Cardiac valve involvement in ADAR-related type I interferonopathy.

BACKGROUND: Adenosine deaminases acting on RNA (ADAR) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported in the context of MDA5 gain-of-function. RESULTS: We describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5-14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5-6.5 years. In one case, disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification. CONCLUSIONS: Type I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with ADAR-related type I interferonopathy may develop childhood-onset multivalvular stenosis and incompetence which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure. Regular surveillance echocardiograms are recommended to detect valvular disease early.

Endomysial fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative activation.

There is considerable interindividual variability in motor function among patients with Duchenne muscular dystrophy (DMD); moreover, pathogenetic mechanisms of motor dysfunction in DMD are not understood. Using multiparametric analysis, we correlated initial histologic alterations in quadriceps muscle biopsies from 25 steroid therapy-free patients with DMD with 13 relevant clinical features assessed by a single clinical team during a long-term period (mean, >10 years). There was no residual muscle dystrophin by immunohistochemistry and Western blot analysis in the biopsies. Myofiber size, hypercontracted fibers, necrotic/basophilic fibers, endomysial and perimysial fibrosis, and fatty degeneration were assessed by morphometry. Endomysial fibrosis was the only myopathologic parameter that significantly correlated with poor motor outcome as assessed by quadriceps muscle strength, manual muscle testing of upper and lower limbs at 10 years, and age at ambulation loss (all p<0.002). Motor outcome and fibrosis did not correlate with genotype. Myofibers exhibited oxidative stress-induced protein alterations and became separated from capillaries by fibrosis that was associated with both increase of CD206+ alternatively activated macrophages and a relative decrease of CD56+ satellite cells (both p<0.0001). This study provides a strong rationale for antifibrotic therapeutic strategies in DMD and supports the view that alternatively activated macrophages that are known to inhibit myogenesis while promoting cellular collagen production play a key role in myofibrosis.

The birth of a monstrous child throughout history: the example of anencephaly between the Egyptian New Empire and the 21st century.

Anencephaly is of special interest for the historical study of human behaviour after the birth of a monstrous child. Examples of anencephalic human births from Egyptian Antiquity to the present time allow us to create a history of teratology, revealing hiatuses in the medical and scientific interpretation of monstrosity that contrast to a relative continuity in the imaginary processes that accompany the birth of a monstrous child.

Does the source of laser energy influence the coagulation of chorionic plate vessels? Comparison of Nd:YAG and diode laser on an ex vivo placental model.

OBJECTIVES: To compare the histological effects of diode and Neodymium-Yttrium Aluminium Garnet (Nd:YAG) laser coagulation of chorionic plate vessels. METHODS: In selected chorionic plate vessels in an ex vivo term placenta perfused with warm saline solution, diode (wavelength 940 nm) and Nd:YAG (wave length 1,064 nm) laser were used with an output of 30, 40, and 50 W, and 55 and 70 W respectively using preset energy and duration of impact. All vessels were examined histologically blindly to the procedures' characteristics. RESULTS: A total of 23 vessels were coagulated. Similar histological lesions were observed using diode and Nd:YAG lasers. The lesions were compatible with an acceptable clinical effect at all power outputs tested. The results were not related to the diameter or type of vessels. Lesions of the endothelium and reduction of the vessel lumen were best achieved with a diode laser at 40 W. CONCLUSION: Nd:YAG and Diode laser induce significant and comparable changes in chorionic plate vessels compatible with an efficient coagulation process under the experimental condition used.

Role of ATP-dependent potassium channels in pulmonary vascular tone of fetal lambs with congenital diaphragmatic hernia.

High mortality in newborn babies with congenital diaphragmatic hernia (CDH) is principally due to persistent pulmonary hypertension. ATP-dependent potassium (K(ATP)) channels might modulate pulmonary vascular tone. We have assessed the effects of Pinacidil, a K(ATP) channel opener, and glibenclamide (GLI), a K(ATP) channel blocker, in near full-term lambs with and without CDH. In vivo, pulmonary hemodynamics were assessed by means of pressure and blood flow catheters. In vitro, we used isolated pulmonary vessels and immunohistochemistry to detect the presence of K(ATP) channels in pulmonary tissue. In vivo, pinacidil (2 mg) significantly reduced pulmonary vascular resistance (PVR) in both controls and CDH animals. GLI (30 mg) significantly increased pulmonary arterial pressure (PAP) and PVR in control animals only. In vitro, pinacidil (10 microM) relaxed, precontracted arteries from lambs with and without CDH. GLI (10(-5) microM) did not raise the basal tone of vessels. We conclude that activation of K(ATP) channels could be of interest to reduce pulmonary vascular tone in fetal lambs with CDH, a condition often associated with persistent pulmonary hypertension of the newborn.

Digestive endoscopy in neonates.

Since the introduction of flexible fiberoptic endoscopy in the early 1970s, esophagogastro-duodenoscopy and colonoscopy have become established procedures for the diagnosis, evaluation and treatment of gastrointestinal tract disease in the pediatric population. The development of safe fiberoptic endoscopes specially designed for neonates has allowed visualization of lesions occurring in the first days of life. Despite an increased understanding of neonatal digestive disorders deriving from this new diagnostic modality, there is little consensus on the appropriate use of endoscopic procedures in routine care of neonates. It is the feeling of the authors that widening the indications of endoscopy in the neonatal period might lead to diagnosis of discrete clinical abnormalities, which might improve the care of neonates. The techniques for performing neonatal endoscopies, the appropriate indications, the common normal and pathologic findings and the complications of these procedures are reviewed.

Connections of the bladder plate and bladder neck with the bony pelvis in a fetus with classic bladder exstrophy.

OBJECTIVES: To demonstrate that the bladder plate and bladder neck in classic bladder exstrophy are laying on smooth muscle fibers that extend laterally to the pubic bones. METHODS: We compared a male fetus of 28 weeks' gestational age with classic bladder exstrophy with a normal fetus of the same age. The specimens were divided into two parts by a midsagittal section, from the bladder neck to the membranous urethra. Thin transverse slices were also obtained on one part, and longitudinal slices on the other part. RESULTS: The smooth musculature of the bladder is normally differentiated cytologically and extends laterally to the bony structures of the pelvis. The musculature of the bladder neck and urethra are normally present compared with the control. CONCLUSIONS: The results of this study demonstrate the musculoskeletal organization of the urogenital system in classic bladder exstrophy. They also indicate that these structures should be clearly individualized and repaired in the reconstruction of classic bladder exstrophy.

Meiotic studies of infertile men in case of non-obstructive azoospermia with normal karyotype and no microdeleted Y-chromosome precise the clinical couple management.

To identify meiotic criteria for infertility management in non-obstructive azoospermic men, a prospective and multicentric study was organized in Andrological Departments of Paris (France), Roma (Italy) and Budapest (Hungary). In 117 non-obstructive azoospermic men with normal karyotype and no Y-chromosome microdeletion, histology and meiotic studies on bilateral bipolar testicular biopsies were done. Histologically, 40 patients (34%) presented spermatocyte or spermatid arrest, 39 (33%) hypospermatogenesis whereas no meiotic cell could be observed in the remaining patients (33%). Cytogenetically, meiotic figures could only be obtained from the two first histological groups. Meiotic abnormalities were observed in a total of 44 patients (37.6%) including nine patients (7.7%) with severe class I and class IIB anomalies and 19 patients (16.2%) with class IIC environmentally linked meiotic abnormalities. These results provided essential clues for an accurate clinical management. For patients with no meiotic figures and patients with class I and class IIB anomalies, an hormonal stimulation is illusory and a sperm gift should be directly proposed. An hormonal stimulation should be proposed to all the other patients, either directly or following the treatment of the testicular microenvironment for the patients presenting class IIC anomalies. The genetic risk and possibility of prenatal chromosomal analysis in case of pregnancy should be clearly exposed to all the couples in all the cases where type IIA, III or IV anomalies are present. This therapeutical strategy has been applied to all the patients in our series.

Intervertebral disc degeneration: the role of the mitochondrial pathway in annulus fibrosus cell apoptosis induced by overload.

Degeneration of the intervertebral disk (IVD) is a major pathological process implicated in low back pain and is a prerequisite to disk herniation. Although mechanical stress is an important modulator of the degeneration, the underlying molecular mechanism remains unclear. The association of human IVD degeneration, assessed by magnetic resonance imaging, with annulus fibrosus cell apoptosis and anti-cytochrome c staining revealed that the activation of the mitochondria-dependent apoptosome was a major event in the degeneration process. Mouse models of IVD degeneration were used to investigate the role of the mechanical stress in this process. The application of mechanical overload (1.3 MPa) for 24 hours induced annulus fibrosus cell apoptosis and led to severe degeneration of the mouse disks. Immunostaining revealed cytochrome c release but not Fas-L generation. The role of the caspase-9-dependent mitochondrial pathway in annulus fibrosus cell apoptosis induced by overload was investigated further with the use of cultured rabbit IVD cells in a stretch device. Mechanical overload (15% area change) induced apoptosis with increased caspase-9 activity and decreased mitochondrial membrane potential. Furthermore, Z-LEHD-FMK, a caspase-9 inhibitor, but not Z-IETD-FMK, a caspase-8 inhibitor, attenuated the overload-induced apoptosis. Our results from human samples, mouse models, and annulus fibrosus culture experiments demonstrate that the mechanical overload-induced IVD degeneration is mediated through the mitochondrial apoptotic pathway in IVD cells.