Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA‐binding protein 43 inclusions) in missense progranulin mutation Cys139Arg

Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau‐negative frontotemporal lobar degeneration with TAR DNA‐binding protein 43‐positive inclusions (FTLD‐TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late‐onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ‐amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD‐TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD‐TDP.     

Novel intra‐genic large deletions of CTNNB1 gene identified in WT desmoid‐type fibromatosis

A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1‐mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases. Low‐frequency (mean reads of 16%) CTNNB1 mutations were discovered in five samples (45%) and two novel intra‐genic deletions in CTNNB1 were detected in two cases. Both deletions and low frequency mutations of CTNNB1 were highly expressed. In conclusion, a minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular alterations in APC and CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases.     

Prevalence of Usutu and West Nile virus antibodies in human sera,Modena, Italy, 2012

A collection of 3069 human sera collected in the area of the municipality of Modena, Emilia Romagna, Italy, was retrospectively investigated for specific antibodies against Usutu (USUV) and West Nile viruses (WNV). All the samples resulting positive using a preliminary screening test were analyzed with the plaque reduction neutralization test. Overall, 24 sera were confirmed as positive for USUV (0.78%) and 13 for WNV (0.42%). The results suggest that in 2012, USUV was circulating more than WNV in North‐eastern Italy.     

Genomic detection of a familial 382 Kb 6q27 deletion in a fetus with isolated severe ventriculomegaly and her affected mother

Terminal deletions of the chromosome 6q27 region are rare genomic abnormalities, linked to specific brain malformations and other neurological phenotypes. Reported cases have variable sized genomic deletions that harbor several genes including the DLL1 and TBP. We report on an inherited 0.38 Mb terminal deletion of chromosome 6q27 in a 22‐week fetus with isolated bilateral ventriculomegaly and her affected mother using microarray‐based comparative genomic hybridization and fluorescent in situ hybridization (FISH). The deleted region harbors at least seven genes including DLL1 and TBP. The affected mother had a history of hydrocephalus, developmental delay, and seizures commonly associated with DLL1 and TBP 6q27 deletions. This deletion is one of the smallest reported isolated 6q27 terminal deletions. Our data provides additional evidence that haploinsufficiency of the DLL1 and TBP genes may be sufficient to cause the ventriculomegaly, seizures, and developmental delays associated with terminal 6q27 deletions, indicating a plausible role in the abnormal development of the central nervous system.     

Reinterpretation of evidence advanced for neo-oogenesis in mammals, in terms of a finite oocyte reserve

The central tenet of ovarian biology, that the oocyte reserve in adult female mammals is finite, has been challenged over recent years by proponents of neo-oogenesis, who claim that germline stem cells exist in the ovarian surface epithelium or the bone marrow. Currently opinion is divided over these claims, and further scrutiny of the evidence advanced in support of the neo-oogenesis hypothesis is warranted - especially in view of the enormous implications for female fertility and health. This article contributes arguments against the hypothesis, providing alternative explanations for key observations, based on published data. Specifically, DNA synthesis in germ cells in the postnatal mouse ovary is attributed to mitochondrial genome replication, and to DNA repair in oocytes lagging in meiotic progression. Lines purported to consist of germline stem cells are identified as ovarian epithelium or as oogonia, from which cultures have been derived previously. Effects of ovotoxic treatments are found to negate claims for the existence of germline stem cells. And arguments are presented for the misidentification of ovarian somatic cells as de novo oocytes. These clarifications, if correct, undermine the concept that germline stem cells supplement the oocyte quota in the postnatal ovary; and instead comply with the theory of a fixed, unregenerated reserve. It is proposed that acceptance of the neo-oogenesis hypothesis is erroneous, and may effectively impede research in areas of ovarian biology. To illustrate, a novel explanation that is consistent with orthodox theory is provided for the observed restoration of fertility in chemotherapy-treated female mice following bone marrow transplantation, otherwise interpreted by proponents of neo-oogenesis as involving stimulation of endogenous germline stem cells. Instead, it is proposed that the chemotherapeutic regimens induce autoimmunity to ovarian antigens, and that the haematopoietic chimaerism produced by bone marrow transplantation circumvents activation of an autoreactive response, thereby rescuing ovarian function. The suggested mechanism draws from animal models of autoimmune ovarian disease, which implicate dysregulation of T cell regulatory function; and from a surmised role for follicular apoptosis in the provision of ovarian autoantigens, to sustain self-tolerance during homeostasis. This interpretation has direct implications for fertility preservation in women undergoing chemotherapy.     

Female Urinary Incontinence at Orgasm: A Possible Marker of a More Severe Form of Detrusor Overactivity. Can Ultrasound Measurement of Bladder Wall Thickness Explain It?

IntroductionCoital incontinence (CI) during orgasm is a form of urinary incontinence possibly because of detrusor overactivity (DO), as the underlying pathophysiological condition. Women with this symptom usually show a pharmacological lower cure rate than those with DO alone. The ultrasound measurement of the bladder wall thickness (BWT) allows an indirect evaluation of detrusor muscle thickness, giving a potential index of detrusor activity.AimWe wanted to understand if CI at orgasm could be a marker of severity of DO by comparing BWT in women with both DO and CI at orgasm vs. women with DO alone. In addition we aimed to confirm if CI during orgasm is related to antimuscarinics treatment failure.MethodsThis is a prospective cohort study performed in two tertiary urogynecological referral departments, recruiting consecutive patients seeking treatment for symptomatic DO.Main Outcome MeasuresAll patients were thoroughly assessed including physical examination, urodynamic evaluation, and BWT measurement according to the International Continence Society/International Urogynecological Association and ICI recommendations. Solifenacine 5 mg once daily was then prescribed and follow-up was scheduled to evaluate treatment. Multiple logistic regression (MLR) was performed to identify risk factors for treatment failure.ResultsBetween September 2007 and March 2010, 31 (22.6%) and 106 (77.4%) women with DO with and without CI at orgasm were enrolled. Women complaining of CI at orgasm had significantly higher BWT than the control group (5.8 ± 0.6 mm vs. 5.2 ± 1.2 mm [P = 0.007]). In patients with CI at orgasm, the nonresponder rate to antimuscarinics was significantly higher than controls (P = 0.01). After MLR, CI at orgasm was the only independent predictor decreasing antimuscarinics efficacy (odds ratio [OR] 3.16 [95% CI 1.22–8.18], P = 0.02).ConclusionsWomen with DO and CI at orgasm showed a significantly higher BWT values and worse cure rates than women with DO alone. CI at orgasm could be a marker of a more severe form of DO. Serati M, Salvatore S, Cattoni E, Siesto G, Soligo M, Braga A, Sorice P, Cromi A, Ghezzi F, Cardozo L, and Bolis P. Female urinary incontinence at orgasm: A possible marker of a more severe form of detrusor overactivity. Can ultrasound measurement of bladder wall thickness explain it?.     

Primeros 3 casos en España de gestación a término tras tratamiento de miomas mediante cirugía no invasiva MRgFUS

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a non-invasive surgical technique based on thermal coagulative necrosis of tissue by focused ultrasound guided by magnetic resonance. This fairly recent technique was approved by the American Food and Drug Administration in 2004 and by the European Union in 2006 for the treatment of uterine fibroids. In 2010 MRgFUS was approved by the European Union (CE label) for the treatment of adenomyosis and is being developed for the non-invasive treatment of other tumoral diseases, mainly in oncology. We present the first three cases of pregnancy achieved at the Instituto Cartuja, the only site in Spain with MRgFUS technology. We conclude that MRgFUS is a safe, reliable and effective technique for the treatment of uterine fibroids, even in women with a desire to preserve fertility.