An integrative approach to space-flight physiology using systems analysis and mathematical simulation

An approach was developed to aid in the integration of many of the biomedical findings of space flight, using systems analysis. The mathematical tools used in accomplishing this task include an automated data base, a biostatistical and data analysis system, and a wide variety of mathematical simulation models of physiological systems. A keystone of this effort was the evaluation of physiological hypotheses using the simulation models and the prediction of the consequences of these hypotheses on many physiological quantities, some of which were not amenable to direct measurement. This approach led to improvements in the model, refinements of the hypotheses, a tentative integrated hypothesis for adaptation to weightlessness, and specific recommendations for new flight experiments

A Systems Approach to the Physiology of Weightlessness

A systems approach to the unraveling of the complex response pattern of the human subjected to weightlessness is presented. The major goal of this research is to obtain an understanding of the role that each of the major components of the human system plays following the transition to and from space. The cornerstone of this approach is the utilization of a variety of mathematical models in order to pose and test alternative hypotheses concerned with the adaptation process. An integrated hypothesis for the human physiological response to weightlessness is developed

A pilot study of performance among hospitalised elderly patients on a novel test of visuospatial cognition: the letter and shape drawing (LSD) test.

peer-reviewedObjectives. Conventional bedside tests of visuospatial function such as the clock drawing (CDT) and intersecting pentagons tests (IPT) are subject to considerable inconsistency in their delivery and interpretation. We compared performance on a novel test – the letter and shape drawing (LSD) test –with these conventional tests in hospitalised elderly patients. Methods. The LSD, IPT, CDT and the Montreal Cognitive Assessment (MoCA) were performed in 40 acute elderly medical inpatients at University Hospital Limerick The correlation between these tests was examined as well as the accuracy of the visuospatial tests to identify significant cognitive impairment on the MoCA. Results. The patients (mean age 81.0±7.71; 21 female) had a median MoCA score of 15.5 (range = 1–29). There was a strong, positive correlation between the LSD and both the CDT (r = 0.56) and IPT (r = 0.71). The correlation between the LSD and MoCA (r = 0.91) was greater than for the CDT and IPT (both 0.67). The LSD correlated highly with all MoCA domains (ranging from 0.54 to 0.86) and especially for the domains of orientation (r = 0.86), attention (0.81) and visuospatial function (r = 0.73). Two or more errors on the LSD identified 90% (26/29) of those patients with MoCA scores of ⩽20, which was substantially higher than for the CDT (59%) and IPT (55%). Conclusion. The LSD is a novel test of visuospatial function that is brief, readily administered and easily interpreted. Performance correlates strongly with other tests of visuospatial ability, with favourable ability to identify patients with significant impairment of general cognition.PUBLISHEDpeer-reviewe

Congenital acute myeloid leukemia with unique translocation t(11;19)(q23;p13.3)

Congenital leukemia is rarely encountered in clinical practice, even in tertiary children's hospitals. Leukemia may cause significant coagulopathy, putting the patient at risk of intracranial hemorrhage. In this case, the authors present a female infant with a unique mixed phenotypic congenital acute myeloid leukemia showing mixed-lineage leukemia (MLL) rearrangement and severe coagulopathy resulting in a large subdural hematoma. Despite the fatal outcome in this case, neurosurgical treatment of patients with acute myeloid leukemia should be considered if coagulopathy and the clinical scenario allow

Human Papillomavirus E6 Triggers Upregulation of the Antiviral and Cancer Genomic DNA Deaminase APOBEC3B

ABSTRACT Several recent studies have converged upon the innate immune DNA cytosine deaminase APOBEC3B (A3B) as a significant source of genomic uracil lesions and mutagenesis in multiple human cancers, including those of the breast, head/neck, cervix, bladder, lung, ovary, and other tissues. A3B is upregulated in these tumor types relative to normal tissues, but the mechanism is unclear. Because A3B also has antiviral activity in multiple systems and is a member of the broader innate immune response, we tested the hypothesis that human papillomavirus (HPV) infection causes A3B upregulation. We found that A3B mRNA expression and enzymatic activity were upregulated following transfection of a high-risk HPV genome and that this effect was abrogated by inactivation of E6. Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause A3B upregulation, and a panel of high-risk E6 proteins triggered higher A3B levels than did a panel of low-risk or noncancer E6 proteins. Knockdown experiments in HPV-positive cell lines showed that endogenous E6 is required for A3B upregulation. Analyses of publicly available head/neck cancer data further support this relationship, as A3B levels are higher in HPV-positive cancers than in HPV-negative cancers. Taken together with the established role for high-risk E6 in functional inactivation of TP53 and published positive correlations in breast cancer between A3B upregulation and genetic inactivation of TP53, our studies suggest a model in which high-risk HPV E6, possibly through functional inactivation of TP53, causes derepression of A3B gene transcription. This would lead to a mutator phenotype that explains the observed cytosine mutation biases in HPV-positive head/neck and cervical cancers

Myxobacteria versus sponge-derived alkaloids: the bengamide family identified as potent immune modulating agents by scrutiny of LC-MS/ELSD libraries.

A nuclear factor-κB (NF-κB) luciferase assay has been employed to identify the bengamides, previously known for their anti-tumor activity, as a new class of immune modulators. A unique element of this study was that the bengamide analogs were isolated from two disparate sources, Myxococcus virescens (bacterium) and Jaspis coriacea (sponge). Comparative LC-MS/ELSD and NMR analysis facilitated the isolation of M. viriscens derived samples of bengamide E (8) and two congeners, bengamide E\u27 (13) and F\u27 (14) each isolated as an insperable mixture of diastereomers. Additional compounds drawn from the UC, Santa Cruz repository allowed expansion of the structure activity relationship (SAR) studies. The activity patterns observed for bengamide A (6), B (7), E (8), F (9), LAF 389 (12) and 13-14 gave rise to the following observations and conclusions. Compounds 6 and 7 display potent inhibition of NF-κB (at 80 and 90 nM, respectively) without cytotoxicity to RAW264.7 macrophage immune cells. Western blot and qPCR analysis indicated that 6 and 7 reduce the phosphorylation of IκBα and the LPS-induced expression of the pro-inflammatory cytokines/chemokines TNFα, IL-6 and MCP-1 but do not effect NO production or the expression of iNOS. These results suggest that the bengamides may serve as therapeutic leads for the treatment of diseases involving inflammation, that their anti-tumor activity can in part be attributed to their ability to serve as immune modulating agents, and that their therapeutic potential against cancer merits further consideration

Lumbar posture and trunk muscle activation during static and dynamic seated tasks on a novel dynamic ergonomic chair

peer-reviewedLow back pain (LBP) is a common musculoskeletal disorder and prolonged sitting often aggravates LBP. A novel dynamic ergonomic chair (‘Back App’), which facilitates less hip flexion while sitting on an unstable base has been developed. This study compared lumbar posture and trunk muscle activation on this novel chair with a standard backless office chair. Twelve painfree participants completed a typing task on both chairs. Lumbar posture and trunk muscle activation were collected simultaneously and were analysed using paired t-tests. Sitting on the novel dynamic chair significantly (p 0.05) between chairs. Maintaining lordosis with less muscle activation during prolonged sitting could reduce the fatigue associated with upright sitting postures. Studies with longer sitting durations, and in people with LBP, are required. Practitioner Summary: Sitting on a novel dynamic chair resulted in less lumbar flexion and less back muscle activation than sitting on a standard backless office chair during a typing task among pain-free participants. Facilitating lordotic sitting with less muscle activation may reduce the fatigue and discomfort often associated with lordotic sitting postures.ACCEPTEDpeer-reviewe

Extending the DAMA annual-modulation region by inclusion of the uncertainties in the astrophysical velocities

The original annual-modulation region, singled out by the DAMA/NaI experiment for direct detection of WIMPs, is extended by taking into account the uncertainties in the galactic astrophysical velocities. Also the effect due to a possible bulk rotation for the dark matter halo is considered. We find that the range for the WIMP mass becomes 30 GeV < m_chi < 130 GeV at 1-sigma C.L. with a further extension in the upper bound, when a possible bulk rotation of the dark matter halo is taken into account. We show that the DAMA results, when interpreted in the framework of the Minimal Supersymmetric extension of the Standard Model, are consistent with a relic neutralino as a dominant component of cold dark matter (on the average in our universe and in our galactic halo). It is also discussed the discovery potential for the relevant supersymmetric configurations at accelerators of present generation.Comment: ReVTeX, 12 pages, 1 table, 7 figure