Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: Left main coronary artery atresia causing sudden death.

Noonan syndrome is a well-known genetic condition associating congenital heart defects, short stature, and distinctive facial features. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most frequent cardiac abnormalities, the latter being associated with a higher mortality. Here we report for the first time, a case of congenital left main coronary artery atresia in a Noonan syndrome associated with RIT1 variant, leading to unrescued sudden death. This case-report supports the already-suspected severity of the RIT1-related Noonan syndrome compared to average Noonan syndrome, and should encourage clinicians to be very cautious with these patients.

Revisited microanatomy of the corneal endothelial periphery: new evidence for continuous centripetal migration of endothelial cells in humans.

The control of corneal transparency depends on the integrity of its endothelial monolayer, which is considered nonregenerative in adult humans. In pathological situations, endothelial cell (EC) loss, not offset by mitosis, can lead to irreversible corneal edema and blindness. However, the hypothesis of a slow, clinically insufficient regeneration starting from the corneal periphery remains debatable. The authors have re-evaluated the microanatomy of the endothelium in order to identify structures likely to support this homeostasis model. Whole endothelia of 88 human corneas (not stored, and stored in organ culture) with mean donor age of 80 ± 12 years were analyzed using an original flat-mounting technique. In 61% of corneas, cells located at the extreme periphery (last 200 µm of the endothelium) were organized in small clusters with two to three cell layers around Hassall-Henle bodies. In 68% of corneas, peripheral ECs formed centripetal rows 830 ± 295 µm long, with Descemet membrane furrows visible by scanning electron microscopy. EC density was significantly higher in zones with cell rows. When immunostained, ECs in the extreme periphery exhibited lesser differentiation (ZO-1, Actin, Na/K ATPase, CoxIV) than ECs in the center of the cornea but preferentially expressed stem cell markers (Nestin, Telomerase, and occasionally breast cancer resistance protein) and, in rare cases, the proliferation marker Ki67. Stored corneas had fewer cell clusters but more Ki67-positive ECs. We identified a novel anatomic organization in the periphery of the human corneal endothelium, suggesting a continuous slow centripetal migration, throughout life, of ECs from specific niches.

A fatal intoxication case involving ropinirole.

Ropinirole, a specific non-ergoline dopamine D2-receptor agonist, belongs to the drugs applied in treatment of Parkinson's disease (PD) and restless legs syndrome (RLS) and acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D3. Therapeutic ropinirole plasma levels in adults are defined between 0.4 and 6 ng/mL. This case report documents a fatal intoxication involving ropinirole. Information about lethal ropinirole concentrations is hitherto lacking in the literature and the assessed ropinirole levels of this case may present a step towards defining potentially lethal concentrations. A 37-year-old man without medical history was found dead in a converted van used as place of residence and an autopsy was performed. The pathological findings did not reveal an apparent cause of death but the toxicological analysis revealed the presence of ropinirole, paracetamol, and alcohol in the peripheral blood sample. Quantitative analysis revealed that ropinirole was present at a peripheral blood concentration of 64 ng/mL. The ropinirole concentrations determined in vitreous humor, urine and bile were respectively, 11 ng/mL, 2670 ng/mL and 826 ng/mL. Paracetamol was detected at a blood level of <2 µg/mL. Based on the autopsy findings and toxicological results, the cause of death was primarily attributed to intoxication with ropinirole in combination with alcohol.

[The medical autopsy: its indications, contraindications, the modalities of its implementation, its cost and its limits. Autopsy of the medical autopsy]. / L'autopsie médicale : ses indications, ses contre-indications, les modalités de sa mise en œuvre, son coût et ses limites. Ou l'Autopsie de l'autopsie.

The decline of the medical autopsy, in spite of the uncontested recognition of its utility, is not to be any more proved. By summarizing the legal frame of this exceptional act, we tried to identify the indications, the contraindications, the precautions for use, the limits, the technical, legal and ethical constraints and the costs of this diagnostic and therapeutic tool. The discussion underlines that the main brake in the realization of the autopsies could be its too strict French legal frame.

Laryngeal teflonoma identified by Fourier-transform infrared microspectroscopy after forensic autopsy: an interesting tool for foreign material identification in forensic cases.

Forensic pathologists are sometimes confronted with microscopic foreign bodies mixed in with soft tissues surrounding wounds and which are thus difficult to identify. This identification, however, could be primordial in investigating a crime and in determining the weapon used. A case of a fatal respiratory distress syndrome due to conjoining suicidal drug intoxication and laryngeal obstruction by a voluminous foreign body giant cell granuloma is presented. The classical histological examination showed exogenous particles in the vocal cord tumor with birefringent qualities. Their analysis with Fourier-Transform infrared (FTIR) spectrometry coupled with infrared microscope allows the determination of their chemical nature as polytetrafluoroethylene and to the diagnosis of teflonoma. This case report put the emphasis on the forensic interest of the FTIR imaging.

Sudden death due to myocardial metastasis of lingual squamous cell carcinoma.

Cardiac metastases are rare events encountered in pathological practice but with often dramatic fatal outcome. Among malignancies associated with cardiac involvement, we would like to draw the attention of clinicians about lingual squamous cell carcinoma by reporting a sudden cardiac death in a 57-year-old woman without prior symptom and considered in remission 1 month before her death. The forensic autopsy led to the diagnosis emphasizing its role in epidemiology and public health.

Primary central nervous system lymphoma: immunohistochemical profile and prognostic significance.

Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma (NHL) with extranodal location affecting only the CNS, meninges and eye, without visceral or lymph node involvement. Its incidence has increased sharply over the past three decades, especially in immunocompetent subjects. Most PCNSL cases are diffuse large B-cell lymphomas (DLBCLs). However, it differs from nodal DLBCL in that it has a worse prognosis. DLBCLs are a heterogeneous entity and according to new genomic discoveries, classifications into prognostic subgroups have been embarked upon. Two prognostic algorithms were then prepared using a panel of immunohistochemical markers (CD10, Bcl6, MUM1/IRF-4, and Bcl2), thus categorizing DLBCL into two subgroups, GCB (germinal centre B-cell-like) or non-GCB, and into Group 1 or Group 2. Our goal is to apply both of these two sub-classifications to 39 PCNSLs, in order to assess their usefulness and prognostic relevance. 74.3% of our PCNSLs were of a non-GCB phenotype, corresponding to an activated postgerminal origin. They were evenly distributed across G1 and G2. Two- and 5-year overall survival rates were 34.8% and 19.6%, respectively. Younger age (<65) and a therapeutic combination of chemotherapy and radiotherapy significantly improved our patients' survival rates. The other clinical or biological markers tested had no prognostic impact. The two classifications did not reveal any significant survival difference. The recent discovery of a specific "transcriptional signature" of PCNSL, marking them out of DLBCL could account for the irrelevance of such prognostic classifications to PCNSL.

Lamina propria of the human vocal fold: histomorphometric study of collagen fibers.

BACKGROUND: Since the seminal work of M. Hirano, which defined the three-layered lamina propria of the human vocal fold, there has been confusion in the labeling of each layer. Recent studies described the composition of fibers and interstitial molecules within the lamina propria leading to various biomechanical properties. However, collagen fibers appear as the most important structure component. METHODS: We used an optical analysis and the picrosirius-polarization method to describe collagen fibers from six adult and two fetal human larynges fixed in formalin and frontally sectioned in the middle part of the vocal fold. RESULTS: The deep layer of the lamina propria is the most densely organized band of collagen fibers penetrating the superficial muscle bundles of the vocal muscle. The mean thickness of this layer is about 36% of the lamina propria and shows a network of strongly birefringent fibers (collagen type I and III). The superficial layer of the lamina propria is a narrow band of collagen fibers immediately below the basement membrane of the epithelium. The mean thickness of this layer is about 13% of the lamina propria and shows strong birefringent fibers. The intermediate layer is the less densely organized band between the deep and superficial layers. The mean thickness of this layer is about 51% of the lamina propria and shows clear, green weakly birefringent fibers characterized as collagen type III. The fetal lamina propria contains only a monolayer distribution of loose collagen fibers between the epithelium and the vocal muscle. CONCLUSION: These results help describe the distribution of collagen fibers within the lamina propria of the human vocal fold and have implications to understand the cover-body theory of voice production both in the adult and newborn.

Ear bleeding: A sign not to be underestimated in cases of strangulation.

Otorrhagia is commonly associated with cranial trauma and diving accidents. In some forensic manuals, bleeding in the ears is anecdotally associated with strangulation. We report 2 cases of criminal strangulation with hemotympanum and otorrhagia, emphasizing the importance of this sign with strangulation. We present the proposed pathophysiology of the injuries and the value of otoscopic evaluation to complete the external examination in forensic cases suspicious for strangulation.

[Medical autopsies: retrospective analysis of indications and relevance of the results for the medical community]. / Les autopsies médicales : analyse rétrospective des demandes et apport de leurs résultats à la communauté hospitalo-universitaire.

AIM: A retrospective study of adult autopsies and its value in a French university hospital. INTRODUCTION: Despite its decline, the medical autopsy remains a major diagnostic tool to understand death mechanisms and to improve the quality of cares. OBJECTIVES: Our purpose is to assess the current motivations of hospital autopsy demands, to analyze the concerned patients' medical characteristics, to determine the contribution of these with regard to the clinicians' questioning and to put the light on its limits. MATERIAL AND METHODS: We reviewed the demands of adults' autopsies made in our hospital center between November 2005 and June 2008. RESULTS: Eighteen demands were sent during the considered period. More than half of these demands came from intensive care units, and had for main motivations to eliminate diagnostic hypotheses or to understand the fast lethal evolution in spite of the administered treatments. The median duration of hospitalization before death was about 12 days. The average age of the patients was about 61 years. These patients had suffered on average three important pathological histories before their admittance at the hospital, which were directly responsible for the death in 56% of the observations. The autopsy allowed to establish a diagnosis in 10 cases, to complete a diagnosis in five observations and to confirm a diagnosis in four cases. The absences of diagnoses are especially due to the fast degradation of the patients' state before the realization of the adapted additional examinations. The diagnostic errors concern pathologies with a poor specific or atypical semiology, or when there is one intricacy of important pathologies. CONCLUSION: The autopsy remains a contributory examination in the reviews of morbimortality and in the improvement of the care. However, for its results to be useful, they have to join a critical multidisciplinary discussion.

[Social vulnerability is more frequent in victims of interpersonal violence: value of the EPICES score]. / La précarité est plus fréquente chez les victimes de violences volontaires : intérêt du score EPICES.

OBJECTIVES: To evaluate social vulnerability of victims of interpersonal violence having consulted a service of forensic medicine with an individual index of social vulnerability. POPULATION AND METHODS: The population of victims of interpersonal violence was composed of 275 subjects having consulted the service of forensic medicine of the CHU of Saint Etienne. The social data were collected by questionnaire. Social vulnerability was measured by an individual index (EPICES) calculated on the basis of 11 weighted questions related to material and social deprivation. This population was compared with a reference population; the reference population was people, aged more than 16, living in the Rhône-Alpes region and examined in 2005 in one of the Health examination Centres (HECs) of the French General Health Insurance System, that is 7553 men and 6002 women. The comparisons between the two populations were made after redressing the population of the HECs on various socio-demographic data of the Rhône-Alpes region. The relations between violence and the variables studied were measured by odds ratios adjusted on age and sex. RESULTS: The population of the victims of violence is younger than the reference population (p<0.001). It is characterized by a lower level of education (p<0.001, 15% in the higher education level vs 23%) and the categories Employees and Manual workers are more frequent (p<0.001). The situation with respect to employment is also different between the two populations, unemployment rate is higher (OR=2.25) and the retired are fewer (OR=0.41). Subjects in social vulnerability are more frequent in the victims (57% vs 36%). All these differences persist after adjustment on age and sex. The context in which the aggression took place (family, public area or at work) varies significantly according to social vulnerability. On the other hand, the majority of the other medico-legal characteristics are not different according to the level of social vulnerability. CONCLUSION: The population of the victims of interpersonal violence has a socio-economic profile different from the reference population. Social vulnerability is associated with interpersonal violence, in particular with violence in the public and family area.

First case report of a fetal synovial sarcoma confirmed by molecular detection of SYT-SSX fusion gene transcripts.

Synovial sarcomas are aggressive malignant soft tissue tumors typically observed in adolescents and young adults. They are often characterized by the chromosomal translocation t(X;18)(p11.2;q11.2), which results in the expression of SYT-SSX fusion transcripts. We describe the first case of synovial sarcoma observed in a human fetus. The tumor occurred in the left upper arm and led to intrauterine fetal demise during gestational week 31. Grossly, the tumor measured 10 x 8 x 8 cm, appeared pinkish in color, and developed in the soft tissues of the left arm surrounding the humerus. Histologically, this large tumor showed a dense proliferation of homogeneous spindle cells with some necrotic areas. The positive detection of the SYT-SSX1 fusion transcripts with reverse-transcription polymerase chain reaction in formalin-fixed and paraffin-embedded tissue confirmed the synovial sarcoma diagnosis.

Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction.

OBJECTIVES: In this study, we evaluated the potential direct role of enterovirus (EV) cardiac infections in the pathogenesis of myocardial infarction (MI). BACKGROUND: Enteroviruses (Picornaviridae) have been suspected to play a role in the development of acute MI. METHODS: The presence of EV ribonucleic acid (RNA) sequences and capsid viral protein 1 (VP1) and the virus-mediated focal disruption of dystrophin were retrospectively investigated by reverse transcriptase-polymerase chain reaction and immunohistochemistry assays in endomyocardial tissues of patients who died suddenly of acute MI by comparison with similar samples of control patients matched for gender, residence area, and year of death. RESULTS: Enterovirus infection markers were detected in 20 (40%) of 50 patients who died suddenly of MI, 2 (4%) of 50 matched subjects without cardiac disease (p < 0.001), and 4 (8%) of 50 matched patients exhibiting a noncoronary chronic cardiopathy (p < 0.001). All of the EV RNA-positive patients exhibited VP1, which provided evidence of viral protein synthesis activity. The VP1 gene sequences amplified after cloning from myocardial or coronary samples of 8 of the MI patients and showed a strong homology with sequences of coxsackievirus B2 and B3 serotypes. Moreover, in the endomyocardial tissue of these 8 patients, immunohistochemical analyses demonstrated that there was disruption of the sarcolemmal localization of dystrophin in the same tissue areas that were infected by coxsackieviruses. CONCLUSIONS: Our findings demonstrate a significantly higher proportion of active coxsackievirus B cardiovascular infections in patients who suddenly died of MI compared with matched control subjects, suggesting that these EVs may significantly contribute to the pathogenesis of acute MI by a focal disruption of the dystrophin-glycoprotein complex.

[Rash and nephrotic syndrome: consider syphilis]. / Eruption et syndrome néphrotique, penser à la syphilis.

INTRODUCTION: Kidney disease is among the clinical manifestations of secondary syphilis, as this case report shows. OBSERVATION: During serologically confirmed secondary syphilis, a 63-year-old man developed a nephrotic syndrome diagnosed after biopsy as membranous nephropathy. DISCUSSION: Membranous nephropathy is an immunological complication of secondary syphilis. Recovery usually follows treatment. It is often associated with signs that may erroneously suggest connective tissue disease.