GLI EFFETTI DELL’ACAMPROSATO SULLA RIMODULAZIONE DELLA TRASMISSIONE GLUTAMMATERGICA ECCITATORIA ED IL SUO IMPIEGO NEL TRATTAMENTO DEL CRAVING DA ALCOLISMO NEL TERRITORIO DELL’A.S.P. 1 AG

Secondo l’OMS definiamo l’alcolismo quel disturbo a genesi multifattoriale (bio-psico-sociale) associato all’assunzione episodica e/o cronica di bevande alcoliche con presenza o meno di dipendenza capace di determinare una sofferenza multidimensionale che si manifesta in maniera diversa da Soggetto a Soggetto. L’assunzione cronica di alcol modifica la normale attività neuronale attraverso il potenziamento dell’attività inibitoria del GABA e l’inibizione dell’effetto eccitatorio del Glutammato che induce il neuro-adattamento attraverso una over-espressione dei recettori del glutammato in modo da ripristinare l’equilibrio del sistema in presenza di alcol. Quando l’assunzione di alcol viene interrotta l’attività neuronale è caratterizzata sia da un aumento dell’eccitabilità dei recettori del glutammato sia dall’attività dei recettori NMDA che rappresenta invece la causa dei caratteristici sintomi dell’astinenza: le convulsioni. L’Acamprosato è un neuro modulatore specifico per il trattamento della dipendenza da alcol determinando il ripristino dell’equilibrio della trasmissione glutammatergica e l’inibizione dell’attività del glutammato agendo su due recettori: NMDA e mGluR5 rispettivamente ionotropico e metabotropico. Contrastando l’iperattività glutammatergica l’Acamprosato riduce il craving negativo e conseguenzialmente diminuisce l’incidenza, la severità e la frequenza delle ricadute. Nello studio clinico effettuato sono stati osservati 30 Pazienti reclutati nel territorio dell’A.S.P.1 di Agrigento suddivisi rispettivamente : > 9 Pazienti di cui 2 donne e 7 uomini presso il Ser.T di Sciacca, > 6 Pazienti di cui 1 donna e 5 uomini presso il Ser.T di Ribera, > 7 Pazienti di cui 2 donne e 5 uomini presso il Ser.T di Agrigento, > 8 Pazienti di cui 4 donne e 4 uomini presso il Ser.T di Canicattì. Riportiamo i dati di alcuni Pazienti reclutati e seguiti ambulatorialmente presso i Ser.T che erano già stati sottoposti a precedenti trattamenti farmacologici con GHB: * 4 Pazienti sui 30 – pari al 13,33% - esito negativo, * 9 Pazienti sui 30 – pari al 30 % - esito positivo, *17 Pazienti sui 30 – pari al 56,67 % - si sottoponevano per la prima volta alla terapia con Acamprosato. Ciascun Paziente è stato valutato mediante 2 questionari: OCDS (Obsessive Compulsive Drinking Scale) costituito da 14 item e SHORT SLEEP INDEX composto da 4 item. Tutti sono stati sottoposti a controlli seriati nel tempo che così abbiamo identificato: – T0 – prima dell’assunzione di Acamprosato; il primo follow –up al 4° mese – T1 - ed all’8 mese – T2 - il secondo. Per quanto riguarda la valutazione del craving si è osservato al T0 una percentuale dell’86,67% ricovero ed una del 13,33% ambulatoriale. Dove per ricovero si intende la percentuale di Pazienti che, rispondendo alle domande del test, ha totalizzato un punteggio relativo al craving >22, valore che richiede un monitoraggio costante da parte del Medico Responsabile del Ser.T e contemporaneamente anche di un maggiore supporto psicologico. Con il termine ambulatoriale si indicano tutti quei Pazienti il cui grado di craving risulta al di sotto dei valori considerati a “rischio ricadute” e tali da permettere al Paziente di proseguire un trattamento esclusivamente diurno ma che prevede comunque l’adeguato supporto psicologico all’interno del Ser.T. Al termine dell’odierno lavoro ed alla luce dei risultati ottenuti è innegabile l’efficacia dell’Acamprosato nel mantenimento dell’astinenza nei Soggetti dipendenti dall’alcol. Efficacia che si è manifestata riducendo il rischio di ricadute da un lato e, dall’altro per i ridotti effetti indesiderati registrati (la diarrea – il prurito) e per la notevole riduzione del craving negativo. Possiamo pertanto concludere dicendo che l’Acamprosato, associato ad un opportuno supporto psicologico, può senza dubbio rappresentare la terapia d’elezione che, certamente, in un futuro prossimo, sarà completata da altri supporti farmacologici-psicologici o altro per la riduzione/annientamento del problema: dipendenza dall’alcol

Use of intravitreal bevacizumab in a patient with a Von Hippel-Lindau-associated retinal haemangioblastoma of the optic nerve head: a case report

<p>Abstract</p> <p>Introduction</p> <p>The optimum management of a capillary haemangioblastoma affecting the optic nerve head is not clear. A number of treatment modalities have been used to treat the tumours and their consequences. Ocular haemangioblastomas express high levels of vascular endothelial growth factor and levels have been correlated with tumour growth and activity. Treatment with vascular endothelial growth factor inhibitors would therefore seem a logical approach.</p> <p>Case presentation</p> <p>We describe a 23-year-old man with an exophytic capillary haemangioblastoma of the optic nerve head that was treated with intravitreal bevacizumab injections.</p> <p>Conclusion</p> <p>Unfortunately, treatment with intravitreal bevacizumab on three occasions had no effect on either tumour size or exudation in this patient.</p

Computational fact checking from knowledge networks

Traditional fact checking by expert journalists cannot keep up with the enormous volume of information that is now generated online. Computational fact checking may significantly enhance our ability to evaluate the veracity of dubious information. Here we show that the complexities of human fact checking can be approximated quite well by finding the shortest path between concept nodes under properly defined semantic proximity metrics on knowledge graphs. Framed as a network problem this approach is feasible with efficient computational techniques. We evaluate this approach by examining tens of thousands of claims related to history, entertainment, geography, and biographical information using a public knowledge graph extracted from Wikipedia. Statements independently known to be true consistently receive higher support via our method than do false ones. These findings represent a significant step toward scalable computational fact-checking methods that may one day mitigate the spread of harmful misinformation

Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of the intravitreal (IVT) injection of Triamcinolone Acetonide (TA) as compared to posterior subtenon (SBT) capsule injection for the treatment of cystoid diabetic macular edema.</p> <p>Methods</p> <p>Fourteen patients with type II diabetes mellitus and on insulin treatment, presenting diffuse cystoid macular edema were recruited. Before TA injection all focal lakes were treated by laser photocoagulation. In the same patients one eye was assigned to 4 mg IVT injection of TA and the fellow eye was then treated with 40 mg SBT injection of TA. Before and one, three and six months after treatment we measured visual acuity with ETDRS chart as well as thickness of the macula with optical coherence tomography (OCT) and intraocular pressure (IOP).</p> <p>Results</p> <p>The eyes treated with an IVT injection displayed significant improvement in visual acuity, both after one (0.491 ± 0.070; p < 0.001) and three months (0.500 ± 0.089; p < 0.001) of treatment. Significant improvement was displayed also in eyes treated with an SBT injection, again after one (0.455 ± 0.069; p < 0.001) and three months (0.427 ± 0.065; p < 0.001). The difference between an IVT injection (0.809 ± 0.083) and SBT injection (0.460 ± 0.072) becomes significant six months after the treatment (p < 0.001).</p> <p>Macular thickness of the eyes treated with IVT injection was significantly reduced both after one (222.7 ± 13.4 μm; p < 0.001) and after three months (228.1 ± 10.6 μm; p < 0.001) of treatment. The eyes treated with SBT injection displayed significant improvement after one (220.1 ± 15.1 μm; p < 0.001) and after three months (231.3 ± 10.9 μm; p < 0.001). The difference between the eyes treated with IVT injection (385.2 ± 11.3 μm) and those treated with SBT injection (235.4 ± 8.7 μm) becomes significant six months after the treatment (p < 0.001).</p> <p>Intraocular pressure of the eyes treated with IVT injection significantly increased after one month (17.7 ± 1.1 mm/Hg; p < 0.020), three (18.2 ± 1.2 mm/Hg; p < 0.003) and six month (18.1 ± 1.3 mm/Hg; p < 0.007) when compared to baseline value (16.1 ± 1.402 mm/Hg). In the SBT injection eyes we didn't display a significant increase of intraocular pressure after one (16.4 ± 1.2 mm/Hg; p < 0.450), three (16.3 ± 1.1 mm/Hg; p < 0.630) and six months (16.2 ± 1.1 mm/Hg; p < 0.720) when compared to baseline value (16.2 ± 1.3 mm/Hg).</p> <p>Conclusion</p> <p>The parabulbar subtenon approach can be considered a valid alternative to the intravitreal injection.</p> <p>Trial registration</p> <p>Current Controlled Trials <b>ISRCTN67086909</b></p

Global and regional brain metabolic scaling and its functional consequences

Background: Information processing in the brain requires large amounts of metabolic energy, the spatial distribution of which is highly heterogeneous reflecting complex activity patterns in the mammalian brain. Results: Here, it is found based on empirical data that, despite this heterogeneity, the volume-specific cerebral glucose metabolic rate of many different brain structures scales with brain volume with almost the same exponent around -0.15. The exception is white matter, the metabolism of which seems to scale with a standard specific exponent -1/4. The scaling exponents for the total oxygen and glucose consumptions in the brain in relation to its volume are identical and equal to $0.86\pm 0.03$, which is significantly larger than the exponents 3/4 and 2/3 suggested for whole body basal metabolism on body mass. Conclusions: These findings show explicitly that in mammals (i) volume-specific scaling exponents of the cerebral energy expenditure in different brain parts are approximately constant (except brain stem structures), and (ii) the total cerebral metabolic exponent against brain volume is greater than the much-cited Kleiber's 3/4 exponent. The neurophysiological factors that might account for the regional uniformity of the exponents and for the excessive scaling of the total brain metabolism are discussed, along with the relationship between brain metabolic scaling and computation.Comment: Brain metabolism scales with its mass well above 3/4 exponen

Morpholino-Mediated Increase in Soluble Flt-1 Expression Results in Decreased Ocular and Tumor Neovascularization

BACKGROUND: Angiogenesis is a key process in several ocular disorders and cancers. Soluble Flt-1 is an alternatively spliced form of the Flt-1 gene that retains the ligand-binding domain, but lacks the membrane-spanning and intracellular kinase domains of the full-length membrane bound Flt-1 (mbFlt-1) protein. Thus, sFlt-1 is an endogenous inhibitor of VEGF-A mediated angiogenesis. Synthetic mopholino oligomers directed against splice site targets can modulate splice variant expression. We hypothesize that morpholino-induced upregulation of sFlt-1 will suppress angiogenesis in clinically relevant models of macular degeneration and breast cancer. METHODS AND FINDINGS: In vivo morpholino constructs were designed to target murine exon/intron 13 junction of the Flt-1 transcript denoted VEGFR1_MOe13; standard nonspecific morpholino was used as control. After nucleofection of endothelial and breast adenocarcinoma cell lines, total RNA was extracted and real-time RT-PCR performed for sFlt-1 and mbFlt-1. Intravitreal injections of VEGFR1_MOe13 or control were done in a model of laser-induced choroidal neovascularization and intratumoral injections were performed in MBA-MD-231 xenografts in nude mice. VEGFR1_MOe13 elevated sFlt-1 mRNA expression and suppressed mbFlt-1 mRNA expression in vitro in multiple cellular backgrounds (p<0.001). VEGFR1_MOe13 also elevated sFlt/mbFlt-1 ratio in vivo after laser choroidal injury 5.5 fold (p<0.001) and suppressed laser-induced CNV by 50% (p = 0.0179). This latter effect was reversed by RNAi of sFlt-1, confirming specificity of morpholino activity through up-regulation of sFlt-1. In the xenograft model, VEGFR1_MOe13 regressed tumor volume by 88.9%, increased sFlt-1 mRNA expression, and reduced vascular density by 50% relative to control morpholino treatment (p<0.05). CONCLUSIONS: Morpholino oligomers targeting the VEGFR1 mRNA exon/intron 13 junction promote production of soluble FLT-1 over membrane bound FLT-1, resulting in suppression of lesional volume in laser induced CNV and breast adenocarcinoma. Thus, morpholino manipulation of alternative splicing offers translational potential for therapy of angiogenic disorders

Identification of a Bacteria-produced Benzisoxazole with Antibiotic Activity against Multi-drug Resistant Acinetobacter baumannii

The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to national healthcare systems. Most pressing is an immediate need for the development of novel antibacterial agents to treat Gram-negative multi-drug resistant infections, including the opportunistic, hospital-derived pathogen, Acinetobacter baumannii. Herein we report a naturally occurring 1,2-benzisoxazole with minimum inhibitory concentrations as low as 6.25 μg ml−1 against clinical strains of multi-drug resistant A. baumannii and investigate its possible mechanisms of action. This molecule represents a new chemotype for antibacterial agents against A. baumannii and is easily accessed in two steps via de novo synthesis. In vitro testing of structural analogs suggest that the natural compound may already be optimized for activity against this pathogen. Our results demonstrate that supplementation of 4-hydroxybenzoate in minimal media was able to reverse 1,2-benzisoxazole’s antibacterial effects in A. baumannii. A search of metabolic pathways involving 4-hydroxybenzoate coupled with molecular modeling studies implicates two enzymes, chorismate pyruvate-lyase and 4-hydroxybenzoate octaprenyltransferase, as promising leads for the target of 3,6-dihydroxy-1,2-benzisoxazole

Population-based estimates of the relation between breast cancer risk, tumor subtype, and family history.

OBJECTIVE: Many studies that have estimated the breast cancer risk attributable to family history have been based on data collected within family units. Use of this study design has likely overestimated risks for the general population. We provide population-based estimates of breast cancer risk and different tumor subtypes in relation to the degree, number, and age at diagnosis of affected relatives. METHODS: Cox Proportional Hazards to calculate risks (hazard ratios; 95% confidence interval) of breast cancer and tumor subtypes for women with a family history of breast cancer relative to women without a family history among a cohort of 75,189 women age >or=40 years of whom 1,087 were diagnosed with breast cancer from June 1, 2001-December 31, 2005 (median follow-up 3.16 years). RESULTS: Breast cancer risk was highest for women with a first-degree family history (1.54; 1.34-1.77); and did not differ substantially by the affected relative's age at diagnosis or by number of affected first-degree relatives. A second-degree family history only was not associated with a significantly increased breast cancer risk (1.15; 0.98-1.35). There was a suggestion that a positive family history was associated with risk of triple positive (Estrogen+/Progesterone+/HER2+) and HER2-overexpressing tumors. CONCLUSIONS: While a family history of breast cancer in first-degree relatives is an important risk factor for breast cancer, gathering information such as the age at diagnosis of affected relatives or information on second-degree relative history may be unnecessary in assessing personal breast cancer risk among women age >or=40 years

Access to electronic health records by care setting and provider type: perceptions of cancer care providers in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>The use of electronic health records (EHRs) to support the organization and delivery of healthcare is evolving rapidly. However, little is known regarding potential variation in access to EHRs by provider type or care setting. This paper reports on observed variation in the perceptions of access to EHRs by a wide range of cancer care providers covering diverse cancer care settings in Ontario, Canada.</p> <p>Methods</p> <p>Perspectives were sought regarding EHR access and health record completeness for cancer patients as part of an internet survey of 5663 cancer care providers and administrators in Ontario. Data were analyzed using a multilevel logistic regression model. Provider type, location of work, and access to computer or internet were included as covariates in the model.</p> <p>Results</p> <p>A total of 1997 of 5663 (35%) valid responses were collected. Focusing on data from cancer care providers (N = 1247), significant variation in EHR access and health record completeness was observed between provider types, location of work, and level of computer access. Providers who worked in community hospitals were half as likely as those who worked in teaching hospitals to have access to their patients' EHRs (OR 0.45 95% CI: 0.24–0.85, p < 0.05) and were six times less likely to have access to other organizations' EHRs (OR 0.15 95% CI: 0.02–1.00, p < 0.05). Compared to surgeons, nurses (OR 3.47 95% CI: 1.80–6.68, p < 0.05), radiation therapists/physicists (OR 7.86 95% CI: 2.54–25.34, p < 0.05), and other clinicians (OR 4.92 95% CI: 2.15–11.27, p < 0.05) were more likely to report good access to their organization's EHRs.</p> <p>Conclusion</p> <p>Variability in access across different provider groups, organization types, and geographic locations illustrates the fragmented nature of EHR adoption in the cancer system. Along with focusing on technological aspects of EHR adoption within organizations, it is essential that there is cross-organizational and cross-provider access to EHRs to ensure patient continuity of care, system efficiency, and high quality care.</p