Adverse Effects of Oseltamivir Phosphate Therapy on the Liver of LDLR-/- Mice Without Any Benefit on Atherosclerosis and Thrombosis.

ABSTRACT: Desialylation, governed by sialidases or neuraminidases, is strongly implicated in a wide range of human disorders, and accumulative data show that inhibition of neuraminidases, such as neuraminidases 1 sialidase, may be useful for managing atherosclerosis. Several studies have reported promising effects of oseltamivir phosphate, a widely used anti-influenza sialidase inhibitor, on human cancer cells, inflammation, and insulin resistance. In this study, we evaluated the effects of oseltamivir phosphate on atherosclerosis and thrombosis and potential liver toxicity in LDLR-/- mice fed with high-fat diet. Our results showed that oseltamivir phosphate significantly decreased plasma levels of LDL cholesterol and elastin fragmentation in aorta. However, no effect was observed on both atherosclerotic plaque size in aortic roots and chemically induced thrombosis in carotid arteries. Importantly, oseltamivir phosphate administration had adverse effects on the liver of mice and significantly increased messenger RNA expression levels of F4/80, interleukin-1ß, transforming growth factor-ß1, matrix metalloproteinase-12, and collagen. Taken together, our findings suggest that oseltamivir phosphate has limited benefits on atherosclerosis and carotid thrombosis and may lead to adverse side effects on the liver with increased inflammation and fibrosis.

Enterovirus but not Parvovirus B19 is associated with idiopathic dilated cardiomyopathy and endomyocardial CD3, CD68, or HLA-DR expression.

We assessed Enterovirus (EV) &Parvovirus B19 (PVB19) genomes and CD3, CD68&HLA-DR detection in dilated cardiomyopathies (DCM). EV&PVB19 genomes and CD3, CD68&HLA-DR were detected by PCR and immunohistochemistry assays in 115 endomyocardial biopsies obtained in 13 idiopathic DCM (iDCM) and 10 explained DCM (eDCM) patients. Results were compared with those of 47 atrial surgical samples (47 surgery controls) and 22 autoptic cardiac samples (11 healthy heart controls) (2008-2014, Reims, France). EV was detected in 23.1% of iDCM patients but not in eDCM and controls (P = 0.003) (viral load 803 copies/µg). PVB19 was detected in 76.9%, 80.0%, 63.6% and 78.2% of iDCM, eDCM, healthy heart and surgery controls (P = 0.99) with a mean viral load of 413, 346, 1,428, and 71 copies/µg. CD3, CD68 or HLA-DR were detected in 100 and 50% of EV and PVB19 "mono-infected" iDCM patients. EV was exclusively detected in iDCM cases in association with CD3, CD68, or HLA-DR indicating that EV could be an etiological cause in a subset of iDCM cases. By contrast the equal frequent detection of PVB19 in iDCM cases and controls without association with CD3, CD68, or HLA-DR suggested that PVB19 could be a bystander in many DCM cases. J. Med. Virol. 89:55-63, 2017. © 2016 Wiley Periodicals, Inc.

[A cause of palatal necrosis not to ignore]. / Une cause de nécrose palatine à ne pas méconnaître.

We report a case of pseudotumoral nasal septum and hard palate perforation in a 42-years-old man. The diagnosis retained after differential diagnosis exclusion was necrotic midfacial lesion due to chronic inhalation of cocaine. This condition can mimic vasculitis, primary tumors and granulomatous infections. Differential diagnosis and pathophysiology of this condition will be discussed in this anatomo-clinical case.

Sirenomelia: a new type, showing VACTERL association with Thomas syndrome and a review of literature.

Sirenomelia or "mermaid syndrome" is a rare congenital anomaly known since antiquity. This congenital anomaly is defined as a polymalformative syndrome that associates major muscle and skeleton abnormalities (unique lower limbs) with visceral abnormalities (unilateral or bilateral renal agenesis, anomalies of the abdominal vascularisation). This phenotype, typical of sirenomelia syndrome, may be more or less severe. The pathogenic mechanisms of this syndrome are still debated and its etiology remains unknown. We report here a new type of sirenomelia that we observed in a fetus belonging to the collection of the Department of Anatomy of Reims, which led us to perform a comprehensive review of the literature on the subject: this type has never been reported and cannot be classified according to the Stocker and Heifetz classification. Moreover, this case also presents a VACTERL association with Thomas syndrome.

Quantitative genomic and antigenomic enterovirus RNA detection in explanted heart tissue samples from patients with end-stage idiopathic dilated cardiomyopathy.

Standardized one-step real-time RT-PCR assay detected enterovirus RNA in cardiac biopsy samples from 4 of 20 patients suffering from idiopathic dilated cardiomyopathy (IDCM). The median viral load was 287 copies per microgram of total extracted nucleic acids, with positive- to negative-strand RNA ratios ranging from 2 to 20. These results demonstrate enterovirus persistence in the heart of IDCM patients, characterized by low viral loads and low positive- to negative-RNA ratios.

Early Detection of Relapse by ctDNA Sequencing in a Patient with Metastatic Thymic Tumor and MEN1 Mosaicism.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by inactivating mutations in the MEN1 gene. In the literature, few cases of MEN1 have been reported because of mosaic MEN1 mutations. OBJECTIVE: We performed an extensive molecular characterization in several lesions and blood samples, including plasmatic circulating cell-free DNA (ccfDNA) in an exceptional case of a patient with MEN1 mosaicism causing primary hyperparathyroidism, multiple pancreatic neuroendocrine tumors (NETs), and a metastatic thymic NET. METHODS: Blood, ccfDNA and multiple tissue analysis were performed by next-generation sequencing. RESULTS: MEN1 mosaicism was confirmed by multiple tissue analysis. Somatic analysis of the largest pancreatic NET revealed the same MEN1 second-hit mutation as found in the thymic lesion, demonstrating its metastatic origin from the thymic lesion. Moreover, in ccfDNA we found the mosaic MEN1 mutation but also the somatic second-hit mutation found in the thymic primary tumor, revealing the presence of circulating tumor DNA (ctDNA). After surgical removal of the pancreatic metastasis, the mutated fraction of both mutations decreased, before increasing again several weeks before a new clinical relapse, suggesting that thymic ctDNA may be used as an early tumor biomarker. CONCLUSION: This exceptional MEN1 case highlighted (1) the importance of looking for MEN1 mosaicism, (2) that MEN1 mosaicism can cause very aggressive disease, and (3) the interest in analyzing ccfDNA for confirming MEN1 mosaicism but also as a potential tumor biomarker for NET.

Antibacterial and Immunomodulatory Properties of Acellular Wharton's Jelly Matrix.

Of all biologic matrices, decellularized tissues have emerged as a promising tool in the field of regenerative medicine. Few empirical clinical studies have shown that Wharton's jelly (WJ) of the human umbilical cord promotes wound closure and reduces wound-related infections. In this scope, we herein investigated whether decellularized (DC)-WJ could be used as an engineered biomaterial. In comparison with devitalized (DV)-WJ, our results showed an inherent effect of DC-WJ on Gram positive (S. aureus and S. epidermidis) and Gram negative (E. coli and P. aeruginosa) growth and adhesion. Although DC-WJ activated the neutrophils and monocytes in a comparable magnitude to DV-WJ, macrophages modulated their phenotypes and polarization states from the resting M0 phenotype to the hybrid M1/M2 phenotype in the presence of DC-WJ. M1 phenotype was predominant in the presence of DV-WJ. Finally, the subcutaneous implantation of DC-WJ showed total resorption after three weeks of implantation without any sign of foreign body reaction. These significant data shed light on the potential regenerative application of DC-WJ in providing a suitable biomaterial for tissue regenerative medicine and an ideal strategy to prevent wound-associated infections.

Post-mortem biochemistry of vitreous humor and glucose metabolism: an update.

Post-mortem biochemistry, also called thanatochemistry, has proved useful in forensics for estimating the time since death and assessing the cause of death. Ketoacidosis is a frequent complication of diabetes mellitus which can be lethal, with possible medicolegal implications. However, interpretation of biochemical analyses is difficult because of post-mortem blood alterations involving glucose metabolic pathways. Vitreous humor is better preserved than blood after death, and therefore is preferentially used in thanatochemistry. However, both the lack of experience of most biochemists with this matrix in clinical practice, and the paucity of post-mortem studies make interpretation of post-mortem analyses difficult. This review examines the recent advances in the knowledge of glucose metabolism in vitreous humor, and the methods used for the post-mortem diagnosis of diabetic complications.

A large extended family with hyperparathyroidism-jaw tumor syndrome due to deletion of the third exon of CDC73: clinical and molecular features.

PURPOSE: We described the phenotype of a large 4-generation family with Hyperparathyrodism-Jaw Tumor syndrome (HPT-JT) associated with a rare deletion of exon 3 of the CDC73 gene. METHODS: We collected medical, genetic data on 24 family members descended from a common ancestor carrying a heterozygous deletion of exon 3. RESULTS: Thirteen carried the deletion, the penetrance was estimated at 50% at 40 years. Seven patients (39 ± 14.5 years) presented with HPT which could start at 13. Median plasmatic calcium and PTH levels were 3.13 ± 0.7 mmol/L and 115 ± 406 pg/ml, respectively. Kidney disease related to hypercalcemia were present in 57.1% of patients. All seven patients underwent surgery to remove a single parathyroid adenoma. One recurrence occurred 7 years post-surgery. No parathyroid carcinoma has been found to date. We found two atypical parathyroid adenomas. We described an additional somatic variant in exon 1 of gene CDC73 in two tumors. Jaw tumors were not necessarily associated with hyperparathyroidism, as shown in one case. Two kidney cysts were also reported. Variable phenotype expressivity was emphasized by clinical presentations in 2 monozygotic twins: acute hypercalcemia, kidney failure and ossifying fibroma in one twin, versus normocalcemic parathyroid adenoma in the other one. CONCLUSION: We report a family carrier of a deletion of exon 3 of the CDC73 gene. This is characterized by a high level of hypercalcemia, deleterious kidney effects and atypical parathyroid adenomas without carcinomas. Onset and intensity of HPT remain unpredictable. The additional somatic mutation found in the parathyroid tumor could lead to these phenotypical variations.

Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall.

Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann-Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.

Added value of 18F-fluorocholine positron emission tomography-computed tomography in presurgical localization of hyperfunctioning parathyroid glands after dual tracer subtraction scintigraphy failure: A retrospective study of 47 patients.

Hyperparathyroidism is a common endocrine disorder. The precise localization of causal parathyroid gland is crucial to guide surgical treatment. Several studies report the added value of 18F-fluorocholine (FCH) positron emission tomography-computed tomography (PET/CT) as second line imaging but rely on suboptimal first-line imaging using 99mTc-sestaMIBI dual phase scintigraphy. The aim of this study is to evaluate the percentage of successful parathyroid localization with FCH PET/CT after failure of a more sensitive first-line detection protocol associating neck ultrasonography and 99mTc-Pertechnetate/99mTc-sestaMIBI dual tracer subtraction scintigraphy.We included retrospectively 47 patients who underwent a FCH PET/CT as second line imaging for biologically proven primary hyperparathyroidism from November 2016 to October 2018 in Godinot Institute (Reims, France). 99mTc-Pertechnetate/99mTc-sestaMIBI dual tracer subtraction scintigraphy and neck ultrasonography were used as first-line imaging and failed to localize the causal parathyroid lesion in all cases.FCH PET/CT demonstrated at least 1 parathyroid target lesion in 29 patients (62%). 21/29 patients underwent surgery. Target lesions corresponded histologically to hyperfunctioning parathyroid glands for all 21 patients and surgery was followed by hyperparathyroidism biological resolution. Calcium serum levels were associated to FCH PET/CT positivity (P = .002) and a trend toward significance was seen for Parathyroid hormone (PTH) levels (P = .09).FCH PET/CT is a promising tool in second-line parathyroid imaging. Large prospective studies and cost-effectiveness analyses are needed to precise its role.

Cytopathology of Vitreous Humor Samples in Routine Practice.

OBJECTIVE: To describe findings in vitreous fluid samples in routine cytology practice. STUDY DESIGN: The pathology archives from 1988 to 2008 at our institution were searched for vitreous samples. The slides were reviewed and clinical and follow-up information was obtained. RESULTS: One hundred and eighty-two vitreous fluid samples from 166 patients were analyzed. Most of the samples had been collected for vitreous hemorrhage (75 cases). The second reason for vitreous sample cytological evaluation was an intraocular inflammatory process (55 cases). A specific cause of inflammation was found by combining clinical, microbiological and cytopathological findings in 19 cases, i.e. infection in 7, sarcoidosis in 3, retinal necrosis in 3, lens-induced endophthalmitis in 2, uveitis associated with systemic disease in 2, retrobulbar neuritis in 1 and sympathetic ophthalmia in 1. Among the 19 samples from 16 patients collected to rule out malignancy, 8 had a confirmed intraocular malignancy. Malignant cells were observed in 5 cases (3 lymphomas, 1 melanoma and 1 carcinoma). Undiagnosed malignancies included 2 lymphomas and 1 choroidal melanoma. Other samples were collected during surgery for retinal detachment and cataracts. CONCLUSIONS: In routine practice, cytology of the vitreous fluid is performed in many and varied situations that are most often nonneoplastic. In nonneoplastic cases, cytology is a useful adjunct to vitrectomy, in spite of its limitations.

Severe apoptotic enteropathy caused by methotrexate treatment for rheumatoid arthritis.

The folic acid antagonist methotrexate is a cornerstone treatment of rheumatoid arthritis. Its use is limited chiefly by gastrointestinal toxicity, which is among the main reasons for methotrexate discontinuation. Here, we report the case of a 40-year-old man on chronic methotrexate therapy in whom life-threatening apoptotic enteropathy with watery diarrhea and hypovolemic shock developed after he was switched from the oral to the intramuscular route, with no change in dosage. Colonic biopsies suggested drug-induced colitis, showing a nonspecific, mildly inflammatory infiltrate of lymphocytes and plasma cells, dilated damaged crypts, and a marked increase in basal crypt apoptosis (>20 apoptotic bodies/100 crypts). Clinicians should be aware that methotrexate can cause life-threatening apoptotic enteropathy. Increased basal crypt apoptosis in colonic biopsies with more than 5 apoptotic bodies/100 crypts should routinely suggest drug-induced enteropathy.

BRAFV600E Gene Mutation in Colonic Adenocarcinomas. Immunohistochemical Detection Using Tissue Microarray and Clinicopathologic Characteristics: An 86 Case Series.

The detection of BRAF mutation in colorectal cancer has several clinical applications: enabling the discrimination between sporadic and Lynch syndrome-related colorectal carcinoma, and providing warning of a poorer prognosis. Few immunohistochemical studies using whole-tissue tumor section staining have recently been performed on colorectal cancer. The aim of this study was to evaluate the detection of BRAF mutation by immunohistochemistry (IHC) on tissue microarray (TMA). IHC was performed with the BRAF-specific antibody using TMA on a retrospective series of 86 colonic adenocarcinomas with known BRAF status. IHC using BRAF-specific antibody allowed to detect 20/21 BRAF mutated colonic adenocarcinomas and 60/65 BRAF wild-type cases. The staining was equivocal because of equivocal staining in 4 cases and heterogeneity in 3 cases. When compared with TaqMan real-time PCR, the sensitivity and specificity were 95.2% and 92.3%, respectively. Comparison with the whole section immunostaining improved sensitivity to 100% and specificity to 95.4%. Furthermore, in this study we found that BRAF mutated colonic adenocarcinoma were significantly more frequent in women, older patients, and right-sided. Moreover, morphologic features significantly associated with BRAF mutation were: serrated adenocarcinoma subtype, adenocarcinomas with a mucinous component, high histologic grade, pushing margins, stromal inflammation. BRAF-specific antibody can be used on TMA to screen BRAF-mutated colorectal carcinomas. Cases with equivocal or heterogenous staining must be compared with whole section staining. Moreover, BRAF mutated colonic carcinomas have distinct clinical and histopathologic features.

Portal hypertension with extensive fibrosis and plasma cell infiltration in multiple myeloma.

Plasma cell infiltration of the liver has been described in about 45% of patient with multiple myeloma in autopsy review; however, it is usually not associated with significant liver dysfunction. Indeed, only rare cases of massive plasma cell infiltration leading to non-obstructive cholestasis and hepatic failure have been described. Here, we report a case with a history of 8 years of MM with extensive liver fibrosis and portal hypertension with no other evidence aetiology unless massive plasma cell infiltration who presented a significant regression of both biological liver abnormalities and liver stiffness after ten months of chemotherapy concomitantly to a significant decrease of the IgG serum monoclonal band.

Filiform polyposis: A benign entity? Case report and literature review.

Filiform polyposis (FP) is a distinctive and unusual form of benign non syndromic polyposis that is occasionally encountered in the colon of patients with inflammatory bowel disease (IBD) history. FP is characterized by one to hundreds, slender, arborizing, vermiform projections in the colon lined by normal or inflammatory colonic mucosa. Only rare cases without history or evidence of IBD have been reported. In those cases, the sigmoid colon was the most common location and none of them showed dysplasia or malignancy neither at first evaluation nor during follow-up. In this report, we present the first case of FP associated with six adenomas developed on filiform polyps and invasive adenocarcinoma in the right colon of a 54 year-old man without a past medical history of IBD.

Post-mortem diagnosis, of cytomegalovirus and varicella zoster virus co-infection by combined histology and tissue molecular biology, in a sudden unexplained infant death.

BACKGROUND: An autopsy case of a two-month-old male infant who suddenly and unexpectedly died during his sleep, eight days after the onset of benign varicella. OBJECTIVES: To describe post-mortem combined histological and tissue molecular biological techniques for the diagnosis of cytomegalovirus and varicella zoster virus co-infection as a cause of death. STUDY DESIGN: Real-time quantitative PCR and RT-PCR assays for Herpesviruses, respiratory viruses, Adenovirus, Enterovirus and Parvovirus B19 were performed on multi-organ frozen samples and paraffin-embedded tissues in combination with histology. RESULTS: Cytomegalovirus and varicella zoster virus were detected by molecular biology with highest viral loads detected in the lungs (4.6×10(7) and 1.9×10(5) genome copies per million of cells, respectively). Pulmonary extensive necrotizing inflammation and immunohistochemistry correlated to virological data. Virological molecular biology was negative on paraffin-embedded tissues. CONCLUSIONS: This case shows that thorough quantitative virological investigations on frozen tissues must be performed in combination with histology and immunohistochemistry for the determination of the cause of a sudden unexplained infant death.

[Investigation of the sudden infant death syndrome: a multidisciplinary approach is required]. / Exploration d'une mort inattendue du nourrisson : nécessité d'une approche multidisciplinaire.

The concept of sudden infant death syndrome (SIDS) is defined as the sudden, unexpected death of an infant less than a year old which remains unexplained after in-depth investigations comprising a complete autopsy, biological analyses, and a clinical examination of the circumstances surrounding the death. This definition underlines the importance of finding the cause of this disease in order to improve preventative measures to reduce the number of deaths due to sudden infant death syndrome. Among the causes of SIDS, pediatric infectious diseases may be neglected and must be systematically sought after. We report upon a SIDS death case of a four and a half month-old that occurred during his sleep. Following the absence of an evident cause of death a scientific autopsy was performed. The histological examination of pulmonary tissue revealed broncolitic lesions associated with numerous micro-abscesses. The post mortem microbiological analyses revealed evidence of an infection by the respiratory syncytial virus complicated by a bacterial infection due to Haemophilus influenzae. The case underlines the necessity of a multidisciplinary approach to researching SIDS, involving both clinicians and biologists, in order to determine the causes of these deaths.

Influenza A/H1N1 (2009) infection as a cause of unexpected out-of-hospital death in the young.

UNLABELLED: In March 2009, a new strain of influenza A/H1N1 virus was identified in Mexico, responsible for a pandemic. Worldwide, more than 13,500 patients died, most often from acute respiratory distress syndrome. Because sudden death cases were rare, involving mostly young apparently healthy persons, influenza A/H1N1 (2009)-related deaths may be misdiagnosed, which can raise medico-legal issues. CASE HISTORY: we report on an unexpected out-of-hospital death involving a young male with no past medical history and no vaccination. Fever was his only symptom. Laboratory tests: histology showed patchy necrotic foci with mononuclear inflammation in the lungs. The heart was histologically normal, but virological analyses using molecular biology on frozen myocardial samples showed high virus load. In conclusion, this case report shows that influenza A/H1N1 (2009) virus can be a cause of sudden cardiac death in the young and demonstrates the importance of quantitative virological analyses for the diagnosis of myocarditis.

A fatal case of Human Herpesvirus 6 chronic myocarditis in an immunocompetent adult.

BACKGROUND: Human Herpesvirus 6 (HHV-6) is an important cause of fulminant or acute viral myocarditis in immunocompromised or immunocompetent patients. However the physiopathological mechanisms of HHV-6 related acute myocarditis and the involvement of subsequent HHV-6 reactivation phases in the development of chronic cardiomyopathies remain to be assessed. OBJECTIVES: To describe a case of fatal HHV-6 chronic myocarditis in an immunocompetent adult. STUDY DESIGN: Case report and detailed histological and viral diagnoses by combination of histology/immunohistochemistry and polymerase chain reaction techniques on cardiac tissues. RESULTS: Histopathological analysis of ventricular tissues showed large interstitial and scarring fibrotic areas with a moderate mononuclear cell infiltrate compatible with histological aspect of chronic myocarditis. Detection of both HHV-6 by real-time PCR and viral glycoproteins in mononuclear and endothelial cells by immunohistochemistry evidenced an ongoing cardiac HHV-6 replication with viral late protein synthesis activity. CONCLUSIONS: This case report indicates that HHV-6 can establish a chronic active myocarditis leading to heart failure in immunocompetent subjects.