Carotid balloon occlusion for large and giant aneurysms: evaluation of a new test occlusion protocol.
Validation of a new angiographic test occlusion protocol before carotid balloon occlusion in patients with carotid aneurysms. Carotid occlusion was considered for 29 consecutive patients. From 1993 to 1995, test occlusion in four patients consisted of clinical observation for 30 minutes and during electroencephalographic registration. From 1996 onward, test occlusion in 25 patients consisted of clinical observation and angiography of collateral vessels. Permanent balloon occlusion was performed only when the cortical veins in both the occluded and the collateral vascular territories filled synchronously. Two of the four patients with normal clinical and electroencephalographic findings during test occlusion developed delayed hypoperfusion infarction after permanent carotid occlusion. Seventeen of 25 patients (68%) demonstrated both clinical and angiographic tolerance, and no ischemic events occurred after permanent carotid occlusion. In one patient with clinical tolerance but angiographic nontolerance, permanent carotid occlusion had to be performed, which resulted in delayed hypoperfusion infarction. In two patients with angiographic nontolerance, venous filling became synchronous after bypass surgery. Long-term clinical follow-up showed an alleviation of the symptoms of mass effect in 14 of 21 patients (67%). Magnetic resonance imaging follow-up (range, 3-70 mo) revealed a reduction in the size of the aneurysm in 19 of 21 patients (90%). Test occlusion with clinical and angiographic control is reliable, safe, and simple to perform.


Exploring reflective 'critical incident' documentation of professionalism lapses in a medical undergraduate setting.
Measuring professionalism in undergraduate medical students is a difficult process, and no one method has currently emerged as the definitive means of assessment in this field. Student skills in reflection have been shown to be highly important in the development of professional behaviours. By studying student reflections on lapses in professional judgement, recorded as 'critical incidents', it is possible to explore themes which are significant for the development of professional behaviour in an undergraduate setting. We examined critical incident reporting combined with optional written student reflection as a method for exploring professionalism in undergraduate medical students. 228 students split between Year 1 and 2 of one academic year of undergraduate medicine were studied retrospectively and a grounded theory approach to analysis was employed. This year generated 16 critical incident reports and corresponding student reflections, all of which were considered. In addition to identifying the nature of the critical incidents, 3 principal themes emerged. These were the impact and consequences of the report having been made, student reactions to the events (both positive and negative), and student responses regarding future actions. This study indicates that unprofessional behaviour can be identified and challenged by both the faculty and the students involved, and suggests that positive behavioural changes might be made with the aim of preventing future occurrences. We provide a low cost approach of measuring and recording professional behaviour.


Academia's Role to Drive Change in the Orthotics and Prosthetics profession.
This position paper outlines the important role of academia in shaping the orthotics and prosthetics (O&P) profession and preparing for its future. In the United States, most healthcare professions including O&P are under intense pressure to provide cost effective treatments and quantifiable health outcomes. Pivotal changes are needed in the way O&P services are provided to remain competitive. This will require the integration of new technologies and data driven processes that have the potential to streamline workflows, reduce errors and inform new methods of clinical care and device manufacturing. Academia can lead this change, starting with a restructuring in academic program curricula that will enable the next generation of professionals to cope with multiple demands such as the provision of services for an increasing number of patients by a relatively small workforce of certified practitioners delivering these services at a reduced cost, with the expectation of significant, meaningful, and measurable value. Key curricular changes will require replacing traditional labor-intensive and inefficient fabrication methods with the integration of newer technologies (i.e., digital shape capture, digital modeling/rectification and additive manufacturing). Improving manufacturing efficiencies will allow greater curricular emphasis on clinical training and education - an area that has traditionally been underemphasized. Providing more curricular emphasis on holistic patient care approaches that utilize systematic and evidence-based methods in patient assessment, treatment planning, dosage of O&P technology use, and measurement of patient outcomes is imminent. Strengthening O&P professionals' clinical decision-making skills and decreasing labor-intensive technical fabrication aspects of the curriculum will be critical in moving toward a digital and technology-centric practice model that will enable future practitioners to adapt and survive.


Hormone therapy and thromboembolic disease.
Hormone therapy increases the risk of venous thromboembolism (VTE). To reduce this risk, changes in dosage, composition and route of administration have been made over the years. This review provides a summary of the available evidence and an update on the most recent findings on the issue. Contraceptives containing third-generation progestagens confer a higher risk of VTE than second-generation compounds. Little data are available on preparations containing less than 30 micarog of estrogen, new progestagens or levonorgestrel-releasing intrauterine devices. Hormone replacement therapy increases the risk of VTE by 2 to 3-fold. Transdermal administration may be less thrombogenic than oral administration, while different estrogens and progestagens may carry a different risk. VTE risk is further increased in carriers of inherited thrombophilia. Despite a similar increase in relative risk of thrombosis associated with hormone therapy, absolute risk is lower in fertile women and higher in postmenopausal ones. Universal screening for thrombophilia before prescribing hormone replacement therapy might be cost-effective. Careful evaluation of individual risk factor is warranted before prescribing hormone therapy. Further investigations are needed to establish whether or not newer compounds are safer than older ones with respect to the risk of thrombosis.


Heterotrophy in the earliest gut: a single-cell view of heterotrophic carbon and nitrogen assimilation in sponge-microbe symbioses.
Sponges are the oldest known extant animal-microbe symbiosis. These ubiquitous benthic animals play an important role in marine ecosystems in the cycling of dissolved organic matter (DOM), the largest source of organic matter on Earth. The conventional view on DOM cycling through microbial processing has been challenged by the interaction between this efficient filter-feeding host and its diverse and abundant microbiome. Here we quantify, for the first time, the role of host cells and microbial symbionts in sponge heterotrophy. We combined stable isotope probing and nanoscale secondary ion mass spectrometry to compare the processing of different sources of DOM (glucose, amino acids, algal-produced) and particulate organic matter (POM) by a high-microbial abundance (HMA) and low-microbial abundance (LMA) sponge with single-cell resolution. Contrary to common notion, we found that both microbial symbionts and host choanocyte (i.e. filter) cells and were active in DOM uptake. Although all DOM sources were assimilated by both sponges, higher microbial biomass in the HMA sponge corresponded to an increased capacity to process a greater variety of dissolved compounds. Nevertheless, in situ feeding data demonstrated that DOM was the primary carbon source for both the LMA and HMA sponge, accounting for ~90% of their heterotrophic diets. Microbes accounted for the majority (65-87%) of DOM assimilated by the HMA sponge (and ~60% of its total heterotrophic diet) but <5% in the LMA sponge. We propose that the evolutionary success of sponges is due to their different strategies to exploit the vast reservoir of DOM in the ocean.


HIV infection among people who inject drugs: the challenge of racial/ethnic disparities.
Racial/ethnic disparities in HIV infection, with minority groups typically having higher rates of infection, are a formidable public health challenge. In the United States, among both men and women who inject drugs, HIV infection rates are elevated among Hispanics and non-Hispanic Blacks. A meta-analysis of international research concluded that among persons who inject drugs, racial and ethnic minorities were twice as likely to acquire an HIV infection, though there was great variation across the individual studies. To examine strategies to reduce racial/ethnic disparities among persons who inject drugs, we reviewed studies on injection drug use and its role in HIV transmission. We identified four sets of evidence-based interventions that may reduce racial/ethnic disparities among persons who inject drugs: HIV counseling and testing, risk reduction services, access to antiretroviral therapy, and drug abuse treatment. Implementation of these services, however, is insufficient in many countries, including the United States. Persons who inject drugs appear to be changing drug use norms and rituals to reduce their risks. The challenges are to (a) develop a validated model of how racial/ethnic disparities in HIV infection arise, persist, and are reduced or eliminated over time and (b) implement evidence-based services on a sufficient scale to eliminate HIV transmission among all persons who inject drugs.


A microfluidic imaging chamber for the direct observation of chemotactic transmigration.
To study the roles of nonmuscle myosin II (NM-II) during invasive cell migration, microfluidic migration chambers have been designed and fabricated using photo- and soft-lithography microfabrication techniques. The chamber consists of two channels separated by a vertical barrier with multiple bays of pores with widths varying from 6 microm to 16 microm, and lengths varying from 25 microm to 50 microm. The cells are plated in the channel on one side of the barrier while a chemoattractant is flowed through the channel on the other side of the barrier. In these chambers, cells can be observed with transmitted light or fluorescence optics while they chemotax through various sized pores that impose differential mechanical resistance to transmigration. As an initial test of this device, we compared breast-cancer cell chemotactic transmigration through different pore sizes with and without inhibition of NM-II. Two distinct rates were observed as cells attempted to pull their nucleus through the smaller pores, and the faster nuclear transit mode was critically dependent on NM-II motor activity. The ability to monitor cells as they chemotax through pores of different dimensions within a single experimental system provides novel information on how pore size affects cell morphology and migration rate, providing a dramatic improvement of imaging potential relative to other in vitro transmigration systems such as Boyden chambers.


In vitro study of the mechanism of potassium transport into human mesothelial cells. I: Effect of hyperosmolality.
To study the mechanism(s) of potassium transport into human mesothelial cells (HMC) exposed to osmotic solutes. Using potassium analog 86Rb, we evaluated its intracellular transport through three pathways: 1. blocked by ouabain; 2. blocked by furosemide but not by ouabain; 3. blocked by neither furosemide nor ouabain. Experiments were performed in a normotonic medium (control) or in a medium supplemented with osmotic solutes (glucose, glycerol, mannitol). Both the acute and chronic effects of osmotic solutes on potassium transport were studied. The acute exposure of mesothelial cells to osmotic solutes modifies the intracellular transport of potassium through all studied channels, and the effect is specific for every solute. In mesothelial cells exposed over 7 days to glucose (90 mM), the intracellular transport via ouabain- and furosemide-blocked channels is decreased, whereas it is increased through the third pathway. Total intracellular accumulation of 86Rb (potassium) ions in mesothelial cells cultured in a medium supplemented with various concentrations of glucose is decreased, and this effect is proportional to the concentration of glucose in the medium. The intracellular transport of potassium in mesothelial cells is regulated through at least three independent mechanisms. Acute or chronic exposure of mesothelial cells to a hypertonic medium affects the intracellular accumulation of potassium, and this effect is specific for the various osmotic solutes.


Association of television viewing with fasting and 2-h postchallenge plasma glucose levels in adults without diagnosed diabetes.
We examined the associations of television viewing time with fasting plasma glucose (FPG) and 2-h postchallenge plasma glucose (2-h PG) levels in Australian adults. A total of 8,357 adults aged > 35 years who were free from diagnosed diabetes and who attended a population-based cross-sectional study (Australian Diabetes, Obesity and Lifestyle Study [AusDiab]) were evaluated. Measures of FPG and 2-h PG were obtained from an oral glucose tolerance test. Self-reported television viewing time (in the previous week) was assessed using an interviewer-administered questionnaire. Homeostasis model assessment (HOMA) of insulin sensitivity (HOMA-%S) and beta-cell function (HOMA-%B) were calculated based on fasting glucose and insulin concentrations. After adjustment for confounders and physical activity time, time spent watching television in women was positively associated with 2-h PG, log fasting insulin, and log HOMA-%B and inversely associated with log HOMA-%S (P < 0.05) but not with FPG. No significant associations were observed with glycemic measures in men. The beta-coefficients across categories of average hours spent watching television per day (< 1.0, 1.0-1.9, 2.0-2.9, 3.0-3.9, and > or = 4.0) for 2-h PG in women were 0 (reference), 0.009, 0.047, 0.473, and 0.501, respectively (P for trend = 0.02). Our findings highlight the unique deleterious relationship of sedentary behavior (indicated by television viewing time) and glycemic measures independent of physical activity time and adiposity status. These relationships differed according to sex and type of glucose measurement, with the 2-h PG measure being more strongly associated with television viewing. The findings suggest an important role for reducing sedentary behavior in the prevention of type 2 diabetes and cardiovascular disease, especially in women.


Sustained local delivery of siRNA from an injectable scaffold.
Controlled gene silencing technologies have significant, unrealized potential for use in tissue regeneration applications. The design described herein provides a means to package and protect siRNA within pH-responsive, endosomolytic micellar nanoparticles (si-NPs) that can be incorporated into nontoxic, biodegradable, and injectable polyurethane (PUR) tissue scaffolds. The si-NPs were homogeneously incorporated throughout the porous PUR scaffolds, and they were shown to be released via a diffusion-based mechanism for over three weeks. The siRNA-loaded micelles were larger but retained nanoparticulate morphology of approximately 100 nm diameter following incorporation into and release from the scaffolds. PUR scaffold releasate collected in vitro in PBS at 37 °C for 1-4 days was able to achieve dose-dependent siRNA-mediated silencing with approximately 50% silencing achieved of the model gene GAPDH in NIH3T3 mouse fibroblasts. This promising platform technology provides both a research tool capable of probing the effects of local gene silencing and a potentially high-impact therapeutic approach for sustained, local silencing of deleterious genes within tissue defects.


Incremental cost of increasing access to maternal health care services: perspectives from a demand and supply side intervention in Eastern Uganda.
High maternal and infant mortality continue to be major challenges to the attainment of the Millennium Development Goals for many low and middle-income countries. There is now evidence that voucher initiatives can increase access to maternal health services. However, a dearth of knowledge exists on the cost implications of voucher schemes. This paper estimates the incremental costs of a demand and supply side intervention aimed at increasing access to maternal health care services. This costing study was part of a quasi-experimental voucher study conducted in two districts in Eastern Uganda to explore the impact of demand and supply - side incentives on increasing access to maternal health services. The provider's perspective was used and the ingredients approach to costing was employed. Costs were based on market prices as recorded in program records. Total, unit, and incremental costs were calculated. The estimated total financial cost of the intervention for the one year of implementation was US$525,472 (US$1 = 2200UgShs). The major cost drivers included costs for transport vouchers (35.3%), health system strengthening (29.2%) and vouchers for maternal health services (18.2%). The average cost of transport per woman to and from the health facility was US$4.6. The total incremental costs incurred on deliveries (excluding caesarean section) was US$317,157 and US$107,890 for post natal care (PNC). The incremental costs per additional delivery and PNC attendance were US$23.9 and US$7.6 respectively. Subsidizing maternal health care costs through demand and supply - side initiatives may not require significant amounts of resources contrary to what would be expected. With Uganda's Gross Domestic Product (GDP) per capita of US$55` (2012), the incremental cost per additional delivery (US$23.9) represents about 5% of GDP per capita to save a mother and probably her new born. For many low income countries, this may not be affordable, yet reliance on donor funding is often not sustainable. Alternative ways of raising additional resources for health must be explored. These include; encouraging private investments in critical sectors such as rural transport, health service provision; mobilizing households to save financial resources for preparedness, and financial targeting for the most vulnerable.


β-elemene inhibits stemness, promotes differentiation and impairs chemoresistance to temozolomide in glioblastoma stem-like cells.
Accumulating evidence indicates that glioblastoma stem-like cells (GSCs) are key factors in tumour development, recurrence and chemoresistance. The impairment of stemness and the enhancement of differentiation contributes to the weakening of radiation and chemotherapy resistance of GSCs. We previously found that β-elemene was an effective anti-glioblastoma agent and chemosensitizer. In this study, we examined the distribution of CD133(+) cells in human glioblastoma tissues by immunohistochemistry. Following treatment with β-elemene, the formation of GSC spheres was investigated by manual counting, the proliferation of GSCs was measured with a Cell Counting Kit-8 (CCK-8) assay, and the dispersion of GSC spheres was observed with an inverted microscope. GSC spheres were treated with β-elemene, and the expression levels of CD133, ATP-binding cassette subfamily G member 2 (ABCG2) and glial fibrillary acidic protein (GFAP) were examined by western blotting. After treatment with β-elemene, the volumes and weights of GSC xenografts were measured, and the expression of CD133, ABCG2 and GFAP was evaluated through immunohistochemistry analysis. After treatment with β-elemene and temozolomide (TMZ), GSC viability was examined by the CCK-8 assay, and the volumes and weights of xenografts were measured. We found that CD133(+) cells were assembled in some vascular walls and also sparsely distributed in other parts of glioblastoma tissues. β-elemene decreased the formation of GSC spheres, dispersed GSC spheres and inhibited the proliferation of GSCs in vitro and in vivo. In the GSC spheres and xenografts treated with β-elemene, the expression of CD133 and ABCG2 was significantly downregulated, and the expression of GFAP increased. Furthermore, the sensitivity of GSCs to TMZ was enhanced in vitro and in vivo. These results suggest that β-elemene impaired the stemness of GSC spheres, promoted their differentiation and sensitized GSCs to TMZ. β-elemene will hopefully become a valuable agent to enhance the effects of radiotherapy and chemotherapy.


The direct mapping of the uptake of platinum anticancer agents in individual human ovarian adenocarcinoma cells using a hard X-ray microprobe.
Uptake of platinum-based anticancer compounds into individual human ovarian andenocarcinoma cells was measured using an X-ray microprobe. The uptake of cisplatin, a platinum-based compound, in drug-resistant cells is decreased by approximately 50% after 24 h, compared with the uptake of the drug in nonresistant cells over the same time period. The Pt103 derivative of the drug, in contrast, showed an increased uptake by an order of magnitude in resistant cells over the same time period. Increased uptake appears to allow Pt103 to overcome the resistance mechanism developed by the cell. This work additionally shows that the X-ray microprobe is able to directly quantify Pt drug uptake on a subcellular level and can measure the mass of Pt down to a detectable limit of 20 attograms of Pt (2 x 10(-17) grams or 6 x 10(4) Pt atoms) in 1 s. Such exquisite elemental sensitivity combined with high spatial resolution paves the way for quantitative submicron three-dimensional mapping of elemental distributions within individual cells.


A two-dimensional layered CdS/C2N heterostructure for visible-light-driven photocatalysis.
In this work, we employ hybrid density functional theory calculations to design a two-dimensional layered CdS/C2N heterostructure for visible light photocatalytic water splitting to produce hydrogen. The calculation results show that the conduction band minimum (CBM) and the valence band maximum (VBM) of C2N monolayers are lower than those of CdS nanosheets by about 0.76 eV and 0.44 eV, respectively. The type-II band alignment, density of states, Bader charge analysis, and charge density difference of the CdS/C2N heterostructure indicate that the photogenerated electrons migrate from the CdS monolayer to the C2N monolayer, favoring the separation and transfer of photogenerated charge carriers, which restrains the recombination of photogenerated carriers and enhances the photocatalytic efficiency. The calculated band gap and optical absorption spectra reveal that the two-dimensional layered CdS/C2N heterostructure may be a potential photocatalyst for photo-electrochemical water splitting because of its appropriate band gap and excellent visible light absorption behavior. Moreover, the electronic and optical properties of the CdS/C2N heterostructure can be effectively modulated by the strain. These findings suggest that the C2N sheets are a promising candidate as metal-free co-catalysts for CdS photocatalysts, and also provide valuable information for experimentalists to design highly active and efficient visible light photocatalysts for water splitting.


Regulation by heparan sulfate and interleukin 1 alpha of the ontogenic expression of T-cell receptor, CD4, and CD8 in developing thymus.
Increasing expression by T-cell precursors of the T-cell antigen receptor and of the CD4 and CD8 glycoproteins during thymus development enables specific interactions between primitive T cells and thymic epithelial cells, which initiate the development of the T-cell repertoire. Given the importance of GAGs, such as HS, in cell-cell interactions in other organs, we asked whether such molecules might participate in the cellular interactions essential for the development of the thymus. Using an organ culture model in which fetal murine thymuses explanted on gestational day 14 undergo phenotypic maturation from CD3-CD4-CD8- to CD3+CD4+/CD8+, the consequences of inhibiting GAG synthesis with 6-diazo-5-oxo-L-norleucine (DON) were explored. Inhibition of GAG synthesis prevented elaboration of cortical thymocyte-associated HS, IL-1, and de novo expression of the TCR, CD4, and CD8. DON did not alter the expression of TCR or CD4/CD8 by mature thymocytes. Synthesis of IL-1 alpha, TCR, CD4, and CD8 was restored by addition of HS to the cultured organs. These findings support the concept that the ontogenic (but not the constitutive) expression of the TCR and of CD4 and CD8 depends on the synthesis in the thymus of IL-1, and that IL-1 synthesis is in turn regulated by the metabolism of GAGs. Our findings suggest that components of the thymic microenvironment, particularly HS, play a critical role in the maturation of T-cell precursors.


Rare variants in the CYP27B1 gene are associated with multiple sclerosis.
Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering. We performed whole exome sequencing to further understand the heightened prevalence of MS in these families. Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10(-5)). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3-9.4; p = 5 × 10(-7)). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10(-9)). A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated.


Analyzing aberrant DNA methylation in colorectal cancer uncovered intangible heterogeneity of gene effects in the survival time of patients.
Colorectal cancer (CRC) involves epigenetic alterations. Irregular gene-methylation alteration causes and advances CRC tumor growth. Detecting differentially methylated genes (DMGs) in CRC and patient survival time paves the way to early cancer detection and prognosis. However, CRC data including survival times are heterogeneous. Almost all studies tend to ignore the heterogeneity of DMG effects on survival. To this end, we utilized a sparse estimation method in the finite mixture of accelerated failure time (AFT) regression models to capture such heterogeneity. We analyzed a dataset of CRC and normal colon tissues and identified 3406 DMGs. Analysis of overlapped DMGs with several Gene Expression Omnibus datasets led to 917 hypo- and 654 hyper-methylated DMGs. CRC pathways were revealed via gene ontology enrichment. Hub genes were selected based on Protein-Protein-Interaction network including SEMA7A, GATA4, LHX2, SOST, and CTLA4, regulating the Wnt signaling pathway. The relationship between identified DMGs/hub genes and patient survival time uncovered a two-component mixture of AFT regression model. The genes NMNAT2, ZFP42, NPAS2, MYLK3, NUDT13, KIRREL3, and FKBP6 and hub genes SOST, NFATC1, and TLE4 were associated with survival time in the most aggressive form of the disease that can serve as potential diagnostic targets for early CRC detection.


Sexual selection accounts for the geographic reversal of sexual size dimorphism in the dung fly, sepsis punctum (Diptera: Sepsidae).
Sexual size dimorphism (SSD) varies widely across and within species. The differential equilibrium model of SSD explains dimorphism as the evolutionary outcome of consistent differences in natural and sexual selection between the sexes. Here, we comprehensively examine a unique cross-continental reversal in SSD in the dung fly, Sepsis punctum. Using common garden laboratory experiments, we establish that SSD is male-biased in Europe and female-biased in North America. When estimating sexual (pairing success) and fecundity selection (clutch size of female partner) on males under three operational sex ratios (OSRs), we find that the intensity of sexual selection is significantly stronger in European versus North American populations, increasing with male body size and OSR in the former only. Fecundity selection on female body size also increases strongly with egg number and weakly with egg volume, however, equally on both continents. Finally, viability selection on body size in terms of intrinsic (physiological) adult life span in the laboratory is overall nil and does not vary significantly across all seven populations. Although it is impossible to prove causality, our results confirm the differential equilibrium model of SSD in that differences in sexual selection intensity account for the reversal in SSD in European versus North American populations, presumably mediating the ongoing speciation process in S. punctum.


The challenge of cancer in middle-income countries with an ageing population: Mexico as a case study.
Mexico is undergoing rapid population ageing as a result of its epidemiological transition. This study explores the interface between this rapid population ageing and the burden of cancer. The number of new cancer cases is expected to increase by nearly 75% by 2030 (107,000 additional cases per annum), with 60% of cases in the elderly (aged ≥ 65). A review of the literature was supplemented by a bibliometric analysis of Mexico's cancer research output. Cancer incidence projections for selected sites were estimated with Globocan software. Data were obtained from recent national census, surveys, and cancer death registrations. The elderly, especially women and those living in rural areas, face high levels of poverty, have low rates of educational attainment, and many are not covered by health insurance schemes. Out of pocket payments and private health care usage remain high, despite the implementation of Seguro Popular that was designed to achieve financial protection for the lowest income groups. A number of cancers that predominate in elderly persons are not covered by the scheme and individuals face catastrophic expenditure in seeking treatment. There is limited research output in those cancer sites that have a high burden in the elderly Mexican population, especially research that focuses on outcomes. The elderly population in Mexico is vulnerable to the effects of the rising cancer burden and faces challenges in accessing high quality cancer care. Based on our evidence, we recommend that geriatric oncology should be an urgent public policy priority for Mexico.


Characterization of Vulnerable and Resilient Spanish Adolescents in Their Developmental Contexts.
Research on resilience and vulnerability can offer very valuable information for optimizing design and assessment of interventions and policies aimed at fostering adolescent health. This paper used the adversity level associated with family functioning and the positive adaptation level, as measured by means of a global health score, to distinguish four groups within a representative sample of Spanish adolescents aged 13-16 years: maladaptive, resilient, competent and vulnerable. The aforementioned groups were compared in a number of demographic, school context, peer context, lifestyles, psychological and socioeconomic variables, which can facilitate or inhibit positive adaptation in each context. In addition, the degree to which each factor tended to associate with resilience and vulnerability was examined. The majority of the factors operated by increasing the likelihood of good adaptation in resilient adolescents and diminishing it in vulnerable ones. Overall, more similarities than differences were found in the factors contributing to explaining resilience or vulnerability. However, results also revealed some differential aspects: psychological variables showed a larger explicative capacity in vulnerable adolescents, whereas factors related to school and peer contexts, especially the second, showed a stronger association with resilience. In addition, perceived family wealth, satisfaction with friendships and breakfast frequency only made a significant contribution to the explanation of resilience. The current study provides a highly useful characterization of resilience and vulnerability phenomena in adolescence.


Patent literature on mosquito repellent inventions which contain plant essential oils--a review.
Bites Bites of mosquitoes belonging to the genera Anopheles Meigen, Aedes Meigen, Culex L. and Haemagogus L. are a general nuisance and are responsible for the transmission of important tropical diseases such as malaria, hemorrhagic dengue and yellow fevers and filariasis (elephantiasis). Plants are traditional sources of mosquito repelling essential oils (EOs), glyceridic oils and repellent and synergistic chemicals. A Chemical Abstracts search on mosquito repellent inventions containing plant-derived EOs revealed 144 active patents mostly from Asia. Chinese, Japanese and Korean language patents and those of India (in English) accounted for roughly 3/4 of all patents. Since 1998 patents on EO-containing mosquito repellent inventions have almost doubled about every 4 years. In general, these patents describe repellent compositions for use in topical agents, cosmetic products, incense, fumigants, indoor and outdoor sprays, fibers, textiles among other applications. 67 EOs and 9 glyceridic oils were individually cited in at least 2 patents. Over 1/2 of all patents named just one EO. Citronella [Cymbopogon nardus (L.) Rendle, C.winterianus Jowitt ex Bor] and eucalyptus (Eucalyptus L'Hér. spp.) EOs were each cited in approximately 1/3 of all patents. Camphor [Cinnamomum camphora (L.) J. Presl], cinnamon (Cinnamomum zeylanicum Blume), clove [Syzygium aromaticum (L.) Merr. & L.M. Perry], geranium (Pelargonium graveolens L'Hér.), lavender (Lavandula angustifolia Mill.), lemon [Citrus × limon (L.) Osbeck], lemongrass [Cymbopogon citratus (DC.) Stapf] and peppermint (Mentha × piperita L.) EOs were each cited in > 10% of patents. Repellent chemicals present in EO compositions or added as pure "natural" ingredients such as geraniol, limonene, p-menthane-3,8-diol, nepetalactone and vanillin were described in approximately 40% of all patents. About 25% of EO-containing inventions included or were made to be used with synthetic insect control agents having mosquito repellent properties such as pyrethroids, N,N-diethyl-m-toluamide (DEET), (±)-p-menthane-3,8-diol (PMD) and dialkyl phthalates. Synergistic effects involving one or more EOs and synthetic and/or natural components were claimed in about 10% of all patents. Scientific literature sources provide evidence for the mosquito repellency of many of the EOs and individual chemical components found in EOs used in patented repellent inventions.


Effect of bilateral salpingo-oophorectomy on the overall survival of premenopausal patients with stage I low-grade endometrial stromal sarcoma; a National Cancer Database analysis.
Investigate the prevalence of bilateral salpingo-oophorectomy (BSO) for women ≤50 years with early stage low-grade endometrial stromal sarcoma (LGESS) and its impact on overall survival (OS). Women ≤50 years, diagnosed with stage I LGESS and managed with hysterectomy between 2004 and 2015 were identified from the National Cancer Database. Patient demographics were recorded and compared with the chi-square test. OS for patients diagnosed between 2004 and 2014 with at least one month of follow-up was assessed using Kaplan-Meier curves, and compared with the log-rank test. A total 743 patients with a median age of 44 years met the inclusion criteria. Use of radiatiotherapy (9%), chemotherapy (0.8%) and hormonal therapy (11%) was infrequent. BSO was performed in 541 (72.8%) patients. Patients who had ovarian preservation (OP) were younger (median age 43 vs 45 years, p < 0.001), less likely to have comorbidities (6.9% vs 12.4%, p = 0.034), or undergo LND (30.7% vs 44.4%, p = 0.001). There were no differences between the two groups in terms of substage or patient race. Five year OS rates for patients who did (n = 490) and did not (n = 191) undergo BSO were 96.2% and 97.1% and there was no difference in OS, p = 0.50. Even after controlling for presence of comorbidities performance of BSO was not associated with better survival (HR: 1.28, 95% CI: 0.51, 3.19). Ovarian function was preserved in approximately one third of women ≤50 years with stage I LGESS with no clear detriment to overall survival. As BSO is associated with long term health effects in this patient population OP could be considered in selected women with stage I LGESS.


Current Applications and Future Perspectives of the Use of 3D Printing in Anatomical Training and Neurosurgery.
3D printing is a form of rapid prototyping technology, which has led to innovative new applications in biomedicine. It facilitates the production of highly accurate three dimensional objects from substrate materials. The inherent accuracy and other properties of 3D printing have allowed it to have exciting applications in anatomy education and surgery, with the specialty of neurosurgery having benefited particularly well. This article presents the findings of a literature review of the Pubmed and Web of Science databases investigating the applications of 3D printing in anatomy and surgical education, and neurosurgery. A number of applications within these fields were found, with many significantly improving the quality of anatomy and surgical education, and the practice of neurosurgery. They also offered advantages over existing approaches and practices. It is envisaged that the number of useful applications will rise in the coming years, particularly as the costs of this technology decrease and its uptake rises.


DNA content analysis by flow cytometry and cytogenetic analysis in mycosis fungoides and Sézary syndrome.
Flow cytometric (FCM) analysis of DNA content was performed on 82 lymph node and peripheral blood specimens from 46 patients with mycosis fungoides and the Sézary syndrome. Overall, 32 of the 46 patients (70%) had aneuploidy detected by FCM. Aneuploidy was present in 63% of the patients at the time of diagnosis before systemic therapy. In these patients, aneuploidy was frequently detected in blood and lymph node specimens scored as negative by cytology and histology, suggesting that unsuspected extracutaneous dissemination is present in many patients at the time of diagnosis. Direct comparison with Giemsa-banded cytogenetic studies showed an excellent correlation of FCM results and cytogenetic chromosome number. However, FCM frequently detected a larger fraction of aneuploid cells, and mitogen-stimulation studies suggest this is the result of preferential stimulation of normal lymphocytes by phytohemagglutinin. Thus, mitogens with a preference for malignant T cells, such as staphylococcal protein A, should be used for cytogenetic analysis of malignant T-cell disorders. At diagnosis, some histologically positive specimens contained only diploid cells by FCM and cytogenetic analysis. These patients had a more indolent clinical course than patients with aneuploidy. Aneuploidy was detected by FCM as either wide G(1) or as discrete aneuploid peaks. The presence of aneuploidy at any time in the clinical course implied a poor prognosis. Discrete hyperdiploid peaks were associated with large cell histology, early relapse, and aggressive clinical course. The development of hyperdiploidy at relapse was documented in four patients and was associated with a transition to large cell histology and a poor prognosis. Similar studies may elucidate differences in natural history and mechanism for transition in histology in other lymphomas and solid tumors.


Early Orthognathic Surgery: A Review.
Management of growing patients with severe developmental jaw abnormalities can be very difficult. Early surgical intervention may be warranted in situations where function (e.g., mastication, swallowing, breathing, or speech) and/or psychological well-being could be negatively affected. Many surgeons and orthodontists are reluctant to recommend a surgical treatment option for growing patients with severe developmental jaw abnormalities because of their age. Specific surgical procedures can be performed during growth to correct developmental jaw abnormalities with predictable results. A sound understanding of the facial growth and the effects of the surgical procedures on subsequent growth is essential when managing growing patients with severe developmental jaw abnormalities. Children with severely progressive congenital deficiencies affecting function/health should be distinguished from ones with severe developmental jaw abnormalities that can be managed later in life. In this review, we will focus on the management of growing patients with developmental jaw abnormalities who seek orthodontic treatment, rather than patients with progressive congenital deformities affecting function and/or health.


Insurance coverage of male infertility: what should the standard be?
Infertility is a disease, and the male partner plays a role in approximately 50% of infertility cases. For most patients, infertility care does not receive insurance coverage like other diseases, leaving them to pay out of pocket for their treatments. Because of the lack of insurance coverage, evaluations and treatments are expensive for patients, with costs often approaching the median annual US income. These increased costs reduce access to care and limit the ability to diagnose the cause of infertility, treat the underlying causes, and downgrade the intensity of the intervention needed to achieve the pregnancy. This leaves much of the burden for infertility care on the female partner. In an ideal health care system, evaluations and interventions for male infertility would receive the same insurance coverage as evaluations and interventions for other diseases.


Evolution and microsynteny of the apyrase gene family in three legume genomes.
Apyrases have been suggested to play important roles in plant nutrition, photomorphogenesis, and nodulation. To help trace the evolution of these genes in the legumes--and possibly, the acquisition of new functions for nodulation--apyrase-containing BACs were sequenced from three legume genomes. Genomic sequences from Medicago truncatula, Glycine max and Lotus japonicus were compared to one another and to corresponding regions in Arabidopsis thaliana. A phylogenetic analysis of apyrase homologs from these regions and sequences from other legume species, as well as other plant families, identified a potentially legume-specific clade that contains a well-characterized soybean ( G. soja) apyrase, Gs52, as well as homologs from Dolichos, Lotus, Medicago and Pisum. Sister clades contain homologs from members of Brassicaceae, Solanaceae, Poaceae and Fabaceae. Comparisons of rates of change at synonymous and nonsynonymous sites in the Gs52 and sister clades show rapid evolution in the potentially legume-specific Gs52 clade. The genomic organization of the apyrase-containing BACs shows evidence of gene duplication, genomic rearrangement, and gene conversion among Gs52 homologs. Taken together, these results suggest a scenario of local apyrase gene duplication in an ancestor of the legumes, followed by functional diversification and increased rates of change in the new genes, and further duplications in the Galegae (which include the genera Medicago and Pisum). The study also provides a detailed comparison of genomic regions between two model genomes which are now being sequenced ( M. truncatulaand L. japonicus), and a genome from an economically important legume species ( G. max).


Female oxytocin gene-knockout mice, in a semi-natural environment, display exaggerated aggressive behavior.
Compared to results from a generation of neuropharmacological work, the phenotype of mice lacking the oxytocin (OT) peptide gene was remarkably normal. An important component of the current experiments was to assay OT-knockout (OTKO) and wild-type (WT) littermate control mice living under controlled stressful conditions designed to mimic more closely the environment for which the mouse genome evolved. Furthermore, our experimental group was comprised of an all-female population, in contrast to previous studies which have focused on all-male populations. Our data indicated that aggressive behaviors initiated by OTKO during a food deprivation feeding challenge were considerably more intense and diverse than aggressive behaviors initiated by WT. From the measures of continuous social interaction in the intruder paradigm, it emerged that OTKO mice were more offensively aggressive (attacking rumps and tails) than WT. In a test of parental behaviors, OTKO mice were 100% infanticidal while WT were 16% infanticidal and 50% maternal. Finally, 'alpha females' (always OTKO) were identified in each experiment. They were the most aggressive, the first to feed and the most dominant at nesting behaviors. Semi-natural environments are excellent testing environments for elucidating behavioral differences between transgenic mice and their WT littermates which may not be ordinarily discernible. Future studies of mouse group behavior should include examining female groupings in addition to the more usual all-male groups.


Australin: a chromosomal passenger protein required specifically for Drosophila melanogaster male meiosis.
The chromosomal passenger complex (CPC), which is composed of conserved proteins aurora B, inner centromere protein (INCENP), survivin, and Borealin/DASRA, localizes to chromatin, kinetochores, microtubules, and the cell cortex in a cell cycle-dependent manner. The CPC is required for multiple aspects of cell division. Here we find that Drosophila melanogaster encodes two Borealin paralogues, Borealin-related (Borr) and Australin (Aust). Although Borr is a passenger in all mitotic tissues studied, it is specifically replaced by Aust for the two male meiotic divisions. We analyzed aust mutant spermatocytes to assess the effects of fully inactivating the Aust-dependent functions of the CPC. Our results indicate that Aust is required for sister chromatid cohesion, recruitment of the CPC to kinetochores, and chromosome alignment and segregation but not for meiotic histone phosphorylation or spindle formation. Furthermore, we show that the CPC is required earlier in cytokinesis than previously thought; cells lacking Aust do not initiate central spindle formation, accumulate anillin or actin at the cell equator, or undergo equatorial constriction.


Evaluation of electrophoretic methods for typing methicillin-resistant Staphylococcus aureus.
Three electrophoretic methods of typing methicillin-resistant Staphylococcus aureus (MRSA) strains--plasmid profiles (PP), whole-cell protein profiles (WCPP) and immunoblotting profiles (IP)--were evaluated and compared with phage typing. The results obtained with isolates from 12 outbreaks were compared both within the outbreaks, to determine the consistency of results, and between outbreaks. There was generally good agreement between the typing methods but in only six outbreaks did all four methods indicate the same relationship between isolates. WCPP comprised more than 50 bands; when differences occurred, they were seen in only a few bands. In contrast, IP comprised only one or two major bands and the differences were much easier to interpret. The PPs of many of the isolates were similar; many isolates contained a plasmid of mol. wt (18-25) x 10(6). In several outbreaks both WCPP and IP showed minor differences between isolates that were not apparent with phage typing. When comparisons were made between the 12 index strains and an isolate representing the London epidemic MRSA strain, phage typing and WCPP were the most discriminatory methods; both gave nine distinct patterns, whereas there were eight IPs and only six PPs amongst the 13 strains. It was concluded that both WCPP and IP could provide valuable epidemiological data on MRSA and that IP was the easiest of the three methods to interpret.


A pilot study of the Video Observations Aarts and Aarts (VOAA): a new software program to measure motor behaviour in children with cerebral palsy.
A new computer software program to score video observations, Video Observations Aarts and Aarts (VOAA) was developed to evaluate paediatric occupational therapy interventions. The VOAA is an observation tool that assesses the frequency, duration and quality of arm/hand use in children, in particular those with cerebral palsy. Reliability studies show that the first module, designed to evaluate a forced-use programme, has an excellent content validity index (0.93) and good intra- and inter-observer reliability (Cohen's kappas ranging from 0.62 to 0.85 for the three activities tested). With the built-in statistical package, paediatric occupational therapy departments can conduct therapeutic evaluations with children with impairments in the upper extremities. Further research is recommended to apply the VOAA in clinical studies in paediatric occupational therapy.


Antidepressant-like effects and mechanisms of flavonoids and related analogues.
Flavonoids, possessing a basic phenylbenzopyrone core, are important components of the human diet, and are found in many medicinal plants. Flavonoids include chalcones, flavanones and their derivatives. Synthetic and natural isolated flavonoids display an enormous number of biological activities such as antitumor, antiplatelet, anti-malarial, anti-inflammatory, antidepressant and anticonvulsant properties. This review article focuses on the antidepressant-like effect, structure-activity relationship and mechanism of action of total flavonoid extracts isolation from natural sources, flavonoid compounds and their related analogues.


Clinical severity of Mycoplasma pneumoniae (MP) infection is associated with bacterial load in oropharyngeal secretions but not with MP genotype.
Disease severity in Mycoplasma pneumoniae (MP) infection could potentially be related to bacterial factors such as MP genotype (MP1 or MP2; distinguished by different adhesions proteins) or bacterial load in airway secretions. We have compared these parameters in patients who were hospitalized for MP pneumonia, with outpatients with mild MP disease. MP bacterial load was measured by real-time PCR in 45 in- and outpatients ("clinical study group") in whom MP DNA had been detected in oropharyngeal secretions by PCR. In addition, genotype and phylogenetic relationships were determined. The phylogenetical assessment was done by partial DNA sequencing of the P1 gene on isolates from 33 patients in the clinical study-group where sufficient DNA was available. The assessment was further extended to isolates from 13 MP-positive family members and 37 unselected MP positive patients from the two subsequent years and two different geographical locations. In total 83 strains were molecular characterized. Mean MP loads were significantly higher in 24 hospitalized patients than in 21 outpatients (1600 vs. 170 genomic equivalents/microL, p = 0.009). This difference remained significant after adjustment for age and days between disease onset and sampling. Hospitalized patients also had higher C-reactive protein levels. Mean levels were 188 vs 20 mg/L (p = 0,001). The genotype assessment showed MP genotype 1 in 17 of the 33 sequenced strains from the clinical study-group, and type 2 in 16 of these patients. Within each genotype, sequence differences were minimal. No association between disease severity and MP genotype was observed. In the extended genotype assessment, MP1 was found in similar proportions. In family contacts it was found in 53% and among patients from the two subsequent years 53% and 40%. A higher MP bacterial load in throat secretions at diagnosis was associated with more advanced respiratory disease in patients, but MP genotype did not influence disease severity. Both MP genotypes co-circulated during recent outbreaks in Sweden.


Discrimination, domestic violence, abuse, and other adverse life events in people with epilepsy: Population-based study to assess the burden of these events and their contribution to psychopathology.
To quantify the experience of discrimination, domestic violence, abuse, and other stressful life events in people with epilepsy in comparison with the general population and people with other chronic conditions. To assess whether any excess relative burden of these adversities could explain the higher rates of depression in people with epilepsy. The Adult Psychiatric Morbidity Survey 2007 used comprehensive interviews with 7,403 individuals living in private residences in England. Doctor-diagnosed epilepsy and other chronic conditions were established by self-report. Discrimination, domestic violence, physical and sexual abuse, and other stressful life events were assessed using computerized self-completion and a face-to-face interview, respectively. People with epilepsy were sevenfold more likely to have reported experiencing discrimination due to health problems (adjusted odds ratio [OR] 7.1; 95% confidence interval [CI] 3.1-16.3), than the general population without epilepsy. This estimate was substantially greater in people with epilepsy than for people with other chronic conditions. People with epilepsy also had greater odds of experiencing domestic violence and sexual abuse than the general population, although these associations were also found in people with other chronic conditions. There was less evidence of an association between epilepsy and a history of physical abuse or having a greater burden of other stressful life events. In exploratory analyses, assuming they lie on the causal pathway, discrimination, domestic violence, and sexual abuse explained 42.7% of the total effect of the relationship between epilepsy and depression or anxiety disorders. People with epilepsy can face a range of psychosocial adversities and extensively report feeling discriminated against as compared to the general population. In addition, if confirmed in longitudinal studies, the results suggest that these psychosocial adversities may have a significant role in the development of psychiatric comorbidity and may be targets for future interventions.


A phylogenetic estimate for golden moles (Mammalia, Afrotheria, Chrysochloridae).
Golden moles (Chrysochloridae) are small, subterranean, afrotherian mammals from South Africa and neighboring regions. Of the 21 species now recognized, some (e.g., Chrysochloris asiatica, Amblysomus hottentotus) are relatively common, whereas others (e.g., species of Chrysospalax, Cryptochloris, Neamblysomus) are rare and endangered. Here, we use a combined analysis of partial sequences of the nuclear GHR gene and morphological characters to derive a phylogeny of species in the family Chrysochloridae. Although not all nodes of the combined analysis have high support values, the overall pattern of relationships obtained from different methods of phylogeny reconstruction allow us to make several recommendations regarding the current taxonomy of golden moles. We elevate Huetia to generic status to include the species leucorhinus and confirm the use of the Linnean binomial Carpitalpa arendsi, which belongs within Amblysominae along with Amblysomus and Neamblysomus. A second group, Chrysochlorinae, includes Chrysochloris, Cryptochloris, Huetia, Eremitalpa, Chrysospalax, and Calcochloris. Bayesian methods make chrysochlorines paraphyletic by placing the root within them, coinciding with root positions favored by a majority of randomly-generated outgroup taxa. Maximum Parsimony (MP) places the root either between chrysochlorines and amblysomines (with Chlorotalpa as sister taxon to amblysomines), or at Chlorotalpa, with the former two groups reconstructed as monophyletic in all optimal MP trees. The inclusion of additional genetic loci for this clade is important to confirm our taxonomic results and resolve the chrysochlorid root. Nevertheless, our optimal topologies support a division of chrysochlorids into amblysomines and chrysochlorines, with Chlorotalpa intermediate between the two. Furthermore, evolution of the chrysochlorid malleus exhibits homoplasy. The elongate malleus has evolved just once in the Cryptochloris-Chrysochloris group; other changes in shape have occurred at multiple nodes, regardless of how the root is resolved.


Efficacy and safety of dendrimer nanoparticles with coexpression of tumor necrosis factor-α and herpes simplex virus thymidine kinase in gene radiotherapy of the human uveal melanoma OCM-1 cell line.
Human uveal melanoma is the most common primary intraocular tumor, and brachytherapy is one of the most common and effective treatment strategies. In order to find a safer and more effective way to increase the radio sensitivity of the tumor, we tried to use the dendrimer nanoparticle performing coexpression gene radiotherapy. In this study, we constructed recombinant DNA plasmids (early growth response-1 tumor necrosis factor-α [pEgr1-TNFα], pEgr1 thymidine kinase [TK], and pEgr1-TNFα-TK) according to the Egr1 promoter sequence. The sequences of human TNFα and herpes simplex virus (HSV) TK that were published by GenBank. Agarose gel electrophoresis and DNA sequencing had proven that we constructed the double-gene recombined plasmids pEgr1-TNF-TK correctly, as well as the plasmids pEgr1-TNFα and pEgr1-TK. The dendrimer nanoparticles combined with plasmid DNA as dendriplexes were verified with agarose gel electrophoresis and observed by transmission electron microscopy (TEM) and scanning electron microscopy to define size and shape. Zeta potential was measured using a Zetasizer analyzer. Optimal size and neutral zeta-potential characteristics of dendriplexes were achieved for the transfection studies. DNase I examination proved that the dendriplexes could protect plasmid DNA for at least 6 hours. The recombinant plasmids were transfected with dendrimer nanoparticles into the human choroidal melanoma OCM-1 cell line, followed by exposure to iodine-125 ((125)I) after transfection. After transfection with dendrimer nanoparticles and the irradiation of (125)I, the gene expressions of TNFα and HSV1-TK were significantly increased at the protein level by enzyme-linked immunosorbent assay and Western blot analysis in OCM-1 cells. The cellular morphology of OCM-1 cells altering was observed by TEM, and a decrease in cell proliferation was revealed in cell-growth curves. Flow cytometry of annexin V/propidium iodide double-dyeing apoptosis and caspase-3 fluorescence staining showed that this treatment method could turn transfected OCM-1 cells into apoptosis and necrosis by the effects of the gene expression. This study indicated that the dendrimer nanoparticles with coexpression of TNF-α and HSV1-TK gene therapy are effective and safe and can provide us with a novel strategy to treat human uveal melanoma in the future.


A technical comparison of evaluating asbestos concentration by phase-contrast microscopy (PCM), scanning electron microscopy (SEM), and analytical transmission electron microscopy (ATEM) as illustrated from data generated from a case report.
As reported in the literature, there are more than 30 different standard methods available for the analysis of asbestos in a variety of situations. The methods include those for determining asbestos concentration in air, water, bulk building materials, surface dust, soil, and lung tissue (Millette, 2006; Dodson, 2006). Knowledge of the various methodologies is essential in determining which methodology is appropriate for any given situation. To better understand the use of various techniques in evaluating asbestos, we use an example of an individual who was a machinist in an auto supply/parts business. His work activity during much of his professional career included grinding, arcing, and drilling brake components. Asbestos has been identified as an important component of friction products, particularly brakes, and exposure to asbestos brake dust is of concern, particularly in workers where grinding, arcing, sanding, and drilling of brake components are recognized as releasing appreciable dust. Various methods can be used to evaluate asbestos in tissue and air. The case reported herein was of an individual who died from a pleural mesothelioma. Paraffin-embedded lung tissue was examined by a laboratory using scanning electron microscopy (SEM) and was reported to contain elevated asbestos body concentrations and five fibers, of which two were asbestos (one chrysotile and one tremolite). Tissue from the same paraffin block was analyzed by the laboratory of one of us (RFD) using analytical transmission electron microscopy (ATEM). While one might think the number of asbestos bodies and fibers would be similar using SEM and ATEM, this was not the case. Slightly elevated numbers of ferruginous asbestos bodies were detected in the digestate by light microscopy. Large numbers of uncoated chrysotile fibers were found by ATEM, but not by SEM. The majority of the chrysotile structures were fibrils whose detection required resolution levels attainable only at higher magnification by ATEM. The findings in this case clearly indicate that analysis of lung tissue digestates by ATEM at a higher magnification (15,000x) identifies significant numbers of asbestos fibers that are not identified by SEM at 1000x. These results further indicate that if causation of an asbestos-induced disease such as mesothelioma is based on asbestos concentration of lung tissue, erroneous conclusions can be made by analyzing tissue only by SEM. Thus, the methodologies that are available to analyze asbestos in lung tissue are extensively discussed here with respect to the type of procedure that should be utilized in various situations.


The impact of basic motor abilities on the specific motoricity performance in elite karateka.
The aim of the study was to identify motor structures that determine high performance in karate. The study included a group of 85 karateka aged 18-29 years, competing as senior category athletes within the Croatian Karate Society. A battery of 22 motor tests (9 basic motoricity tests and 13 specific motoricity tests) were used. Factor analysis of the basic motor variables pointed to the existence of three significant factors: coordination, explosive strength and movement frequency; whereas factor analysis of the specific motoricity area indicated two significant factors, i.e., factor of technical efficiency and factor of specific agility. Canonical correlation analysis showed the isolated set of basic motor factors to significantly determine both technical efficiency and specific agility-mobility of the karateka, with a predominance of the explosive strength (force) factor, followed by the speed and coordination factors.


Predicting all-cause readmissions using electronic health record data from the entire hospitalization: Model development and comparison.
Incorporating clinical information from the full hospital course may improve prediction of 30-day readmissions. To develop an all-cause readmissions risk-prediction model incorporating electronic health record (EHR) data from the full hospital stay, and to compare "full-stay" model performance to a "first day" and 2 other validated models, LACE (includes Length of stay, Acute [nonelective] admission status, Charlson Comorbidity Index, and Emergency department visits in the past year), and HOSPITAL (includes Hemoglobin at discharge, discharge from Oncology service, Sodium level at discharge, Procedure during index hospitalization, Index hospitalization Type [nonelective], number of Admissions in the past year, and Length of stay). Observational cohort study. All medicine discharges between November 2009 and October 2010 from 6 hospitals in North Texas, including safety net, teaching, and nonteaching sites. Thirty-day nonelective readmissions were ascertained from 75 regional hospitals. Among 32,922 admissions (validation = 16,430), 12.7% were readmitted. In addition to many first-day factors, we identified hospital-acquired Clostridium difficile infection (adjusted odds ratio [AOR]: 2.03, 95% confidence interval [CI]: 1.18-3.48), vital sign instability on discharge (AOR: 1.25, 95% CI: 1.15-1.36), hyponatremia on discharge (AOR: 1.34, 95% CI: 1.18-1.51), and length of stay (AOR: 1.06, 95% CI: 1.04-1.07) as significant predictors. The full-stay model had better discrimination than other models though the improvement was modest (C statistic 0.69 vs 0.64-0.67). It was also modestly better in identifying patients at highest risk for readmission (likelihood ratio +2.4 vs. 1.8-2.1) and in reclassifying individuals (net reclassification index 0.02-0.06). Incorporating clinically granular EHR data from the full hospital stay modestly improves prediction of 30-day readmissions. Given limited improvement in prediction despite incorporation of data on hospital complications, clinical instabilities, and trajectory, our findings suggest that many factors influencing readmissions remain unaccounted for. Further improvements in readmission models will likely require accounting for psychosocial and behavioral factors not currently captured by EHRs. Journal of Hospital Medicine 2016;11:473-480. © 2016 Society of Hospital Medicine.


CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells.
Centrosome duplication and separation are linked inextricably to certain cell cycle events, in particular activation of cyclin-dependent kinases (CDKs). However, relatively few CDK targets driving these events have been uncovered. Here, we have performed a screen for CDK substrates and have isolated a target, CP110, which is phosphorylated by CDKs in vitro and in vivo. Human CP110 localizes to centrosomes. Its expression is strongly induced at the G1-to-S phase transition, coincident with the initiation of centrosome duplication. RNAi-mediated depletion of CP110 indicates that this protein plays an essential role in centrosome duplication. Long-term disruption of CP110 phosphorylation leads to unscheduled centrosome separation and overt polyploidy. Our data suggest that CP110 is a physiological centrosomal CDK target that promotes centrosome duplication, and its deregulation may contribute to genomic instability.


A new parameter in the detection of tuberculosis activity: reactive oxygen metabolites.
In countries with a high frequency of tuberculosis, there are problems not only with active lung tuberculosis but also with past lung tuberculosis. Cases with sequel tuberculosis very frequently present with complaints like tuberculosis, and it is very hard to determine whether it is a sequel tuberculosis complication or reactivation of tuberculosis. In this study, we measured the serum reactive oxygen metabolite (ROM) levels of patients with active pulmonary tuberculosis and healthy controls, and investigated if these metabolites can be used as a criterion for differentiation between active pulmonary tuberculosis and sequel pulmonary tuberculosis. 40 patients with active tuberculosis, 35 patients with sequel pulmonary tuberculosis and 30 healthy control subjects with a similar age range and sex distribution were included in the study. Serum total ROM levels were detected in the patients and control group. Mean serum ROM values were 994+/-236, 551+/-135 and 236+/-59 U/l among active lung tuberculosis cases, sequel lung tuberculosis cases and the healthy control group, respectively. As a result of these findings, serum ROM levels of active lung tuberculosis cases and sequel lung tuberculosis cases were significantly higher than those of the control group (both p<0.001). The serum ROM levels of active lung tuberculosis cases were also significantly higher than those of sequel lung tuberculosis cases (p<0.001). In the light of our findings, it may be assumed that serum total ROM values can be used as an activity criterion in the differentiation of active lung tuberculosis and sequel lung tuberculosis.


Activity of Ca -activated Cl channels contributes to regulating receptor- and store-operated Ca entry in human pulmonary artery smooth muscle cells.
Intracellular Ca(2+) plays a fundamental role in regulating cell functions in pulmonary arterial smooth muscle cells (PASMCs). A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. [Ca(2+)](cyt) is increased mainly by Ca(2+) release from intracellular stores and Ca(2+) influx through plasmalemmal Ca(2+)-permeable channels. Given the high concentration of intracellular Cl(-) in PASMCs, Ca(2+)-activated Cl(-)(Cl(Ca)) channels play an important role in regulating membrane potential and cell excitability of PASMCs. In this study, we examined whether activity of Cl(Ca) channels was involved in regulating [Ca(2+)](cyt) in human PASMCs via regulating receptor- (ROCE) and store- (SOCE) operated Ca(2+) entry. The data demonstrated that an angiotensin II (100 nM)-mediated increase in [Ca(2+)](cyt) via ROCE was markedly attenuated by the Cl(Ca) channel inhibitors, niflumic acid (100 μM), flufenamic acid (100 μM), and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (100 μM). The inhibition of Cl(Ca) channels by niflumic acid and flufenamic acid significantly reduced both transient and plateau phases of SOCE that was induced by passive depletion of Ca(2+) from the sarcoplasmic reticulum by 10 μM cyclopiazonic acid. In addition, ROCE and SOCE were abolished by SKF-96365 (50 μM) and 2-aminoethyl diphenylborinate (100 μM), and were slightly decreased in the presence of diltiazem (10 μM). The electrophysiological and immunocytochemical data indicate that Cl(Ca) currents were present and TMEM16A was functionally expressed in human PASMCs. The results from this study suggest that the function of Cl(Ca) channels, potentially formed by TMEM16A proteins, contributes to regulating [Ca(2+)](cyt) by affecting ROCE and SOCE in human PASMCs.


Central pattern generation of locomotion: a review of the evidence.
Neural networks in the spinal cord, referred to as "central pattern generators" (CPGs), are capable of producing rhythmic movements, such as swimming, walking, and hopping, even when isolated from the brain and sensory inputs. This article reviews the evidence for CPGs governing locomotion and addresses other factors, including supraspinal, sensory, and neuromodulatory influences, that interact with CPGs to shape the final motor output. Supraspinal inputs play a major role not only in initiating locomotion but also in adapting the locomotor pattern to environmental and motivational conditions. Sensory afferents involved in muscle and cutaneous reflexes have important regulatory functions in preserving balance and ensuring stable phase transitions in the locomotor cycle. Neuromodulators evoke changes in cellular and synaptic properties of CPG neurons, conferring flexibility to CPG circuits. Briefly addressed is the interaction of CPG networks to produce intersegmental coordination for locomotion. Evidence for CPGs in humans is reviewed, and although a comprehensive clinical review is not an objective, examples are provided of animal and human studies that apply knowledge of CPG mechanisms to improve locomotion. The final section deals with future directions in CPG research.


Fullerene-like MoSe2 nanoparticles-embedded CNT balls with excellent structural stability for highly reversible sodium-ion storage.
Three-dimensional (3D) porous-structured carbon nanotube (CNT) balls embedded with fullerene-like MoSe2 nanocrystals were successfully prepared by the spray pyrolysis process and subsequent selenization process. The MoO2-CNT composite balls prepared by spray pyrolysis transformed into the fullerene-like MoSe2/CNT (F-MoSe2/CNT) composite balls by the selenization process. The F-MoSe2/CNT composite balls exhibited superior sodium-ion storage properties to bare MoSe2 and MoSe2/CNT with a filled structure (N-MoSe2/CNT), both of which were prepared as comparison samples. The 250(th) discharge capacities of bare MoSe2, N-MoSe2/CNT composite balls, and F-MoSe2/CNT composite balls were 144, 200, and 296 mA h g(-1), respectively, at a high current density of 1.0 A g(-1), and their capacity retentions measured from the second cycle were 37%, 66%, and 83%, respectively. The 10(th) discharge capacities of the F-MoSe2/CNT composite balls were 382, 346, 310, 280, and 255 mA h g(-1) at current densities of 0.2, 0.5, 1.5, 3.0, and 5.0 A g(-1), respectively. The synergetic effect of the fullerene-like MoSe2 nanocrystals with ultrafine sizes and the CNT balls with a tangled and 3D porous structure and high electrical conductivity resulted in excellent sodium-ion storage properties of the F-MoSe2/CNT composite balls.


Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: An analysis from the EAACI AIT Guidelines Project.
Adequate quality is essential for any medicinal product to be eligible for marketing. Quality includes verification of the identity, content and purity of a medicinal product in combination with a specified production process and its control. Allergen products derived from natural sources require particular considerations to ensure adequate quality. Here, we describe key aspects of the documentation on manufacturing and quality aspects for allergen immunotherapy products in the European Union and the United States. In some key parts, requirements in these areas are harmonized while other fields are regulated separately between both regions. Essential differences are found in the use of Reference Preparations, or the requirement to apply standardized assays for potency determination. As the types of products available are different in specific regions, regulatory guidance for such products may also be available in one specific region only, such as for allergoids in the European Union. Region-specific issues and priorities are a result of this. As allergen products derived from natural sources are inherently variable in their qualitative and quantitative composition, these products present special challenges to balance the variability and ensuring batch-to-batch consistency. Advancements in scientific knowledge on specific allergens and their role in allergic disease will consequentially find representation in future regulatory guidelines.


Changes in Waist Circumference and the Incidence of Type 2 Diabetes in Community-Dwelling Men and Women: The Suita Study.
The association between weight gain and the incidence of type 2 diabetes is well known. The aim of our study was to investigate the relationship between change in waist circumference (WC) and type 2 diabetes incidence. The participants in the Suita Study, a population-based cohort study in an urban area of Japan, underwent a baseline survey between 1989 and 1994 (Exam 1) and were examined at follow-up every 2 years. We performed a 9.3-year cohort study of 946 men and 1327 women with no history of diabetes who underwent Exam 1 and Exam 2 (between 1997 and 1999). Participants were stratified by sex and median WC at Exam 1, and, in each stratum, participants were further classified into three categories by tertile of WC change per year between Exam 1 and Exam 2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for type 2 diabetes incidence were calculated by Cox proportional hazard models. The endpoints were first diagnosis of type 2 diabetes or March 2011. During follow-up, 287 participants developed type 2 diabetes. In both sexes with median WC or higher, participants in the highest tertile of WC change had a significantly higher risk of developing type 2 diabetes. Multivariable adjusted HRs were 1.84 (95% CI, 1.10-3.08) in men and 2.30 (95% CI, 1.31-4.04) in women. No significant association was observed among participants with WC below median. Preventing WC gain is important in preventing type 2 diabetes in the Japanese population, especially among individuals with a relatively high WC.


Zinc and heme iron intakes and risk of colorectal cancer: a population-based prospective cohort study in Japan.
Food sources and intakes of zinc and heme iron may differ between Western and Asian populations. However, all of the studies on the association between zinc and heme iron intakes and colorectal cancer have been conducted in Western populations. We investigated the association between zinc and heme iron intakes and colorectal cancer risk in a Japanese general population. We conducted a large, population-based prospective study in 39,721 men and 45,376 women aged 45-74 y. Heme iron and zinc intakes were measured by using a validated food-frequency questionnaire in either 1995 or 1998. During as many as 808,053 person-years of follow-up until the end of 2006, 1284 colorectal cancer cases were identified. In multivariate-adjusted models, zinc and heme iron intakes were not associated with colorectal cancer in either men or women. In comparison with the lowest quartile, the HRs (95% CIs) for developing colorectal cancer in the fourth quartile of zinc and heme iron intakes were 0.77 (0.58, 1.03; P-trend = 0.2) and 1.06 (0.79, 1.42; P-trend = 0.6), respectively, for men and 1.05 (0.77, 1.44; P-trend = 0.4) and 0.88 (0.61, 1.29; P-trend = 0.4), respectively, for women. Our results in a Japanese population with lower intakes and different major food sources of zinc and heme iron in comparison with those of Western populations suggest that zinc and heme iron intakes are not associated with colorectal cancer.


Identifying and managing adverse environmental health effects: 1. Taking an exposure history.
Public concern and awareness are growing about adverse health effects of exposure to environmental contaminants. Frequently patients present to their physicians with questions or concerns about exposures to such substances as lead, air pollutants and pesticides. Most primary care physicians lack training in and knowledge of the clinical recognition, management and avoidance of such exposures. We have found that it can be helpful to use the CH2OPD2 mnemonic (Community, Home, Hobbies, Occupation, Personal habits, Diet and Drugs) as a tool to identify a patient's history of exposures to potentially toxic environmental contaminants. In this article we discuss why it is important to take a patient's environmental exposure history, when and how to take the history, and how to interpret the findings. Possible routes of exposure and common sources of potentially toxic biological, physical and chemical substances are identified. A case of sick-building syndrome is used to illustrate the use of the mnemonic.


Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease.
Mutations in PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD). We produced a mouse model of ARPKD by replacing exons 1-3 of Pkhd1 with a lacZ reporter gene utilizing homologous recombination. This approach yielded heterozygous Pkhd1 (lacZ/+) mice, that expressed beta-galactosidase in tissues where Pkhd1 is normally expressed, and homozygous Pkhd1 (lacZ/lacZ) knockout mice. Heterozygous Pkhd1 (lacZ/+) mice expressed beta-galactosidase in the kidney, liver, and pancreas. Homozygous Pkhd1 (lacZ/lacZ) mice lacked Pkhd1 expression and developed progressive renal cystic disease involving the proximal tubules, collecting ducts, and glomeruli. In the liver, inactivation of Pkhd1 resulted in dilatation of the bile ducts and periportal fibrosis. Dilatation of pancreatic exocrine ducts was uniformly seen in Pkhd1 (lacZ/lacZ ) mice, with pancreatic cysts arising less frequently. The expression of beta-galactosidase, Pkd1, and Pkd2 was reduced in the kidneys of Pkhd1 (lacZ/lacZ ) mice compared with wild-type littermates, but no changes in blood urea nitrogen (BUN) or liver function tests were observed. Collectively, these results indicate that deletion of exons 1-3 leads to loss of Pkhd1 expression and results in kidney cysts, pancreatic cysts, and biliary ductal plate malformations. The Pkhd1 (lacZ/lacZ ) mouse represents a new orthologous animal model for studying the pathogenesis of kidney cysts and biliary dysgenesis that characterize human ARPKD.


Safety of tomatillos and products containing tomatillos canned by the water-bath canning method.
Three studies were conducted to evaluate the safety of tomatillos and products containing tomatillos canned by the water-bath processing method. In the first study, plain tomatillos were processed for 25, 37.5, 50 and 62.5 min. In the second study, five tomatillo/onion combinations were prepared while five tomatillo/green chile combinations were prepared in the third study. pH evaluations were conducted to determine safety in all studies using pH 4.2 as the cut-off value. No differences in the pH of plain tomatillos were detected due to processing time. All jars of plain tomatillos had pH values below 4.1. All combinations of tomatillos/onions and tomatillos/green chile containing more than 50% tomatillo had pH values below the 4.2 cut-off value. Results of the three studies indicate (1) acidification of plain tomatillos is probably unnecessary for canning by the water-bath processing method and (2) combinations of acidic tomatillos and low-acid onions or green chile must contain more than 50% tomatillos to have a pH low enough for safe water-bath processing.


Transferrin-polycation conjugates as carriers for DNA uptake into cells.
We have developed a high-efficiency nucleic acid delivery system that uses receptor-mediated endocytosis to carry DNA macromolecules into cells. We accomplished this by conjugating the iron-transport protein transferrin to polycations that bind nucleic acids. Human transferrin, as well as the chicken homologue conalbumin, has been covalently linked to the small DNA-binding protein protamine or to polylysines of various sizes through a disulfide linkage. These modified transferrin molecules maintain their ability to bind their cognate receptor and to mediate efficient iron transport into the cell. The transferrin-polycation molecules form electrophoretically stable complexes with double-stranded DNA, single-stranded DNA, and modified RNA molecules independent of nucleic acid size (from short oligonucleotides to DNA of 21 kilobase pairs). When complexes of transferrin-polycation and a bacterial plasmid DNA containing the gene for Photinus pyralis luciferase are supplied to eukaryotic cells, high-level expression of the luciferase gene occurs, demonstrating transferrin receptor-mediated endocytosis and expression of the imported DNA. We refer to this delivery system as "transferrinfection."


Increased intracellular cyclic adenosine monophosphate inhibits T lymphocyte-mediated cytolysis by two distinct mechanisms.
Cholera toxin (CT), but not pertussis toxin (PT), treatment of cloned murine CTL inhibited target cell lysis in a dose-dependent fashion. The effects of CT were mimicked by forskolin and cyclic adenosine monophosphate (cAMP) analogues. Inhibition of cytotoxicity by CT and cAMP analogs was mediated in part by attenuation of conjugate formation. Additionally, both CT and cAMP analogs blocked the increase in intracellular Ca2+ induced by stimulation of the TCR complex by mAbs. These findings indicate that cAMP inhibits the activity of CTL by two distinct mechanisms and suggests a role for this second messenger in CTL-mediated cytolysis.


Class II phosphoinositide 3-kinases contribute to endothelial cells morphogenesis.
The question of whether the distinct isoforms of the family of enzymes phosphoinositide 3-kinases (PI3Ks) play redundant roles within a cell or whether they control distinct cellular processes or distinct steps within the same cellular process has gained considerable importance in the recent years due to the development of inhibitors able to selectively target individual isoforms. It is important to understand whether inhibition of one PI3K can result in compensatory effect from other isoform(s) and therefore whether strategies aimed at simultaneously blocking more than one PI3K may be needed. In this study we investigated the relative contribution of distinct PI3K isoforms to endothelial cells (EC) functions specifically regulated by the sphingolipid sphingosine-1-phosphate (S1P) and by high density lipoproteins (HDL), the major carrier of S1P in human plasma. Here we show that a co-ordinated action of different PI3Ks is required to tightly regulate remodelling of EC on Matrigel, a process dependent on cell proliferation, apoptosis and migration. The contribution of each isoform to this process appears to be distinct, with the class II enzyme PI3K-C2β and the class IB isoform p110γ mainly regulating the S1P- and HDL-dependent EC migration and PI3K-C2α primarily controlling EC survival. Data further indicate that PI3K-C2β and p110γ control distinct steps involved in cell migration supporting the hypothesis that different PI3Ks regulate distinct cellular processes.


Mutational analysis of the autoinhibitory domain of calmodulin kinase II.
Calmodulin (CaM)-kinase II is inactive in the absence of Ca2+/CaM due to interaction of its autoinhibitory domain with its catalytic domain. Previous studies using synthetic autoinhibitory domain peptides (residues 281-302) identified several residues as important for inhibitory potency and suggested that His282 may interact with the ATP-binding motif of the catalytic domain. To further examine the autoinhibitory domain, site-specific mutants were expressed using the baculovirus/Sf9 cell system. The purified mutants had many biochemical properties identical to wild-type kinase, but mutants H282Q, H282R, R283E, and T286D had 10-20% constitutive Ca(2+)-independent activities, indicating that these residues are involved in the autoinhibitory interaction. The Ca(2+)-independent activities of the H282Q, H282R, and R283E mutants exhibited 10-fold lower Km values for ATP than the wild-type kinase. Wild-type and mutant kinases, except T286A and T286D, generated Ca2+ independence upon autophosphorylation in the presence of Ca2+/CaM, and those mutants having constitutive Ca2+ independence also exhibited enhanced Ca2+/CaM-independent autophosphorylation. This Ca(2+)-independent autophosphorylation resulted in a decrease in total kinase activity, but there was little increase in Ca(2+)-independent activity, consistent with autophosphorylation of predominantly Thr306 rather than Thr286. These results are consistent with an inhibitory interaction of His282 and possibly Arg283 with the ATP-binding motif of the catalytic domain, and they indicate that constitutively active CaM-kinase II cannot autophosphorylate on Thr286 in the absence of bound Ca2+/CaM. Based on these and other biochemical characterizations, we propose a molecular model for the interaction of a bisubstrate autoinhibitory domain with the catalytic domain of CaM-kinase II.


Thiourea-based fluorescent chemosensors for aqueous metal ion detection and cellular imaging.
We describe three significant advances in the use of thioureas as reporting elements for metal-responsive fluorescent chemosensors. First, on the basis of the crystal structure of a chemosensor analogue, we provide a deeper understanding of the details of the thiourea coordination environment. Second, we describe a new generation of chemosensors with higher affinities for Zn(2+) and Cd(2+) than were observed for earlier probes, expanding the scope of this type of probe beyond Hg(2+) detection. Third, we show that a thiourea-based chemosensor can be employed for fluorescence microscopy imaging of Hg(2+) ion concentrations in living mammalian cells.


Analogy of strain energy density based bone-remodeling algorithm and structural topology optimization.
In bone-remodeling studies, it is believed that the morphology of bone is affected by its internal mechanical loads. From the 1970s, high computing power enabled quantitative studies in the simulation of bone remodeling or bone adaptation. Among them, Huiskes et al. (1987, "Adaptive Bone Remodeling Theory Applied to Prosthetic Design Analysis," J. Biomech. Eng., 20, pp. 1135-1150) proposed a strain energy density based approach to bone remodeling and used the apparent density for the characterization of internal bone morphology. The fundamental idea was that bone density would increase when strain (or strain energy density) is higher than a certain value and bone resorption would occur when the strain (or strain energy density) quantities are lower than the threshold. Several advanced algorithms were developed based on these studies in an attempt to more accurately simulate physiological bone-remodeling processes. As another approach, topology optimization originally devised in structural optimization has been also used in the computational simulation of the bone-remodeling process. The topology optimization method systematically and iteratively distributes material in a design domain, determining an optimal structure that minimizes an objective function. In this paper, we compared two seemingly different approaches in different fields-the strain energy density based bone-remodeling algorithm (biomechanical approach) and the compliance based structural topology optimization method (mechanical approach)-in terms of mathematical formulations, numerical difficulties, and behavior of their numerical solutions. Two numerical case studies were conducted to demonstrate their similarity and difference, and then the solution convergences were discussed quantitatively.


Hologram formation with red light in methylene blue sensitized dichromated gelatin.
The spectral sensitization of hardened dichromated gelatin to red light is carried out using methylene blue as sensitizer. The sensitized dichromated gelatin plate can be stored for over 1 month in an ammonia atmosphere without loss of photosensitivity. Holograms recorded in the sensitized dichromated gelatin using a He-Ne laser have high diffraction efficiency and low noise if they are swelled at a temperature near the gelatin gel melting point during development processing. Maximum diffraction efficiency has been found to be as high as 88%. The energy required to obtain 80% diffraction efficiency is 150-400 mJ/cm(2).


Homologous sugar transport proteins in Escherichia coli and their relatives in both prokaryotes and eukaryotes.
Separate proteins for proton-linked transport of D-xylose, L-arabinose, D-galactose, L-rhamnose and L-fucose into Escherichia coli are being studied. By cloning and sequencing the appropriate genes, the amino acid sequences of proteins for D-xylose/H+ symport (XylE), L-arabinose/H+ symport (AraE), and part of the protein for D-galactose/H+ symport (GalP) have been determined. These are homologous, with at least 28% identical amino acid residues conserved in the aligned sequences, although their primary sequences are not similar to those of other E. coli transport proteins for lactose, melibiose, or D-glucose. However, they are equally homologous to the passive D-glucose transport proteins from yeast, rat brain, rat adipocytes, human erythrocytes, human liver, and a human hepatoma cell line. The substrate specificity of GalP from E. coli is similar to that of the mammalian glucose transporters. Furthermore, the activities of GalP, AraE and the mammalian glucose transporters are all inhibited by cytochalasin B and N-ethylmaleimide. Conserved residues in the aligned sequences of the bacterial and mammalian transporters are identified, and the possible roles of some in sugar binding, cation binding, cytochalasin binding, and reaction with N-ethylmaleimide are discussed. Each protein is independently predicted to form 12 hydrophobic, membrane-spanning alpha-helices with a central hydrophilic segment, also comprised of alpha-helix. This unifying structural model of the sugar transporters shares features with other ion-linked transport proteins for citrate or tetracycline.


Effect of liposome-encapsulated hemoglobin on antigen-presenting cells in mice.
Liposome-encapsulated hemoglobin (LEH) is removed from the circulation and degraded in the reticuloendothelial system, including dendritic cells (DCs) and macrophages. Therefore, LEH at a large dose may overload the system, cause a competitive inhibition in antigen-presenting activity, and impair the immune response of the host. Changes in cellularity of immunocompetent cells were monitored serially up to 4 weeks by flow cytometry in wild-type mice receiving 20 mL/kg of LEH, syngeneic red blood cells (RBCs), or saline. DCs were collected from the host spleen 1, 7, and 28 days after receiving the solution and were cocultured with naïve cluster of differentiation 4 T cells from T-cell receptor transgenic mice in the absence or presence of third-party antigens. After LEH administration, the cellularity of DCs and macrophages in the recipient spleen remained unchanged from control mice receiving RBCs or saline. While subset populations and costimulatory molecule expressions were different, DCs from LEH-administered mice expressed high levels of interleukin-2 production and helper T-cell activation in response to a third-party antigen and superantigens, as did the DCs from control mice receiving RBCs or saline. The results suggest that 20 mL/kg of LEH does not greatly alter antigen-presenting activity to third-party antigens.


Ultraspecific and highly sensitive nucleic acid detection by integrating a DNA catalytic network with a label-free microcavity.
Nucleic acid detection with label-free biosensors circumvents costly fluorophore functionalization steps associated with conventional assays by utilizing transducers of impressive ultimate detection limits. Despite this technological prowess, molecular recognition at a surface limits the biosensors' sensitivity, specificity, and reusability. It is therefore imperative to integrate novel molecular approaches with existing label-free transducers to overcome those limitations. Here, we demonstrate this concept by integrating a DNA strand displacement circuit with a micron-scale whispering gallery mode (WGM) microsphere biosensor. The integrated biosensor exhibits at least 25-fold improved nucleic acid sensitivity, and sets a new record for label-free microcavity biosensors by detecting 80 pM (32 fmol) of a 22nt oligomer; this improvement results from the catalytic behavior of the circuit. Furthermore, the integrated sensor exhibits extremely high specificity; single nucleotide variants yield 40- to 100-fold lower signal. Finally, the same physical sensor was demonstrated to alternatingly detect 2 different nucleic acid sequences through 5 cycles of detection, showcasing both its reusability and its versatility.


Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease.
Monoclonal antibodies (mAbs) inhibiting cytokines have recently emerged as new drug modalities for the treatment of chronic inflammatory diseases. Interleukin-17 (IL-17) is a T-cell-derived central mediator of autoimmunity. Immunization with Qβ-IL-17, a virus-like particle based vaccine, has been shown to produce autoantibodies in mice and was effective in ameliorating disease symptoms in animal models of autoimmunity. To characterize autoantibodies induced by vaccination at the molecular level, we generated mouse mAbs specific for IL-17 and compared them to germline Ig sequences. The variable regions of a selected hypermutated high-affinity anti-IL-17 antibody differed in only three amino acid residues compared to the likely germline progenitor. An antibody, which was backmutated to germline, maintained a surprisingly high affinity (0.5 nM). The ability of the parental hypermutated antibody and the derived germline antibody to block inflammation was subsequently tested in murine models of multiple sclerosis (experimental autoimmune encephalomyelitis), arthritis (collagen-induced arthritis), and psoriasis (imiquimod-induced skin inflammation). Both antibodies were able to delay disease onset and significantly reduced disease severity. Thus, the mouse genome unexpectedly encodes for antibodies with the ability to functionally neutralize IL-17 in vivo.


[Seroprevalence of the infection and risk factors of hepatitis B and C in healthy military personnel].
Determine the prevalence of infections by the hepatitis B (HBV) and C (HCV) viruses and the risk factors associated with their acquisition in clinically healthy military personnel. Correlational and analytic transversal study. The population was made up of active, clinically healthy military personnel from the Peruvian Air Force that volunteered for a screening program between October and December 2007. The HBsAg and anti-HBc markers of HBV and the anti-HCV marker of HVC were evaluated. Of the 3,343 military personnel studied, 93.2% (3,116) were male and 6.8% (227) were female, with an average age of 38.9+/-8.6 years (range: 18 to 60 years old), mostly non-commissioned officers (79.5%). An HBsAg prevalence of 0.33% was found, with an anti-HBc prevalence of 0.58%, while the prevalence of anti-HCV was 0.21%. The risk factor associated with active infection by HBV (HBsAG) was risky sexual behavior (OR: 8.3; IC 95%:1.6-42.4 and p=0.01). On the hand, for the past infection by HBV (anti-HBc), the associated risk factors were risky sexual behavior (OR: 6.3; IC 95%:1.7-23.4 and p=0.006) and tattoos (OR: 5.5; IC 95%:1.2-25.8 and p=0.031). No association was found between the risk factors studied and seropositivity by HCV. We found a low prevalence of the serological markers of infection by hepatitis B and C viruses in active military personnel. The risk factors associated with infection by HBV were risky sexual conduct and the use of tattoos. There was no risk factor found to be associated with infection by HCV in this population.