Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells

Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34(+) hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells.The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah(-/-) mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV.Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah(-/-) mice by 5-100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia.Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis.Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called liver chimeric mice with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens

Loneliness of Older Immigrant Groups in Canada: Effects of Ethnic-Cultural Background

This study aimed to explore the loneliness of several groups of older immigrants in Canadacompared to native-born older adults. Data from the Canadian General Social Survey, Cycle 22 (Nolder adults = 3,692) were used. The dependent variable is the 6 item De Jong Gierveld lonelinessscale. Determinants of loneliness included country of birth, ethnic background (cultural context);belongingness (community context) and social networks (social context). Results showed that onlysome immigrant groups are significantly lonelier than older adults born in Canada. Immigrants withsimilar language and culture are not lonelier; while those from countries that differ in nativelanguage/culture are significantly higher on loneliness. Multivariate analyses showed the importanceof cultural background, of composition of the network of relatives and friends, and of localparticipation and feelings of belonging to the Canadian society in explaining loneliness of olderimmigrants

CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD

OBJECTIVE: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis. METHODS: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37). RESULTS: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased. CONCLUSIONS: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies

One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis

Objective: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Design: Retrospective study conducted between 1997 and 2004. Setting: University-affiliated paediatric intensive care unit (PICU). Patients and participants: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Interventions: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12h and 24h. To assess disease severity, PRISM score and selected laboratory parameters were determined. Measurements and main results: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24h after admission. Conclusions: Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24h. It might therefore increase risk of death

Topological mechanochemistry of graphene

In view of a formal topology, two common terms, namely, connectivity and adjacency, determine the quality of C-C bonds of sp2 nanocarbons. The feature is the most sensitive point of the inherent topology of the species so that such external action as mechanical deformation should obviously change it and result in particular topological effects. The current paper describes the effects caused by uniaxial tension of a graphene molecule in due course of a mechanochemical reaction. Basing on the molecular theory of graphene, the effects are attributed to both mechanical loading and chemical modification of edge atoms of the molecule. The mechanical behavior is shown to be not only highly anisotropic with respect to the direction of the load application, but greatly dependent on the chemical modification of the molecule edge atoms thus revealing topological character of the graphene deformation.Comment: 9 pages, 10 figures, 1 table. arXiv admin note: text overlap with arXiv:1301.094

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Frequency of occurrence of medication discrepancies and associated risk factors in cases of acute hospital admission

Background: Medication discrepancies are a common occurrence following hospital admission and carry the potential for causing harm. However, little is known about the potential risk factors involved in medication discrepancies. Objective: The objective of this study was to determine how frequently medication discrepancies occur and their associated risk factors, in patients hospitalized via the emergency department of the Spaarne Gasthuis Hospital, located in The Netherlands. Methods: This retrospective observational study examines 832 hospital admissions which took place between April 1st and June 30th, 2015. Medication reconciliation was performed within 24 hours of admission and medication discrepancies were registered. The primary outcome recorded in the study was the proportion of patients experiencing one or more medication discrepancies, as verified by the physician. As a secondary outcome, the association between these discrepancies and pre-specified variables was analyzed using univariate and multivariate logistic regression. Results: At least one medication discrepancy was found to have occurred with 97 of the 832 patients (11.7%), the most common discrepancies involving incorrect drug dose (44.9%) and omission of medication (36.4%). In the univariate analysis, age (OR=1.03 [95% CI 1.02:1.04] p<0.001) and number of pre-admission medications taken (OR=1.13 [95%CI 1.09:1.17] p<0.001) were revealed to be significantly associated with the risk of medication discrepancies. Sex, type of medical specialty, and surgical versus non-surgical specialty were found not to be significantly associated with discrepancies. In the multivariate analysis, both the number of pre-admission medications (OR=1.10 [95%CI 1.06:1.15] p<0.001) and age (OR=1.02 [95%CI 1.01:1.03] p=0.004) were independently associated with the risk of medication discrepancy. Conclusions: Of the total number of patients, 11.7% experienced one or more medication discrepancies following admission to the hospital. Elderly patients taking multiple drugs were found to be particularly at risk