Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints

Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher–like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue

Correlations of differentially expressed gap junction connexins cx26, cx30, cx32, cx43 and cx46 with breast cancer progression and prognosis.

BACKGROUND AND AIMS: Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers. MATERIALS AND METHODS: Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models. RESULTS: The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo- and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively. CONCLUSION: Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers

La responsabilit\ue0 del consulente tecnico del pubblico ministero : revisione critica ed ipotesi di soluzione

Gli autori analizzano nel presente contributo le principali caratteristiche della figura del consulente tecnico del pubblico ministero, con particolare riferimento alle attivit\ue0 di indagine disciplinate dall\u2019art. 359 c.p.p. Per quanto l\u2019elaborato tecnico abbia un peso non indifferente nella formulazione della decisione giuridica ultima, l\u2019attivit\ue0 di consulenza viene generalmente condotta senza l\u2019applicazione di alcuna forma di controllo formale e sostanziale. Gli autori, di dubbia utilit\ue0 sul versante pratico l\u2019introduzione di un sistema sanzionatorio, propongono dunque l\u2019applicazione di strumenti di controllo interni, coerenti con il contesto processuale generale attuale, cos\uec come gi\ue0 previsti in alcuni casi, che se da un lato comporterebbero la rinuncia di uno dei caratteri peculiari delle indagini del pubblico ministereo, la segretezza, dall\u2019altro garantirebbero una plurilateralit\ue0 di prospettiva di approccio tecnico con impatto indiscutibilmente positivo sullo svolgimento del process

Infrared tympanic thermography as a substitute for a probe in the evaluation of ear temperature for post-mortem interval determination: a pilot study

Reported methods which have been used to measure tympanic temperatures on cadavers up to now are quite invasive. They involve the use of a probe which can perforate the tympanic membrane and frequently causes bleeding from the ear. For this reason a non traumatic method for estimating tympanic temperature should be applied. Infrared tympanic thermometry seems to be a plausible option. Reliability of infrared tympanic thermometry (ITT) has been largely assessed on living individuals but only one author up to now has assessed its applicability for post-mortem interval determination. Thus the authors set out to test the difference between ear temperatures taken with a probe vs. ITT, differences between left and right ear and reproducibility of measurements of ITT. The aim of the study was to verify whether ITT could be a plausible option for measuring ear temperature for PMI estimation. Ear temperatures were taken on 25 cadavers (15 males, 10 females). Temperatures were taken alternately by similarly trained personnel by two technical methods (Checktemp 1 thermocouple probe and First Temp Genius infrared thermometer) for a total of 93 measurements. Statistical analysis of the data was performed using SAS statistical software. The range of temperature measured was from 20 to 28 degrees C, statistical analysis revealed no differences within the two technical methods, both for right and left ear (ITT: 22.33+/-0.35 vs. probe: 23.08+/-0.25; P=0.087). The study shows the ITT method can be considered as a possible alternative to the probe for measuring ear temperative and further studies should be considered