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OBJECTIVE To determine the effectiveness of a brief intervention in increasing influenza vaccination coverage compared with the usual advice in people who refuse it, and to record the main reasons for refusing to be vaccinated. METHOD A cluster randomized clinical trial was conducted in which the study population was individuals with high risk factors who initially had refused to be vaccinated against influenza. Professionals (doctors and nurses) who voluntarily accepted to participate were assigned randomly to the intervention group (brief intervention) and the control group (usual advice). RESULTS 57 professionals recruited 524 people who had previously declined the influenza vaccination (271 in the control group and 253 in the intervention group). Brief intervention showed its effectiveness with an odds ratio of 2.48 (1.61-3.82; p

Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax.This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUCBetween Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUCFor the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting.GlaxoSmithKline and Medicines for Malaria Venture.For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

Introduction The aim of this study was to investigate the accuracy of liver and spleen stiffness measurement by transient elastography for the prediction of gastroesophageal varices in patients with HCV-associated cirrhosis treated with new direct-acting antiviral agents. Patients and methods This cross-sectional observational study included patients with compensated HCV-related cirrhosis and sustained virological response after direct-acting antiviral therapy. Patients underwent liver and spleen stiffness measurement, abdominal ultrasound and oesophago-gastroduodenoscopy. Clinical and laboratory data and non-invasive markers such as the liver stiffness–spleen diameter to platelet ratio score, variceal risk index and platelet count to spleen diameter ratio were analyzed. Results Ninety-seven consecutive patients were included. Liver stiffness measurement (12.2 vs 16; p = 0.02), spleen stiffness measurement (39.4 vs 46.05; p = 0.04), liver stiffness–spleen diameter to platelet ratio score (1.21 vs 2.02; p = 0.008), platelet count to spleen diameter ratio (1102.19 vs 829.7; p = 0.04) and variceal risk index (−3.4 vs −1.02; p = 0.01) showed significant differences between patients without/with gastroesophageal varices. The best cut-off value to discard the presence of gastroesophageal varices was 12.3 kPa for liver stiffness measurement and 27 kPa for spleen stiffness measurement. However, diagnostic accuracy was moderate (AUROC: 0.671 and 0.624 respectively). Combining different non-invasive parameters did not significantly improve the overall performance. Discussion Liver and spleen stiffness measurement showed suboptimal results for non-invasive assessment of gastroesophageal varices in HCV cirrhotic patients treated with direct-acting antiviral agents. Our results suggest that non-invasive methods cannot substitute standard procedures for predicting gastroesophageal varices in this population.

The centrosome linker component C-Nap1 (encoded by CEP250) anchors filaments to centrioles that provide centrosome cohesion by connecting the two centrosomes of an interphase cell into a single microtubule organizing unit. The role of the centrosome linker during development of an animal remains enigmatic. Here, we show that male CEP250

Background: The importance of artificial nutritional therapy is underrecognized, typically being considered an adjunctive rather than a primary therapy. We aimed to evaluate the influence of nutritional therapy on mortality in critically ill patients.Methods: This multicenter prospective observational study included adult patients needing artificial nutritional therapy for >48 h if they stayed in one of 38 participating intensive care units for ≥72 h between April and July 2018. Demographic data, comorbidities, diagnoses, nutritional status and therapy (type and details for ≤14 days), and outcomes were registered in a database. Confounders such as disease severity, patient type (e.g., medical, surgical or trauma), and type and duration of nutritional therapy were also included in a multivariate analysis, and hazard ratios (HRs) and 95% confidence intervals (95%CIs) were reported.Results: We included 639 patients among whom 448(70.1%) and 191(29.9%) received enteral and parenteral nutrition, respectively. Mortality was 25.6%, with non-survivors having the following characteristics: older age; more comorbidities; higher Sequential Organ Failure Assessment (SOFA) scores (6.6±3.3 vs 8.4±3.7; P); greater nutritional risk (Nutrition Risk in the Critically Ill [NUTRIC] score: 3.8±2.1 vs 5.2±1.7; P); more vasopressor requirements (70.4% vs 83.5%; P=0.001); and more renal replacement therapy (12.2% vs 23.2%; P=0.001). Multivariate analysis showed that older age (HR: 1.023; 95% CI: 1.008–1.038; P=0.003), higher SOFA score (HR: 1.096; 95% CI: 1.036–1.160; P=0.001), higher NUTRIC score (HR: 1.136; 95% CI: 1.025–1.259; P=0.015), requiring parenteral nutrition after starting enteral nutrition (HR: 2.368; 95% CI: 1.168–4.798; P=0.017), and a higher mean Kcal/Kg/day intake (HR: 1.057; 95% CI: 1.015–1.101; P=0.008) were associated with mortality. By contrast, a higher mean protein intake protected against mortality (HR: 0.507; 95% CI: 0.263–0.977; P=0.042).Conclusions: Old age, higher organ failure scores, and greater nutritional risk appear to be associated with higher mortality. Patients who need parenteral nutrition after starting enteral nutrition may represent a high-risk subgroup for mortality due to illness severity and problems receiving appropriate nutritional therapy. Mean calorie and protein delivery also appeared to influence outcomes.Trial Registration: ClinicaTrials.gov NCT: 03634943.

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.

Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC). A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized. A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6 years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800 mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2 months. The median time on treatment was 10.0 months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9 months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%). Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib. Novartis Pharmaceuticals Corporation, Inc.

The cytotoxic synapse formed between cytotoxic T lymphocytes or natural killer cells expressing CD95L and target cells with CD95 on their surface is a key pathway for apoptosis induction by the immune system. Despite similarities with the immune synapse in antigen presenting cells, little is known about the role of the spatiotemporal organization of agonistic proteins/receptor interactions for CD95 signaling. Here, we have developed an artificial cytotoxic synapse to examine how mobility and geometry of an anti-CD95 agonistic antibody affect receptor aggregation and mobility, ie the first step of receptor activation. By measuring the distribution, diffusion coefficient, and fraction of immobile CD95 receptor in living cells, we show that at short times, the initial activation of CD95 occurs locally and is limited to the contact region of the cytotoxic synapse. This anisotropic activation of apoptotic signaling supports a role for confined interactions on the efficiency of signal transduction that may have implications for biomedical applications of extrinsic apoptosis induction. Fil: Sánchez, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina Fil: Murad, Fabronia. Universität Tübingen; Alemania Fil: Gülcüler Balta, Gülce S.. German Cancer Research Center; Alemania. Heidelberg University; Alemania Fil: Martin Villalba, Ana. German Cancer Research Center; Alemania Fil: García Sáez, Ana J.. Universität Tübingen; Alemania Fil: Carrer, Dolores Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Regulation of adult neural stem cell (NSC) number is critical for lifelong neurogenesis. Here, we identified a post-transcriptional control mechanism, centered around the microRNA 204 (miR-204), to control the maintenance of quiescent (q)NSCs. miR-204 regulates a spectrum of transcripts involved in cell cycle regulation, neuronal migration, and differentiation in qNSCs. Importantly, inhibition of miR-204 function reduced the number of qNSCs in the subependymal zone (SEZ) by inducing pre-mature activation and differentiation of NSCs without changing their neurogenic potential. Strikingly, we identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 that is released into the cerebrospinal fluid to control number of NSCs within the SEZ. Taken together, our results describe a novel mechanism to maintain adult somatic stem cells by a niche-specific miRNA repressing activation and differentiation of stem cells.

Purpose To evaluate clinical and radiological outcomes after surgical treatment of difficult scaphoid nonunion in adults with a vascularized thumb metacarpal periosteal pedicled flap (VTMPF). Materials and methods Thirty-two patients at least 18 years old, with scaphoid nonunion and characteristics associated with a poor prognosis, who underwent a VTMPF procedure, were included in this retrospective cohort study with a mean follow-up of 17 months. Factors associated with a poor prognosis were a delay in presentation of over 5 years, the presence of avascular necrosis, and previous nonunion surgery. All patients had at least 1 poor prognostic factor and 25% had 2 or more. Results In 30 men and 2 women, the mean age was 36 years (range, 19–56 years). There were 11 type D3 nonunions (Herbert classification) and 15 type D4. Five patients had delayed presentation of over 5 years. Fourteen patients had previously undergone an unsuccessful surgical attempt to treat their nonunion. The patients experienced no postoperative complications. Overall union rate was 97% (31 of 32 patients), with 72% cross-sectional trabecular percentage bridging at 12 weeks. Pain subsided after surgery and patients experienced improvements in both their Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Modified Mayo Wrist Score (MMWS). Overall 41% and 42% gains in strength and wrist motion, relative to the contralateral normal side, were observed. At final follow-up, there were no differences between the treated and the untreated (healthy) hands, in terms of wrist range of motion, grip, or pinch strength. Conclusions In this study, the use of VTMPF for difficult scaphoid nonunion in adults was associated with good general outcomes. Type of study/level of evidence Therapeutic IV.

Cell growth is coupled to cell-cycle progression in mitotically proliferating mammalian cells, but the underlying molecular mechanisms are not well understood. CyclinD-Cdk4/6 is known to phosphorylate RB to promote S-phase entry, but recent work suggests they have additional functions. We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. Pharmacological inhibition of Cdk4/6 leads to a rapid, TSC2-dependent reduction of mTORC1 activity in multiple human and mouse cell lines, including breast cancer cells. By simultaneously driving mTORC1 and E2F, CyclinD-Cdk4/6 couples cell growth to cell-cycle progression. Consistent with this, we see that mTORC1 activity is cell cycle dependent in proliferating neural stem cells of the adult rodent brain. We find that Cdk4/6 inhibition reduces cell proliferation partly via TSC2 and mTORC1. This is of clinical relevance, because Cdk4/6 inhibitors are used for breast cancer therapy.

Summary: The death receptor CD95 is expressed in every cancer cell, thus providing a promising tool to target cancer. Activation of CD95 can, however, lead to apoptosis or proliferation. Yet the molecular determinants of CD95’s mode of action remain unclear. Here, we identify an optimal distance between CD95Ligand molecules that enables specific clustering of receptor-ligand pairs, leading to efficient CD95 activation. Surprisingly, efficient CD95 activation leads to apoptosis in cancer cells in vitro and increased tumor growth in vivo. We show that allowing a 3D aggregation of cancer cells in vitro switches the apoptotic response to proliferation. Indeed, we demonstrate that the absence or presence of cell-cell contacts dictates the cell response to CD95. Cell contacts increase global levels of phosphorylated tyrosines, including CD95’s tyrosine. A tyrosine-to-alanine CD95 mutant blocks proliferation in cells in contact. Our study sheds light into the regulatory mechanism of CD95 activation that can be further explored for anti-cancer therapies. : Gülcüler Balta et al. show that CD95 receptor activation is determined through the presentation of its ligand at a certain intermolecular distance. The type of signaling triggered by CD95 is, however, decided by the cellular environment. CD95 triggers survival in cancer cells in contact with other cells and death in isolated ones. Keywords: CD95, CD95 ligand, death receptors, apoptosis, survival, cell-cell contact, cancer, tyrosine kinase, supported membrane

Dialectical behaviour therapy skills training (DBT-ST) has proven effective to treat individuals with borderline personality disorder (BPD). However, therapy still faces the problem of early dropout. The aim of the present study is to examine which factors are associated with early dropout from DBT-ST in a sample of subjects with BPD.118 subjects with BPD diagnosis were included in the study. Apart from socio-demographic and clinical variables, childhood trauma history, personality dimensions, and comorbidities with other psychiatric disorders were collected. Differences in regards to the aforementioned variables were compared between individuals who dropped out prematurely from therapy and those who finalized it.Significant differences between groups regarding socio-demographic and clinical variables, including childhood trauma history and comorbid personality disorders, were not found. Both groups differed significantly in regards to trait impulsiveness and in comorbidity with Eating Disorders (ED) and Cocaine Use Disorder (CUD). The regression analyses showed that ED and CUD significantly predicted drop-out (p=0.011 and p=0.031 respectively), while scores in trait impulsivity showed a tendency towards signification (p=0.063).Comorbidities between BPD and axis I disorders (i.e., ED and CUD) should be taken into account when referring patients to DBT-ST.

Cilia perform essential signalling functions during development and tissue homeostasis. The mother centriole plays a key role during ciliogenesis. The distal appendages of the mother centriole form a platform that docks ciliary vesicles and removes CP110/Cep97 inhibitory complexes from the mother centriole. Here, we analysed the role of LRRC45 in appendage formation and ciliogenesis. We show that the core appendage proteins Cep83 and SCLT1 recruit LRRC45 to the mother centriole. Once there LRRC45 recruits FBF1. The association of LRRC45 with the basal body of primary and motile cilia in differentiated and stem cells reveals a broad function in ciliogenesis. In contrast to the appendage components Cep164 and Cep123, LRRC45 was neither essential for docking of early ciliary vesicles nor for removal of CP110. Rather, LRRC45 promotes cilia biogenesis in CP110-uncapped centrioles by organising centriolar satellites, establishing transition zone and promoting the docking of Rab8 GTPase-positive vesicles. We propose that, instead of acting solely as a platform to recruit early vesicles, centriole appendages form discrete scaffolds of cooperating proteins that execute specific functions that promote the initial steps of ciliogenesis.

Vitamin D review and supplementation recommendations for women diagnosed with breast or ovary cancer have been defined in the context of bone health and cancer prognosis/risk taking as reference wider cancer patients and postmenopausal women. This specific group has been selected due to its higher osteoporosis risk versus postmenopausal women. Early vitamin D supplementation could help maintain bone health, as well as potentially enhance cancer survival rate. Factors considered for supplementation include daily dose, periodicity, chemical form, administration, and serum levels. Sufficient vitamin D serum levels are recommended to be above 30 ng/ml (75 nmol/l). Maintenance oral supplementation equivalent to a minimum daily dosage of 800-1000 IU (20-25 μg) cholecalciferol provided in a daily to monthly bases is preferred, also advised to start with higher dosages when vitamin D serum levels are10 ng/ml (25 nmol/l). Calcidiol supplementation is more effective, making it advantageous for cases with very low or difficult to raise vitamin D serum levels.

Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial–mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC.

Whether new neurons are added in the postnatal cerebral cortex is still debated. Here, we report that the meninges of perinatal mice contain a population of neurogenic progenitors formed during embryonic development that migrate to the caudal cortex and differentiate into Satb2+ neurons in cortical layers IIIV. The resulting neurons are electrically functional and integrated into local microcircuits. Single-cell RNA sequencing identified meningeal cells with distinct transcriptome signatures characteristic of (1) neurogenic radial glia-like cells (resembling neural stem cells in the SVZ), (2) neuronal cells, and (3) a cell type with an intermediate phenotype, possibly representing radial glia-like meningeal cells differentiating to neuronal cells. Thus, we have identified a pool of embryonically derived radial glia-like cells present in the meninges that migrate and differentiate into functional neurons in the neonatal cerebral cortex.

Despite extensive effort on studying inflammatory processes in the CNS of Parkinson’s disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte-recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a “second hit”. These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1345-4) contains supplementary material, which is available to authorized users.

Acinar cells make up the majority of all cells in the pancreas, yet the source of new acinar cells during homeostasis remains unknown. Using multicolor lineage-tracing and organoid-formation assays, we identified the presence of a progenitor-like acinar cell subpopulation. These cells have long-term self-renewal capacity, albeit in a unipotent fashion. We further demonstrate that binuclear acinar cells are terminally differentiated acinar cells. Transcriptome analysis of single acinar cells revealed the existence of a minor population of cells expressing progenitor markers. Interestingly, a gain of the identified markers accompanied by a transient gain of proliferation was observed following chemically induced pancreatitis. Altogether, our study identifies a functionally and molecularly distinct acinar subpopulation and thus transforms our understanding of the acinar cell compartment as a pool of equipotent secretory cells.

Adult somatic stem cells are generally defined as cells with the ability to differentiate into multiple different lineages and to self-renew during long periods of time. These features were long presumed to be represented in one single tissue-specific stem cell. Recent development of single-cell technologies reveals the existence of diversity in fate and activation state of somatic stem cells within the blood, skin and intestinal compartments [1] but also in the adult brain. Here we review how recent advances have expanded our view of neural stem cells (NSCs) as a diverse pool of cells and how the specialized microenvironment in which they reside acts to maintain this diversity. In addition, we discuss the plasticity of the system in the injured brain.

The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific deletion thereof reduces both neurovascular complexity and synaptic activity in the brain. CD95L-induced neuronal and vascular growth is mediated through src-family kinase (SFK) and PI3K signaling. Together, our study highlights a coordinated neurovascular development instructed by CNS macrophage-derived CD95L, and it underlines the importance of macrophages for the establishment of the neurovascular network during CNS development.

Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy.

Influenza is an important cause of morbidity and mortality in older people, especially in those with some high-risk conditions such as diabetes mellitus. This study assessed the relationship between influenza vaccination status and winter mortality among diabetics 65 y and over during four consecutive influenza seasons.Population-based cohort study including 2,650 community-dwelling individuals 65 y or older with diabetes mellitus followed between January 2002 and April 2005 in Tarragona, Spain. Influenza vaccination status was evaluated every year of the study and the primary endpoint was considered all-cause death during the study period. Deaths were classified as occurring within influenza periods (January-April) or non-influenza periods. The relationship between vaccination and winter mortality was evaluated by multivariable discrete-time hazard models.Influenza immunization was associated with a reduction of 33% (95% confidence interval: 4-53) in the adjusted risk of all-cause mortality throughout the overall influenza periods 2002-2005. The attributable risk to vaccination in reducing mortality was 13.5 per 100,000 person-weeks within influenza periods, estimating that one death was prevented for every 435 annual vaccinations.Our data confirm the benefit of influenza vaccination in reducing mortality and supports the strategy of annual vaccination in diabetics aged at least 65 y.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem–like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFβR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem–like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFβR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma. Cancer Res; 71(23); 7155–67. ©2011 AACR.

Incompletely resectable ependymomas are associated with poor prognosis despite intensive radio- and chemotherapy. Novel treatments have been difficult to develop due to the lack of appropriate models. Here, we report on the generation of a high-risk cytogenetic group 3 and molecular group C ependymoma model (DKFZ-EP1NS) which is based on primary ependymoma cells obtained from a patient with metastatic disease. This model displays stem cell features such as self-renewal capacity, differentiation capacity, and specific marker expression. In vivo transplantation showed high tumorigenic potential of these cells, and xenografts phenotypically recapitulated the original tumor in a niche-dependent manner. DKFZ-EP1NS cells harbor transcriptome plasticity, enabling a shift from a neural stem cell-like program towards a profile of primary ependymoma tumor upon in vivo transplantation. Serial transplantation of DKFZ-EP1NS cells from orthotopic xenografts yielded secondary tumors in half the time compared with the initial transplantation. The cells were resistant to temozolomide, vincristine, and cisplatin, but responded to histone deacetylase inhibitor (HDACi) treatment at therapeutically achievable concentrations. In vitro treatment of DKFZ-EP1NS cells with the HDACi Vorinostat induced neuronal differentiation associated with loss of stem cell-specific properties. In summary, this is the first ependymoma model of a cytogenetic group 3 and molecular subgroup C ependymoma based on a human cell line with stem cell-like properties, which we used to demonstrate the differentiation-inducing therapeutic potential of HDACi.

SummaryInjury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.

Glioblastoma multiforme (GBM) is the most common malignant brain tumour in adults. One main source of its high malignancy is the invasion of isolated tumour cells into the surrounding parenchyma, which makes surgical resection an insufficient therapy in nearly all cases. The invasion is triggered by several cell surface receptors including receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), TGF-beta receptor, integrins, immunoglobulins, tumour necrosis factor (TNF) family, cytokine receptors, and protein tyrosine phosphatase receptors. The cross-talk between cell-surface receptors and the redundancy of downstream effectors make analysis of invasive signals even more complex. Therapies involving inhibition of single receptors do not give promising outcomes and a thorough knowledge of invasive signals of common and exclusive signalling components is required for design of best combinatory treatment schemes to fight the disease.

The description of neuroglia by Virchow in 1848 may be considered the starting point of our understanding of primary brain tumors. At the beginning of the 20th century, surgical removal of primary brain tumors became possible, and therefore, tissue for microscopic analysis and clinical data on survival became available. During this time, research on gliomas beyond improving surgical procedures focused on their classification. The classification schemes developed emphasized parameters for sorting tumors with regard to (i) cytological aspects; (ii) presumed tumor cell origin; (iii) histological appearance of the tissue; or (iv) clinical outcome. Over the years, experimental studies have greatly improved our knowledge on gliomas. Gliomas induced by viruses, chemicals, radiation, transgenes and knock-out technology contributed to the understanding of their pathogenesis and still serve as preclinical models for the testing of novel therapies. Recent advances in developmental neurobiology and the identification of stem cells provided new insights into the origin of brain tumors and the molecular mechanisms of tumor formation. This review briefly compiles the evolution of our concepts on gliomas, focusing on the latest developments.

Background A combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) may be a convenient alternative to separate Hib and MenC conjugate vaccines. Methods Healthy infants randomized in a previous study for priming at 2, 4, and 6 months: Hib-MenC-TT primed group, 3 doses of Hib-MenC-TT + DTPa-HBV-IPV (N = 87); MenC-TT primed group, 2 doses of MenC-TT (NeisVac-C; Baxter Healthcare SA, Zuurich, Switzerland) + 3 doses of DTPa/Hib containing vaccines (N = 178); MenC-CRM primed group, 3 doses of MenC-CRM197(Meningitec; Wyeth Corporation Delaware, Madison, NJ) + DTPa-HBV-IPV/Hib (N = 93). At 13-14 months of age, Hib-MenC-TT and MenC-TT primed groups received a Hib-MenC-TT booster dose and the MenC-CRM primed group a booster dose of DTPa-HBV-IPV/Hib. Blood samples were taken before and at 1 and 18 months postbooster. Results Before the booster dose, persistence of anti-polyribosyl ribitol phosphate (PRP) antibody concentration > or =0.15 microg/mL in the Hib-MenC-TT (96.4%) and MenC-TT (96.1%) primed groups and of MenC bactericidal titers > or =1:8 in the Hib-MenC-TT primed group (96.3%) was statistically significantly higher than in the MenC-CRM primed group (86.4% and 85.4%, respectively). One month after the Hib-MenC-TT booster, 99.2% subjects in the Hib-MenC-TT primed + MenC-TT primed pooled groups had anti-PRP levels > or =1 microg/mL, and 99.6% had SBA-MenC titers > or =1:128. The Hib-MenC-TT booster tended to be less reactogenic than the DTPa-HBV-IPV/Hib control and no serious adverse events related to vaccination were reported. Eighteen months after boosting with Hib-MenC-TT, SBA-MenC titers > or =1:8 persisted in 92.7% subjects and anti-PRP > or =0.15 microg/mL persisted in 99.4%. Conclusions Primary immunization with 3 doses of Hib-MenC-TT coadministered with DTPa-HBV-IPV induced antibodies that persisted up to the second year of life. The Hib-MenC-TT booster administered to primed toddlers induced robust and persistent antibody responses to both the Hib and MenC components and had an acceptable safety profile.

Medialization thyroplasty is an accepted method for improving non-compensated unilateral vocal cord palsy. Most surgeons decide the depth of penetration of the prosthesis by monitoring the voice changes in the patient during the surgical procedure. General anesthesia with intubation is incompatible with this procedure. Sedation is recommended. In this study we want to objectivize and quantify the influence of sedation and position on voice in order to know if this anesthetic procedure is justified in medialization thyroplasties.A prospective study.This study involved 15 adult patients who underwent sedation. Voice recordings were performed in each patient in three different positions and conditions: the seated position without sedation, the supine position without sedation, and the supine position under the effects of sedation. The sedation drugs used were midazolam, fentanyl, and propofol. The level of sedation was monitored using the observational scale and the bispectral index.The acoustic data obtained from sustained vowel sounds from patient recordings showed that sedation significantly affected the values of pitch. Compared to recordings from patients without sedation, pitch values in patients under sedation were significantly higher for jitter local and shimmer local recordings and significantly lower for pitch and harmonics-to-noise ratio. The supine position was shown not to influence on the voice.Sedation exerts an important influence on voice quality. General anesthesia could be an alternative, focusing our attention on monitoring the glottis with a fibrolaryngoscope during the surgical procedure. No sedation at all can also be an alternative.

The spinal cord can be compared to a highway connecting the brain with the different body levels lying underneath, with the axons being the ultimate carriers of the electrical impulse. After spinal cord injury (SCI), many cells are lost because of the injury. To reconstitute function, damaged axons from surviving neurons have to grow through the lesion site to their initial targets. However, the territory they have to traverse has changed: the highway is full of inhibitory signals (myelin and scar components); the pavement itself has become bumpy (demyelination); and specialized cells are recruited to clear the way (inflammatory cells). Thus, actual strategies to treat spinal injuries aim at providing a permissive environment for regenerating axons and boosting the endogenous potential of axons to regenerate while limiting progression of secondary damage. Here we review some of the strategies currently under consideration to treat spinal injuries.

Mitochondrial dysfunction might play a central role in the pathogenesis of nonalcoholic steatohepatitis (NASH). The aims of this study were to evaluate whether free fatty acid (FFA) transport into the mitochondria or the activity of mitochondria respiratory chain (MRC) complexes are impaired in NASH. In patients with NASH and control subjects, we measured free carnitine, short-chain acylcarnitine (SCAC) and long-chain acylcarnitine (LCAC) esters, carnitine palmitoyltransferase (CPT) activity, and MRC enzyme activity in liver tissue as well as serum concentration of tumor necrosis factor α (TNF-α), homeostatic metabolic assessment of insulin resistance (HOMA IR ), and body mass index (BMI). In patients with NASH, the LCAC/free carnitine ratio was significantly increased and the SCAC/free carnitine ratio was decreased. In patients with NASH, the activity of the MRC complexes was decreased to 63% ± 20% (complex I), 58.5% ± 16.7% (complex II), 70.6% ± 10.3% (complex III), 62.5% ± 13% (complex IV), and 42.4% ± 9.1% (adenosine triphosphate synthase) of the corresponding control values. Activity of these complexes correlated significantly with serum TNF-α and HOMA IR . Serum TNF-α (36.3 ± 23.1 pg/mL), HOMA IR (4-5 ± 2.38), and BMI (29.9 ± 3.5 kg/m 2 ) values were significantly increased in patients with NASH. In conclusion, activities of MRC complexes were decreased in liver tissue of patients with NASH. This dysfunction correlated with serum TNF-α, insulin resistance, and BMI values.

New neurons are continuously generated and added to neural circuits in the adult brain. However, increasing age imposes changes in neural progenitor cells and their microenvironment that lead to a reduction of neurogenesis. Age-related decreased production of new neurons in the neurogenic dentate gyrus has been associated with memory impairments. Several mechanisms are known that might counteract this decline in cognitive functions. Here, we give an overview of ageing-related changes in neurogenesis in the brain of humans and rodents. We discuss possible causes for reduced neurogenesis with age, its consequences on cognition, and how neurogenesis might be restored in old age.

The role of CD95 (Fas/Apo1) in cancer has been a matter of debate for over 30 years. First discovered as an apoptosis-inducing molecule, CD95 soon emerged as a potential anticancer therapy. Yet accumulating evidence indicates a profound role for CD95 in alternative nonapoptotic signaling pathways that increase tumorigenesis. This fact challenges the initial clinical idea of using CD95 as a 'tumor killer' while setting the stage for clinical studies targeting the nonapoptotic signaling branch of CD95. This review summarizes the findings surrounding manipulation of the CD95 pathway for cancer therapy, considering how one receptor can both promote and prevent cell growth.

Aim Current guidelines recommend atrioventricular junction (AVJ) ablation in patients with atrial fibrillation (AF) treated with cardiac resynchronization therapy (CRT). Our study compared the CRT response of patients in sinus rhythm (SR) vs. AF. Methods and results In this observational, prospective, multicentre study, patients were grouped by intrinsic rhythm. For the first 2 months, the negative chronotropic drug was optimized in the AF group. If ventricular pacing was ≤85%, AVJ ablation was recommended. Responders were defined as patients who survived without requiring heart transplant and had a ≥ 10% reduction in left ventricular end-systolic volume (LVESV) at 12 months after implantation. Of 202 patients included, 156 (77%) were in SR and 46 (23%) had AF. After drug optimization, only 13/46 (28%) of the AF patients required AVJ ablation (AF + AVJ). The percentage of responders was 83/156 (53%) for SR vs. 22/46 (48%) AF (P = 0.4). Among AF patients the response was 16/33 (48%) for AF with non-AVJ ablation vs. 6/13 (46%) AF + AVJ, P = 0.56. The LVESV decreased in all three groups: −30 ± 39 mL, −24 ± 43 mL, and −22 ± 36 mL, respectively (P = 0.75). Mortality was higher in patients with AF compared with SR: 10/46 (21%) vs. 9/156 (5.7%), log rank 10.6, P

In isolated congenital diaphragmatic hernia, lung size and/or the position of the liver are predictive of neonatal outcome. Percutaneous Fetal Endoscopic Tracheal Occlusion (FETO) by a balloon can be undertaken to prompt lung growth in the worst cases. The feasibility and safety of FETO is no longer at stake, and it is associated with an apparent increase in neonatal survival. The gestational age at birth, the pre-existing lung size, the ability to remove the balloon prior to birth, and the lung response are predicting outcome. The most frequent complication is preterm premature rupture of the membranes, and as a consequence preterm delivery, which also complicates balloon removal. We have set up a randomized trial for the formal evaluation of FETO in Europe, including criteria for fetoscopy centers. Training of European as well as North American centers is taking place, so that the procedure could be safely and more widely offered.

Knowledge of the available sensing polarities in biventricular pacemakers is necessary for appropriate troubleshooting and avoiding possible pitfalls of cardiac resynchronization therapy programming, as illustrated through this case presentation.

Apoptosis or programmed cell-death is an important process involved in tissue homeostasis, development and a variety of immune responses.(1) The apoptotic program can be activated via transmembrane receptors stimulated by their cognate ligands. The presence of a well-conserved region of 80 amino acids in their intracellular tail, the Death-Domain (DD), has conferred those receptors the general name of "death receptors". Death receptors are a subfamily of the TNF receptor superfamily, which includes the TNF receptor-I (TNFR1), TRAMP, DR3/APO-3, TRAIL-receptor 1 (TRAIL-R1/DR4), TRAIL-receptor 2 (TRAIL-R1/DR5), DR6 and CD95 (Fas/Apo-1). The pro-apoptotic properties of the CD95 system have been extensively studied during the past decades. Nevertheless, CD95 has now emerged as an important activator of other major signaling pathways leading to a variety of phenotypes. In the last years, stimulation of CD95 has been described to activate the MAPK pathways p38, JNK and ERK. (2-6) CD95 has also been shown to activate the transcription factor NFkB. (67-9) However, the molecular mechanisms leading to activation of such pathways are not fully understood and their contribution to the final phenotype is still unclear. CD95 has been shown to be particularly involved in tumor cell invasion, (6) neurite sprouting and outgrowth,(5,10) as well as cell proliferation(11,12)--functions that lay to rest the general assumption of CD95 as a death receptor. In our group we have recently described a novel molecular link between CD95 and the phosphatydilinositol-3-kinase (PI3K) pathway in Glioblastoma multiforme. In the present review we will discuss the past and present knowledge of the CD95/CD95L system and its role in PI3K signaling.

SummaryInvasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-β pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.

BACKGROUND This phase II study evaluated the immunogenicity and reactogenicity of primary vaccination with a novel Hib-MenC conjugate vaccine (GlaxoSmithKline [GSK] Biologicals) coadministered with DTPa-HBV-IPV (GSK Biologicals) at 2, 4 and 6 months. METHODS Healthy infants were randomized to receive Hib-MenC coadministered with DTPa-HBV-IPV (N = 117) or MenC-CRM (Wyeth) coadministered with DTPa-HBV-IPV/Hib (GSK Biologicals; N = 120) at 2, 4 and 6 months. Antibody concentrations were measured before vaccination and after doses 2 and 3. Solicited local and general symptoms, unsolicited symptoms and serious adverse events (SAEs) were recorded. RESULTS All subjects in the Hib-MenC group had seroprotective titers of anti-PRP antibodies (>or=0.15 microg/mL) and SBA-MenC titers (>or=1:8) 1 month after the third dose. These responses were noninferior to those seen in the control group, in which a 99.1% seroprotection rate was observed for both Hib and MenC. At that time, anti-PRP and SBA-MenC GMTs were significantly higher in the Hib-MenC group (12.8 microg/mL and 2467.1 microg/mL, respectively) than in the control group (3.8 microg/mL and 1833.7 microg/mL). High seroprotection rates were already observed after the second dose of Hib-MenC; 96.4% and 100% of subjects were seroprotected to Hib and MenC, respectively. Immune responses to coadministered antigens were unimpaired; seroprotection/vaccine response rates >or=96.5% were recorded postdose 3 in the Hib-MenC group. No differences in reactogenicity were seen between the 2 study groups. CONCLUSIONS Coadministration of a Hib-MenC conjugate vaccine with DTPa-HBV-IPV is well tolerated and immunogenic, and does not impair the immune response to any of the coadministered antigens.

This study evaluated the concurrent use of meningococcal C tetanus conjugate (MenC-TT) vaccine (NeisVac-C) with DTaP-based combinations, according to 2 vaccination schedules, one of which included hepatitis B vaccination at birth (Trial DTaP-HBV-IPV/Hib-097).Healthy infants were randomized to receive either DTaP-HBV-IPV/Hib (Infanrix hexa) at 2, 4, and 6 months (N = 115) or HBV at birth followed by DTaP-HBV-IPV/Hib at 2 and 6 months and DTaP-IPV/Hib (Infanrix-IPV Hib) at 4 months (N = 115). In both groups 2 doses of MenC-TT conjugate were coadministered at 2 and 4 months, and compared with 3 doses of MenC-CRM197 conjugate (Meningitec) coadministered at 2, 4, and 6 months with DTaP-HBV-IPV/Hib (N = 120). Antibody concentrations were measured at 2, 6 and 7 months. Solicited local and general symptoms, unsolicited symptoms, and serious adverse events (SAEs) were recorded.All MenC-TT recipients had seroprotective concentrations of anti-PRP antibodies (or = 0.15 microg/mL) 1 month after the third vaccine dose and all had SBA-MenC titersor = 1:8 after the second dose of MenC-TT. These responses were noninferior to those seen after 3 doses of DTaP-HBV-IPV/Hib and MenC-CRM. Anti-PRP antibody GMCs were significantly higher in MenC-TT than MenC-CRM vaccinees (7.9, 7.3, 3.8 microg/mL, respectively). Immune responses to all other coadministered antigens were unimpaired, with seroprotection/seropositivity ratesor = 98.1% in MenC-TT vaccinees. All schedules studied were well tolerated, with no differences in reactogenicity between the study groups.Coadministration of DTaP-HBV-IPV/Hib or DTaP-IPV/Hib with 2 doses of MenC-TT conjugate vaccine is safe, well tolerated, and immunogenic, with no impairment of the response to the coadministered antigens.

Objective To examine whether apoptosis contributes to the pathogenesis of skin lesions in patients with cutaneous lupus erythematosus (CLE) after ultraviolet (UV) irradiation. Methods In situ nick translation and TUNEL were performed to detect apoptosis in 85 skin biopsy specimens from patients with various subtypes of CLE. Specimens from normal healthy donors and patients with polymorphous light eruption were used as controls. In addition to assessment of primary lesions, provocative phototesting was carried out to investigate events occurring secondary to UV irradiation during a very early stage of lesion formation. Results A significant increase in apoptotic nuclei was found in the upper epidermal layer of primary and UV light–induced skin lesions of CLE patients compared with controls. In tissue sections obtained from control subjects at 24 hours after a single exposure to UV light, a slight increase in the count of epidermal apoptotic nuclei was present as compared with skin tissue from CLE patients obtained under the same conditions before lesion formation. In sections obtained from controls at 72 hours after irradiation, a significant decrease in the apoptotic nuclei count was observed, consistent with a proper clearance of apoptotic cells in the period between 24 and 72 hours after irradiation. In striking contrast, the number of apoptotic nuclei increased significantly within this period in tissue sections from patients with CLE. Conclusion These data support the hypothesis that apoptotic cells accumulate in the skin of patients with CLE after UV irradiation, as a result of impaired or delayed clearance. The nonengulfed cells may undergo secondary necrosis and release proinflammatory compounds and potential autoantigens, which may contribute to the inflammatory micromilieu that leads to formation of skin lesions in this disease.

Incontinentia pigmenti is an X-linked genodermatosis, lethal in males. Affected females survive because of X-chromosome dizygosity and negative selection of cells carrying the mutant X-chromosome, and for this reason the skewed X inactivation pattern is often used to confirm the diagnosis. The most frequent mutation is a deletion of part of the NEMO gene (NEMODelta4-10), although other mutations have been reported. Mutations of NEMO which do not abolish NF-kappaB activity totally permit male survival, causing an allelic variant of IP called hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). We present a non-classical IP female patient who also suffered transient immunodeficiency because of a late and progressive selection against peripheral blood cells carrying an active mutated X-chromosome. This finding suggests that in the absence of known mutation the X-inactivation studies used in genetic counselling can induce mistakes with some female patients. At the age of 3 years and 6 months, all immunodeficiency signs disappeared, and the X-chromosome inactivation pattern was completely skewed. The low T cell proliferation and CD40L expression corroborate the important role of NEMO/ NF-kappaB pathway in T cell homeostasis. The decreased NEMO protein amount and the impaired IkBalpha degradation suggest that this new mutation, NM_003639: c.1049dupA, causes RNA or protein instability. To our knowledge, this is the first time that selection against the mutated X-chromosome in X-linked disease has been documented in vivo.

Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

In the adult hippocampus, neurogenesis—the process of generating mature granule cells from adult neural stem cells—occurs throughout the entire lifetime. In order to investigate the involved regulatory mechanisms, knockout (KO) experiments, which modify the dynamic behaviour of this process, were conducted in the past. Evaluating these KOs is a non-trivial task owing to the complicated nature of the hippocampal neurogenic niche. In this study, we model neurogenesis as a multicompartmental system of ordinary differential equations based on experimental data. To analyse the results of KO experiments, we investigate how changes of cell properties, reflected by model parameters, influence the dynamics of cell counts and of the experimentally observed counts of cells labelled by the cell division marker bromodeoxyuridine (BrdU). We find that changing cell proliferation rates or the fraction of self-renewal, reflecting the balance between symmetric and asymmetric cell divisions, may result in multiple time phases in the response of the system, such as an initial increase in cell counts followed by a decrease. Furthermore, these phases may be qualitatively different in cells at different differentiation stages and even between mitotically labelled cells and all cells existing in the system.