Role of fragile X messenger ribonucleoprotein 1 in the pathophysiology of brain disorders: a glia perspective.

Fragile X messenger ribonucleoprotein 1 (FMRP) is a widely expressed RNA binding protein involved in several steps of mRNA metabolism. Mutations in the FMR1 gene encoding FMRP are responsible for fragile X syndrome (FXS), a leading genetic cause of intellectual disability and autism spectrum disorder, and fragile X-associated tremor-ataxia syndrome (FXTAS), a neurodegenerative disorder in aging men. Although FMRP is mainly expressed in neurons, it is also present in glial cells and its deficiency or altered expression can affect functions of glial cells with implications for the pathophysiology of brain disorders. The present review focuses on recent advances on the role of glial subtypes, astrocytes, oligodendrocytes and microglia, in the pathophysiology of FXS and FXTAS, and describes how the absence or reduced expression of FMRP in these cells can impact on glial and neuronal functions. We will also briefly address the role of FMRP in radial glial cells and its effects on neural development, and gliomas and will speculate on the role of glial FMRP in other brain disorders.

Predicting the long-term impact of rotavirus vaccination in 112 countries from 2006 to 2034: A transmission modeling analysis.

Rotavirus vaccination has been shown to reduce rotavirus burden in many countries, but the long-term magnitude of vaccine impacts is unclear, particularly in low-income countries. We use a transmission model to estimate the long-term impact of rotavirus vaccination on deaths and disability adjusted life years (DALYs) from 2006 to 2034 for 112 low- and middle-income countries. We also explore the predicted effectiveness of a one- vs two- dose series and the relative contribution of direct vs indirect effects to overall impacts. To validate the model, we compare predicted percent reductions in severe rotavirus cases with the percent reduction in rotavirus positivity among gastroenteritis hospital admissions for 10 countries with pre- and post-vaccine introduction data. We estimate that vaccination would reduce deaths from rotavirus by 49.1 % (95 % UI: 46.6-54.3 %) by 2034 under realistic coverage scenarios, compared to a scenario without vaccination. Most of this benefit is due to direct benefit to vaccinated individuals (explaining 69-97 % of the overall impact), but indirect protection also appears to enhance impacts. We find that a one-dose schedule would only be about 57 % as effective as a two-dose schedule 12 years after vaccine introduction. Our model closely reproduced observed reductions in rotavirus positivity in the first few years after vaccine introduction in select countries. Rotavirus vaccination is likely to have a substantial impact on rotavirus gastroenteritis and its mortality burden. To sustain this benefit, the complete series of doses is needed.

Differences in Placental Histology Between Zika Virus-infected Teenagers and Older Women.

In pregnant women, Zika virus (ZIKV) is associated with a congenital syndrome, most frequently involving damage to embryo brain formation and the development of microcephaly. The mechanism(s) by which ZIKV enters the maternal-fetal interface and is transmitted to the fetus remains incompletely determined. We sought to evaluate histologic changes in the placenta of ZIKV-infected pregnant women and to determine if this varied by maternal age. Placental samples were obtained from 66 women, 33 of whom were positive for ZIKV. Histologic evaluations were performed on 4 areas of the placenta: fetal surface, maternal surface, umbilical cord, and membranes. Samples were analyzed by the tissue microarray technique and tested for CD4, CD8, CD20, CD68, FOXP3, and cyclooxygenase-2 expression. Data were evaluated using Fisher exact test. ZIKV infection was more frequent in women less than 18 yr of age (9/11, 81.8%) than in women above 18 yr old (24/55, 43.6%) (P=0.0440). ZIKV detection was associated with neutrophilic chorioamnionitis (P=0.0332) and with septal (P=0.0244) and villous (P=0.0534) calcification. Hofbauer cell hyperplasia (P=0.0260) and cyclooxygenase-2 expression (P=0.0346) were more prevalent in ZIKV-positive women aged 18 yr and below than in the older ZIKV-positive women. ZIKV infection during pregnancy occurs more frequently in adolescents and induces higher rates of damage at the maternal-fetal interface than in older women.

Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes.

Fragile X syndrome (FXS) is a common form of intellectual disability and autism caused by the lack of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA transport and protein synthesis. Upon cellular stress, global protein synthesis is blocked and mRNAs are recruited into stress granules (SGs), together with RNA-binding proteins including FMRP. Activation of group-I metabotropic glutamate (mGlu) receptors stimulates FMRP-mediated mRNA transport and protein synthesis, but their role in SGs formation is unexplored. To this aim, we pre-treated wild type (WT) and Fmr1 knockout (KO) cultured astrocytes with the group-I-mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) and exposed them to sodium arsenite (NaAsO2), a widely used inducer of SGs formation. In WT cultures the activation of group-I mGlu receptors reduced SGs formation and recruitment of FMRP into SGs, and also attenuated phosphorylation of eIF2α, a key event crucially involved in SGs formation and inhibition of protein synthesis. In contrast, Fmr1 KO astrocytes, which exhibited a lower number of SGs than WT astrocytes, did not respond to agonist stimulation. Interestingly, the mGlu5 receptor negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine (MPEP) antagonized DHPG-mediated SGs reduction in WT and reversed SGs formation in Fmr1 KO cultures. Our findings reveal a novel function of mGlu5 receptor as modulator of SGs formation and open new perspectives for understanding cellular response to stress in FXS pathophysiology.

The analysis of Treg lymphocyte blood percentage changes in patients with head and neck cancer during combined oncological treatment: a preliminary report.

INTRODUCTION: In patients with cancer, Treg lymphocytes seem to play an important role in promoting tumour growth. The number of circulating Treg cells has been associated with poor survival among patients suffering from various types of cancers. The aim of the present study was to evaluate the changes in the percentage levels of Treg lymphocytes in the blood samples of patients with head and neck cancer during combined treatment with respect to the stage of the disease and the intensity of the radiation reaction as monitored using the Dische scale. MATERIAL AND METHODS: Peripheral blood samples were collected from 20 head and neck cancer patients prior to the combined oncological treatment, during, and then one week after the completion of the therapy. RESULTS: A statistically significantly higher percentage of CD3+/CD4+/CD25+/FoxP3+/CD127(-/low) T cells within the CD3+/CD4+ T cell population was detected in patients during radiotherapy (RTH), chemotherapy (CTH), and chemoradiotherapy (CRT) than before the treatment began (p < 0.0001). A statistically significantly higher percentage of CD3+/CD4+/CD25+/FoxP3+/CD127(-/low) T cells within the CD3+/CD4+ T cell population was detected after RTH/CRT than before treatment, with respect to the radiation reaction as evaluated using the Dische scale (p = 0.0150). CONCLUSIONS: The increase in the percentage of Treg cells correlated with an increase in the intensity of the radiation reaction measured using the Dische scale which indicates the advance of the oral mucositis reaction to RTH. In conclusion, because the role of Treg lymphocytes in cancer patients is complex, it is necessary to monitor the percentages of these cells in patients during combined oncological therapies.

Nuck canal cyst involving right femoral vein: management and therapy of a rare clinical case.

We present a very rare case of a 49-year old woman suffering from Nuck canal cyst reaching and compressing femoral vein. Nuck canal cyst is very uncommon event because the pouch accompanying the gubernaculum during intrauterine descent of ovaries usually obliterates, whereas when it persists a cystic cavity containing citrine fluid develops. A gravid 0 para 0 49 old woman was admitted to Catania University Surgery Department owing to suspected lymphatic tumor compressing right femoral vein and causing groin pain with ipsilateral leg partial stasis. Patient believed right venous stasis was due to fibromatous uterus. Ultrasounds and computed tomography (CT) scan defined size (7.1 × 4.2 × 1.5 cm), structure (cystic) of mass and its relation with femoral vein, although they were not diriment for diagnosing its nature. Color Doppler detected circulatory function of compressed femoral vein. Surgery was challenging and Nuck cyst was removed after accurate separation from the right femoral venous walls. A case of Nuck cyst involving femoral vein has never been reported so far.

A sampler prototype for the simultaneous collection of exhaled air and breath condensate.

Exhaled air and breath condensate contain a large number of health biomarkers, such as volatile and semi-volatile organic compounds, proteins and lipids. Nowadays, the collection of breath samples is carried out by commercial or lab-made sampling systems that collect only one type of sample (e.g. gaseous or condensate phase), thus limiting the diagnostic capability of breath tests. This work presents a portable prototype optimized for the simultaneous collection of gaseous exhaled breath and exhaled breath condensate within five minutes. The system is fully portable and has a total weight of about 1 Kg. An illustrative determination of ethanol, isoprene, acetone, isopropyl alcohol, 1-propanol, 2-butanone, 2-pentanone, toluene and xylenes in breath, and cortisol and 8-iso-prostaglandin F2α in breath condensate is discussed.

Comparison of helminth community of Apodemus agrarius and Apodemus flavicollis between urban and suburban populations of mice.

The growing human population and the development of urban areas have led to fragmentation and destruction of many natural habitats but have also created new urban habitats. These environmental changes have had a negative impact on many species of plants and animals, including parasite communities. The aim of present study was to compare the helminth communities of Apodemus flavicollis and Apodemus agrarius in natural and urban habitats. Helminth burdens were assessed in 124 mice, 48 A. flavicollis, and 76 A. agrarius from two managed forests close to the city boundaries and two city parks within Warsaw, Central Poland. In total, eight species of helminths, Nematoda (n = 3), Digenea (n = 2), and Cestoda (n = 3), were identified. Helminth community structure and prevalence/abundance of individual helminth species differed significantly between the two Apodemus species. Overall, prevalence and abundance of helminth species were significantly higher in A. agrarius compared to A. flavicollis. For A. flavicollis, higher prevalence and abundance of helminths were detected in individuals from managed forest habitats in comparison to city parks. In striped field mice, much higher prevalence and mean abundance were recorded in rodents trapped in city parks than in managed forests. This phenomenon may be explained by better adaptation of A. agrarius, compared to A. flavicollis, to city habitats, resulting in high local densities of mice and the full range of parasite species affecting this host species. Our data confirm also that the established routes of infection exist for selected helminth species in the urban environment.

Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway.

Endothelin-1 (ET-1) is a vasoactive peptide produced by activated astrocytes and microglia and is implicated in initiating and sustaining reactive gliosis in neurodegenerative diseases. We have previously suggested that ET-1 can play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Indeed, we reported that this peptide is abundantly expressed in reactive astrocytes in the spinal cord of SOD1-G93A mice and ALS patients and exerts a toxic effect on motor neurons (MNs) in an in vitro model of mixed spinal cord cultures enriched with reactive astrocytes. Here, we explored the possible mechanisms underlying the toxic effect of ET-1 on cultured MNs. We show that ET-1 toxicity is not directly caused by oxidative stress or activation of cyclooxygenase-2 but requires the synthesis of nitric oxide and is mediated by a reduced activation of the phosphoinositide 3-kinase pathway. Furthermore, we observed that ET-1 is also toxic for microglia, although its effect on MNs is independent of the presence of this type of glial cells. Our study confirms that ET-1 may contribute to MN death and corroborates the view that the modulation of ET-1 signaling might be a therapeutic strategy to slow down MN degeneration in ALS.

In vivo biocompatibility of nanostructured Chitosan/Peo membranes / Biocompatibilidade in vivo de membranas nanoestruturadas de Quitosana/Peo

Electrospinning is a technique that allows the preparation of nanofibers from various materials. Chitosan is a natural and abundant easily obtained polymer, which, in addition to those features, proved to be biocompatible. This work used nanostructured chitosan and polyoxyethylene membranes as subcutaneous implants in Wistar rats to evaluate the biocompatibility of the material. Samples of the material and tissues adjacent to the implant were collected 7, 15, 30, 45 and 60 days post-implantation. Macroscopic integration of the material to the tissues was observed in the samples and slides for histopathological examination that were prepared. It was noticed that the material does not stimulate the formation of adherences to the surrounding tissues and that there is initial predominance of neutrophilia and lymphocytosis, with a declining trend according to the increase of time, featuring a non-persistent acute inflammatory process. However, the material showed fast degradation, impairing the macroscopic observation after fifteen days of implantation. It was concluded that the material is biocompatible and that new studies should be conducted, modifying the time of degradation by changes in obtaining methods and verifying the biocompatibility in specific tissues for biomedical applications.

A eletrofiação é uma técnica que permite a preparação de nanofibras mediante o uso de diversos materiais. A quitosana é um polímero natural, abundante e de fácil obtenção, que, além dessas características, demonstrou ser biocompatível. Este trabalho utilizou membranas nanoestruturadas de quitosana e polióxido de etileno como implantes subcutâneos em ratos Wistar para avaliar a biocompatibilidade do biomaterial. As amostras do material e de tecidos adjacentes ao implante foram retiradas sete, 15, 30, 45 e 60 dias pós-implantação para a observação da integração macroscópica do material aos tecidos e para a preparação de lâminas para exame histopatológico. Verificou-se que o material não estimula a formação de aderências com os tecidos circunvizinhos e que há predominância inicial de neutrofilia e linfocitose, que tendem a decrescer em razão do aumento do tempo, caracterizando um processo inflamatório agudo não persistente. No entanto, o material apresentou degradação rápida, não sendo possível observá-lo macroscopicamente após 15 dias de implantação. Concluiu-se que o material é biocompatível, o que indica que novos estudos devem ser conduzidos, com modificação do tempo de degradação por alterações nos métodos de obtenção e verificação da biocompatibilidade em tecidos específicos para aplicações biomédicas.

Cancer Incidence in Five Continents: Inclusion criteria, highlights from Volume X and the global status of cancer registration.

Cancer Incidence in Five Continents (CI5), a longstanding collaboration between the International Agency for Research on Cancer and the International Association of Cancer Registries, serves as a unique source of cancer incidence data from high-quality population-based cancer registries around the world. The recent publication of Volume X comprises cancer incidence data from 290 registries covering 424 populations in 68 countries for the registration period 2003-2007. In this article, we assess the status of population-based cancer registries worldwide, describe the techniques used in CI5 to evaluate their quality and highlight the notable variation in the incidence rates of selected cancers contained within Volume X of CI5. We also discuss the Global Initiative for Cancer Registry Development as an international partnership that aims to reduce the disparities in availability of cancer incidence data for cancer control action, particularly in economically transitioning countries, already experiencing a rapid rise in the number of cancer patients annually.

Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development.

Fragile X syndrome is caused by the lack of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA transport and translation. FMRP is a component of mRNA ribonucleoprotein complexes and it can interact with a range of proteins either directly or indirectly, as demonstrated by two-hybrid selection and co-immunoprecipitation, respectively. Most of FMRP-interacting proteins are RNA-binding proteins such as FXR1P, FXR2P and 82-FIP. Interestingly, FMRP can also interact directly with the cytoplasmic proteins CYFIP1 and CYFIP2, which do not bind RNA and link FMRP to the RhoGTPase pathway. The interaction with these different proteins may modulate the functions of FMRP by influencing its affinity to RNA and by affecting the FMRP ability of cytoskeleton remodeling through Rho/Rac GTPases. To better define the relationship of FMRP with its interacting proteins during brain development, we have analyzed the expression pattern of FMRP and its interacting proteins in the cortex, striatum, hippocampus and cerebellum at different ages in wild type (WT) mice. FMRP and FXR2P were strongly expressed during the first week and gradually decreased thereafter, more rapidly in the cerebellum than in the cortex. FXR1P was also expressed early and showed a reduction at later stages of development with a similar developmental pattern in these two regions. CYFIP1 was expressed at all ages and peaked in the third post-natal week. In contrast, CYFIP2 and 82-FIP (only in forebrain regions) were moderately expressed at P3 and gradually increased after P7. In general, the expression pattern of each protein was similar in the regions examined, except for 82-FIP, which exhibited a strong expression at P3 and low levels at later developmental stages in the cerebellum. Our data indicate that FMRP and its interacting proteins have distinct developmental patterns of expression and suggest that FMRP may be preferentially associated to certain proteins in early and late developmental periods. In particular, the RNA-binding and cytoskeleton remodeling functions of FMRP may be differently modulated during development.

Pathological evaluation in colorectal polyps endoscopic treatment.

This retrospective study shows that endoscopic polypectomy is the technique of choice to remove the majority of polyps; follow-up and pathologic examinations shed light on the carcinogenesis of colorectal lesions. From January 1990 to December 2001, 1302 adenomatous polyps were removed, 1175 endoscopically, 127 with surgical procedures. The anatomical and morphologic conditions of the colon and some characteristics of the polyps represent limits to the feasibility and to the efficacy of polypectomy, and the most important variables for the correct management of the patients affected by colorectal adenomatous polyps.

[Varicose disease of lower limbs: our actual orientation]. / La malattia varicosa degli arti inferiori: nostro attuale orientamento.

A retrospective analysis of a series of patients treated during 5 years was made evaluating, on the basis of the clinical and ultrasonographic examination, the results obtained in the treatment of the varicose disease of the lower limbs for each one of three surgical methodic employed (crossectomy, long or short stripping) as well as patients compliance. All the patients previously underwent ultrasonographic examination to evaluate the reflux rank of the internal saphena and to point out every insufficient veins. On the basis of specific indications, from routinary pre-operative and anaesthesiologic examinations, all the patients were operated. Totally, 784 operations were performed. Thanks to the follow-up, carried out through an objective evaluation (echocolor-Doppler) and subjective one (degree of satisfaction fullfilled through some tests), it is concluded that the most favourable method, among those used, is that of short stripping with wrapping up a silk thread, in accordance to Van der Stricht.

[Retroperitoneal leiomyosarcoma: a case report]. / Il leiomiosarcoma del retroperitoneo: descrizione di un caso clinico.

The Authors report a rare case of retroperitoneal leiomyosarcoma in a 80 years woman with respiratory symptoms and right abdominal pain. A large neoplasm occupied the right abdomen, looking asymmetric. Upper abdominal CT showed a retroperitoneal neoplasm close to right kidney, liver, aponeurosis of right oblique muscles, producing a left-side dislocation of the intraabdominal organs. A surgical "en bloc" resection of the neoplasm was performed; neoplasm was plurilobed and capsulated. The histologic examination confirmed the diagnosis of leiomyosarcoma. The best treatment of these neoplasms is surgery, that in the last years has drawn advantage from more sensible and specific diagnostic procedures, which show a more radical surgical option. Though metastases are occasional, local recurrences can be taken into consideration and, after a careful tumoral re-staging, they can be resected once more. Therefore, a careful follow-up is necessary on the basis of neoplastic grading, extension and involvement of the closer structures.

[Gastric lymphomas: surgical indications]. / I linfomi gastrici: indicazioni all'intervento chirurgico.

Primary gastric lymphoma (PGL) are lymphomas with an exclusive gastric localization. Histologically they are B-like non-Hodgkin lymphomas. Aim of Authors' study is to define the role of surgery in the treatment of PGL, on the basis of their series casistics and a review of the more recent literature data. The Authors observed 41 patients (23 F and 18 M) in a period of 10 years: 35 patients underwent to surgical operation associated in 18 of them to chemotherapic treatment; in 6 cases medical eradication of Helicobacter Pylori (H.P.) was performed as unique treatment. Antibiothic treatment allows the eradication of H.P. in 97% of the patients and a histologic decreasing of MALT lymphoma in 70% of the patients in about 6 months. That represents the first therapeutic choice for the low grade of malignancy MALT PGL at I and II stages. In the cases of partial decreasing or progression of PGL, the Authors consider opportune surgical operation. In the majority of the cases the surgical option represents, according to our advise, the best choice for the high percentage of definitive recoveries, allowing a 10 or more years of surviving of the 90%, if it is done in the first stages of the disease. The results of the association with neoadjuvant or aduvant chemotherapy are still controversial. On the basis of their experience total gastrectomy can be considered the elective choice operation, with IID level lymphadenectomy and possible splenectomy.

[Day-hospital treatment of inguinal hernia]. / Il trattamento delle ernie inguinali in regime di day-hospital.

Aim of the Authors' research was to evaluate advantages of day-surgery treatment for inguinal hernias. The study has been performed on a series of 138 patients, operated because of unrelapsed and uncomplicated monolateral inguinal hernia. Up-to-date therapeutic behaviour relating to hernia is the result of brilliant intuitions: technical order (tension-free repair), technological progresses (using new prosthetic materials), and refinement of anaesthesiological procedures (local and loco-regional anaesthesia). As regards surgical and anaesthesiological methods, general principles have been accepted by now from the most of the Authors. The new frontier of hernias' treatment is the possibility of operate in a day-hospital way: that means real advantages, both as regards patients' compliance and, in consideration of the high incidence of such pathology, as regards the high economic savings and more reasonable management of hospital stays. The significative increase of day-hospital hernioplastic operations in last years is due to standardization of restrictiveless criteria of choice for patients who can be treated with such modality.

[Recurrence after hernioplasty according to Lichtenstein: analysis of the cause]. / Le recidive dopo ernioplastica secondo Lichtenstein: analisi delle cause.

The performance of surgical interventions of tension-free hernia repair has certainly reduced the recurrence rate in comparison with the previous techniques; notwithstanding this it is not uncommon to observe some recurrences also after a Lichtenstein hernia repair. The aim of this study is that to analyse the causes. In the last 2 years, 42 patients (mean age of 68 years) with recurrent hernia have been operated by Lichtenstein technique; 11 of the 42 patients had been treated before with an useful mesh hernia repair. In 8 of these patients the recurrence was produced by an insufficient medial extension of the mesh; in the other 3 patients the cause was the presence of an unrecognized indirect hernia in patients operated for a direct inguinal hernia. All the patients treated have been submitted to a 18 months time of follow-up.