oxidative damage to the liver. Treatment of diabetic rats with VOSO4 decreased the hepatotoxic markers, significantly restored the activities of antioxidant enzymes, and attenuated histopathological changes in liver tissue. In nondiabetic rats, VOSO4 treatment increased most of the hepatotoxic markers, reduced antioxidant enzyme activities, and induced pronounced oxidative damage in liver tissue. These data suggest that treatment with VOSO4 exerts toxic effects in healthy animals and significantly prevents liver oxidative damage in streptozotocin-induced diabetic rats, but without total safety. Further studies are needed to clarify its mechanism of action.

Mechanisms of chromium hexavalent-induced apoptosis in rat testes.

Hexavalent chromium (CrVI)-containing compounds, present in industrial settings and in the environment, are known as carcinogens and mutagens. The present study is designed to test the hypothesis that oxidative stress mediates CrVI-induced apoptosis in testis. Male Wistar rats received an intraperitoneal injection of potassium dichromate at doses of 1 and 2 mg kg-1. Superoxide anion production was assessed by the determination of the reduction of cytochrome c and iodonitrotetrazolium, lipid peroxidation (LPO), metallothioneins (MTs), and catalase (CAT) activity. Apoptosis was evaluated by DNA fragmentation detected by agarose gel electrophoresis. Germinal cells apoptosis was detected by toluidine blue staining. The expression of Bax and Bcl-2 proteins (Pts) was also investigated. After 15 days of treatment, an increase of LPO and MT levels occurred, while CAT activity was decreased. Testicular tissues of treated rats showed pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern. Intense apoptosis was observed in germinal cells of Cr-exposed rats. Bax Pt expression was induced in spermatogonia and spermatocytes cells of CrVI-treated rats. In contrast, Bcl-2 Pt was occasionally observed in germ cells of CrVI-exposed rats. These results clearly suggest that CrVI subacute treatment causes oxidative stress in rat testis leading to apoptosis.

TCTN3 mutations cause Mohr-Majewski syndrome.

Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.

PHACES syndrome associated with carcinoid endobronchial tumor.

PHACES syndrome consists of the constellation of manifestations including posterior fossa anomalies of the brain (most commonly Dandy-Walker malformations), hemangiomas of the face and scalp, arterial abnormalities, cardiac defects, eye anomalies and sternal defects. We present a case with a possible PHACES syndrome including sternal cleft and supraumbilical raphé, precordial skin tag, persistent left superior vena cava and subtle narrowing of the aorta with an endobronchial carcinoid tumor. All these anomalies were discovered on chest multi-detector CT. This is a unique case of PHACES syndrome associated with carcinoid tumor. Review of the literature revealed 3 cases of PHACES syndrome with glial tumor. The authors tried to find the relationship between PHACES syndrome and carcinoid tumors or gliomas, which all derive from the neural crest cells.

A rare case of cerebral phaeohyphomycosis caused by Fonsecaea species in a renal transplant patient.

Cerebral phaeohyphomycosis (CP) is a serious form of phaeohyphomycosis. We report a case of CP caused by Fonsecaea species in a 66-year-old immunocompromised renal transplant recipient female. Craniotomy was performed on an irregularly enhancing right cerebellar hemisphere lesion and abscess and tissue samples collected for microbiological and histological evaluation, showing fungal elements and Fonsecaea species was isolated. Antifungal treatment with voriconazole & liposomal amphotericin B was initiated with a temporary improvement in the patient's condition. Deep vein thrombosis jeopardized patient's prognosis. Despite aggressive surgical and medical intervention, our patient succumbed to the disease. Historically, CP has been linked with fatality rates as high as 65 %, despite surgical intervention and systemic antifungal medication.

Imaging features of the renal lymphoma: case report and literature review.

Renal affection is common in disseminated non-Hodgkin's lymphoma (NHL) which is known as secondary renal lymphoma (SRL). Primary renal lymphoma (PRL) is an exceedingly uncommon disease, which accounts for less than 1% of all renal masses. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in both primary as well as secondary renal lymphomas. PRL is of paramount importance clinically as it is usually managed with neo-adjuvant chemotherapy followed by nephrectomy in contrast to the more frequently seen renal cell carcinoma, which is treated surgically. This outstanding difference in management challenges the longstanding approach that preoperative biopsies are not mandatory prior to nephrectomy for renal masses. Because of its relative rarity, the imaging features of PRL have been described in a few studies, and having an understanding of these typical imaging patterns is crucial for making an accurate diagnosis and differentiation from other renal malignancies. Here, we present a case of a secondary renal lymphoma and discuss its differential imaging features.

Screening for NLRP7 mutations in familial and sporadic recurrent hydatidiform moles: report of 2 Tunisian families.

A familial or sporadic recurrent hydatidiform mole is a rare autosomal recessive condition that has been associated with biallelic mutations in the nucleotide-binding, leucine-rich repeat, pyrin domain 7 (NLRP7) gene (19q13.42). Cases from different ethnic origins have been reported earlier. Here we report the first Tunisian patients: 2 sisters with homozygous NLRP7 mutations (p.E570X) and 1 sporadic case with no mutation in NLRP7. Our results extend the number of familial recurrent reproductive wastages due to mutations in NLRP7. We suggest that mutations screening of NLRP7 could be proposed more systematically in women with recurrent pathologic pregnancy outcomes of unknown origin. The rare cases with a typical clinical picture, which were not related to NLRP7 mutation as in our sporadic case, should be investigated more to identify the causative gene.

Embryotoxicity and fetotoxicity following intraperitoneal administrations of hexavalent chromium to pregnant rats.

Heavy metals are omnipresent in the environment, and industrial use has greatly increased their presence in soil, water and air. Their inevitable transfer to the human food chain remains an important environmental issue as many heavy metals cause a range of toxic effects, including developmental toxicity. Administration of chromium VI (1 and 2 mg/kg as potassium dichromate) through intraperitoneal (i.p.) injection during organogenesis (days 6 to 15 of gestation) in rats revealed embryo- and fetotoxic effects. Reduced fetal weight, retarded fetal development, number of fetuses per mother and high incidences of dead fetuses and resorptions in treated mothers were also observed. Gross morphological abnormalities, such as displayed form of edema, facial defect, lack of tail, hypotrophy, severs subdermal haemorrhage patches and hypotrophy of placenta were observed in fetuses after chromium VI-treated mothers. A skeletal development of fetuses presented an incomplete ossification in nasal, cranium, abdominal or caudal bones in rats treated with 1 mg/kg of chromium, whereas rats treated with 2 mg/kg showed ossification and absence of the sacral vertebrae compared with the control. At a higher dose of chromium, histological changes were found in fetuses with atrophy of theirs vital organs. Placental histological observations revealed a pronounced morphological alteration, with atrophy of decidual cells, a degenerated of chorionic villi and hypertrophy of blood lacuna. The present study suggests a risk to the developing embryo when the mother is exposed to a high concentration of chromium VI during organogenesis.

Leiomyoadenomatoid tumors: A type of rare benign epididymal tumor.

Primary tumors of the epididymis are mostly benign in nature, and the most common type is adenomatoid tumors followed by leiomyomas. Leiomyoadenomatoid tumors are very rare benign epididymal neoplasms composed of two components: gland-like structures lined by cuboidal cells and bundles of smooth muscle components. The goal of treatment is testicular-preserving surgery. A preoperative and intraoperative evaluation plays an important role in proper management. To the best of our knowledge, few cases have been reported in the literature. We report a case of a right epididymal tail leiomyoadenomatoid tumor in a 49-year-old male who underwent trans-scrotal exploration and tumor excision.

Resveratrol, a red wine polyphenol, attenuates lipopolysaccharide-induced oxidative stress in rat liver.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of gram-negative bacteria inducing deleterious effects on several organs including the liver and eventually leading to septic shock and death. Endotoxemia-induced hepatotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation inducing DNA, proteins and membrane lipid damages. Resveratrol (trans-3,5,4' trihydroxystilbene) is a phytoalexin polyphenol exhibiting antioxidant and anti-inflammatory properties. In this study, we investigated the effect of subacute pre-treatment with this natural compound on LPS-induced hepatotoxicity in rat. Resveratrol counteracted LPS-induced lipoperoxidation and depletion of antioxidant enzyme activities as superoxide dismutase (SOD) and catalase (CAT) but slightly glutathione peroxidase (GPx) activity. The polyphenol also abrogated LPS-induced liver and plasma nitric oxide (NO) elevation and attenuated endotoxemia-induced hepatic tissue injury. Importantly resveratrol treatment abolished LPS-induced iron sequestration from plasma to liver compartment. Our data suggest that resveratrol is capable of alleviating LPS-induced hepatotoxicity and that its mode of action may involve differential iron compartmentalization via iron shuttling proteins.

Schneckenbecken dysplasia in fetus: report of four cases.

Several different types of lethal short-limbed skeletal dysplasia with platyspondylia have been recognized with a different mode of inheritance. Schneckenbecken dysplasia, a very rare lethal osteochondrodysplasia, is included in these entities, with an autosomal recessive mode of inheritance. We describe 4 new Tunisian cases with clinical, radiographic and histopathological features. The fetuses were of consanguineous parents. Prenatal diagnostics of short limbs were carried out on ultrasounds at 20, 22, 23 and 28 weeks of gestation. The radiographic findings were typical, showing especially the small ilia with medial snail-like projection. The chondro-osseous histology of the 4 cases was compatible with the diagnostics demonstrating cartilage anomalies characterized by hypercellularity, hypervascularisation and chondrocytes with central large round nucleus. Schneckenbecken dysplasia should be considered when the phenotype of dwarfism and snail feature of iliac bone associated with histological finding are presented. Frozen fetal samples should be taken in order to look for candidate genes.

[Lethal osteo-chondro-dysplasia: feto-pathological study of 32 cases]. / Les ostéochondrodysplasies létales: etude foetopathologique de 32 cas.

BACKGROUND: The lethal osteochondrodysplasias are rare, their prevalence is estimated at 1 per 10 000 births. Mostly have genetic determinism. AIMS: To describe the malformations and dysmorphic features in lethal osteochondrodysplasias METHODS: Our study involved 32 cases of lethal fetal Osteochondrodysplasias, collected over a period of 14 years in the pathological department of Sousse. RESULTS: Our series consisted of 23 foetuses from a medical termination of pregnancy, 6 newborns and 3 stillbirths. The mean age of mothers was 28 years old, consanguinity was observed in 61%. 3 cases of recurrence of the disease in three families were noted. The bone abnormalities were detected in antenatal ultrasonography in 25 cases (87%) and at birth in 7 cases. Ultrasound showed micromelia in all cases, a narrow chest in 5 cases and spina bifida in 3 cases. The feto-pathological exam, including a macroscopic examination, radiological and histological samples of bone, has allowed us, based on the International Classification of 2001 to classify the 32 cases of Osteochondrodysplasias in: 8 cases of Achondrogenesis type I (type Parenti-Fraccaro), 3 cases of Achondrogenesis type II (Langer Saldino), 9 cases of lethal osteogenesis imperfecta, 8 cases of thanatophoric dysplasia, 4 cases of Schneckenbecken dysplasia, 2 cases of Short rib polydactyly syndrome, Majewski type and 1 case of asphyxiating thoracic dysplasia.

Immunohistochemical analysis of c-erbB-2, Bcl-2, p53, p21WAF1/Cip1, p63 and Ki-67 expression in hydatidiform moles.

Hydatidiform moles (HM) are characterized by an abnormal proliferating trophoblast with a potential for a malignant transformation. Similar to other human tumors, trophoblastic pathogenesis is likely a multistep process involving several molecular and genetic alterations. The study was performed to investigate the expression patterns of c-erbB-2 and Bcl-2 oncoproteins, p53, p21WAF1/CIP1 and p63 tumor suppressor proteins and Ki-67 cell proliferation marker in HM. We conducted a retrospective study of 220 gestational products, including 39 hydropic abortions (HA), 41 partial HM (PHM) and 140 complete HM (CHM). The expression of c-erbB-2, Bcl-2, p53, p21WAF1/CIP1, p63 and Ki-67 was investigated by immunohistochemistry on archival tissues. c-erbB-2 expression was observed in three PHM and 10 CHM. Bcl-2 immunostaining was significantly higher in PHM (61%) and CHM (70.7%) compared with HA (7.7%, p = 0.001 and p < 0.0001, respectively). p53 expression was stronger in CHM (73.6%) compared with PHM (24.4%, p < 0.0001) and HA (12.8%, p < 0.0001). p21WAF1/CIP1 staining was observed as well in molar and non-molar gestations (p > 0.05). p63 immunoexpression was significantly described in CHM (85.7%) and PHM (78%) compared with HA (10.2%, p < 0.0001 and p = 0.0001, respectively). Ki-67 was significantly expressed in CHM (72.1%) compared with HA (46.2%, p = 0.005). Altered expression of Bcl-2, p53, p63 and Ki-67 reflects the HM pathological development. Immunohistochemical analysis is beneficial to recognize the HM molecular and pathogenic mechanisms. Furthermore, it could serve as a useful adjunct to conventional methods for refining HM diagnosis.

Prognostic significance of MGMT methylation and expression of MGMT, P53, EGFR, MDM2 and PTEN in glioblastoma multiforme.

The study investigated the pattern of MGMT promoter methylation and the expression of MGMT, P53, EGFR, MDM2 and PTEN proteins in glioblastomas multiforme (GBM) and evaluated their prognostic significance. We carried out a retrospective study of 80 GBM. Expression of MGMT as well as of P53, EGFR, MDM2 and PTEN was investigated by immunohistochemistry. MGMT promoter methylation was investigated by methylation specific-PCR of bisulfite-treated DNA. Twenty-five GBM exhibited MGMT expression. Methylation of MGMT promoter was detected in 35.1% of cases. No significant concordance was reported between MGMT promoter methylation and protein expression (κ=-0.047, p=0.11). MGMT promoter methylation was significantly associated only with PTEN expression (p=0.001): no other significant association was identified with clinical parameters as well as with expression of P53, EGFR and MDM2 (p >0.05). Tumor recurrence was significantly associated with unmethylated MGMT promoter (p=0.01) but not with MGMT expression (p=0.51). Recurrence-free survival (RFS) was significantly better among patients with methylated MGMT promoter (log rank, p <0.0001) and PTEN expression (log rank, p=0.025) but not with MGMT expression (log rank, p=0.308). As well, using univariate analysis, MGMT promoter methylation (p=0.001) and PTEN expression (p=0.044) were significantly associated with RFS. In multivariate analysis, only MGMT promoter methylation was significantly associated with RFS (p=0.003). Together, our findings support that MGMT protein expression doesn't reflect the MGMT promoter methylation status. Furthermore, MGMT promoter methylation remains a useful prognostic marker in Tunisian patients with GBM. PTEN expression could be a potential prognostic marker of this tumor.

A case of spinal immature teratoma.

We report a rare case of intradural immature teratoma in 2-year-old girl, interesting conus medullaris to sacrum, worsening neurological deficits. The neoplasm discovered by magnetic resonance imaging, was completely resected. We describe the clinical, radiological and pathological findings of this tumor with a review of the Literature and we insist in the difficulty of treatment.

Immunohistochemical Characterization Improves the Reproducibility of the Histological Diagnosis of Ovarian Carcinoma

Background: Ovarian cancer is the leading cause of gynecologic cancer-related death. Histological assessment remains the standard clue for the diagnosis of ovarian carcinoma. Misinterpretation and inconsistent application of histological criteria may lead to significant interobserver variability and poor reproducibility of the diagnosis. In this study, we investigated the discrepancy in histological diagnosis and the significance of a designed panel of immunohistochemical markers for the improvement of the diagnostic reproducibility of ovarian carcinomas. Methods: We performed a retrospective study on 74 ovarian carcinomas. All tumor slides were independently reviewed by two pathologists. The results for seven available immunomarkers as p53, WT-1, p16INK4A, CK7, CK20, and estrogen and progesterone receptors were determined for all cases by immunohistochemistry. Results: The histological diagnosis review performed using standard histology showed a concordance of diagnoses in 86% of cases with Cohen's kappa of 0.80. Immunohistochemical results increased significantly the diagnosis reproducibility with a concordance of 91% and a Cohen's kappa of 0.86 (P = 0.001). Conclusion: Although the histological diagnosis remains reliable, the use of a designed panel of immunohistochemical markers improves significantly the interobserver concordance and the classification accuracy of ovarian carcinomas.

Effects of oral administration of 2,4-dichlorophenoxyacetic acid (2,4-D) on reproductive parameters in male Wistar rats.

The 2,4-dichlorophenoxyacetic acid (2,4-D) is used worldwide in agriculture as a selective herbicide. It has been shown to produce a wide range of adverse effects on the health of both animals and humans from embryotoxicity and teratogenicity to neurotoxicity. In the present study, we have examined the effect of 2,4-D on male reproductive function of rats. Male Wistar rats received daily by force-feeding 100 or 200 mg of 2,4-D/kg body weight for 30 consecutive days. Rats exposed to 100 and 200 mg of 2,4-D/kg showed a significant decrease in body weights only after 24 days of treatment and in relative weights of testis, seminal vesicles and prostate at killing day, when compared with controls. Moreover, a decrease in testosterone and an increase in FSH and LH serum levels were detected in treated rats. Besides, exposure to this herbicide induced pronounced testicular histological alterations with enlarged intracellular spaces, tissue loosening and dramatic loss of gametes in the lumen of the seminiferous tubules. In addition, a decreased motility and a number of epididymal spermatozoa with an increased sperm abnormality rate were found in treated rats in comparison with control. With the highest dose, histological observations of seminal vesicles indicated a considerable decrease of secretions in the lumen, a thinness of the muscle layer surrounding the epithelium with branched mucosal crypts and reduced luminal space. In prostate, the heights of the cells decreased while acinar lumen were enlarged and they lost the typical invaginations. Our results suggest that a subacute treatment of 2,4-D promotes reproductive system toxicity.

Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.

It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.