Somatic cell gene therapy for diabetes mellitus: engineering a surrogate B-cell

Improved methods of insulin delivery are required for the treatment of insulin-dependent diabetes mellitus (IDDM) to achieve a more physiological profile of glucose homeostasis. Somatic cell gene therapy offers the prospect that insulin could be delivered by an autologous cell implant, engineered to secrete insulin in response to glucose. This study explores the feasibility of manipulating somatic cells to behave as a surrogate insulin-secreting β-cells. Initial studies were conducted using mouse pituitary AtT20 cells as a model, since these cells possess an endogenous complement of enzymes capable of processing proinsulin to mature insulin. Glucose sensitive insulin secretion was conferred to these cells by transfection with plasmids containing the human preproinsulin gene (hppI-1) and the GLUT2 gene for the glucose transporter isoform 2. Insulin secretion was responsive to changes in the glucose concentration up to about 50μM. Further studies to up-rate this glucose sensitivity into the mM range will require manipulation of the hexokinase and glucokinase enzymes. Intraperitoneal implantation of the manipulated AtT20 cells into athymic nude mice with streptozotocin-induced diabetes resulted in decreased plasma glucose concentrations. The cells formed vascularised tumours in vivo which were shown to contain insulin-secreting cells. To achieve proinsulin processing in non-endocrine cells, co-transfection with a suitable enzyme, or mutagenesis of the proinsulin itself are necessary. The mutation of the human preproinsulin gene to the consensus sequence for cleavage by the subtilisin-like serine protease, furin, was carried out. Co-transfection of human fibroblasts with wild-type proinsulin and furin resulted in 58% conversion to mature insulin by these cells. Intraperitoneal implantation of the mature-insulin secreting human fibroblasts into the diabetic nude mouse animal model gave less encouraging results than the AtT20 cells, apparently due to poor vascularisation. Cell aggregations removed from the mice at autopsy were shown to contain insulin secreting cells only at the periphery. This thesis provides evidence that it is possible to construct, by cellular engineering, a glucose-sensitive insulin-secreting surrogate β-cell. Therefore, somatic cell gene therapy offers a feasible alternative for insulin delivery in IDDM patients.

Further studies on the patterns of senile plaques in senile dementia of the Alzheimer type (SDAT) with a hypothesis on the colonization of the cortex

The pattern of senile plaques was investigated in various brain regions of six SDAT brains. In 91 pattern analyses, the regularly spaced clump was the most common pattern found in 64.8% of analyses. Clumping due to large aggregations of uncored plaques in sulci was also common. Regularly spaced clumps were equally common in the hippocampus and neocortex. The pattern of plaques varied in different tissue sections from the same brain region. Cored and uncored plaques presented a similar range of patterns but their pattern varied when they were both present in the same tissue section. Both clump diameter and the intensity of clumping were positively correlated with cored but unrelated to uncored plaque density. Plaques may develop in regular clumps on subcortical afferents and during development of the disease the clumps may spread laterally and ultimately coalesce.

Spatial patterns of phosphorylation-dependent TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.

Redefining neuromarketing as an integrated science of influence

Multiple transformative forces target marketing, many of which derive from new technologies that allow us to sample thinking in real time (i.e., brain imaging), or to look at large aggregations of decisions (i.e., big data). There has been an inclination to refer to the intersection of these technologies with the general topic of marketing as “neuromarketing”. There has not been a serious effort to frame neuromarketing, which is the goal of this paper. Neuromarketing can be compared to neuroeconomics, wherein neuroeconomics is generally focused on how individuals make “choices”, and represent distributions of choices. Neuromarketing, in contrast, focuses on how a distribution of choices can be shifted or “influenced”, which can occur at multiple “scales” of behavior (e.g., individual, group, or market/society). Given influence can affect choice through many cognitive modalities, and not just that of valuation of choice options, a science of influence also implies a need to develop a model of cognitive function integrating attention, memory, and reward/aversion function. The paper concludes with a brief description of three domains of neuromarketing application for studying influence, and their caveats.

Medical emergency alarm dissemination in urban environments

During medical emergencies, the ability to communicate the state and position of injured individuals is essential. In critical situations or crowd aggregations, this may result difficult or even impossible due to the inaccuracy of verbal communication, the lack of precise localization for the medical events, and/or the failure/congestion of infrastructure-based communication networks. In such a scenario, a temporary (ad hoc) wireless network for disseminating medical alarms to the closest hospital, or medical field personnel, can be usefully employed to overcome the mentioned limitations. This is particularly true if the ad hoc network relies on the mobile phones that people normally carry, since they are automatically distributed where the communication needs are. Nevertheless, the feasibility and possible implications of such a network for medical alarm dissemination need to be analysed. To this aim, this paper presents a study on the feasibility of medical alarm dissemination through mobile phones in an urban environment, based on realistic people mobility. The results showed the dependence between the medical alarm delivery rates and both people and hospitals density. With reference to the considered urban scenario, the time needed to delivery medical alarms to the neighbour hospital with high reliability is in the order of minutes, thus revealing the practicability of the reported network for medical alarm dissemination. © 2013 Elsevier Ltd. All rights reserved.