Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Bolus tracking with nanofilter-based multispectral videography for capturing microvasculature hemodynamics

Multispectral imaging is a highly desirable modality for material-based analysis in diverse areas such as food production and processing, satellite-based reconnaissance, and biomedical imaging. Here, we present nanofilter-based multispectral videography (nMSV) in the 700 to 950 nm range made possible by the tunable extraordinary-optical-transmission properties of 3D metallic nanostructures. Measurements made with nMSV during a bolus injection of an intravascular tracer in the ear of a piglet resulted in spectral videos of the microvasculature. Analysis of the multispectral videos generated contrast measurements representative of arterial pulsation, the distribution of microvascular transit times, as well as a separation of the venous and arterial signals arising from within the tissue. Therefore, nMSV is capable of acquiring serial multispectral images relevant to tissue hemodynamics, which may have application to the detection and identification of skin cancer

Il Partito Comunista d'Italia e l'organizzazione delle masse (1929-1934)

ItQuesto saggio analizza i condizionamenti che l'Internazionale Comunista (IC) esercitò sul Partito Comunista d'Italia (PCd'I) nella sua attività estera nel periodo 1929-1934. Secondo l'IC, la crisi economica del 1929 (a) costituiva la fine della fase di «relativa stabilizzazione» del capitalismo, (b) intensificava i processi di «radicalizzazione delle masse» e (c) riapriva per i partiti comunisti dell'IC la prospettiva di una nuova fase rivoluzionaria. A livello ideologico, sebbene con qualche esitazione, il Parito Comunista italiano adottò la categoria del «socialfascismo» e si impegnò in una dura lotta contro l'«opportunismo», tanto all'interno del gruppo dirigente quanto tra i quadri intermedi e alla base del partito. A livello politico vennero espulsi noti dirigenti, quali Angelo Tasca, Alfonso Leonetti, Pietro Tresso, Paolo Ravazzoli, Ignazio Silone. Analogamente, anche Vincenzo Gigante, un funzionario intermedio, fu costretto ad abbandonare l'attività politica: quest'ultimo avvenimento costituisce il caso di studio del presente lavoro.EnThis article analyses the restrictions that the Communist International (CI) imposed to the leadership of the Communist Party of Italy (CPI) to their abroad activity during the period 1929-1934. According to the CI, the crisis of the 1929 (a) caused the end of the «relative stabilization» of the capitalism, (b) intensified the process of «radicalization of the masses» and (c) opened up the perspective of a new revolutionary phase for the communist parties belonging to the CI itself. On the theoretical level and with some hesitation, the CPI endorsed the «social fascism» category and started to struggle heavily against the «opportunism» in the leadership, among the middle-ranking officers and in the party's base. On the political level, relevant leaders were expelled, such as Angelo Tasca, Alfonso Leonetti, Pietro Tresso, Paolo Ravazzoli, Ignazio Silone, while Antonio Vincenzo Gigante, an - intermediate officer - was forced to leave the political activity: this latter event is the study case presented in this paper