Cranial Ultrasound Is an Important Tool in the Recognition of Life-Threatening Infratentorial Hemorrhage in Newborns.

Timely detection of severe infratentorial hemorrhage in neonates is crucial, especially in case of life-threatening brain stem compression and/or acute obstructive hydrocephalus, which need lifesaving neurosurgical intervention. Although the detection of infratentorial hemorrhage by ultrasound scanning is often considered as difficult, the use of additional acoustic windows and recognition of characteristic ultrasound features facilitate early diagnosis. In this case series, we report on newborns with severe, symptomatic infratentorial hemorrhage detected primarily by cranial ultrasound. We demonstrate the characteristic ultrasound features present in all cases and discuss how ultrasound diagnosis contributed to early diagnosis and treatment.

Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.

The CHOPIn Study: a Multicenter Study on Cerebellar Hemorrhage and Outcome in Preterm Infants.

Cerebellar hemorrhage (CBH) is a frequent complication of preterm birth and may play an important and under-recognized role in neurodevelopment outcome. Association between CBH size, location, and neurodevelopment is still unknown. The main objective of this study was to investigate neurodevelopmental outcome at 2 years of age in a large number of infants with different patterns of CBH. Of preterm infants (≤ 34 weeks) with known CBH, perinatal factors, neuro-imaging findings, and follow-up at 2 years of age were retrospectively collected. MRI scans were reassessed to determine the exact size, number, and location of CBH. CBH was divided into three groups: punctate (≤ 4 mm), limited (> 4 mm but < 1/3 of the cerebellar hemisphere), or massive (≥ 1/3 of the cerebellar hemisphere). Associations between pattern of CBH, perinatal factors, and (composite) neurodevelopmental outcome were assessed. Data of 218 preterm infants with CBH were analyzed. Of 177 infants, the composite outcome score could be obtained. Forty-eight out of 119 infants (40%) with punctate CBH, 18 out of 35 infants (51%) with limited CBH, and 18 out of 23 infants (78%) with massive CBH had an abnormal composite outcome score. No significant differences were found for the composite outcome between punctate and limited CBH (P = 0.42). The risk of an abnormal outcome increased with increasing size of CBH. Infants with limited CBH have a more favorable outcome than infants with massive CBH. It is therefore important to distinguish between limited and massive CBH.

Molecular, biochemical, and proteomic analyses of transplastomic tobacco plants expressing an endoglucanase support chloroplast-based molecular farming for industrial scale production of enzymes.

The successful production of recombinant enzymes by tobacco transplastomic plants must maintain compatibility of the heterologous enzyme with chloroplast metabolism and its long-time enzyme stability. Based on previous reports, it has been taken for granted that following biolistic-transformation, homoplasticity could be obtained from the initially heteroplastic state following successive rounds of selection in the presence of the selection agent. However, several studies indicated that this procedure does not always ensure the complete elimination of unmodified wild-type plastomes. The present study demonstrates that CelK1 transplastomic plants, which were photosyntetically as active as untransformed ones, remain heteroplastomic even after repeated selection steps and that this state does not impair the relatively high-level production of the recombinant enzyme. In fact, even in the heteroplastomic state, the recombinant protein represented about 6% of the total soluble proteins (TSP). Moreover, our data also show that, while the recombinant endoglucanase undergoes phosphorylation, this post-translation modification does not have any significant impact on the enzymatic activity. Biomass storage might be required whenever the enzyme extraction process could not be performed immediately following the harvest of tobacco mature plants. In this respect, we have observed that enzyme activity in the detached leaves stored at 4 °C is maintained up to 20 weeks without significant loss of activity. These findings may have major implications in the future of chloroplast genetic engineering-based molecular farming to produce industrial enzymes in transplastomic plants.

Cross-protective efficacy from a immunogen firstly identified in Leishmania infantum against tegumentary leishmaniasis.

Experimental vaccine candidates have been evaluated to prevent leishmaniasis, but no commercial vaccine has been proved to be effective against more than one parasite species. LiHyT is a Leishmania-specific protein that was firstly identified as protective against Leishmania infantum. In this study, LiHyT was evaluated as a vaccine to against two Leishmania species causing tegumentary leishmaniasis (TL): Leishmania major and Leishmania braziliensis. BALB/c mice were immunized with rLiHyT plus saponin and lately challenged with promastigotes of the two parasite species. The immune response generated was evaluated before and 10 weeks after infection, as well as the parasite burden at this time after infection. The vaccination induced a Th1 response, which was characterized by the production of IFN-γ, IL-12 and GM-CSF, as well as by high levels of IgG2a antibodies, after in vitro stimulation using both the protein and parasite extracts. After challenge, vaccinated mice showed significant reductions in their infected footpads, as well as in the parasite burden in the tissue and organs evaluated, when compared to the control groups. The anti-Leishmania Th1 response was maintained after infection, being the IFN-γ production based mainly on CD4(+) T cells. We described one conserved Leishmania-specific protein that could compose a pan-Leishmania vaccine.

Prophylactic properties of a Leishmania-specific hypothetical protein in a murine model of visceral leishmaniasis.

In this work, the effect of vaccination of a newly described Leishmania infantum antigenic protein has been studied in BALB/c mice infected with this parasite species. The LiHyD protein was characterized after a proteomic screening performed with the sera from dogs suffering visceral leishmaniasis (VL). Its recombinant version was expressed, purified and administered to BALB/c mice in combination with saponin. As a result of vaccination and 10 weeks after challenge using an infective dose of L. infantum stationary promastigotes, vaccinated mice showed lower parasite burdens in different organs (liver, spleen, bone marrow and footpads' draining lymph nodes) than mice inoculated with the adjuvant alone or the vaccine diluent. Protected mice showed anti-Leishmania IgG2a antibodies and a predominant IL-12-driven IFN-γ production (mainly produced by CD4(+) T cells) against parasite proteins, whereas unprotected controls showed anti-Leishmania IgG1 antibodies and parasite-mediated IL-4 and IL-10 responses. Vaccinated mice showed an anti-LiHyD IgG2a humoral response, and their spleen cells were able to secrete LiHyD-specific IFN-γ, IL-12 and GM-CSF cytokines before and after infection. The protection was correlated with the Leishmania-specific production on nitric oxide. Altogether, the results indicate that the new LiHyD protein could be considered in vaccine formulations against VL.

Ultrasound and thyroiditis in patient candidates for thyroidectomy.

AIM: Thyroiditis is often associated with nodules based on the Bethesda classification system, and the presence of thyroiditis can make thyroid surgery difficult using both conventional techniques and minimally invasive videoassisted approaches (MIVAT). METHODS: We analyzed 326 patients who underwent total thyroidectomy in 2012. We collected all data in dedicated database. The patients were divided in 4 groups: group 1 no affected by thyroiditis, group 2 affected by thyroiditis, group 3 only histological diagnosis of thyroiditis, group 4all patients affected by thyroiditis. RESULTS: Group 1 included 201 cases, group 2 included 64 patients, group 3 included 61 patients. No statistically significant difference between group 2 and 3 about Ultrasound (US) examination. Statistically significant difference in incidence of "THYR 3-4" between group 1 and group 4. No differences in MIVAT vs. Conventional group. CONCLUSION: US examination of the thyroid is essential for the diagnostic study of the gland also in the selection of a surgical approach. Thyroiditis is a relative contraindication to MIVAT but the experience of the endocrine surgeon is the most important factor to reduce intra and postoperative complications together a correct collaboration in multidisciplinart endocrinological team.

Comparison of facial features in fetuses and newborns following natural delivery with cephalic presentation: a pilot study

BACKGROUND: Malocclusions are usually diagnosed around 3-4 years of age according to specific criteria. The purpose of this protocol is to validate a method to understand how the type of delivery can influence the development of malocclusions. MATERIALS: This pilot study, conducted at the Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico of Milan, evaluated the relationship between the type of delivery, fetal presentation, and the presence of malocclusions in children. The sample included 5 healthy term newborns, all born to healthy mothers with uncomplicated pregnancies by vaginal delivery. Measurements were taken, via ultrasound, at the 37th week of gestation (T0) and on the second day of life (T1), using a craniometer, caliper and goniometer, including head circumference, lower facial angle, frontonasal angle, labial fissure length, and interpupillary distance. CONCLUSION: The results suggest that further research is necessary to better understand the influence of delivery mode and fetal presentation on the development of malocclusions. This study represents an important first step, highlighting the need for larger samples and more in-depth investigation methods to obtain more conclusive results.

A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

Lies tell the truth about cognitive dysfunction in essential tremor: an experimental deception study with the guilty knowledge task.

BACKGROUND: Research conducted in the past decade challenges the traditional view that essential tremor (ET) is characterised exclusively by movement disorder, and increasingly shows that these patients have deficits in cognitive and behavioural functioning. The available evidence suggests that this impairment might arise from dysfunction in either the fronto-subcortical or cortico-cerebellar circuits. Although abnormalities in the fronto-subcortical circuits could imply difficulty in lying, no study has investigated deception in patients with ET. AIMS: To examine the cognitive functions regulating deception in patients with ET, we used a computerised task, the Guilty Knowledge Task (GKT). We also tested a group of patients with Parkinson's disease (PD), a disease associated with a known difficulty in lie production, and a group of healthy subjects (HS). RESULTS: In the GKT for deception, patients with ET responded less accurately than HS (p=0.014) but similarly to patients with PD (p=0.955). No differences between groups were found in truthful responses (p=0.488). CONCLUSIONS: Besides confirming impaired deception in patients with PD, our results show a lie production deficit in patients with ET also. These findings suggest that difficulty in lying is an aspecific cognitive feature in movement disorders characterised by fronto-subcortical circuit dysfunction, such as PD and ET. Current knowledge along with our new findings in patients with ET--possibly arising from individually unrecognised extremely mild, cognitive difficulties--should help in designing specific rehabilitative programmes to improve cognitive and behavioural disturbances in patients.

Protein-lipid Association in Lizard Chemical Signals.

Chemical communication in terrestrial vertebrates is often built on complex blends, where semiochemical and structural compounds may form an integrated functional unit. In lizards, many species have specialized epidermal glands whose secretions are waxy, homogeneous blends of lipids and proteins, both active in communication. The intimate co-occurrence of such compounds allows us to hypothesize that they should undergo a certain degree of covariation, considering both their semiochemical role and the support-to-lipid function hypothesized for the protein fraction. In order to assess the occurrence and level of protein-lipid covariation, we compared the composition and complexity of the two fractions in the femoral gland secretions of 36 lizard species, combining phylogenetically-informed analysis with tandem mass spectrometry. We found the composition and complexity of the two fractions to be strongly correlated. The composition of the protein fraction was mostly influenced by the relative proportion of cholestanol, provitamin D3, stigmasterol, and tocopherol, while the complexity of the protein pattern increased with that of lipids. Additionally, two identified proteins (carbonic anhydrase and protein disulfide isomerase) increased their concentration as provitamin D3 became more abundant. Although our approach does not allow us to decrypt the functional relations between the proteinaceous and lipid components, nor under the semiochemical or structural hypothesis, the finding that the proteins involved in this association were enzymes opens up to new perspectives about protein role: They may confer dynamic properties to the blend, making it able to compensate predictable variation of the environmental conditions. This may expand the view about proteins in the support-to-lipid hypothesis, from being a passive and inert component of the secretions to become an active and dynamic one, thus providing cues for future research.

(Italian) RiassuntoLa comunicazione chimica nei vertebrati terrestri è spesso costituita da miscele complesse, in cui composti semiochimici e strutturali possono formare un"unità funzionale integrata. Nelle lucertole, molte specie hanno ghiandole epidermiche specializzate le cui secrezioni sono miscele cerose e omogenee di lipidi e proteine, entrambe attive nella comunicazione. L"intima coesistenza di tali composti lascia ipotizzare che essi debbano subire un certo grado di co-variazione, sia considerando il loro ruolo semiochimico, sia la funzione di supporto ai lipidi ipotizzata per la frazione proteica. Per valutare la presenza e il livello di covariazione proteine-lipidi, abbiamo confrontato la composizione e la complessità delle due frazioni nelle secrezioni della ghiandola femorale di 36 specie di lucertole, combinando l"analisi filogenetica comparativa con la spettrometria di massa. Abbiamo riscontrato una forte correlazione tra la composizione e la complessità delle due frazioni. La composizione della frazione proteica è stata influenzata soprattutto dalla proporzione relativa di colestanolo, provitamina D3, stigmasterolo e tocoferolo, mentre la complessità del pattern proteico è aumentata con quella dei lipidi. Inoltre, due proteine identificate (anidrasi carbonica e disolfuro isomerasi) hanno aumentato la loro concentrazione al crescere dell'abbondanza della provitamina D3. Sebbene il nostro approccio non consenta di decifrare le relazioni funzionali tra le componenti proteiche e lipidiche, né secondo l"ipotesi semiochimica né secondo quella strutturale, la scoperta che le proteine coinvolte in questa associazione sono enzimi apre a nuove prospettive sul ruolo delle proteine stesse: esse potrebbero conferire proprietà dinamiche alla miscela, rendendola capace di compensare le prevedibili variazioni delle condizioni ambientali. Questo può ampliare la visione delle proteine nell'ipotesi che esse siano di supporto ai lipidi, da componente passiva e inerte delle secrezioni a componente attiva e dinamica, fornendo così spunti per ricerche future.

An evolutionary history of the selectin gene cluster in humans.

Molecules involved in leukocyte trafficking have a central role in the development of inflammatory and immune responses. We performed F(ST) analysis of the selectin cluster, as well as of SELPLG, ICAM1 and VCAM1. Peaks of significantly high population genetic differentiation were restricted to two regions in SELP and one in SELPLG. Resequencing data indicated that the region covering SELP exons 11-13 displays high nucleotide diversity in Africans and Europeans (CEU), and a high level of within-species diversity compared with inter-specific divergence. Analysis of inferred haplotypes revealed a complex phylogeny with two deeply separated clades that coalesce at ~3.5 million years (MY) plus a minor clade with a TMRCA (time to the most recent common ancestor) of ~2.2 MY. A splicing assay indicated no haplotype-specific effect on SELP exon 14 inclusion. These data are consistent with a model of multiallelic balancing selection; single-nucleotide polymorphism analysis indicated that the Val640Leu variant represents a likely selection target. In populations of Asian ancestry a distinct haplotype, possibly carrying regulatory variants, has been driven to high frequency by positive selection. No deviation from neutrality was observed for the SELPLG region. Resequencing of SELP in chimpanzees revealed a haplotype phylogeny with extremely deep basal branches, suggesting either long-standing balancing selection or ancestral population structure. Thus, SELP has experienced a complex selective history, possibly as a result of local adaptation. Variants in the gene have been associated with autoimmune and cardiovascular diseases. Association studies would benefit from both taking the complex SELP haplotype structure into account and from analysis of possible regulatory variants in the gene.

Pregnancy and neonatal respiratory outcome.

Preterm labor is the final common pathway of different complications of pregnancy and despite substantial progress in antenatal care, preterm birth remains a major health issue across the globe. Preterm deliveries in the larger group of spontaneous preterm labor or preterm prelabor rupture of membranes (PPROM) are often associated with intrauterine chorioamnionitis. Current evidence underlines the role of "inflammatory" and "placental dysfunction" disorders in pregnancy on prematurity-associated morbidity, particularly respiratory outcome. (www.actabiomedica.it).

Right colon laparoscopic resection with three-trocar access and associated gynecological procedures in patients with colorectal cancer and ovarian metastases.

BACKGROUND: Right laparoscopic colectomy was introduced to colorectal surgery later than the left colon procedure. Three-trocar laparoscopy has already been used successfully in the treatment of gynecological cancers. In the present study, we aimed to analyze the feasibility of performing an associated gynecological procedure following abdominal laparoscopic exploration and to evaluate the suitability of laparoscopic right colectomy for treating elderly patients. METHODS: We conducted a review of prospectively collected data on 100 consecutive patients who were treated with right laparoscopic colectomy using three trocars from January 2005 to April 2010. We recorded the patients' age (<70 or > 70 years), ASA status, body mass index (BMI), pain on postoperative days 1 and 2 (POD 1, 2), nodes retrieved, laparotomic conversion, mean operative time, time to intestinal recovery, and length of postoperative stay. RESULTS: All subjects were treated for cancer. Conversion to the laparotomic procedure was performed in 13/100, with no difference in terms of age. Operative time was longer for laparotomic conversion (p <0.05), with a longer postoperative stay. Elderly patients had higher ASA scores (p < 0.005); age did not influence the conversion rate or BMI status. Pain on POD 1 and 2 differed between the laparotomic and laparoscopic groups (p <0.0001). Associated procedures were performed in five subjects (3 oophorectomy and 2 cholecystectomy). CONCLUSIONS: Laparoscopy using the three-trocar technique is a safe procedure for treating colon cancer, including in elderly patients, and enables associated gynecological laparoscopic procedures to be performed.

Long-term balancing selection maintains trans-specific polymorphisms in the human TRIM5 gene.

The human TRIM5 genes encodes a retroviral restriction factor (TRIM5α). Evolutionary analyses of this gene in mammals have revealed a complex and multifaceted scenario, suggesting that TRIM5 has been the target of exceptionally strong selective pressures, possibly exerted by recurrent waves of retroviral infections. TRIM5 displays inter-individual expression variability in humans and high levels of TRIM5 mRNA have been associated with a reduced risk of HIV-1 infection. We resequenced TRIM5 in chimpanzees and identified two polymorphisms in intron 1 that are shared with humans. Analysis of the gene region encompassing the two trans-specific variants in human populations identified exceptional nucleotide diversity levels and an excess of polymorphism compared to fixed divergence. Most tests rejected the null hypothesis of neutral evolution for this region and haplotype analysis revealed the presence of two deeply separated clades. Calculation of the time to the most recent common ancestor (TMRCA) for TRIM5 haplotypes yielded estimates ranging between 4 and 7 million years. Overall, these data indicate that long-term balancing selection, an extremely rare process outside MHC genes, has maintained trans-specific polymorphisms in the first intron of TRIM5. Bioinformatic analyses indicated that variants in intron 1 may affect transcription factor-binding sites and, therefore, TRIM5 transcriptional activity. Data herein confirm an extremely complex evolutionary history of TRIM5 genes in primates and open the possibility that regulatory variants in the gene modulate the susceptibility to HIV-1.

Anorectal malformations and neurospinal dysraphism: is this association a major risk for continence?

BACKGROUND/PURPOSE: Anorectal malformations (ARM) are a spectrum of defects ranging from the very minor ones, with an excellent functional prognosis, to those that are more complex, often associated with other anomalies, difficult to manage and with a poor functional outcome. A significant number of these children suffer from fecal and urinary incontinence despite major advances in the management of ARM patients have significantly improved the quality of life. The role of sacrovertebral anomalies/dysraphism (SD) and neurospinal cord anomalies/dysraphism (ND) associated with ARM on the continence of these patients is still controversial. The authors made a review of their experience in a period of 5 years, focusing on the role of neurospinal cord anomalies in patients with ARM. MATERIALS: At colorectal clinic of our department of pediatric surgery 215 patients who underwent a procedure of posterior sagittal anorectoplasty for ARM are followed-up in a multidisciplinary clinic. Among them 60 patients with either SD or ND were documented. In 37 patients the anomaly involved the spinal cord (ND). 12 of these 37 patients underwent neurosurgical treatment and 25 were managed conservatively. Data collected from their follow-up were analyzed and compared, focusing on their bowel and urinary continence. RESULTS: All 37 patients acquired regular bowel movements with an appropriate bowel management according to Peña's protocols. Urinary incontinence required clean intermittent catheterization in four cases. None of the patients who did not receive neurosurgical treatment developed acute complications due to the progression of the neurospinal anomaly, like acute urinary retention, orthopedic and motility problems or acute hydrocephalus. From literature review we were unable to find good evidence that the presence of ND worsens the functional prognosis of patients with ARM. We were also unable to find convincing evidence to support the practice of prophylactic neurosurgical procedures. CONCLUSIONS: The present study supports the theory that for ARM patients the prognosis in terms of continence depends mainly on the type of malformation and is not complicated by the association with ND. In our series neurosurgical treatments did not have any effect in improving the continence of ARM patients and a conservative management of ND did not expose the patients to the sequelae of progressive deterioration, reported elsewhere, requiring rescue neurosurgery. We believe that the correct practice of pediatric surgeons following-up ARM patients is a protocol which includes appropriate investigations to detect the presence of a SD or ND and, once these entities are detected, it is mandatory to manage the patient with a multidisciplinary team, where a conservative non-operative management is initially justified and advocated in the absence of neurosensorymotor symptoms.

Gender-related differences in moral judgments.

The moral sense is among the most complex aspects of the human mind. Despite substantial evidence confirming gender-related neurobiological and behavioral differences, and psychological research suggesting gender specificities in moral development, whether these differences arise from cultural effects or are innate remains unclear. In this study, we investigated the role of gender, education (general education and health education) and religious belief (Catholic and non-Catholic) on moral choices by testing 50 men and 50 women with a moral judgment task. Whereas we found no differences between the two genders in utilitarian responses to non-moral dilemmas and to impersonal moral dilemmas, men gave significantly more utilitarian answers to personal moral (PM) dilemmas (i.e., those courses of action whose endorsement involves highly emotional decisions). Cultural factors such as education and religion had no effect on performance in the moral judgment task. These findings suggest that the cognitive-emotional processes involved in evaluating PM dilemmas differ in men and in women, possibly reflecting differences in the underlying neural mechanisms. Gender-related determinants of moral behavior may partly explain gender differences in real-life involving power management, economic decision-making, leadership and possibly also aggressive and criminal behaviors.

Multisession radiosurgery for intracranial meningioma treatment: study protocol of a single arm, monocenter, prospective trial.

BACKGROUND: Single session radiosurgery represents a widely accepted treatment for intracranial meningiomas. However, this approach could involve a high risk of treatment-related complications when applied to large volume lesions. In these cases and for those not suitable for surgical resection, radiosurgery in multisession setting could represents a viable option. The literature results are reassuring in terms of correlated adverse events as well as in terms of tumor control. However, no prospective long-term results are available. In this scenario, we design a prospective monocentric phase II study, in order to verify the safety of a multisession radiosurgery schedule delivering 25 Gy in 5 daily fractions. METHODS: Patients diagnosed with large and/or near to critical structures, intracranial meningiomas have been treated by means of multisession radiosurgery in both exclusive and postoperative settings. The primary study aim is safety that has been being prospectively scored based on international scales, including NCI Common Toxicity criteria, version 4.03, Barrow Neurological Institute pain intensity score, Barrow Neurological Institute facial numbness score and House-Brackmann Facial Nerve Grading System for qualitative analysis. Secondary aim is treatment efficacy in terms of local control that has been being assessed on volumetric analysis. DISCUSSION: This is the first prospective phase II trial on multisession radiosurgery for large and/or near to critical structures intracranial meningiomas. If positive results will be found, this study could represent the starting point for a phase III trial exploring the role of multisession radiosurgery in the exclusive and postoperative radiation therapy treatment of intracranial meningiomas. TRIAL REGISTRATION: Trial registration: clinicaltrials.gov platform (Multisession Radiosurgery in Large Meningiomas -MuRaLM- identifier NCT02974127). Registered: November 28, 2016. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02974127?term=radiosurgery&cond=Intracranial+Meningioma&draw=2&rank=1.

Structural brain anomalies in Cri-du-Chat syndrome: MRI findings in 14 patients and possible genotype-phenotype correlations.

INTRODUCTION: Cri-du-Chat Syndrome (CdCS) is a genetic condition due to deletions showing different breakpoints encompassing a critical region on the short arm of chromosome 5, located between p15.2 and p15.3, first defined by Niebuhr in 1978. The classic phenotype includes a characteristic cry, peculiar facies, microcephaly, growth retardation, hypotonia, speech and psychomotor delay and intellectual disability. A wide spectrum of clinical manifestations can be attributed to differences in size and localization of the 5p deletion. Several critical regions related to some of the main features (such as cry, peculiar facies, developmental delay) have been identified. The aim of this study is to further define the genotype-phenotype correlations in CdCS with particular regards to the specific neuroradiological findings. PATIENTS AND METHODS: Fourteen patients with 5p deletions have been included in the present study. Neuroimaging studies were conducted using brain Magnetic Resonance Imaging (MRI). Genetic testing was performed by means of comparative genomic hybridization (CGH) array at 130 kb resolution. RESULTS: MRI analyses showed that isolated pontine hypoplasia is the most common finding, followed by vermian hypoplasia, ventricular anomalies, abnormal basal angle, widening of cavum sellae, increased signal of white matter, corpus callosum anomalies, and anomalies of cortical development. Chromosomal microarray analysis identified deletions ranging in size from 11,6 to 33,8 Mb on the short arm of chromosome 5. Then, we took into consideration the overlapping and non-overlapping deleted regions. The goal was to establish a correlation between the deleted segments and the neuroradiological features of our patients. CONCLUSIONS: Performing MRI on all the patients in our cohort, allowed us to expand the neuroradiological phenotype in CdCS. Moreover, possible critical regions associated to characteristic MRI findings have been identified.

A population genetics study of the familial Mediterranean fever gene: evidence of balancing selection under an overdominance regime.

Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3' gene region (from exon 5 to the 3' UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.