The impact of informal cancer caregiving: A literature review on psychophysiological studies.
Caregiving can be experienced as a stressful process, which can cause psychological and physical consequences. The combination of prolonged stress and the physical demands of caregiving may impair the physiological functioning of caregivers and increase the risk of health problems creating considerable stress in the life of caregivers regarding emotional, physical, social and financial areas. This literature review explored studies that used measures of the autonomic nervous system in caregivers of oncology patients such as electrodermal and cardiovascular (re)activity. The results revealed that caregivers had elevated stress levels and a serious autonomic imbalance that may, in the long term, trigger negative health consequences such as infectious diseases, cancer progression, cardiovascular disease and even premature death. The results showed the need to carry out preventive strategies in this population, in order to improve the autonomic profile of caregivers of cancer patients.


A framework for discrete stochastic simulation on 3D moving boundary domains.
We have developed a method for modeling spatial stochastic biochemical reactions in complex, three-dimensional, and time-dependent domains using the reaction-diffusion master equation formalism. In particular, we look to address the fully coupled problems that arise in systems biology where the shape and mechanical properties of a cell are determined by the state of the biochemistry and vice versa. To validate our method and characterize the error involved, we compare our results for a carefully constructed test problem to those of a microscale implementation. We demonstrate the effectiveness of our method by simulating a model of polarization and shmoo formation during the mating of yeast. The method is generally applicable to problems in systems biology where biochemistry and mechanics are coupled, and spatial stochastic effects are critical.


Fructose 2,6-bisphosphate in Dictyostelium discoideum. Independence of cyclic AMP production and inhibition of fructose-1,6-bisphosphatase.
The occurrence of fructose 2,6-bisphosphate was detected in Dictyostelium discoideum. The levels of this compound were compared with those of cyclic AMP and several glycolytic intermediates during the early stages of development. Removal of the growth medium and resuspension of the organism in the differentiation medium decreased the content of fructose 2,6-bisphosphate to about 20% within 1 h, remaining low when starvation-induced development was followed for 8 h. The content of cyclic AMP exhibited a transient increase that did not correlate with the change in fructose 2,6-bisphosphate. If after 1 h of development 2% glucose was added to the differentiation medium, fructose 2,6-bisphosphate rapidly rose to similar levels to those found in the vegetative state, while the increase in cyclic AMP was prevented. The contents of hexose 6-phosphates, fructose 1,6-bisphosphate and triose phosphates changed in a way that was parallel to that of fructose 2,6-bisphosphate, and addition of sugar resulted in a large increase in the levels of these metabolites. The content of fructose 2,6-bisphosphate was not significantly modified by the addition of the 8-bromo or dibutyryl derivatives of cyclic AMP to the differentiation medium. These results provide evidence that the changes in fructose 2,6-bisphosphate levels in D. discoideum development are not related to a cyclic-AMP-dependent mechanism but to the availability of substrate. Fructose 2,6-bisphosphate was found to inhibit fructose-1,6-bisphosphatase activity of this organism at nanomolar concentrations, while it does not affect the activity of phosphofructokinase in the micromolar range. The possible physiological implications of these phenomena are discussed.


From research to practice: challenges to implementing national diabetes guidelines with five community health centers on the U.S.-Mexico border.
Given the dramatic increase in type 2 diabetes in the United States, the development of effective strategies to prevent and control this potentially devastating illness is more important than ever. In the Southwest, diabetes is a far too common and rapidly growing problem among Mexican Americans living near the U.S.-Mexico border. A project designed to address this problem enabled faculty from the University of Arizona to work with community health centers to evaluate and improve diabetes care in border communities. This project was a component of the Border Health Strategic Initiative (Border Health iSI!) and Racial and Ethnic Approaches to Community Health 2010 (REACH 2010), both funded by the Centers for Disease Control and Prevention. University of Arizona faculty worked in partnership with five community health centers funded by the Health Resources and Services Administration. The goal of the faculty was to assist the community health centers with 1) development of measures of diabetes care based on national clinical practice guidelines, 2) identification of gaps in care based on those measures, and 3) implementation of strategies for closing those gaps. All five centers prioritized their top four or five indicators of diabetes care (e.g., annual dilated eye examination). Different community health centers selected different indicators. Baseline medical record audits were performed using the chosen indicators. Individual results were shared confidentially with providers; overall center results were shared and discussed with providers and staff. Each clinic chose its own strategies for closing gaps in care. At one-year follow-up, there was evidence of improvement for the majority of indicators in all community health centers. However, some gaps remained. Of the three community health centers having a second-year evaluation, two maintained or increased the improvements made, but one lost ground. Our experience with these five border clinics was that translating guidelines into practice is easier said than done. Factors that favored success included an onsite champion, staff buy-in, a willingness to see systems change, and the availability of additional resources, particularly for chart reviews.


Is meniscal allograft transplantation chondroprotective? A systematic review of radiological outcomes.
The primary aim of this systematic review was to examine the hypothesis that meniscal allograft transplantation is chondroprotective by identifying and appraising studies that have assessed the progression of osteoarthritis following meniscal allograft transplantation. The secondary aim was to identify and appraise radiological measures of meniscal allograft integrity following surgery. Clinical studies on human participants undergoing meniscal allograft transplantation with a minimum follow-up of 6 months were included. The primary outcome measure was any radiological osteoarthritis progression measure. Secondary outcomes included magnetic resonance measures of meniscal integrity including meniscal size, shape, healing, extrusion and signal intensity. Thirty-eight studies with 1056 allografts were included. The weighted mean joint space loss was 0.032 mm at 4.5 years across 11 studies. Other radiological classification systems were reported in small numbers and with variable progression rates. Meniscal extrusion was present in nearly all cases, but was not associated with clinical or other radiological outcomes. Meniscal healing rates were high, although the size, shape and signal intensity were commonly altered from that of the native meniscus. The quality of the included studies was low, with a high risk of bias. There is some evidence to support the hypothesis that meniscal allograft transplantation reduces the progression of osteoarthritis, although it is unlikely to be as effective as the native meniscus. If this is proven, there may be a role for prophylactic meniscal allograft transplantation in selected patients. Well-designed randomised controlled trials are needed to further test this hypothesis. Systematic review of studies, Level IV.


Implementing an operating room pharmacy satellite.
Implementation of an operating room (OR) pharmacy satellite is described, and its impact on cost-effectiveness and efficiency of drug distribution is analyzed. The OR satellite provided pharmacy coverage for 30-35 patients per day in 10 centralized surgical suites, 2 obstetric suites, and 1 burn-unit suite in a 401-bed teaching hospital. Objectives of the satellite were to consolidate accountability for drug distribution and control, reduce controlled substance loss and waste, reduce inventory costs, and improve recording of patient charges. Stock on the OR supply cart was reduced, controlled substances were dispensed to anesthesiologists from the satellite, and a system of standardized anesthesiology exchange trays was developed. A new billing form served as both the charging document and replacement list. Reduction in the medication cart stock resulted in smaller discrepancies in patient charges. For the five most commonly used controlled substances, accounting discrepancies were reduced. Inventory turnover increased and inventory dollar value and cost per patient were reduced. The percent of nurses who believed that a pharmacist should work in the area increased from 31% before implementation of the satellite to 95% after. The pilot OR pharmacy satellite was a financial success. Efficiency and effectiveness in drug distribution and control were improved, and communication between pharmacists and other medical personnel working in the OR areas was enhanced.


Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action.
The antiapoptotic protein PED/PEA-15 features an Akt phosphorylation motif upstream from Ser(116). In vitro, recombinant PED/PEA-15 was phosphorylated by Akt with a stoichiometry close to 1. Based on Western blotting with specific phospho-Ser(116) PED/PEA-15 antibodies, Akt phosphorylation of PED/PEA-15 occurred mainly at Ser(116). In addition, a mutant of PED/PEA-15 featuring the substitution of Ser(116)-->Gly (PED(S116-->G)) showed 10-fold-decreased phosphorylation by Akt. In intact 293 cells, Akt also induced phosphorylation of PED/PEA-15 at Ser(116). Based on pull-down and coprecipitation assays, PED/PEA-15 specifically bound Akt, independently of Akt activity. Serum activation of Akt as well as BAD phosphorylation by Akt showed no difference in 293 cells transfected with PED/PEA-15 and in untransfected cells (which express no endogenous PED/PEA-15). However, the antiapoptotic action of PED/PEA-15 was almost twofold reduced in PED(S116-->G) compared to that in PED/PEA-15(WT) cells. PED/PEA-15 stability closely paralleled Akt activation by serum in 293 cells. In these cells, the nonphosphorylatable PED(S116-->G) mutant exhibited a degradation rate threefold greater than that observed with wild-type PED/PEA-15. In the U373MG glioma cells, blocking Akt also reduced PED/PEA-15 levels and induced sensitivity to tumor necrosis factor-related apoptosis-inducing ligand apoptosis. Thus, phosphorylation by Akt regulates the antiapoptotic function of PED/PEA-15 at least in part by controlling the stability of PED/PEA-15. In part, Akt survival signaling may be mediated by PED/PEA-15.


Oct4 links multiple epigenetic pathways to the pluripotency network.
Oct4 is a well-known transcription factor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cell reprogramming. However, limited information is available on Oct4-associated protein complexes and their intrinsic protein-protein interactions that dictate Oct4's critical regulatory activities. Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners important for self-renewal and pluripotency of mESCs. Notably, we found that Oct4 is associated with multiple chromatin-modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming. Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor-based reprogramming strategies.


[Evaluation of scientific quality using citation analysis and other bibliometric methods].
Bibliometric methods for scientific evaluation are examined. The citation frequency for scientific publications, as given in the Science Citation Index, is influenced by various forms of citation bias as well as by the characteristic dynamics and citation practices of the various scientific fields, and therefore cannot be taken as an unequivocal measure of scientific quality. Even for single authors the citation frequency is very variable; therefore this parameter should not be used for graded evaluation of individual scientists or research groups. At higher aggregate levels (large institutes etc) bibliometric indicators may, as part of a more general evaluation, give relevant information about research activity, provided due corrections are made for variable research field effects. The journal impact factor, i e the mean citation frequency of all articles in a journal, has been suggested as a rapid indicator of article quality. However, the distribution of citation frequency values within a journal is extremely broad and skewed; therefore assigning the same value to all articles would not seem to serve the purpose of evaluation particularly well. Furthermore the citation frequencies of articles published by individual authors or research groups are found to correlate extremely poorly with the corresponding journal impact factors. The latter parameter would thus appear to be unsuitable as an indicator of scientific quality.


What role do Death Doulas play in end-of-life care? A systematic review.
Current health and social care systems do not always meet the needs of the dying in our communities. As a result, patients and families are choosing to place their trust in those who can advocate for them or fill the gaps in care. Birth Doulas have been working with women during pregnancy and after birth for many years, and we are now seeing a new role, that of a Death Doula emerging in the end-of-life care space. How Death Doulas work within health and social care systems is not understood and we conducted a systematic review to explore the published literature to explore the role and potential implications for models of care delivery. Following the PRISMA recommendations, we searched the literature in January 2018 via bibliographic databases and the grey literature without search date parameters to capture all published literature. We looked for articles that describe the role/work of a death doula or a death midwife in the context of end-of-life care, or death and dying. Our search retrieved 162 unique records of which five papers were included. We analysed the papers in relation to relationship to health service, funding source, number and demand for services, training, licensing and ongoing support, and tasks undertaken. Death Doulas are working with people at the end of life in varied roles that are still little understood, and can be described as similar to that of "an eldest daughter" or to a role that has similarities to specialist palliative care nurses. Death doulas may represent a new direction for personalised care directly controlled by the dying person, an adjunct to existing services, or an unregulated form of care provision without governing oversight.


Multivesicular bodies in the enigmatic amoeboflagellate Breviata anathema and the evolution of ESCRT 0.
Endosomal sorting complexes required for transport (ESCRTs) are heteromeric protein complexes required for multivesicular body (MVB) morphogenesis. ESCRTs I, II, III and III-associated are ubiquitous in eukaryotes and presumably ancient in origin. ESCRT 0 recruits cargo to the MVB and appears to be opisthokont-specific, bringing into question aspects of the current model of ESCRT mechanism. One caveat to the restricted distribution of ESCRT 0 was the previous limited availability of amoebozoan genomes, the supergroup closest to opisthokonts. Here, we significantly expand the sampling of ESCRTs in Amoebozoa. Our electron micrographic and bioinformatics evidence confirm the presence of MVBs in the amoeboflagellate Breviata anathema. Searches of genomic databases of amoebozoans confirm the ubiquitous nature of ESCRTs I-III-associated and the restriction of ESCRT 0 to opisthokonts. Recently, an alternate ESCRT 0 complex, centering on Tom1 proteins, has been proposed. We determine the distribution of Tom1 family proteins across eukaryotes and show that the Tom1, Tom1L1 and Tom1L2 proteins are a vertebrate-specific expansion of the single Tom1 family ancestor, which has indeed been identified in at least one member of each of the major eukaryotic supergroups. This implies a more widely conserved and ancient role for the Tom1 family in endocytosis than previously suspected.


Fixed-dose telmisartan/hydrochlorothiazide in comparison with losartan/hydrochlorothiazide in decreasing serum hepatocyte growth factor and improving endothelial dysfunction in hypertensive patients.
Combined treatment with an angiotensin II receptor blocker and hydrochlorothiazide (HCT) is advocated to control hypertension (HT). Hepatocyte growth factor (HGF) may be a new marker to evaluate endothelial dysfunction (ED), which is a potential target in treating HT. The aim of the present study was to compare the effects of Telmisartan/HCT with Losartan/HCT on serum HGF and ED in hypertensive patients. Hypertensive patients were randomly divided into a Telmisartan/HCT (group T) or Losartan/HCT group (group L) and received one tablet of either drug per day for 8 weeks. Serum HGF, nitric oxide (NO), plasma von Willebrand factor (vWF), and endothelin (ET) were measured before treatment and after 8 weeks of treatment. Twenty healthy subjects were selected as controls (control group). HGF, vWF, ET, and the ET/NO ratio were higher, and NO was lower in hypertensive patients than those in the control group (all P < 0.01). After treatment for 8 weeks, HGF, vWF and ET decreased, and NO increased significantly in both groups (all P < 0.01). The reductions in BP and HGF and increase in NO (DeltaNO) were not significantly different between the two groups (all P > 0.05), but the reductions in vWF and ET (DeltaET) and DeltaET/DeltaNO ratio were more obvious in group T than in group L (all P < 0.01). There was no significant correlation between the changes in most of the measured parameters and the extent of BP reduction in either group. Both Telmisartan/HCT and Losartan/HCT could decrease serum HGF and improve ED, which was independent of the antihypertensive effects. However, the improvement in ED may be superior with Telmisartan/HCT than Losartan/HCT when the BP-lowering effects are the same.


Message passing theory for percolation models on multiplex networks with link overlap.
Multiplex networks describe a large variety of complex systems, including infrastructures, transportation networks, and biological systems. Most of these networks feature a significant link overlap. It is therefore of particular importance to characterize the mutually connected giant component in these networks. Here we provide a message passing theory for characterizing the percolation transition in multiplex networks with link overlap and an arbitrary number of layers M. Specifically we propose and compare two message passing algorithms that generalize the algorithm widely used to study the percolation transition in multiplex networks without link overlap. The first algorithm describes a directed percolation transition and admits an epidemic spreading interpretation. The second algorithm describes the emergence of the mutually connected giant component, that is the percolation transition, but does not preserve the epidemic spreading interpretation. We obtain the phase diagrams for the percolation and directed percolation transition in simple representative cases. We demonstrate that for the same multiplex network structure, in which the directed percolation transition has nontrivial tricritical points, the percolation transition has a discontinuous phase transition, with the exception of the trivial case in which all the layers completely overlap.


Fast and robust generation of feature maps for region-based visual attention.
Visual attention is one of the important phenomena in biological vision which can be followed to achieve more efficiency, intelligence, and robustness in artificial vision systems. This paper investigates a region-based approach that performs pixel clustering prior to the processes of attention in contrast to late clustering as done by contemporary methods. The foundation steps of feature map construction for the region-based attention model are proposed here. The color contrast map is generated based upon the extended findings from the color theory, the symmetry map is constructed using a novel scanning-based method, and a new algorithm is proposed to compute a size contrast map as a formal feature channel. Eccentricity and orientation are computed using the moments of obtained regions and then saliency is evaluated using the rarity criteria. The efficient design of the proposed algorithms allows incorporating five feature channels while maintaining a processing rate of multiple frames per second. Another salient advantage over the existing techniques is the reusability of the salient regions in the high-level machine vision procedures due to preservation of their shapes and precise locations. The results indicate that the proposed model has the potential to efficiently integrate the phenomenon of attention into the main stream of machine vision and systems with restricted computing resources such as mobile robots can benefit from its advantages.


Functional Decoupling of Emotion Coping Network Subsides Automatic Emotion Regulation by Implementation Intention.
Automatic emotion regulation (AER) plays a vital role in the neuropathology underlying both suicide and self-harm via modifying emotional impact effortlessly. However, both the effortless account and the neural mechanisms of AER are undetermined. To investigate the neural changes at AER, we collected functional MRI (fMRI) in 31 participants who attended to neutral and disgust pictures in three conditions: watching, goal intention (GI), and reappraisal by implementation intention (RII). Results showed that RII (but not GI) decreased negative feelings and bilateral amygdala activity without increasing cognitive efforts, evidenced by the reduced effort rating and less prefrontal engagement during RII compared with during watching and GI. These emotion-regulatory effects of RII cannot be explained by emotional habituation, as the supplementary experiment (N = 31) showed no emotional habituation effects when the same disgust pictures were presented repeatedly three times for each watching and GI condition. Task-based network analysis showed both RII and GI relative to watching increased functional connectivities (FCs) of the ventral anterior cingulate cortex to the left insula and right precuneus during conditions, two FCs subserving goal setup. However, RII relative to GI exhibited weaker FCs in brain networks subserving effortful control, memory retrieval, aversive anticipation, and motor planning. In these FCs, the FC intensity of putamen-operculum/lingual and paracentral-superior temporal gyri positively predicted regulatory difficulty ratings. These findings suggest that the setup of implementation intention automatizes emotion regulation by reducing the online mobilization of emotion-coping neural systems.


Cognitive functioning in young children with type 1 diabetes.
The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time.


Renal transplantation in patients with carcinoma.
Four patients in terminal renal failure who had various malignant tumours were treated by haemodialysis and cadaveric renal transplantation. One patient with a testicular seminoma and one with leiomyosarcomatous changes in polycystic kidneys were successfully grafted after removal of the tumours and both were healthy at three and two-and-a-half years afterwards without evidence of recurrence of tumour.One patient with an invasive carcinoma of the renal pelvis was successfully transplanted and remained well for eight months but rapidly deteriorated and died of extensive metastases. Another patient with a malignant melanoma died more than one year after unsuccessful grafting.The presence of concomitant malignant disease in patients with chronic renal failure need not necessarily exclude them from the chance of long-term treatment, including renal transplantation. Each patient should be considered individually from the point of view of the nature of the malignancy, its duration, and treatment.


Catastrophic health expenditure and rural household impoverishment in China: what role does the new cooperative health insurance scheme play?
To determine whether the New Cooperative Medical Insurance Scheme (NCMS) is associated with decreased levels of catastrophic health expenditure and reduced impoverishment due to medical expenses in rural households of China. An analysis of a national representative sample of 38,945 rural households (129,635 people) from the 2008 National Health Service Survey was performed. Logistic regression models used binary indicator of catastrophic health expenditure as dependent variable, with household consumption, demographic characteristics, health insurance schemes, and chronic illness as independent variables. Higher percentage of households experiencing catastrophic health expenditure and medical impoverishment correlates to increased health care need. While the higher socio-economic status households had similar levels of catastrophic health expenditure as compared with the lowest. Households covered by the NCMS had similar levels of catastrophic health expenditure and medical impoverishment as those without health insurance. Despite over 95% of coverage, the NCMS has failed to prevent catastrophic health expenditure and medical impoverishment. An upgrade of benefit packages is needed, and effective cost control mechanisms on the provider side needs to be considered.


Evolutionary dynamics of host-plant use in a genus of leaf-mining moths.
We used nuclear 28S rDNA sequence data to estimate the phylogeny of 77 leaf-mining Phyllonorycter (Gracillariidae) moth species, including all 55 British species, feeding on 44 different plant genera. There was strong support for both the monophyly of Phyllonorycter and the placement of the genus Cameraria as its sister group. Host-plant use was mapped onto the moth phylogeny and investigated statistically in several ways. First, we show that the estimated level of cospeciation between leaf miners and their host plants is not greater than expected by chance, despite the physical intimacy of the association. Nevertheless, the pattern of host-plant use is far from random, with closely related Phyllonorycter species generally feeding on closely related plants. However, although Phyllonorycter species from a given host plant tend to form distinct clades, there is also statistical support for multiple independent colonizations of some host-plant taxa (e.g. the order Rosales and the genus Corylus). Despite numerous host shifts, most Phyllonorycter species feed on trees and the few species that attack shrubs or herbs have mostly acquired these habits independently. There is also limited evidence that host shifts to herbs are more likely from shrubs than from trees. Similarly, most species mine the lower surface of leaves but the few upper-surface miners have each evolved the habit independently. Consequently, these shifts to new adaptive zones have not led to substantial radiations.


Genomic characterization of methylotrophy of Oharaeibacter diazotrophicus strain SM30T.
Oharaeibacter diazotrophicus strain SM30T, isolated from rice rhizosphere, is an aerobic, facultative lanthanide (Ln3+)-utilizing methylotroph and diazotroph that belongs to the Methylocystaceae family. In this research, the complete genome sequence of strain SM30T was determined, and its methylotrophy modules were characterized. The genome consists of one chromosome and two plasmids, comprising a total of 5,004,097 bp, and the GC content was 71.6 mol%. A total of 4497 CDSs, 67 tRNA, and 9 rRNA were encoded. Typical alpha-proteobacterial methylotrophy genes were found: pyrroloquinoline quinone (PQQ)-dependent methanol dehydrogenase (MDH) (mxaF and xoxF1-4), methylotrophy regulatory proteins (mxbDM and mxcQE), PQQ synthesis, H4F pathway, H4MPT pathway, formate oxidation, serine cycle, and ethylmalonyl-CoA pathway. SDS-PAGE and subsequent LC-MS analysis, and qPCR analysis revealed that MxaF and XoxF1 were the dominant MDH in the absence or presence of lanthanum (La3+), respectively. The growth of MDH gene-deletion mutants on alcohols and qPCR results indicated that mxaF and xoxF1 are also involved in ethanol and propanol oxidation, xoxF2 participates in methanol oxidation in the presence of La3+, while xoxF3 was associated with methanol and ethanol oxidation in the absence of La3+, implying that XoxF3 is a calcium (Ca2+)-binding XoxF. Four Ln3+ such as La3+, cerium (Ce3+), praseodymium (Pr3+), and neodymium (Nd3+) served as cofactors for XoxF1 by supporting ΔmxaF growth on methanol. Some heavier lanthanides inhibited growth of SM30 on methanol. This study contributes to the understanding of the function of various XoxF-type MDHs and their roles in methylotrophs.


Do South Asian women with PCOS have poorer health-related quality of life than Caucasian women with PCOS? A comparative cross-sectional study.
Polycystic ovary syndrome (PCOS) is the most common chronic endocrine disorder affecting women of reproductive age. This study aimed to compare the HRQoL of South Asian and white Caucasian women with PCOS, given that it is particularly common among women of South Asian origin and they have been shown to have more severe symptoms. The Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36) were administered in a cross-sectional survey to 42 South Asian and 129 Caucasian women diagnosed with PCOS recruited from the gynaecology outpatient clinics of two university teaching hospitals in Sheffield and Leeds. Additional clinical data was abstracted from medical notes. Normative data, collected as part of the Oxford Health and Lifestyles II survey, was obtained to compare SF-36 results with ethnically matched women from the general UK population. Using the SF-36, normative HRQoL scores for women of South Asian origin were lower than for Caucasian women. Given this lower baseline we tested whether the same relationship holds true among those with PCOS. Although HRQoL scores for women with PCOS were lower than normative data for both groups, South Asian women with PCOS did not have poorer HRQoL than their Caucasian counterparts. For both the SF-36 and PCOSQ, mean scores were broadly the same for both Asian and Caucasian women. For both groups, the worst two HRQoL domains as measured on the PCOSQ were 'infertility' and 'weight', with respective scores of 35.3 and 42.3 for Asian women with PCOS compared to 38.6 and 35.4 for Caucasian women with PCOS. The highest scoring domain for South Asian women with PCOS was 'menstrual problems' (55.3), indicating best health, and was the only statistically significant difference from Caucasian women (p = 0.01). On the SF-36, the lowest scoring domain was 'Energy & Vitality' for Caucasian women with PCOS, but this was significantly higher for Asian women with PCOS (p = 0.01). The best health status for both groups was 'physical functioning', although this was significantly lower for South Asian women with PCOS (p = 0.005). Interestingly, only two domains differed significantly from the normative data for the Asian women with PCOS, while seven domains were significantly different for the Caucasian women with PCOS compared to their normative counterparts. The HRQoL differences that exist between South Asian and Caucasian women in the general population do not appear to be replicated amongst women with PCOS. PCOS reduces HRQoL to broadly similar levels, regardless of ethnicity and differences in the normative baseline HRQoL of these groups.


Meta-Heuristics in Short Scale Construction: Ant Colony Optimization and Genetic Algorithm.
The advent of large-scale assessment, but also the more frequent use of longitudinal and multivariate approaches to measurement in psychological, educational, and sociological research, caused an increased demand for psychometrically sound short scales. Shortening scales economizes on valuable administration time, but might result in inadequate measures because reducing an item set could: a) change the internal structure of the measure, b) result in poorer reliability and measurement precision, c) deliver measures that cannot effectively discriminate between persons on the intended ability spectrum, and d) reduce test-criterion relations. Different approaches to abbreviate measures fare differently with respect to the above-mentioned problems. Therefore, we compare the quality and efficiency of three item selection strategies to derive short scales from an existing long version: a Stepwise COnfirmatory Factor Analytical approach (SCOFA) that maximizes factor loadings and two metaheuristics, specifically an Ant Colony Optimization (ACO) with a tailored user-defined optimization function and a Genetic Algorithm (GA) with an unspecific cost-reduction function. SCOFA compiled short versions were highly reliable, but had poor validity. In contrast, both metaheuristics outperformed SCOFA and produced efficient and psychometrically sound short versions (unidimensional, reliable, sensitive, and valid). We discuss under which circumstances ACO and GA produce equivalent results and provide recommendations for conditions in which it is advisable to use a metaheuristic with an unspecific out-of-the-box optimization function.


Hybridization and adaptive radiation.
Whether interspecific hybridization is important as a mechanism that generates biological diversity is a matter of controversy. Whereas some authors focus on the potential of hybridization as a source of genetic variation, functional novelty and new species, others argue against any important role, because reduced fitness would typically render hybrids an evolutionary dead end. By drawing on recent developments in the genetics and ecology of hybridization and on principles of ecological speciation theory, I develop a concept that reconciles these views and adds a new twist to this debate. Because hybridization is common when populations invade new environments and potentially elevates rates of response to selection, it predisposes colonizing populations to rapid adaptive diversification under disruptive or divergent selection. I discuss predictions and suggest tests of this hybrid swarm theory of adaptive radiation and review published molecular phylogenies of adaptive radiations in light of the theory.


Fresh Red Cells for Transfusion in Critically Ill Adults: An Economic Evaluation of the Standard Issue Transfusion Versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) Clinical Trial.
Trials comparing the effects of transfusing RBC units of different storage durations have considered mortality or morbidity as outcomes. We perform the first economic evaluation alongside a full age of blood clinical trial with a large population assessing the impact of RBC storage duration on quality-of-life and costs in critically ill adults. Quality-of-life was measured at 6 months post randomization using the EuroQol 5-dimension 3-level instrument. The economic evaluation considers quality-adjusted life year and cost implications from randomization to 6 months. A generalized linear model was used to estimate incremental costs (2016 U.S. dollars) and quality-adjusted life years, respectively while adjusting for baseline characteristics. Fifty-nine ICUs in five countries. Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit. Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service. EuroQol 5-dimension 3-level utility scores were similar at 6 months-0.65 in the short-term and 0.63 in the long-term storage group (difference, 0.02; 95% CI, -0.00 to 0.04; p = 0.10). There were no significant differences in resource use between the two groups apart from 3.0 fewer hospital readmission days (95% CI, -5.3 to -0.8; p = 0.01) during follow-up in the short-term storage group. There were no significant differences in adjusted total costs or quality-adjusted life years between the short- and long-term storage groups (incremental costs, -$2,358; 95% CI, -$5,586 to $711) and incremental quality-adjusted life years: 0.003 quality-adjusted life years (95% CI, -0.003 to 0.008). Without considering the additional supply cost of implementing a freshest available RBC strategy for critical care patients, there is no evidence to suggest that the policy improves quality-of-life or reduces other costs compared with standard transfusion practice.


Epidemiology of pediatric hydrocephalus in Haiti: analysis of a surgical case series.
OBJECTIVEHydrocephalus is recognized as a common disabling pediatric disease afflicting infants and children disproportionately in the developing world, where access to neurosurgical care is limited and risk of perinatal infection is high. This surgical case series describes the Project Medishare Hydrocephalus Specialty Surgery (PMHSS) program experience treating hydrocephalus in Haiti between 2008 and 2015.METHODSThe authors conducted a retrospective review of all cases involving children treated for hydrocephalus within the PMHSS program in Port-au-Prince, Haiti, from 2008 through 2015. All relevant epidemiological information of children treated were prospectively collected including relevant demographics, birth history, hydrocephalus etiology, head circumference, and operative notes. All appropriate associations and statistical tests were performed using univariate and multivariate logistic regression analyses.RESULTSAmong the 401 children treated within PMHSS, postinfectious hydrocephalus (PIH) accounted for 39.4% (n = 158) of cases based on clinical, radiographic, and endoscopic findings. The majority of children with hydrocephalus in Haiti were male (54.8%, n = 197), born in the rainy season (59.7%, n = 233), and born in a coastal/inland location (43.3%, n = 61). The most common surgical intervention was endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) (45.7%, n = 175). Multivariate logistic regression analysis yielded coastal birth location (OR 3.76, 95% CI 1.16-12.18) as a statistically significant predictor of PIH. Increasing head circumference (adjusted OR 1.06, 95% CI 0.99-1.13) demonstrated a slight trend toward significance with the incidence of PIH.CONCLUSIONSThis information will provide the foundation for future clinical and public health studies to better understand hydrocephalus in Haiti. The 39.4% prevalence of PIH falls within observed rates in Africa as does the apparently higher prevalence for those born during the rainy season. Although PIH was the most frequent etiology seen in almost all birth locations, the potential relationship with geography noted in this series will be the focus of further research in an effort to understand the link between climate and PIH in Haiti. The ultimate goal will be to develop an appropriate public health strategy to reduce the burden of PIH on the children of Haiti.


Impact of academic majors on entrepreneurial intentions of Vietnamese students: An extension of the theory of planned behavior.
This article investigates the effect of academic majors on entrepreneurial intentions of engineering and business students. The research model was established based on the extension of the theory of planned behavior (TPB) through combining the TPB model, perceived risks, academic majors and personalities of students. A sample of 1844 students from the four largest universities in engineering and business in Vietnam were surveyed. The main findings indicated that (i) the relationship in the TPB model was accepted except the effect of subjective norms on entrepreneurial intentions; (ii) perceived risks have negative impacts on perceived behavioral control; (iii) male engineering students have a higher entrepreneurial intentions than female students, but this result was not found in business students; (iv) engineering students have a higher entrepreneurial intentions than business students; (vi) there are no differences between the entrepreneurial intention of students coming from rural and urban areas. The study also contributes to some policy discussion to extend the current debate about the role of academic majors that students take in university in the entrepreneurial process as well as the importance of entrepreneurial students to society.


Colon Surgery Risk With Corticosteroids Versus Immunomodulators or Biologics in Inflammatory Bowel Disease Patients With Clostridium difficile Infection.
Inflammatory bowel disease (IBD) is an independent risk factor for Clostridium difficile infection (CDI), and CDI often precipitates IBD exacerbation. Because CDI cannot be distinguished clinically from an IBD exacerbation, management is difficult. We aimed to assess factors associated with adverse outcomes in IBD with CDI, including the role of escalating or de-escalating IBD therapy and CDI treatment. Records for patients with IBD and CDI from 2008 to 2013 were abstracted for variables including IBD severity before CDI diagnosis, CDI management, subsequent IBD exacerbation, CDI recurrence, and colon surgery. Colon surgery was defined as resection of any colonic segment within 1 year after CDI diagnosis. We included 137 IBD patients (median age, 46 years; 55% women): 70 with ulcerative colitis (51%), 63 with Crohn's disease (46%), and 4 with indeterminate colitis (3%). Overall, 70% of CDIs were mild-moderate, 14% were severe, and 15% were severe-complicated. Clostridium difficile infection treatment choice did not vary by infection severity (P = 0.27). Corticosteroid escalation (odds ratio [OR], 5.94; 95% confidence interval [CI], 2.03-17.44) was a positive predictor of colon surgery within 1 year after CDI; older age (OR, 0.09; 95% CI, 0.01-0.44) was a negative predictor. Modifying the corticosteroid regimen did not affect CDI recurrence or risk of future IBD exacerbation. Adverse outcomes did not differ with CDI antibiotic regimens or biologic or immunomodulator regimen modification. Corticosteroid escalation for IBD during CDI was associated with higher risk of colon surgery. Type of CDI treatment did not influence IBD outcomes. Prospective studies are needed to further elucidate optimal management in this high-risk population.


Sonogashira coupling on an extended gold surface in vacuo: reaction of phenylacetylene with iodobenzene on Au(111).
Temperature-programmed reaction measurements supported by scanning tunneling microscopy have shown that phenylacetylene and iodobenzene react on smooth Au(111) under vacuum conditions to yield biphenyl and diphenyldiacetylene, the result of homocoupling of the reactant molecules. They also produce diphenylacetylene, the result of Sonogashira cross-coupling, prototypical of a class of reactions that are of paramount importance in synthetic organic chemistry and whose mechanism remains controversial. Roughened Au(111) is completely inert toward all three reactions, indicating that the availability of crystallographically well-defined adsorption sites is crucially important. High-resolution X-ray photoelectron spectroscopy and near-edge X-ray absorption fine structure spectroscopy show that the reactants are initially present as intact, essentially flat-lying molecules and that the temperature threshold for Sonogashira coupling coincides with that for C-I bond scission in the iodobenzene reactant. The fractional-order kinetics and low temperature associated with desorption of the Sonogashira product suggest that the reaction occurs at the boundaries of islands of adsorbed reactants and that its appearance in the gas phase is rate-limited by the surface reaction. These findings demonstrate unambiguously and for the first time that this heterogeneous cross-coupling chemistry is an intrinsic property of extended, metallic pure gold surfaces: no other species, including solvent molecules, basic or charged (ionic) species are necessary to mediate the process.


Dementia care costs and outcomes: a systematic review.
We reviewed evidence on the cost-effectiveness of prevention, care and treatment strategies in relation to dementia. We performed a systematic review of available literature on economic evaluations of dementia care, searching key databases and websites in medicine, social care and economics. Literature reviews were privileged, and other study designs were included only to fill gaps in the evidence base. Narrative analysis was used to synthesise the results. We identified 56 literature reviews and 29 single studies offering economic evidence on dementia care. There is more cost-effectiveness evidence on pharmacological therapies than other interventions. Acetylcholinesterase inhibitors for mild-to-moderate disease and memantine for moderate-to-severe disease were found to be cost-effective. Regarding non-pharmacological treatments, cognitive stimulation therapy, tailored activity programme and occupational therapy were found to be more cost-effective than usual care. There was some evidence to suggest that respite care in day settings and psychosocial interventions for carers could be cost-effective. Coordinated care management and personal budgets held by carers have also demonstrated cost-effectiveness in some studies. Five barriers to achieving better value for money in dementia care were identified: the scarcity and low methodological quality of available studies, the difficulty of generalising from available evidence, the narrowness of cost measures, a reluctance to implement evidence and the poor coordination of health and social care provision and financing.


Can a targeted GP-led clinic improve outcomes for street sex workers who use heroin?
Female street sex workers in the UK are often addicted to heroin, and sex work may be a result of the economic drive to fund this addiction. This study looks at outcomes of a primary care drugs treatment intervention for street sex workers who use heroin, using prescribed maintenance treatment with intensive health and psychosocial support. Thirty-four sex workers entered the study and 100% were retained in the study at 1 year. After 1 year, only 33% of participants were still sex workers. Quality of life had improved significantly and heroin use had reduced.


Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).


A comparison of laparoscopic and robotic assisted suturing performance by experts and novices.
Surgical robotics has been promoted as an enabling technology. This study tests the hypothesis that use of the robotic surgical system can significantly improve technical ability by comparing the performance of both experts and novices on a complex laparoscopic task and a robotically assisted task. Laparoscopic experts (LE) with substantial laparoscopic and robotic experience (n = 9) and laparoscopic novices (LN) (n = 20) without any robotic experience performed sequentially 10 trials of a suturing task using either robotic or standard laparoscopic instrumentation fitted to the ProMIS surgical simulator. Objective performance metrics provided by ProMIS (total task time, instrument pathlength, and smoothness) and an assessment of learning curves were analyzed. Compared with LNs, the LEs demonstrated significantly better performance on all assessment measures. Within the LE group, there was no difference in smoothness (328 +/- 159 vs 355 +/- 174; P = .09) between robot-assisted and standard laparoscopic tasks. An improvement was noted in total task time (113 +/- 41 vs 132 +/- 55 sec; P < .05) and instrument pathlengths (371 +/- 163 vs 645 +/- 269 cm; P < .05) when using the robot. This advantage in terms of total task time, however, was lost among the LEs by the last 3 trials (114 +/- 40 vs 118 +/- 49 s; P = .84), while instrument pathlength remained better consistently throughout all the trials. For the LNs, performance was significantly better in the robotic trials on all 3 measures throughout all the trials. The ProMIS surgical simulator was able to distinguish between skill levels (expert versus novice) on robotic suturing tasks, suggesting that the ProMIS is a valid tool for measuring skill in robot-assisted surgery. For all the ProMIS metrics, novices demonstrated consistently better performance on a suturing task using robotics as compared to a standard laparoscopic setup. This effect was less evident for experts who demonstrated improvements only in their economy of movement (pathlength), but not in the speed or smoothness of performance. Robotics eliminated the early learning curve for novices, which was present when they used standard laparoscopic tools. Overall, this study suggests that, when performing complex tasks such as knot tying, surgical robotics is most useful for inexperienced laparoscopists who experience an early and persistent enabling effect. For experts, robotics is most useful for improving economy of motion, which may have implications for the highly complex procedures in limited workspaces (eg, prostatectomy).


No effects of Bacillus thuringiensis maize on nontarget organisms in the field in southern Europe: a meta-analysis of 26 arthropod taxa.
Maize with the insecticidal properties of the entomopathogenic bacterium Bacillus thuringiensis Berliner, known as Bt maize, has been sown in Europe since 1998. For several years, EU and Spanish regulations have required laboratory and field trials to assess risks of genetically modified crops for nontarget organisms prior to their authorization. Thirteen field trials were conducted in Spain to measure the effects of Bt maize on a broad range of arthropod taxa; no effects were found in accordance with most literature records. However, statistical analyses of single trials rarely have the statistical power to detect low effect sizes if they do not have a sufficient sample size. When sample size is low, meta-analysis may improve statistical power by combining several trials and assuming a common measure of effect size. Here we perform a meta-analysis of the results of 13 independent field trials conducted in Spain in which effects of single or stacked Bt traits on several arthropod taxa were measured with no significant results. Since the taxa included in each single trial were not the same for all trials, for the meta-analysis we selected only those taxa recorded in a minimum of six trials, resulting finally in 7, 7, and 12 taxa analyzed in visual counts, pitfall traps and yellow sticky traps, respectively. In comparison with single trial analysis, meta-analysis dramatically increased the detectability of treatment effects for most of the taxa regardless of the sampling technique; of the 26 taxa analyzed, only three showed poorer detectability in the meta-analysis than the best recorded in the 13 single trials. This finding reinforces the conclusion that Bt maize has no effect on the most common herbivore, predatory and parasitoid arthropods found in the maize ecosystems of southern Europe.


Propofol Exposure Disturbs the Differentiation of Rodent Neural Stem Cells via an miR-124-3p/Sp1/Cdkn1b Axis.
Accumulating studies have indicated that propofol may lead to neurotoxicity and its effect on neural stem cells (NSCs) may play pivotal role in propofol-related neurotoxicity. Previously, we found that propofol could promote NSCs proliferation and could regulate several microRNA expressions. However, the underlying mechanism between microRNAs and NSCs development after propofol exposure is still unclear. Our data first observed that rat primary neural stem cells exposed to propofol exhibited a cell cycle arrest status and an inclination to differentiate into GFAP+ or S100β+ cells. This phenomenon was accompanying with a lower miR-124-3p expression and could be reversed via overexpression miR-124-3p in NSCs. Using bioinformatic predictions and luciferase assay we confirmed that Sp1 (Specificity Protein 1) is the target gene of miR-124-3p, indicating that miR-124-3p may regulate NSCs development through Sp1. Further, knockdown of Sp1 rescue the effect of propofol on NSCs differentiation. Finally, we demonstrated that Sp1 could bind cdkn1b promoter region through chromatin immunoprecipitation assay, indicating that Sp1 affect NSC's cell cycle through cdkn1b directly. Overall, our study highlights the miR-124-3p/Sp1/cdkn1b axis to be important in propofol interfering the differentiation of NSCs.


Visual-somatosensory integration and balance: evidence for psychophysical integrative differences in aging.
Research detailing multisensory integration (MSI) processes in aging and their association with clinically relevant outcomes is virtually non-existent. To our knowledge, the relationship between MSI and balance has not been well-established in aging. Given known alterations in unisensory processing with increasing age, the aims of the current study were to determine differential behavioral patterns of MSI in aging and investigate whether MSI was significantly associated with balance and fall-risk. Seventy healthy older adults (M = 75 years; 58% female) participated in the current study. Participants were instructed to make speeded responses to visual, somatosensory, and visual-somatosensory (VS) stimuli. Based on reaction times (RTs) to all stimuli, participants were classified into one of two groups (MSI or NO MSI), depending on their MSI RT benefit. Static balance was assessed using mean unipedal stance time. Overall, results revealed that RTs to VS stimuli were significantly shorter than those elicited to constituent unisensory conditions. Further, the current experimental design afforded differential patterns of multisensory processing, with 75% of the elderly sample demonstrating multisensory enhancements. Interestingly, 25% of older adults did not demonstrate multisensory RT facilitation; a finding that was attributed to extremely fast RTs overall and specifically in response to somatosensory inputs. Individuals in the NO MSI group maintained significantly better unipedal stance times and reported less falls, compared to elders in the MSI group. This study reveals the existence of differential patterns of multisensory processing in aging, while describing the clinical translational value of MSI enhancements in predicting balance and falls risk.


Perceptions of HIV, AIDS and tuberculosis among patients on antiretroviral therapy in Bulawayo, Zimbabwe: implications for the provision of HIV and TB care services.
The objectives of the research were to explore perceptions of HIV, AIDS and tuberculosis (TB) among individuals enrolled in antiretroviral therapy (ART) at two municipal clinics in Bulawayo, Zimbabwe, and to assess the implications of these perceptions on the provision of HIV and TB care services. Data were collected using the freelist technique to elicit the elements of a cultural domain as well as open-ended interviews with ART clients, conducted during June and July 2009. Participants were recruited through non-probability convenience sampling. The freelist data were analysed using multidimensional scaling and hierarchical clustering, and the interview data were analysed using the grounded theory method. The results suggest that: 1) the participants had substantial knowledge about HIV, AIDS and TB; 2) the participants' perceptions of HIV, AIDS and TB constituted three distinct, though overlapping, cultural domains; 3) because of the availability of ART and TB treatment, a diagnosis of HIV infection or TB alone was generally perceived with hope that one would be able to live a normal life, while AIDS illness or TB/HIV coinfection were associated with notions of death and despair; and, 4) such perceptions may negatively impact the uptake of testing for HIV and TB, and thereby contribute to delayed start of the respective treatment. Health messages should build on these meanings which have the potential to either enhance or compromise available health programmes and their use by people living with HIV or TB.


Generalized cable formalism to calculate the magnetic field of single neurons and neuronal populations.
Neurons generate magnetic fields which can be recorded with macroscopic techniques such as magnetoencephalography. The theory that accounts for the genesis of neuronal magnetic fields involves dendritic cable structures in homogeneous resistive extracellular media. Here we generalize this model by considering dendritic cables in extracellular media with arbitrarily complex electric properties. This method is based on a multiscale mean-field theory where the neuron is considered in interaction with a "mean" extracellular medium (characterized by a specific impedance). We first show that, as expected, the generalized cable equation and the standard cable generate magnetic fields that mostly depend on the axial current in the cable, with a moderate contribution of extracellular currents. Less expected, we also show that the nature of the extracellular and intracellular media influence the axial current, and thus also influence neuronal magnetic fields. We illustrate these properties by numerical simulations and suggest experiments to test these findings.


Potential approaches for the pricing of cancer medicines across Europe to enhance the sustainability of healthcare systems and the implications.
Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems.Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines.Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments.


Long-term effects of medical management on growth and weight in individuals with urea cycle disorders.
Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.


Central and peripheral indices of sympathetic activity after blood pressure lowering with enalapril (MK-421) or hydralazine in normotensive rats.
Various antihypertensive drugs have different effects on vasoactive mechanisms. In normotensive Wistar rats, we investigated the effects on plasma and tissue catecholamines of chronic treatment with two agents: MK-421, an angiotensin converting-enzyme inhibitor (CEI), and hydralazine, a vascular smooth muscle relaxant. Both agents lowered blood pressure via arteriolar dilation, to the same final level. However, hydralazine stimulated the renin-angiotensin system and elevated the plasma norepinephrine (NE) and epinephrine (E) levels, whereas MK-421 did not. In MK-421-treated animals, NE, E, and the ratio of E/NE were decreased in the brain stem, and this ratio was increased in the heart. In hydralazine-treated rats, the catecholamine levels were unchanged in the brain stem and heart. The turnover rate of NE was significantly reduced in the brain stem and heart of MK-421-treated rats, whereas, after hydralazine, the turnover rate in the heart was increased (decreasing the half-life of NE by about 50%), indicating increased sympathetic activity. Thus, elimination of angiotensin II (AII) by CEI is associated with decreased sympathetic activity in both the brain stem and heart, whereas an equipotent antihypertensive action by smooth muscle relaxation leads to stimulation of both the renin-angiotensin and the sympathetic systems. These differences are more readily apparent by measurement of catecholamine turnover rates in tissues than of catecholamine levels, and they may account for the different hemodynamic effects of the two agents, even though both drugs act through arteriolar dilation.


IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.
The realization that alterations in inhibitor of apoptosis (IAP) proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis, has sparked a worldwide frenzy in the development of small pharmacological inhibitors of IAPs. The development of such inhibitors has radically changed our knowledge of the signalling processes that are regulated by IAPs. Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis.


Genomic insights into an obligate epibiotic bacterial predator: Micavibrio aeruginosavorus ARL-13.
Although bacterial predators play important roles in the dynamics of natural microbial communities, little is known about the molecular mechanism of bacterial predation and the evolution of diverse predatory lifestyles. We determined the complete genome sequence of Micavibrio aeruginosavorus ARL-13, an obligate bacterial predator that feeds by "leeching" externally to its prey. Despite being an obligate predator depending on prey for replication, M. aeruginosavorus encodes almost all major metabolic pathways. However, our genome analysis suggests that there are multiple amino acids that it can neither make nor import directly from the environment, thus providing a simple explanation for its strict dependence on prey. Remarkably, despite apparent genome reduction, there is a massive expansion of genomic islands of foreign origin. At least nine genomic islands encode many genes that are likely important for Micavibrio-prey interaction such as hemolysin-related proteins. RNA-Seq analysis shows substantial transcriptome differences between the attack phase, when M. aeruginosavorus seeks its prey, and the attachment phase, when it feeds and multiplies. Housekeeping genes as well as genes involved in protein secretion were all dramatically up-regulated in the attachment phase. In contrast, genes involved in chemotaxis and flagellum biosynthesis were highly expressed in the attack phase but were shut down in the attachment phase. Our transcriptomic analysis identified additional genes likely important in Micavibrio predation, including porins, pilins and many hypothetical genes. The findings from our phylogenomic and transcriptomic analyses shed new light on the biology and evolution of the epibiotic predatory lifestyle of M. aeruginosavorus. The analysis reported here and the availability of the complete genome sequence should catalyze future studies of this organism.


Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells.
Satisfactory therapeutic strategies for septic shock are still missing. Previously we found elevated levels of Wnt5A in patients with severe sepsis and septic shock. Wnt5A is released by activated macrophages but knowledge of its effects in the vascular system remains scant. Here we investigate the response of human coronary artery endothelial cells (HCAEC) to Wnt5A. We used a genome-wide differential expression approach to define novel targets regulated by Wnt5A. Gene ontology analysis of expression profiles revealed clusters of genes involved in actin cytoskeleton remodeling as the predominant targets of Wnt5A. Wnt5A targeted Rho-associated protein serine/threonine kinase (ROCK), leading to phosphorylation of LIM kinase-2 (LIMK2) and inactivation of the actin depolymerization factor cofilin-1 (CFL1). Functional experiments recording cytoskeletal rearrangements in living cells showed that Wnt5A enhanced stress fiber formation as a consequence of reduced actin depolymerization. The antagonist Wnt inhibitory factor 1 (WIF1) that specifically interferes with the WIF domain of Ryk receptors prevented actin polymerization. Wnt5A disrupted β-catenin and VE-cadherin adherens junctions forming inter-endothelial gaps. Functional experiments targeting the endothelial monolayer integrity and live recording of trans-endothelial resistance revealed enhanced permeability of Wnt5A-treated HCAEC. Ryk silencing completely prevented Wnt5A-induced endothelial hyperpermeability. Wnt5A decreased wound healing capacity of HCAEC monolayers; this was restored by the ROCK inhibitor Y-27632. Here we show that Wnt5A acts on the vascular endothelium causing enhanced permeability through Ryk interaction and downstream ROCK/LIMK2/CFL1 signaling. Wnt5A/Ryk signaling might provide novel therapeutic strategies to prevent capillary leakage in systemic inflammation and septic shock.


Psychometric properties of the UngDOK: A structured interview for adolescents with substance-use problems.
This article describes and discusses the Swedish UngDOK interview and its psychometric properties. The study is based on empirical data from 1633 intake interviews collected by 15 units in ten cities and focused primarily on the two central sections of intake form: alcohol and drug use and mental health. The statistical analyses concern internal consistency, test-retest reliability, discriminant validity and internal non-response. The reliability of AUDIT-C and the mental health domain was good with regard to both internal consistency and test-retest. The test-retest values were generally satisfactory, except for frequency of drug use and association with peers who use drugs. The discriminant validity shows that the interview clearly distinguishes adolescents with more profound problems from a group with milder problems and that a minor degree of inconsistency and non-response bias may occur in empirical material based upon self-reported information. The study showed that the psychometric properties of the UngDOK interview are generally satisfactory and may be regarded as a valuable option for practices engaged in treating adolescents with substance-use problems.


Analysis of the prognostic value of soluble epidermal growth factor receptor plasma concentration in advanced non-small-cell lung cancer patients.
Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies including lung cancer. A soluble fragment of the EGFR extracellular domain (sEGFR) can be detected in the blood of patients who have non-small-cell lung cancer (NSCLC), but its clinical/ prognostic role must be further elucidated. sEGFR concentration was retrospectively determined by enzyme-linked immunosorbent assay in plasma samples from 308 advanced NSCLC patients (before treatment) and 109 healthy controls and correlated with clinico-pathological variables. The concentration of sEGFR was lower in NSCLC patients than in controls (P < .0001). sEGFR behaves as a sensitive but not specific screening biomarker. No significant associations were observed between sEGFR concentration and demographic/clinical characteristics such as gender, Eastern Cooperative Oncology Group performance status, stage, and number or location of the metastatic sites. sEGFR was lower in patients with progressive disease or in squamous cell carcinoma compared with adenocarcinoma, but these differences were not significant. Patients with sEGFR ≤ 34.56 ng/mL showed a shorter overall survival (median 9.1 versus 12.2 months, P = .019) than others. Moreover, in multivariate analysis, sEGFR remained a significant independent prognostic marker. Low baseline sEGFR is associated with reduced survival in advanced NSCLC. Therefore, our findings in this large cohort of patients suggest that the determination of sEGFR concentration provides valuable prognostic information.


The HTN3-MSANTD3 Fusion Gene Defines a Subset of Acinic Cell Carcinoma of the Salivary Gland.
The spectrum of tumors arising in the salivary glands is wide and has recently been shown to harbor a network of tumor-specific fusion genes. Acinic cell carcinoma (AciCC) is one of the more frequently encountered types of salivary gland carcinoma, but it has remained a genetic orphan until recently when a fusion between the HTN3 and MSANTD3 genes was described in one case. Neither of these 2 genes is known to be implicated in any other malignancy. This study was undertaken to investigate whether the HTN3-MSANTD3 fusion is a recurrent genetic event in AciCC and whether it is a characteristic of one of its histological variants. Of the 273 AciCCs screened, 9 cases showed rearrangement of MSANTD3 by break-apart fluorescence in situ hybridization, 2 had 1 to 2 extra signals, and 1 had gain, giving a total of 4.4% with MSANTD3 aberrations. In 6 of 7 available cases with MSANTD3 rearrangement, the HTN3-MSANTD3 fusion transcript was demonstrated with real-time polymerase chain reaction. Histologically, all fusion-positive cases were predominantly composed of serous tumor cells growing in solid sheets, with serous tumor cells expressing DOG-1 and the intercalated duct-like cell component being CK7 positive and S-100 positive in 6/9 cases. All but one case arose in the parotid gland, and none of the patients experienced a recurrence during follow-up. In contrast, the case with MSANTD3 gain metastasized to the cervical lymph nodes and lungs. In conclusion, we find the HTN3-MSANTD3 gene fusion to be a recurrent event in AciCC with prominent serous differentiation and an indolent clinical course.


Excessive daytime sleepiness in asthma: What are the risk factors?
Previous studies have found that excessive daytime sleepiness (EDS) is a more common problem in asthmatic subjects than in the general population. The aim of this study was to investigate whether the prevalence of EDS is increased in asthmatic subjects and, if so, to analyse the occurrence of potential risk factors for EDS in asthmatics. Cross-sectional epidemiological study. In 2008, a postal questionnaire was sent out to a random sample of 45,000 individuals aged 16-75 years in four Swedish cities. Of the 25,160 persons who participated, 7.3% were defined as having asthma. The prevalence of EDS was significantly higher in asthmatic subjects (42.1% vs. 28.5%, p < 0.001) compared with non-asthmatic subjects. Asthma was an independent risk factor for EDS (adjusted OR 1.29) and the risk of having EDS increased with asthma severity. Risk factors for EDS in subjects with asthma included insomnia (OR, 3.87; 95% CI, 3.10-4.84); chronic rhinosinusitis (OR, 2.00; 95% CI, 1.53-2.62); current smoking (OR, 1.60; 95% CI, 1.15-2.22) and obesity (OR, 1.53; 95% CI, 1.09-2.13). EDS is a common problem among subjects with asthma. Asthma is an independent risk factor for having EDS. Furthermore, subjects with asthma often have other risk factors for EDS, many of them potentially modifiable.


A high-resolution anatomical atlas of the transcriptome in the mouse embryo.
Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.


A complex of Pdi1p and the mannosidase Htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum.
Endoplasmic reticulum (ER)-resident mannosidases generate asparagine-linked oligosaccharide signals that trigger ER-associated protein degradation (ERAD) of unfolded glycoproteins. In this study, we provide in vitro evidence that a complex of the yeast protein disulfide isomerase Pdi1p and the mannosidase Htm1p processes Man(8)GlcNAc(2) carbohydrates bound to unfolded proteins, yielding Man(7)GlcNAc(2). This glycan serves as a signal for HRD ligase-mediated glycoprotein disposal. We identified a point mutation in PDI1 that prevents complex formation of the oxidoreductase with Htm1p, diminishes mannosidase activity, and delays degradation of unfolded glycoproteins in vivo. Our results show that Pdi1p is engaged in both recognition and glycan signal processing of ERAD substrates and suggest that protein folding and breakdown are not separated but interconnected processes. We propose a stochastic model for how a given glycoprotein is partitioned into folding or degradation pathways and how the flux through these pathways is adjusted to stress conditions.


Characterization of the Na+, K(+)-ATPase in isolated bovine articular chondrocytes; molecular evidence for multiple alpha and beta isoforms.
We have used isoform-specific antibodies against the Na+, K(+)-ATPase alpha (alpha 1, alpha 2 and alpha 3) and beta (beta 1 and beta 2) subunit isoforms in order to establish their specific localization in isolated bovine articular chondrocytes. Immunoblotting confirmed the presence of the alpha 1 and alpha 3 isoforms, although alpha 1 expression was significantly greater than alpha 3 as assessed by immunofluorescence confocal laser scanning microscopy and PCR. A similar approach revealed the presence of the beta 1 and beta 2 isoforms in chondrocytes, although beta 2 immunostaining on the plasma membrane was more punctate than beta 1 which in contrast predominated in a subcellular compartment. The plasma membrane abundance of the Na+, K(+)-ATPase was found to be sensitive to the extracellular ionic concentration and long-term elevation of extracellular Na+ concentration significantly upregulated Na+, K(+)-ATPase density as measured by specific 3H-ouabain binding. Our observations suggest that the expression of alpha 3 and beta 2 is not restricted to excitable tissues as previously reported. The physiological relevance of alpha 3 expression in chondrocytes may be related to its low affinity for intracellular Na+ in an extracellular environment where Na+ concentration is unusually high (260-350 mM) compared to other cell types (140 mM). Glycoproteins and their branched carbohydrates have been implicated in cell recognition events, thus the beta 2 subunit glycoprotein may allow the chondrocyte to detect changes in its extracellular environment by physically interacting with components of the cellular cytoskeleton and matrix macromolecules.


Vascular Proteomics Reveal Novel Proteins Involved in SMC Phenotypic Change: OLR1 as a SMC Receptor Regulating Proliferation and Inflammatory Response.
Neointimal hyperplasia of vascular smooth muscle cells (VSMC) plays a critical role in atherosclerotic plaque formation and in-stent restenosis, but the underlying mechanisms are still incompletely understood. We performed a proteomics study to identify novel signaling molecules organizing the VSMC hyperplasia. The differential proteomics analysis in a balloon-induced injury model of rat carotid artery revealed that the expressions of 44 proteins are changed within 3 days post injury. The combination of cellular function assays and a protein network analysis further demonstrated that 27 out of 44 proteins constitute key signaling networks orchestrating the phenotypic change of VSMC from contractile to epithelial-like synthetic. Among the list of proteins, the in vivo validation specifically revealed that six proteins (Rab15, ITR, OLR1, PDHβ, PTPε) are positive regulators for VSMC hyperplasia. In particular, the OLR1 played dual roles in the VSMC hyperplasia by directly mediating oxidized LDL-induced monocyte adhesion via NF-κB activation and by assisting the PDGF-induced proliferation/migration. Importantly, OLR1 and PDGFRβ were associated in close proximity in the plasma membrane. Thus, this study elicits the protein network organizing the phenotypic change of VSMC in the vascular injury diseases such as atherosclerosis and discovers OLR1 as a novel molecular link between the proliferative and inflammatory responses of VSMCs.


A novel water-resistant and thermally stable black lead halide perovskite, phenyl viologen lead iodide C22H18N2(PbI3)2.
A novel black organoammonium iodoplumbate semiconductor, namely phenyl viologen lead iodide C22H18N2(PbI3)2 (PhVPI), was successfully synthesized and characterized. This material showed physical and chemical properties suitable for photovoltaic applications. Indeed, low direct allowed band gap energy (Eg = 1.32 eV) and high thermal stability (up to at least 300 °C) compared to methylammonium lead iodide CH3NH3PbI3 (MAPI, Eg = 1.5 eV) render PhVPI potentially attractive for solar cell fabrication. The compound was extensively characterized by means of X-ray diffraction (performed on both powder and single crystals), UV-Vis diffuse reflectance spectroscopy (UV-Vis DRS), UV-photoelectron spectroscopy (UPS), FT-IR spectroscopy, TG-DTA, and CHNS analysis. Reactivity towards water was monitored through X-ray powder diffraction carried out after prolonged immersion of the material in water at room temperature. Unlike its methyl ammonium counterpart, PhVPI proved to be unaffected by water exposure. The lack of reactivity towards water is to be attributed to the quaternary nature of the nitrogen atoms of the phenyl viologen units that prevents the formation of acid-base equilibria when in contact with water. On the other hand, PhVPI's thermal stability was evaluated by temperature-controlled powder XRD measurements following an hour-long isothermal treatment at 250 and 300 °C. In both cases no signs of decomposition could be detected. However, the compound melted incongruently at 332 °C producing, upon cooling, a mostly amorphous material. PhVPI was found to be slightly soluble in DMF (∼5 mM) and highly soluble in DMSO. Nevertheless, its solubility in DMF can be dramatically increased by adding an equimolar amount of DMSO. Therefore, phenyl viologen lead iodide can be amenable for the fabrication of solar devices by spin coating as actually done for MAPI-based cells. The crystal structure, determined by means of single crystal X-ray diffraction using synchrotron radiation, turned out to be triclinic and consequently differs from the prototypal perovskite structure. In fact, it comprises infinite double chains of corner-sharing PbI6 octahedra along the a-axis direction with phenyl viologen cations positioned between the columns. Finally, the present determination of PhVPI's electronic band structure achieved through UPS and UV-Vis DRS is instrumental in using the material for solar cells.


Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region.
High-throughput (HTP) protein-interaction assays, such as the yeast two-hybrid (Y2H) system, are enormously useful in predicting the functions of novel gene-products. HTP-Y2H screens typically do not include all of the reconfirmation and specificity tests used in small-scale studies, but the effects of omitting these steps have not been assessed. We performed HTP-Y2H screens that included all standard controls, using the predicted intracellular proteins expressed from the human MHC class III region, a region of the genome associated with many autoimmune diseases. The 91 novel interactions identified provide insight into the potential functions of many MHC genes, including C6orf47, LSM2, NELF-E (RDBP), DOM3Z, STK19, PBX2, RNF5, UAP56 (BAT1), ATP6G2, LST1/f, BAT2, Scythe (BAT3), CSNK2B, BAT5, and CLIC1. Surprisingly, our results predict that 1/3 of the proteins may have a role in mRNA processing, which suggests clustering of functionally related genes within the human genome. Most importantly, our analysis shows that omitting standard controls in HTP-Y2H screens could significantly compromise data quality.


The "Pseudocommando" mass murderer: part II, the language of revenge.
In Part I of this article, research on pseudocommandos was reviewed, and the important role that revenge fantasies play in motivating such persons to commit mass murder-suicide was discussed. Before carrying out their mass shootings, pseudocommandos may communicate some final message to the public or news media. These communications are rich sources of data about their motives and psychopathology. In Part II of this article, forensic psycholinguistic analysis is applied to clarify the primary motivations, detect the presence of mental illness, and discern important individual differences in the final communications of two recent pseudocommandos: Seung-Hui Cho (Virginia Tech) and Jiverly Wong (Binghamton, NY). Although both men committed offenses that qualify them as pseudocommandos, their final communications reveal striking differences in their psychopathology.


Vitamin D: molecular mechanism of action.
Vitamin D maintains calcium homeostasis and is required for bone development and maintenance. Recent evidence has indicated an interrelationship between vitamin D and health beyond bone, including effects on cell proliferation and on the immune system. New developments in our lab related to the function and regulation of target proteins have provided novel insights into the mechanisms of vitamin D action. Studies in our lab have shown that the calcium-binding protein, calbindin, which has been reported to be a facilitator of calcium diffusion, also has an important role in protecting against apoptotic cell death in different tissues including protection against cytokine destruction of osteoblastic and pancreatic beta cells. These findings have important implications for the therapeutic intervention of many disorders including diabetes and osteoporosis. Recent studies in our laboratory of intestinal calcium absorption using calbindin-D(9k) null mutant mice as well as mice lacking the 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inducible epithelial calcium channel, TRPV6, provide evidence for the first time of calbindin-D(9k) and TRPV6 independent regulation of active calcium absorption. Besides calbindin, the other major target of 1,25(OH)(2)D(3) in intestine and kidney is 25(OH)D(3) 24 hydroxylase (24(OH)ase), which is involved in the catabolism of 1,25(OH)(2)D(3). In our laboratory we have identified various factors that cooperate with the vitamin D receptor in regulating 24(OH)ase expression including C/EBP beta, SWI/SNF (complexes that remodel chromatin using the energy of ATP hydrolysis) and the methyltransferases, CARM1 and G9a. Evidence is also presented for C/EBP beta as a nuclear coupling factor that coordinates regulation of osteopontin by 1,25(OH)(2)D(3) and PTH. Our findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)(2)D(3) mediates its multiple biological effects.


Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging.
The aging of tissue-specific stem and progenitor cells is believed to be central to the pathophysiological conditions arising in aged individuals. While the mechanisms driving stem cell aging are poorly understood, mounting evidence points to age-dependent DNA damage accrual as an important contributing factor. While it has been postulated that DNA damage may deplete stem cell numbers with age, recent studies indicate that murine hematopoietic stem cell (HSC) reserves are in fact maintained despite the accrual of genomic damage with age. Evidence suggests this to be a result of the quiescent (G0) cell cycle status of HSC, which results in an attenuation of checkpoint control and DNA damage responses for repair or apoptosis. When aged stem cells that have acquired damage are called into cycle under conditions of stress or tissue regeneration however, their functional capacity was shown to be severely impaired. These data suggest that age-dependent DNA damage accumulation may underlie the diminished capacity of aged stem cells to mediate a return to homeostasis after acute stress or injury. Moreover, the cytoprotection afforded by stem cell quiescence in stress-free, steady-state conditions suggests a mechanism through which potentially dangerous lesions can accumulate in the stem cell pool with age.


Pancreas after kidney transplants in posturemic patients with type I diabetes mellitus.
Pancreas after previous kidney (PAK) transplants are an attractive option for type 1 diabetic patients because of the short waiting time and use of living kidney donors. Factors associated with the increased success rate of PAK transplants in four immunosuppressive eras were analyzed. Between July 1, 1978, and April 30, 2000, 406 PAK transplants were performed in posturemic patients. Four immunosuppressive eras were analyzed: (1) the precyclosporine era, era 1 (n = 65; 16%); (2) the cyclosporine era, era 2 (n = 109; 27%); (3) the tacrolimus era with monoclonal or polyclonal antibody induction therapy, era 3 (n = 104; 26%); and (4) the tacrolimus era with monoclonal and polyclonal antibody induction therapy, era 4 (n = 128; 31%). Patient and graft survival, rejection, and technical failure rates were calculated. Patient survival rates have remained high over time, from 91% (era 1) to 96% (era 4) at 1 yr posttransplant. Pancreas graft survival rates with primary cadaver transplants have significantly increased, from 17% (era 1) to 81% (era 4) at 1 yr. The rate of graft loss from rejection has significantly decreased, from 78% (era 1) to 9% (era 4) at 1 yr. Results were best when donors and recipients were matched for at least one antigen per HLA locus. Kidney graft survival was higher in PAK transplant recipients compared with diabetic recipients of kidney transplants alone from the time of the kidney as well as the pancreas transplants. PAK recipients now enjoy >80% graft survival at 1 yr. This improvement in outcome results from better immunosuppression, good matching, and close posttransplant monitoring for rejection.


Accelerated protein evolution and origins of human-specific features: Foxp2 as an example.
Genes responsible for human-specific phenotypes may have been under altered selective pressures in human evolution and thus exhibit changes in substitution rate and pattern at the protein sequence level. Using comparative analysis of human, chimpanzee, and mouse protein sequences, we identified two genes (PRM2 and FOXP2) with significantly enhanced evolutionary rates in the hominid lineage. PRM2 is a histone-like protein essential to spermatogenesis and was previously reported to be a likely target of sexual selection in humans and chimpanzees. FOXP2 is a transcription factor involved in speech and language development. Human FOXP2 experienced a >60-fold increase in substitution rate and incorporated two fixed amino acid changes in a broadly defined transcription suppression domain. A survey of a diverse group of placental mammals reveals the uniqueness of the human FOXP2 sequence and a population genetic analysis indicates possible adaptive selection behind the accelerated evolution. Taken together, our results suggest an important role that FOXP2 may have played in the origin of human speech and demonstrate a strategy for identifying candidate genes underlying the emergences of human-specific features.


A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events.
The high-density lipoprotein (HDL) cholesterol level is a strong predictor of cardiovascular events in epidemiologic studies. Until recently, it has been less extensively studied as a therapeutic target. To assess the angiographic and clinical effects of a pharmacologic strategy to increase HDL cholesterol levels. Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1996. Outpatient specialty clinic of a large U.S. military medical center. 143 military retirees younger than 76 years of age with low HDL cholesterol levels and angiographically evident coronary disease. Gemfibrozil, niacin, and cholestyramine or corresponding placebos, with aggressive dietary and lifestyle intervention at baseline. Change from baseline to 30 months and a composite measure of clinical events that included hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death, and cardiovascular procedures. At baseline, mean (+/-SD) lipid values were as follows: total cholesterol, 5.1 +/- 0.8 mmol/L (196 +/- 31 mg/dL); low-density lipoprotein (LDL) cholesterol, 3.3 +/- 0.7 mmol/L (128 +/- 27 mg/dL); and HDL cholesterol, 0.9 +/- 0.2 mmol/L (34 +/- 6 mg/dL). Compared with placebo, the pharmacologically treated group experienced a 20% (95% CI, 14.8% to 24.3%) decrease in total cholesterol level, a 36% (CI, 28.4% to 43.5%) increase in HDL cholesterol level, a 26% (CI, 19.1% to 33.7%) decrease in LDL cholesterol level, and a 50% (CI, 40.5% to 59.2%) reduction in triglyceride levels. Focal coronary stenosis increased by 1.4% in the placebo group but decreased by 0.8% in the drug group (difference, -2.2 percentage points [CI, -4.2 to -0.1 percentage points]). A composite cardiovascular event end point was reached in 26% of patients in the placebo group and 13% of those in the drug group (difference, 13.7 percentage points [CI, 0.9 to 26.5 percentage points]). Side effects, particularly flushing and gastrointestinal intolerance, were more common in the drug group but rarely led to withdrawal from the study. The study was small and used a composite clinical outcome. Whether improvements in angiographic findings were due to reductions in LDL cholesterol or increases in HDL cholesterol was not established. Flushing may have led to inadvertent unblinding in patients who were randomly assigned to active study drugs. A combination regimen aimed at increasing HDL cholesterol levels improves cholesterol profiles, helps prevent angiographic progression of coronary stenosis, and may prevent cardiovascular events in some people who exercise regularly and eat low-fat diets.


Haemorrheological response to plasma exchange in Raynaud's syndrome.
Eight patients with Raynaud's syndrome were treated by weekly plasma exchange for four weeks using a Haemonetics Model 30 Blood Processor. The mean whole-blood viscosity at a shear rate of 0.77/s was significantly lower after treatment, and the mean index of red-cell deformability was significantly improved. In four patients studied serially the mean percentage fall in whole-blood viscosity after a single plasma exchange was 49% at 0.77/s but only 14% at 91/s. All patients noticed symptomatic improvement including healing of ischaemic digital ulcers. In six patients the number of digital arterial segments containing detectable blood flow was measured by directional Doppler; in all six the number increased. It is concluded that plasma exchange is an effective means of haemorrheological treatment and may be beneficial in patients with digital ischaemia.