Long-Term Recovery After Endothelial Colony-Forming Cells or Human Umbilical Cord Blood Cells Administration in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (NHIE) is a dramatic perinatal complication, associated with poor neurological prognosis despite neuroprotection by therapeutic hypothermia, in the absence of an available curative therapy. We evaluated and compared ready-to-use human umbilical cord blood cells (HUCBC) and bankable but allogeneic endothelial progenitors (ECFC) as cell therapy candidate for NHIE. We compared benefits of HUCBC and ECFC transplantation 48 hours after injury in male rat NHIE model, based on the Rice-Vannucci approach. Based on behavioral tests, immune-histological assessment and metabolic imaging of brain perfusion using single photon emission computed tomography (SPECT), HUCBC, or ECFC administration provided equally early and sustained functional benefits, up to 8 weeks after injury. These results were associated with total normalization of injured hemisphere cerebral blood flow assessed by SPECT/CT imaging. In conclusion, even if ECFC represent an efficient candidate, HUCBC autologous criteria and easier availability make them the ideal candidate for hypoxic-ischemic cell therapy. Stem Cells Translational Medicine 2017;6:1987-1996

Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease

Introduction: Numerous results suggest the implication of infectious agents in the onset of Alzheimer's disease (AD).Methods: In the Bordeaux‐3C prospective cohort, we assessed the impact of herpes simplex virus type 1 (HSV‐1) infection on the incidence of AD according to apolipoprotein E (APOE) status, a genetic susceptibility factor. Cox models were performed to estimate the 10‐year risk of AD associated with anti‐HSV antibodies in 1037 participants according to APOE4 status.Results: Among APOE4 carriers, subjects for whom the frequency of HSV‐1 reactivation is supposed to be high, that is, immunoglobulin M (IgM) positive or elevated levels of IgG, had an increased risk of AD with adjusted hazard ratios (HRs) of 3.68 (1.08–12.55) and 3.28 (1.19–9.03), respectively. No significant association was found in APOE4‐negative subjects.Discussion: These results, in accordance with a solid pathophysiological rationale, suggest a role for HSV‐1 in AD development among subjects with a genetic susceptibility factor, the APOE4 allele

Thermal Conversion of Guanylurea Dicyanamide into Graphitic Carbon Nitride via Prototype CNx Precursors

Guanylurea dicyanamide, [(H2N)C(-O)NHC(NH2)2][N(CN)2], has been synthesized by ion exchange reaction in aqueous solution and structurally characterized by single-crystal X-ray diffraction (C2/c, a = 2249.0(5) pm, b = 483.9(1) pm, c = 1382.4(3) pm, β = 99.49(3)°, V = 1483.8(5) × 106 pm3, T = 130 K). The thermal behavior of the molecular salt has been studied by thermal analysis, temperature-programmed X-ray powder diffraction, FTIR spectroscopy, and mass spectrometry between room temperature and 823 K. The results were interpreted on a molecular level in terms of a sequence of thermally induced addition, cyclization, and elimination reactions. As a consequence, melamine (2,4,6-triamino-1,3,5-triazine) is formed with concomitant loss of HNCO. Further condensation of melamine yields the prototypic CNx precursor melem (2,6,10-triamino-s-heptazine, C6N7(NH2)3), which alongside varying amounts of directly formed CNxHy material transforms into layered CNxHy phases without significant integration of oxygen into the core framework owing to the evaporation of HNCO. Thus, further evidence can be added to melamine and its condensation product melem acting as “key intermediates” in the synthetic pathway toward graphitic CNxHy materials, whose exact constitution is still a point at issue. Due to the characteristic formation process and hydrogen content a close relationship with the polymer melon is evident. In particular, the thermal transformation of guanylurea dicyanamide clearly demonstrates that the formation of volatile compounds such as HNCO during thermal decomposition may render a large variety of previously not considered molecular compounds suitable CNx precursors despite the presence of oxygen in the starting material

Usefulness of electroanatomical mapping during transseptal endocardial left ventricular lead implantation

AimFailure rate to implant left ventricular (LV) lead transvenously is 4-8% in cardiac resynchronization therapy (CRT) patients. Epicardial lead placement is an alternative method and if not applicable case reports and small series showed the feasibility of endocardial LV lead implantation. Electroanatomical mapping might be a useful tool to guide this procedure.Methods and resultsFour patients had undergone endocardial LV lead implantation after unsuccessful transvenous implantation or epicardial LV lead dysfunction using the transseptal approach. Electroanatomical mapping was used to mark the location of the transseptal puncture. This location point guided the mapping catheter from the subclavian access and facilitated positioning of the LV lead at the adjacent latest activation area of the left ventricle detected by activation mapping. Endocardial active fixation LV leads were successfully implanted in all patients with stable electrical parameters immediately after implantation and over a mean follow-up of 18.3 months (lead impedance 520 +/- 177 vs. 439 +/- 119 Omega and pacing threshold 0.8 +/- 0.2 V, 0.5 ms vs. 0.6 +/- 0.1 V, 0.5 ms, respectively). Patients were maintained on anticoagulation therapy with a target international normalized ratio of 3.5-4.5 and did not show any thromboembolic, haemorrhagic events, or infection. Echocardiography showed significant improvement of LV systolic function with marked improvement of the functional status.ConclusionsElectroanatomical mapping is a useful technical tool to guide endocardial LV lead implantation. It helps to identify the location of the transseptal puncture and the use of activation mapping might facilitate location of the optimal lead positions during CRT

The waters of São Tomé: a calving ground for West African humpback whales?

In the Southern Hemisphere, humpback whales Megaptera novaeangliae feed in Antarctic waters during the austral summer and migrate to their breeding grounds in subtropical and tropical waters during the winter. Historical whaling records suggest that the Archipelago of Sao Tome and Principe, located in the Gulf of Guinea, serves as a possible breeding ground. In order to investigate the temporal occurrence and group composition of humpback whales around Sao Tome Island, annual surveys were conducted during the breeding season between 2002 and 2006. A total of 186 boat-based surveys took place during this period. Data collected during each sighting included geographical positions, group size, group composition and behavioural classifications. Of the 66 groups encountered, mother/calf pairs made up a large proportion (65.15%), followed by solitary individuals (15.15%). Mother/calf pairs were seen in the region into November and resightings of identified animals indicate periods of occupancy that extended over three weeks. Few behaviours typically associated with mating activity were observed. Given the high percentage of mother/calf pairs, sometimes with very young calves, and the low frequency of mating activity, the waters of Sao Tome may primarily serve as a calving and nursing or resting area for humpback whales.Projecto Delfim; Rolas Island Resort; ECOFAC (Conservation et utilisation rationnelle des Ecosystemes Forestiers en Afrique Centrale); Wildlife Conservation Society

Analysis of the TGFβ functional pathway in epithelial ovarian carcinoma

Epithelial ovarian carcinoma is often diagnosed at an advanced stage of disease and is the leading cause of death from gynaecological neoplasia. The genetic changes that occur during the development of this carcinoma are poorly understood. It has been proposed that IGFIIR, TGFβ1 and TGFβRII act as a functional unit in the TGFβ growth inhibitory pathway, and that somatic loss-of-function mutations in any one of these genes could lead to disruption of the pathway and subsequent loss of cell cycle control. We have examined these 3 genes in 25 epithelial ovarian carcinomas using single-stranded conformational polymorphism analysis and DNA sequence analysis. A total of 3 somatic missense mutations were found in the TGFβRII gene, but none in IGFRII or TGFβ1. An association was found between TGFβRII mutations and histology, with 2 out of 3 clear cell carcinomas having TGFβRII mutations. This data supports other evidence from mutational analysis of the PTEN and β-catenin genes that there are distinct developmental pathways responsible for the progression of different epithelial ovarian cancer histologic subtypes. © 2001 Cancer Research Campaign http://www.bjcancer.co

Surveillance of active human cytomegalovirus infection in hematopoietic stem cell transplantation (HLA sibling identical donor): search for optimal cutoff value by real-time PCR

<p>Abstract</p> <p>Background</p> <p>Human cytomegalovirus (CMV) infection still causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, it is extremely important to diagnosis and monitor active CMV infection in HSCT patients, defining the CMV DNA levels of virus replication that warrant intervention with antiviral agents in order to accurately prevent CMV disease and further related complications.</p> <p>Methods</p> <p>During the first 150 days after allogeneic HSTC, thirty patients were monitored weekly for active CMV infection by <it>pp65 </it>antigenemia, nested-PCR and real-time PCR assays. Receiver operating characteristic (ROC) plot analysis was performed to determine a threshold value of the CMV DNA load by real-time PCR.</p> <p>Results</p> <p>Using ROC curves, the optimal cutoff value by real-time PCR was 418.4 copies/10⁴PBL (sensitivity, 71.4%; specificity, 89.7%). Twenty seven (90%) of the 30 analyzed patients had active CMV infection and two (6.7%) developed CMV disease. Eleven (40.7%) of these 27 patients had acute GVHD, 18 (66.7%) had opportunistic infection, 5 (18.5%) had chronic rejection and 11 (40.7%) died - one died of CMV disease associated with GVHD and bacterial infection.</p> <p>Conclusions</p> <p>The low incidence of CMV disease in HSCT recipients in our study attests to the efficacy of CMV surveillance based on clinical routine assay. The quantification of CMV DNA load using real-time PCR appears to be applicable to the clinical practice and an optimal cutoff value for guiding timely preemptive therapy should be clinically validated in future studies.</p

Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus

Human cytomegalovirus (HCMV) expresses a viral ortholog (CMVIL-10) of human cellular interleukin-10 (cIL-10). Despite only ∼26% amino acid sequence identity, CMVIL-10 exhibits comparable immunosuppressive activity with cIL-10, attenuates HCMV antiviral immune responses, and contributes to lifelong persistence within infected hosts. The low sequence identity between CMVIL-10 and cIL-10 suggests vaccination with CMVIL-10 may generate antibodies that specifically neutralize CMVIL-10 biological activity, but not the cellular cytokine, cIL-10. However, immunization with functional CMVIL-10 might be detrimental to the host because of its immunosuppressive properties.Structural biology was used to engineer biologically inactive mutants of CMVIL-10 that would, upon vaccination, elicit a potent immune response to the wild-type viral cytokine. To test the designed proteins, the mutations were incorporated into the rhesus cytomegalovirus (RhCMV) ortholog of CMVIL-10 (RhCMVIL-10) and used to vaccinate RhCMV-infected rhesus macaques. Immunization with the inactive RhCMVIL-10 mutants stimulated antibodies against wild-type RhCMVIL-10 that neutralized its biological activity, but did not cross-react with rhesus cellular IL-10.This study demonstrates an immunization strategy to neutralize RhCMVIL-10 biological activity using non-functional RhCMVIL-10 antigens. The results provide the methodology for targeting CMVIL-10 in vaccine, and therapeutic strategies, to nullify HCMV's ability to (1) skew innate and adaptive immunity, (2) disseminate from the site of primary mucosal infection, and (3) establish a lifelong persistent infection

Protection from ultraviolet damage and photocarcinogenesis by vitamin d compounds

© Springer Nature Switzerland AG 2020. Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds