Clinical connectome fingerprints of cognitive decline

Brain connectome fingerprinting is rapidly rising as a novel influential field in brain network analysis. Yet, it is still unclear whether connectivity fingerprints could be effectively used for mapping and predicting disease progression from human brain data. We hypothesize that dysregulation of brain activity in disease would reflect in worse subject identification. We propose a novel framework, Clinical Connectome Fingerprinting, to detect individual connectome features from clinical populations. We show that “clinical fingerprints” can map individual variations between elderly healthy subjects and patients with mild cognitive impairment in functional connectomes extracted from magnetoencephalography data. We find that identifiability is reduced in patients as compared to controls, and show that these connectivity features are predictive of the individual Mini-Mental State Examination (MMSE) score in patients. We hope that the proposed methodology can help in bridging the gap between connectivity features and biomarkers of brain dysfunction in large-scale brain networks

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.Fil: Grewal, Prabhjit K.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Aziz, Peter V.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Uchiyama, Satoshi. University of California at San Diego; Estados UnidosFil: Rubio, Gabriel R.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Lardone, Ricardo Dante. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Le, Dzung. University of California at San Diego; Estados UnidosFil: Varki, Nissi M.. University of California at San Diego; Estados UnidosFil: Nizet, Victor. University of California at San Diego; Estados UnidosFil: Marth, Jamey D.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados Unido

A night of sleep deprivation alters brain connectivity and affects specific executive functions

Sleep is a fundamental physiological process necessary for efficient cognitive functioning especially in relation to memory consolidation and executive functions, such as attentional and switching abilities. The lack of sleep strongly alters the connectivity of some resting-state networks, such as the default mode network and attentional network. In this study, by means of magnetoencephalography (MEG) and specifc cognitive tasks, we investigated how brain topology and cognitive functioning are affected by 24 h of sleep deprivation (SD). Thirty-two young men underwent resting-state MEG recording and evaluated in letter cancellation task (LCT) and task switching (TS) before and after SD. Results showed a worsening in the accuracy and speed of execution in the LCT and a reduction of reaction times in the TS, evidencing thus a worsening of attentional but not of switching abilities. Moreover, we observed that 24 h of SD induced large-scale rearrangements in the functional network. These findings evidence that 24 h of SD is able to alter brain connectivity and selectively affects cognitive domains which are under the control of different brain network

Difference in outcome between curative intent vs marginal excision as a first treatment in dogs with oral malignant melanoma and the impact of adjuvant CSPG4-DNA electrovaccination: A retrospective study on 155 cases

Canine oral malignant melanoma is locally invasive and highly metastatic. At present, the best option for local control is en bloc excision followed by radiation if excision margins are incomplete. Adjuvantly, the role of chemotherapy is dubious while immunotherapy appears encouraging. This retrospective study evaluated 155 dogs with oral malignant melanomas (24 stage I, 54 stage II, 66 stage III and 11 stage IV) managed in a single institution. The aim was to evaluate the differences in median survival time (MST) and disease‐free interval (DFI) between dogs which, at presentation, were treated surgically with a curative intent (group 1) vs those marginally excised only (group 2). MST in group 1 was longer than in group 2 (594 vs 458 days), but no significant difference was found (P = .57); a statistical difference was, however, found for DFI (232 vs 183 days, P = .008). In the subpopulation of vaccinated dogs, the impact of adjuvant anti‐CSPG4 DNA electrovaccination was then evaluated (curative intent, group 3, vs marginal, group 4); a significant difference for both MST (1333 vs 470 days, respectively, P = .03) and DFI (324 vs 184 days, respectively, P = .008) was found. Progressive disease was significantly more common in dogs undergoing marginal excision than curative intent excision for both the overall population (P = .03) and the vaccinated dogs (P = .02). This study pointed out that, after staging, wide excision together with adjuvant immunotherapy was an effective approach for canine oral malignant melanoma

Prolongation of survival of dogs with oral malignant melanoma treated by en bloc surgical resection and adjuvant CSPG4-antigen electrovaccination

Reported post-surgery 1-year survival rate for oral canine malignant melanoma (cMM) is around 30%; novel treatments are needed as the role of adjuvant chemotherapy is unclear. This prospective study regards adjuvant electrovaccination with human chondroitin sulfate proteoglycan-4 (hCSPG4)-encoded plasmid in 23 dogs with resected II/III-staged CSPG4-positive oral cMM compared with 19 dogs with resected only II/III-staged CSPG4-positive oral cMM. Vaccination resulted in 6-, 12-, 18- and 24-month survival rate of 95.6, 73.9, 47.8 and 30.4%, respectively [median survival time (MST) 684 days, range 78–1694, 8 of 23 dogs alive] and 6-, 12-, 18- and 24-month disease-free interval (DFI) rate of 82.6, 47.8, 26.1 and 17.4%, respectively (DFI 477 days, range 50–1694). Non-vaccinated dogs showed 6-, 12-, 18- and 24-month survival rate of 63.2, 26.3, 15.8 and 5.3%, respectively (MST 200 days, range 75–1507, 1 of 19 dogs alive) and 6-, 12-, 18- and 24-month DFI rate of 52.6, 26.3, 10.5 and 5.3%, respectively (DFI 180 days, range 38–1250). Overall survival and DFI of vaccinated dogs was longer in those <20 kg. In vaccinated and non-vaccinated dogs local recurrence rate was 34.8 and 42%, respectively while lung metastatic rate was 39 and 79%, respectively

P450-aromatase activity and expression in human testicular tissues with severe spermatogenic failure

There is evidence that impaired spermatogenesis is associated with an imbalance in the oestradiol/testosterone ratio and with Leydig cell (LC) dysfunction. In testis, P450-aromatase, encoded by CYP19, is responsible for the conversion of testosterone to oestradiol. The aims of this study were to quantify CYP19 mRNA expression, aromatase activity and protein localization, and to measure the oestradiol to testosterone ratio in testicular tissues of men with spermatogenic impairment. Twenty-four men with complete Sertoli cell-only syndrome (SCOS), 14 with focal SCOS, 14 with maturation arrest (MA), 8 with mixed atrophy and 30 controls with normal spermatogenesis were subjected to testicular biopsy. All subjects underwent a physical examination, cytogenetic and serum hormonal studies. Testicular CYP19 mRNA was quantified using real time RT-PCR. Testicular aromatase activity was measured using the 3H 20 assay and protein expression was evaluated using immunohistochemistry. In cases, serum

DAX-1 and DAX-1A expression in human testicular tissues with primary spermatogenic failure

DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenital (AHC) critical region on the X chromosome gene 1; NR0B1] is an orphan nuclear receptor that acts as a transcriptional repressor in adrenal/gonadal development, steroidogenesis and probably spermatogenesis. An alternatively spliced form called DAX-1A (NR0B1A) has been described in several tissues including the testis, and in vitro studies have shown an inhibitory effect on DAX-1 transcriptional function. We aimed to study the mRNA and protein expression of DAX-1 in testicular tissues of 65 men with primary spermatogenic failure [complete Sertoli cell only syndrome (SCOS), focal SCOS, maturation arrest and mixed atrophy] compared with 33 controls with normal spermatogenesis. As a novel finding, we observed intense immunostaining, not only in the nucleus of Sertoli cells, but also in pachytene spermatocytes and round spermatids. The quantitative mRNA expression of DAX-1 and DAX-1A was similar between cases and controls an