Bridge to Transplantation With Long-Term Mechanical Assist Devices in Adults With Transposition of the Great Arteries.
Prior to the widespread adoption of the arterial switch operation, patients with transposition of the great arteries (TGA) commonly underwent atrial switch operation (Mustard or Senning). It is not uncommon for these patients to progress to end stage heart failure and increasingly ventricular assist devices (VADs) are used to support these patients as a bridge to transplantation, though there is limited experience with this worldwide. A retrospective review of our institution's VAD database was undertaken and revealed seven adult patients with a history of TGA and subsequent systemic ventricular failure were implanted with a VAD: four of whom received the VAD as a bridge to transplantation (BTT) at the time of implantation, two who were initially designated as destination therapy secondary to severe pulmonary hypertension, and one who was designated as destination therapy secondary to a high risk of life-threatening non-compliance. Seven patient cases who received a VAD for severe systemic ventricular failure were included in this study. The mean age of the patients was 40 years and the majority of patients were male (6/7, 85%). Five of the patients (71.4%) had previously undergone an atrial switch operation and all of these were Mustard procedures. Two of the seven patients (28.5%) had congenitally corrected transposition of the great arteries (CC-TGA). Two of the seven patients (28.5%) had supra-systemic pulmonary pressures before VAD implantation and were designated as destination therapy (DT). One of these patients was later designated as BTT as an improvement in his pulmonary vascular resistance was observed, and subsequently underwent heart transplantation. Because of anatomic considerations, four of the patients (57%) underwent redo-sternotomy with outflow cannula anastomosis to the ascending aorta, one patient underwent VAD implantation via a left subcostal incision with anastomosis of the outflow graft to the descending thoracic aorta, and two patients (28.5%) underwent VAD implantation via a left thoracotomy and anastomosis of the outflow cannula to the descending thoracic aorta. Six of the seven patients had a HeartWare HVAD VAD implanted; one received a Thoratec Heartmate II VAD. Two patients underwent VAD explant and orthotopic heart transplant, 222 days and 444 days after VAD implant, respectively. One patient died on postoperative day 17 after complications from recurrent VAD thrombosis despite multiple pump exchanges. Four patients remain on VAD support, three of these patients are awaiting transplantation at last follow-up (mean days on support, 513 days). Bridge to transplantation with a durable VAD is technically feasible and relatively safe in patients with TGA. Multiple redo-sternotomies can be avoided with a left posterior thoracotomy approach and outflow graft anastomosis to the descending thoracic aorta after careful anatomic considerations.


Effects of hemodialysis therapy on sit-to-walk characteristics in end stage renal disease patients.
Patients with end stage renal diseases (ESRD) undergoing hemodialysis (HD) have high morbidity and mortality due to multiple causes; one of which is dramatically higher fall rates than the general population. In spite of the multiple efforts aiming to decrease the high mortality and improve quality of life in ESRD patients, limited success has been achieved. If adequate interventions for fall prevention are to be achieved, the functional and mobility mechanisms consistent with falls in this population must be understood. Human movements such as sit-to-walk (STW) tasks are clinically significant, and analysis of these movements provides a meaningful evaluation of postural and locomotor performance in elderly patients with functional limitations indicative of fall risks. In order to assess the effects of HD therapy on fall risks, 22 sessions of both pre- and post-HD measurements were obtained in six ESRD patients utilizing customized inertial measurement units (IMU). IMU signals were denoised using ensemble empirical mode decomposition and Savistky-Golay filtering methods to detect relevant events for identification of STW phases. The results indicated that patients were slower to get out of the chair (as measured by trunk flexion angular accelerations, time to peak trunk flexion, and overall STW completion time) following the dialysis therapy session. STW is a frequent movement in activities of daily living, and HD therapy may influence the postural and locomotor control of these movements. The analysis of STW movement may assist in not only assessing a patient's physical status, but in identifying HD-related fall risk as well. This preliminary study presents a non-invasive method of kinematic measurement for early detection of increased fall risk in ESRD patients using portable inertial sensors for out-patient monitoring. This can be helpful in understanding the pathogenesis better, and improve awareness in health care providers in targeting interventions to identify individuals at risk for fall.


Mechanical induction of arrhythmias during ventricular repolarization: modeling cellular mechanisms and their interaction in two dimensions.
Nonpenetrating mechanical stimulation of the precordial chest is particularly likely to instantaneously induce sustained rhythm disturbances if timed to coincide with ventricular repolarization. A number of possible mechanisms have been proposed, including mechanoelectric feedback acting via stretch-activated ion channels. The cellular effects of such channel activation have been studied and mathematically modeled in great detail. In this study, we investigate their dynamic interaction with the trailing wave of action potential repolarization in a two-dimensional model of ventricular tissue. The model identifies how stretch activation of cation-nonselective ion channels causes ectopic excitation in fully repolarized tissue and functional block of conduction at the intersection of the mechanical stimulus and the repolarization wave end, which may give rise to both trigger and sustaining mechanisms of ventricular arrhythmia. Simulation of stretch activation of K(+)-selective ion channels alone is insufficient in causing instantaneous arrhythmia, although it may, via action potential shortening, contribute to its sustenance.


Point-of-care autofluorescence imaging for real-time sampling and treatment guidance of bioburden in chronic wounds: first-in-human results.
Traditionally, chronic wound infection is diagnosed by visual inspection under white light and microbiological sampling, which are subjective and suboptimal, respectively, thereby delaying diagnosis and treatment. To address this, we developed a novel handheld, fluorescence imaging device (PRODIGI) that enables non-contact, real-time, high-resolution visualization and differentiation of key pathogenic bacteria through their endogenous autofluorescence, as well as connective tissues in wounds. This was a two-part Phase I, single center, non-randomized trial of chronic wound patients (male and female, ≥18 years; UHN REB #09-0015-A for part 1; UHN REB #12-5003 for part 2; clinicaltrials.gov Identifier: NCT01378728 for part 1 and NCT01651845 for part 2). Part 1 (28 patients; 54% diabetic foot ulcers, 46% non-diabetic wounds) established the feasibility of autofluorescence imaging to accurately guide wound sampling, validated against blinded, gold standard swab-based microbiology. Part 2 (12 patients; 83.3% diabetic foot ulcers, 16.7% non-diabetic wounds) established the feasibility of autofluorescence imaging to guide wound treatment and quantitatively assess treatment response. We showed that PRODIGI can be used to guide and improve microbiological sampling and debridement of wounds in situ, enabling diagnosis, treatment guidance and response assessment in patients with chronic wounds. PRODIGI is safe, easy to use and integrates into the clinical workflow. Clinically significant bacterial burden can be detected in seconds, quantitatively tracked over days-to-months and their biodistribution mapped within the wound bed, periphery, and other remote areas. PRODIGI represents a technological advancement in wound sampling and treatment guidance for clinical wound care at the point-of-care. ClinicalTrials.gov NCT01651845; ClinicalTrials.gov NCT01378728.


Intestinal fatty acid binding protein is available for diagnosis of intestinal ischaemia: immunochemical analysis of two patients with ischaemic intestinal diseases.
Mesenteric infarction and other acute ischaemic intestinal diseases are still a challenging diagnostic problem. Based on animal experiments, intestinal fatty acid binding protein (I-FABP), which is uniquely localised to the bowel, has recently been proposed as a new serum marker for intestinal ischaemia. This paper reports on two cases with acute intestinal ischaemic diseases, and the measurement of serum I-FABP by western blot analysis. The concentrations of ordinary serum markers were normal and the bowel necrosis was not diagnosed until surgical exploration. Immunochemical analysis showed that the I-FABP concentrations in the patients' serum samples were high at the time of admission, and that I-FABP was undetectable in the samples obtained after bowel resection and in healthy control subjects. This paper suggests that I-FABP is released into the circulation in the acute phase of intestinal ischaemia and that I-FABP can be used in establishing the diagnosis of ischaemic intestinal diseases.


Directed insertion of a selectable marker into a circular plasmid of Borrelia burgdorferi.
Studies of the biology of Borrelia burgdorferi and the pathogenesis of Lyme disease are severely limited by the current lack of genetic tools. As an initial step toward facile genetic manipulation of this pathogenic spirochete, we have investigated gene inactivation by allelic exchange using a mutated borrelial gyrB gene that confers resistance to the antibiotic coumermycin A1 as a selectable marker. We have transformed B. burgdorferi by electroporation with a linear fragment of DNA in which this selectable marker was flanked by sequences from a native borrelial 26-kb circular plasmid. We have identified coumermycin A1-resistant transformants in which gyrB had interrupted the targeted site on the 26-kb plasmid via homologous recombination with the flanking sequences. Antibiotic resistance conferred by the mutated gyrB gene on the plasmid is dominant, and transformed spirochetes carrying this plasmid do not contain any unaltered copies of the plasmid. Coumermycin A1 resistance can be transferred to naive B. burgdorferi by transformation with borrelial plasmid DNA from the initial transformants. This work represents the first example of a directed mutation in B. burgdorferi whereby a large segment of heterologous DNA (gyrB) has been inserted via homologous recombination with flanking sequences, thus demonstrating the feasibility of specific gene inactivation by allelic exchange.


Clonal variation in the B-lineage acute lymphoblastic leukemia response to multiple cytokines and bone marrow stromal cells.
The acquisition of genetic abnormalities in human B-lineage acute lymphoblastic leukemia (ALL) culminates in the clonal expansion of bone marrow (BM)-derived leukemic blasts. However, the response of leukemic cells to signals transduced by the BM microenvironment is not completely understood. The present study describes a new human B-lineage ALL cell line designated BLIN-4 (B LINeage-4). BLIN-4 cells respond to multiple cytokines/human BM stromal cell-derived molecules. One subline (BLIN-4E) undergoes cell death in the absence of BM stromal cells or cytokines and slowly proliferates on human BM stromal cells supplemented with interleukin (IL)-7 + FLT3-ligand. Another subline (BLIN-4L) slowly proliferates in the absence of cytokines and BM stromal cells and shows robust proliferation on BM stromal cells supplemented with IL-7 + FLT3-ligand. Although human BM stromal cells are comparable with IL-7 + FLT3-ligand in supporting proliferation of BLIN-4L cells, neutralizing antibody experiments demonstrate that BLIN-4L expansion on BM stromal cells is IL-7/FLT3-ligand independent. BLIN-4L could also respond to human thymic stromal lymphopoietin. BLIN-4E and BLIN-4L have the identical immunoglobulin heavy chain rearrangement and a CD10(+)/CD19(+)/CD20(-)/CD22(+)/CD40(+)/mu heavy chain(-) phenotype. The original BM leukemic blasts harbored a ring chromosome 4 with a low percentage of cells also having either trisomy 8 or trisomy 18. The BLIN-4 sublines maintained the ring chromosome 4, but the trisomy 8 and trisomy 18 segregated into BLIN-4E and BLIN-4L, respectively. Thus, the BLIN-4 sublines exhibit biological characteristics consistent with a potential evolution in B-lineage ALL involving subclones with decreasing requirements on the BM microenvironment.


A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas.
Uncontrolled local growth is the cause of death in ∼ 30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk. The authors compared DS, PBS, and IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test. Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p < 0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6-53.8 and 34.9-52.4 Gy for duodenum using DS and PBS, respectively; p < 0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (<5% and 10%, respectively; p < 0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning. Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.


Exploring the tunable excitation of QDs to maximize the overlap with the absorber for inner filter effect-based phosphorescence sensing of alkaline phosphatase.
The inner filter effect (IFE) is an effective way for fluorescence modulation and thus has been extensively explored for the development of fluorescence assays. Theoretically, the key to maximize the sensitivity of IFE-based fluorescence assays is to enlarge the overlap between the absorption of the absorber and the excitation/emission of the fluorophore. Therefore, in this work, the tunable excitation of quantum dots (QDs) was explored for screening of the IFE pair having the best IFE-based assay sensitivity. A series of QDs, including CdTe QDs with different sizes, carbon dots, Cu-doped CdS QDs, and Mn-doped ZnS QDs, were investigated. PNPP (p-nitrophenylphosphate) was chosen as the absorber since its absorption overlapped with the above QDs. Besides, it can be catalytically converted to p-nitrophenol (PNP) by alkaline phosphatase (ALP) together with an absorption spectrum change (red-shift). Interestingly, it was found that the IFE efficiency of different PNPP-QD pairs increased almost linearly with the corresponding spectral overlap, and Mn-doped ZnS QDs were eventually chosen for the IFE assay of ALP because of the maximum spectral overlap and thus the best sensitivity. A simple and sensitive turn-on phosphorescence ALP assay was developed, with a detection limit of 4 × 10-4 U L-1. Because of the high sensitivity, we also found that ALP of different origins possessed different enzymatic activities. The developed ALP phosphorescence assay was successfully employed for the analysis of ALP in serum samples.


Relationship between quantity of undergraduate science preparation and preclinical performance in medical school.
The primary purpose of this study was to determine whether a relationship existed between the quantities of undergraduate science education completed by medical students and their subsequent preclinical performances in medical school. The secondary purpose of the study was to determine the nature of any relationship present and to re-verify standard predictors of preclinical performance in medical school. This study was undertaken at Albany Medical College in conjunction with Sage Graduate School, Albany, New York. The analysis encompassed 120 systematically and 80 randomly selected medical student academic records (200 total cases) from the entering classes of 1977 through 1992. Twelve distinct variables were collected. Data transformations were completed as required, and the data subsequently standardized. Standard descriptive statistics, correlation between variables, t-tests between systematically and randomly selected groups, and factor analysis were performed on the data collected. It was determined that there was no significant relationship between total hours of undergraduate science completed and average preclinical performance in medical school. In addition, correlation between subdivisions of total hours of undergraduate science (total hours of chemistry, total hours of biology, total hours of math, and total hours of physics) and subdivisions of average preclinical performance (year-one preclinical performance and year-two preclinical performance) also proved to be nonsignificant. However, significant relationships between average preclinical performance and its subdivisions and other standard predictors of preclinical performance (Medical College Admission Test score and science grade-point average) were found to be in line with values in recent literature. In addition, significant relationships were found with the National Board of Medical Examiners Part I examination. Factor analysis of all variables yielded three underlying factors: medical school preclinical performance factor, undergraduate performance factor, and quantity of non-life-sciences factor. Quantity of science-based undergraduate premedical education, either in its entirety or in subdivisions, did not materially affect the performances of the selected medical school students in their preclinical years of medical school.


Scattered light measurements on textured crystalline silicon substrates using an angle-resolved Mueller matrix polarimeter.
Dry plasma etching is a promising technique for crystalline silicon surface texturing aimed at improving solar cell efficiencies by reducing incident light reflection and backscattering at the cell front surface. In this work we present a new optical characterization technique for textured surfaces based on a Mueller polarimeter coupled with a high numerical aperture microscope operated either in real or in angular spaces. This tool provides both the specularly reflected and the angle-resolved backscattered intensities in a very efficient manner, due to the absence of moving parts. Three different silicon samples were etched in a standard reactor with SF(6)/O(2) plasmas at various RF powers, resulting in different textures that were characterized by scanning electron microscopy, standard reflectometry, and by our tool. The three techniques yielded consistent results. However, reflectometry could not take into account the backscattered light from highly textured surfaces, leading to significant underestimation of the overall amount of the reflected light. In contrast, our tool has demonstrated the potential to measure both reflected and backscattered light quickly and efficiently for all samples, paving the way for a new characterization technique for textured solar cells both at the development and at the production stage.


Untangling the role of diverse social dimensions in the diffusion of microfinance.
Ties between individuals on a social network can represent different dimensions of interactions, and the spreading of information and innovations on these networks could potentially be driven by some dimensions more than by others. In this paper we investigate this issue by studying the diffusion of microfinance within rural India villages and accounting for the whole multilayer structure of the underlying social networks. We define a new measure of node centrality, diffusion versatility, and show that this is a better predictor of microfinance participation rate than previously introduced measures defined on aggregated single-layer social networks. Moreover, we untangle the role played by each social dimension and find that the most prominent role is played by the nodes that are central on layers concerned with trust, shedding new light on the key triggers of the diffusion of microfinance.


Dietary inflammatory index and inflammatory biomarkers in adolescents from LabMed physical activity study.
The dietary inflammatory index (DII) is a tool to measure the diet's inflammatory potential and has been used with adults to predict low-grade inflammation. The present study aims to assess whether this dietary score predicts low-grade inflammation in adolescents. The sample comprises 329 adolescents (55.9% girls), aged 12-18 years, from LabMed Physical Activity Study. DII score was calculated based on a food-frequency questionnaire and categorized into tertiles. We collected blood samples to determine the follow inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), complement component 3 (C3), and 4 (C4). In addition we calculated an overall inflammatory biomarker score. Odds ratios (OR) and 95% confidence intervals (95%CI) were computed from binary logistic regression models. DII score, comparing first with third tertile, was positively associated with IL-6 in crude model (OR = 1.88, 95%CI:1.09-3.24, p trend = 0.011) and in fully adjusted (for biological and lifestyle variables) (OR = 3.38, 95%CI:1.24-9.20, p trend = 0.023). Also, DII score was positively associated with C4, when fully adjusted (OR = 3.12, 95%CI:1.21-8.10, p trend = 0.016). DII score was negatively associated with C3 in crude model, comparing first with second but not with third tertile, and no significant associations in fully adjusted model were observed, although a trend was found (OR = 1.71, 95%CI:0.63-4.66, p trend = 0.044). No significant associations were observed between DII score and CRP. However, DII score was positively associated with the overall inflammatory biomarker score, when fully adjusted (OR = 5.61, 95%CI:2.00-15.78, p trend = 0.002). DII score can be useful to assess the diet's inflammatory potential and its association with low-grade inflammation in adolescents.


Nitric oxide activation of p38 mitogen-activated protein kinase in 293T fibroblasts requires cGMP-dependent protein kinase.
An increase in cellular levels of cyclic nucleotides activates serine/threonine-dependent kinases that lead to diverse physiological effects. Recently we reported the activation of the p38 mitogen-activated protein kinase (MAPK) pathway in neutrophils by a cGMP-dependent mechanism. In this study we demonstrated that exogenously supplied nitric oxide leads to activation of p38 MAPK in 293T fibroblasts. Phosphorylation of p38 corresponded with an increase in ATF-2-dependent gene expression. The effect of nitric oxide was mimicked by addition of 8-bromo-cGMP, indicating that activation of soluble guanylyl cyclase was involved. The importance of cGMP-dependent protein kinase in the activation of p38 MAPK by nitric oxide in 293T cells was assessed in a transfection based assay. Overexpression of cGMP-dependent protein kinase-1alpha caused phosphorylation of p38 in these cells and potentiated the effectiveness of cGMP. Overexpression of a catalytically inactive mutant form of this enzyme (T516A) blocked the ability of both nitric oxide and 8-bromo-cGMP to activate p38 as measured by both p38 phosphorylation and ATF-2 driven gene expression. Together, these data demonstrate that nitric oxide stimulates a novel pathway leading to activation of p38 MAPK that requires activation of cGMP-dependent protein kinase.


Individualized estimates of overdiagnosis in screen-detected prostate cancer.
The chance that a prostate cancer detected by screening is overdiagnosed (ie, it would not have been detected in the absence of screening) can vary widely depending on the patient's age and tumor characteristics. The purpose of this study is to use age, Gleason score, and prostate-specific antigen (PSA) level to help inform patients with screen-detected prostate cancers about the chances their cancers were overdiagnosed. A computer microsimulation model of prostate cancer natural history was used to generate virtual life histories in the presence and absence of PSA screening, including an indicator of whether screen-detected cancers are overdiagnosed. A logistic regression model was fit to nonmetastatic patients diagnosed by screening with PSA less than 10 ng/mL, and a nomogram was created to predict the individualized risk of overdiagnosis given age, Gleason score, and PSA at diagnosis. The calibrated microsimulation model closely reproduces observed incidence trends in the Surveillance, Epidemiology, and End Results registries by age, stage, and Gleason score. The fitted logistic regression predicts risks of overdiagnosis among PSA-detected patients with an area under the curve of 0.75. Chances of overdiagnosis range from 2.9% to 88.1%. The chances of overdiagnosis vary considerably by age, Gleason score, and PSA at diagnosis. The overdiagnosis nomogram presents tailored estimates of these risks based on patient and tumor information known at diagnosis and can be used to inform decisions about treating PSA-detected prostate cancers.


Antiviral combination therapy with peginterferon and ribavirin does not induce a therapeutically resistant mutation in the HCV core region regardless of genetic polymorphism near the IL28B gene.
An association has been reported between genetic polymorphism near IL28B gene and the prevalence of mutation of hepatitis C virus (HCV) core region residue 70, both of which have been associated with a lack of virologic response to antiviral combination therapy with peginterferon (PEG-IFN) and ribavirin. This study investigated whether PEG-IFN/ribavirin combination therapy induces amino acid (AA) mutation at residue 70 of HCV and whether genetic polymorphism near IL28B gene affects it. AA substitutions at residue 70 of the HCV core region were measured and compared before and after combination therapy in 65 non-responders and 88 relapsers to the combination therapy. In three patients in whom both wild-type AA (arginine) and mutant-type AA (glutamine or histidine) were detected at residue 70 before treatment, only mutant-type AA was identified after treatment. In two patients who had wild-type AA solely before treatment, both wild-type and mutant-type AAs were identified at residue 70 after treatment. In five patients, in whom the AA had changed at residue 70 between before and after treatment, four patients carried the TT genotype at a polymorphic locus (rs8099917) near the IL28B gene and one carried the TG/GG genotype. No difference was found in the prevalence of this change of AA at residue 70 between the TT and the TG/GG genotype. Antiviral combination therapy with PEG-IFN and ribavirin does not appear to induce mutation of HCV core region residue 70 regardless of genetic polymorphism near the IL28B gene in Japanese patients infected with HCV genotype 1b.


The energetically optimal cadence decreases after prolonged cycling exercise.
This study investigated the change in the energetically optimal cadence after prolonged cycling. The energetically optimal cadence (EOC) was determined in 14 experienced cyclists by pulmonary gas exchange at six different cadences (100-50 rpm at 10 rpm intervals). The determination of the EOC was repeated after a prolonged cycling exercise of 55 min duration, where cadence was fixed either at high (>95 rpm) or low (<55 rpm) pedalling rates. The EOC decreased after prolonged cycling exercise at a high as well as at a low fixed cadence (P < 0.01). According to the generalized muscle equations of Hill, this indicates that most likely more type I muscle fibres contribute to muscular power output after fatiguing cycling exercise compared to cycling in the beginning of an exercise bout. We suggest that the determination of EOC might be a potential non-invasive method to detect the qualitative changes in activated muscle fibres, which needs further investigation.


Does low-molecular-weight heparin influence the antimyeloma effects of thalidomide? A retrospective analysis of data from the GIMEMA, Nordic and Turkish myeloma study groups.
Low-molecular-weight heparin (LMWH) has been shown to prolong survival among patients with solid tumors, but its role among myeloma patients is unknown. Data from the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto), Nordic and Turkish myeloma study groups comparing melphalan and prednisolone with (MPT, n: 404) or without thalidomide (MP, n: 393) are analyzed for effects of LMWH. Forty percent (159/394) of the patients on MPT and 7.4% (29/390) in the MP arm received LMWH. Thalidomide improved response and progression-free survival (PFS). Regardless of thalidomide treatment, response rate was higher among those receiving LMWH vs. none vs. other anticoagulants (58.1 vs. 44.9 vs. 50.4%, p = 0.01). PFS was significantly longer (median 32 vs. 21 and 17 vs. 17 months, p = 0.004) only among international scoring system (ISS) I patients receiving MPT ± LMWH vs. MP ± LMWH. The group of MPT patients who also received LMWH had a better OS compared to those who did not [45 months, 95% confidence interval (CI) 27.7-62.3, vs. 32 months, 95% CI 26.1-37.9; p = 0.034]. When multivariate analysis was repeated in subgroups, thalidomide was no longer a significant factor (response, PFS) among those receiving LMWH. Addition of LMWH to MPT, in particular in patients with low ISS, suggests additive effects, but the results are limited by the retrospective design of our study.


Acoustic mirrors as sensory traps for bats.
Sensory traps pose a considerable and often fatal risk for animals, leading them to misinterpret their environment. Bats predominantly rely on their echolocation system to forage, orientate, and navigate. We found that bats can mistake smooth, vertical surfaces as clear flight paths, repeatedly colliding with them, likely as a result of their acoustic mirror properties. The probability of collision is influenced by the number of echolocation calls and by the amount of time spent in front of the surface. The echolocation call analysis corroborates that bats perceive smooth, vertical surfaces as open flyways. Reporting on occurrences with different species in the wild, we argue that it is necessary to more closely monitor potentially dangerous locations with acoustic mirror properties (such as glass fronts) to assess the true frequency of fatalities around these sensory traps.


Age and Environment Influences on Mouse Prion Disease Progression: Behavioral Changes and Morphometry and Stereology of Hippocampal Astrocytes.
Because enriched environment (EE) and exercise increase and aging decreases immune response, we hypothesized that environmental enrichment and aging will, respectively, delay and increase prion disease progression. Mice dorsal striatum received bilateral stereotaxic intracerebral injections of normal or ME7 prion infected mouse brain homogenates. After behavior analysis, animals were euthanized and their brains processed for astrocyte GFAP immunolabeling. Our analysis related to the environmental influence are limited to young adult mice, whereas age influence refers to aged mice raised on standard cages. Burrowing activity began to reduce in ME7-SE two weeks before ME7-EE, while no changes were apparent in ME7 aged mice (ME7-A). Object placement recognition was impaired in ME7-SE, NBH-A, and ME7-A but normal in all other groups. Object identity recognition was impaired in ME7-A. Cluster analysis revealed two morphological families of astrocytes in NBH-SE animals, three in NBH-A and ME7-A, and four in NBH-EE, ME7-SE, and ME7-EE. As compared with control groups, astrocytes from DG and CA3 prion-diseased animals show significant numerical and morphological differences and environmental enrichment did not reverse these changes but induced different morphological changes in GFAP+ hippocampal astroglia. We suggest that environmental enrichment and aging delayed hippocampal-dependent behavioral and neuropathological signs of disease progression.


The appearance of an L1-like molecule in the chick primary visual pathway.
A monoclonal antibody, 8D9, has been obtained that binds to axons in the chick nervous system. Biochemical and immunological experiments indicate that the 8D9 antigen is related to the mouse L1 cell-adhesion molecule. The results of immunohistochemical experiments using monoclonal antibody 8D9 to study the development of the chick visual system are consistent with the 8D9 antigen functioning in axon fasciculation.


Evidence-based decision-making within Australia's pharmaceutical benefits scheme.
In Australia, most prescription drugs are subsidized through the Pharmaceutical Benefits Scheme (PBS), one of several government programs in which evidence-based decision making is applied to the funding of health technologies. PBS processes are intended to ensure "value for money" for the Australian taxpayer and to support affordable, equitable access to prescription medicines; they are not intended as a mechanism for cost containment. The inclusion of a drug on the national formulary depends on the recommendation of the Pharmaceutical Benefits Advisory Committee (PBAC), which considers not only the comparative effectiveness but also the comparative cost-effectiveness of drugs proposed for listing. While some decisions have been controversial, the PBS retains strong public support. Moreover, evidence does not suggest that the consideration of cost-effectiveness has created a negative environment for the drug industry: Australia has a high penetration of patented medicines, with prices for some recently approved drugs at U.S. levels.


Two-photon spectral imaging with high temporal and spectral resolution.
We introduce a fast spectral imaging system using an electron-multiplying charge-coupled device (EM-CCD) as a detector. Our system is combined with a custom-built two-photon excitation laser scanning microscope and has 80 detection channels, which allow for high spectral resolution and fast frame acquisition without any loss of spectral information. To demonstrate the efficiency of our approach, we applied this technology to monitor fluorescent proteins and quantum dot-labeled G protein-coupled receptors in living cells as well as autofluorescence in tissue samples.


PET Imaging Reveals Early Pulmonary Perfusion Abnormalities in HIV Infection Similar to Smoking.
Chronic obstructive pulmonary disease (COPD) is the most common noninfectious pulmonary disease among people living with HIV, independent of smoking. However, the cause for this enhanced susceptibility remains unclear, and the effects of HIV on pulmonary perfusion and ventilation are unknown. Methods: We used PET/CT in 46 smokers and nonsmokers, 23 of whom had documented HIV infection. Emphysema was assessed by CT and perfusion by 13N (13NN) PET scans. After removal of image noise, vertical and axial gradients in perfusion were calculated. We tested for differences in the total spatial heterogeneity of perfusion (CV2Qtotal) and its components (CV2Qtotal = CV2Qvgrad [vertical gradient] + CV2Qzgrad [axial gradient] + CV2Qr [residual heterogeneity]) among groups. Results: There were no significant differences in demographic parameters among groups, and all subjects had minimal radiographic evidence of emphysema. Compared with controls, nonsmokers living with HIV had a significantly greater CV2Qr/CV2Qtotal (0.48 vs. 0.36, P = 0.05) and reduced CV2Qvgrad/CV2Qtotal (0.46 vs. 0.65, P = 0.038). Smokers also had a reduced CV2Qvgrad/CV2Qtotal, however, there was no significant difference in CV2Qvgrad/CV2Qtotal between smokers living with and without HIV (0.39 vs. 0.34, P = 0.58), despite a decreased vertical perfusion gradient (Qvgrad) in smokers living with HIV. Conclusion: In nonsmokers living with well-controlled HIV and minimal radiographic emphysema, HIV infection contributes to pulmonary perfusion abnormalities similar to smokers. These data indicate the onset of subclinical pulmonary perfusion abnormalities that could herald the development of significant lung disease in these susceptible individuals.


Internal structure and early thermal evolution of Mars from Mars Global Surveyor topography and gravity.
Topography and gravity measured by the Mars Global Surveyor have enabled determination of the global crust and upper mantle structure of Mars. The planet displays two distinct crustal zones that do not correlate globally with the geologic dichotomy: a region of crust that thins progressively from south to north and encompasses much of the southern highlands and Tharsis province and a region of approximately uniform crustal thickness that includes the northern lowlands and Arabia Terra. The strength of the lithosphere beneath the ancient southern highlands suggests that the northern hemisphere was a locus of high heat flow early in martian history. The thickness of the elastic lithosphere increases with time of loading in the northern plains and Tharsis. The northern lowlands contain structures interpreted as large buried channels that are consistent with northward transport of water and sediment to the lowlands before the end of northern hemisphere resurfacing.


Ligand discrimination in signaling through an ErbB4 receptor homodimer.
The epidermal growth factor (EGF)-like family of growth factors elicits cellular responses by stimulating the dimerization, autophosphorylation, and tyrosine kinase activities of the ErbB family of receptor tyrosine kinases. Although several different EGF-like ligands are capable of binding to a single ErbB family member, it is generally thought that the biological and biochemical responses of a single receptor dimer to different ligands are indistinguishable. To test whether an ErbB receptor dimer is capable of discriminating among ligands we have examined the effect of four EGF-like growth factors on signaling through the ErbB4 receptor homodimer in CEM/HER4 cells, a transfected human T cell line ectopically expressing ErbB4 in an ErbB-null background. Despite stimulating similar levels of gross receptor tyrosine phosphorylation, the EGF-like growth factors betacellulin, neuregulin-1beta, neuregulin-2beta, and neuregulin-3 exhibited different biological potencies in a cellular growth assay. Moreover, the different ligands induced different patterns of recruitment of intracellular signaling proteins to the activated receptor and induced differential usage of intracellular kinase signaling cascades. Finally, two-dimensional phosphopeptide mapping of ligand-stimulated ErbB4 revealed that the different growth factors induce different patterns of receptor tyrosine phosphorylation. These results indicate that ErbB4 activation by growth factors is not generic and suggest that individual ErbB receptors can discriminate between different EGF-like ligands within the context of a single receptor dimer. More generally, our observations significantly modify our understanding of signaling through receptor tyrosine kinases and point to a number of possible models for ligand-mediated signal diversification.


Different Segments within Vertebrate Muscles Can Operate on Different Regions of Their Force-Length Relationships.
To relate in vivo behavior of fascicle segments within a muscle to their in vitro force-length relationships, we examined the strain behavior of paired segments within each of three vertebrate muscles. After determining in vivo muscle activity patterns and length changes of in-series segments within the semimembranosus muscle (SM) in the American Toad (Bufo americanus) during hopping and within the sternohyoid (SH) muscle in the rat (Rattus rattus) during swallowing, and of spatially separated fascicles within the medial gastrocnemius (MG) muscle in the rat during trotting, we measured their corresponding in vitro (toad) or in situ (rat) force-length relationships (FLRs). For all three muscles, in vivo strain heterogeneity lasted for about 36-57% of the behavior cycle, during which one segment or fascicle shortened while the other segment or fascicle simultaneously lengthened. In the toad SM, the proximal segment shortened from the descending limb across the plateau of its FLR from 1.12 to 0.91 of its optimal length (Lo), while the distal segment lengthened (by 0.04 ± 0.04 Lo) before shortening down the ascending limb from 0.94 to 0.83 Lo. In the rat SH muscle, the proximal segment tended to shorten on its ascending limb from 0.90 to 0.85 Lo while the distal segment tended to lengthen across Lo (0.96-1.12 Lo). In the rat MG muscle, in vivo strains of proximal fascicles ranged from 0.72 to 1.02 Lo, while the distal fascicles ranged from 0.88 to 1.11 Lo. Even though the timing of muscle activation patterns were similar between segments, the heterogeneous strain patterns of fascicle segments measured in vivo coincided with different operating ranges across their FLRs simultaneously, implying differences in force-velocity behavior as well. The three vertebrate skeletal muscles represent a diversity of fiber architectures and functions and suggest that patterns of in vivo contractile strain and the operating range over the FLR in one muscle region does not necessarily represent other regions within the same muscle.


Analysis of fimbrial gene clusters and their expression in enterohaemorrhagic Escherichia coli O157:H7.
The sequence of two enterohaemorrhagic Escherichia coli (EHEC) O157:H7 strains reveals the possession of at least 16 fimbrial gene clusters, many of the chaperone/usher class. The first part of this study examined the distribution of these clusters in a selection of EHEC/EPEC (enteropathogenic E. coli) serotypes to determine if any were likely to be unique to E. coli O157:H7. Six of the clusters, as determined by the presence of amplified main subunit or usher gene sequences, were detected only in the E. coli O157 and O145 serotypes tested. With the exception of one serotype O103 strain that contained an lpf2 cluster, lpf sequences were only detected in E. coli O157 of the serotypes tested. Expression from each cluster was measured by the construction of chromosomally integrated lacZ promoter fusions and plasmid-based eGFP fusions in E. coli O157:H7. This analysis demonstrated that the majority (11/15) of main fimbrial subunit genes were not expressed under the majority of conditions tested in vitro. One of the clusters showing promoter activity, loc8, has a temperature expression optimum indicating a possible role outside the host. From the presence of pseudogenes in three of the clusters, the lack of FimH-like minor adhesins in the clusters and their limited expression in vitro, it would appear that E. coli O157:H7 has a limited repertoire of expressed functional fimbriae. This restricted selection of fimbriae may be important in bringing about the tropism E. coli O157:H7 demonstrates for the terminal rectum of cattle.


Enhanced systolic myocardial function in elite endurance athletes during combined arm-and-leg exercise.
The aim here was to employ color tissue velocity imaging (TVI), to test the hypothesis that highly trained endurance athletes exhibit enhanced systolic function of the left ventricular (LV) myocardium both at rest and during combined arm-and-leg exercise in comparison with untrained subjects. For each of the ten elite male (EG) and ten matched control participants (CG), LV dimensions and systolic function were assessed at rest using echocardiography. Subsequently, these subjects exercised continuously on a combined arm-and-leg cycle ergometer for 3 min each at 50, 60, 70, 80, 90 and 100% of VO(2max). Oxygen uptake, heart rate, systolic blood pressure (SBP) and peak contraction systolic velocities of the LV myocardium (PSV) were recorded in the end of each level. At rest, the trained and untrained groups differed with respect to LV dimensions, but not systolic function. At 60-100% VO(2max), the EG group demonstrated both higher PSV and SBP. The observation that the EG athletes had higher PSV than CG during exercise at 60-100% VO(2max), but not at rest or at 50% of VO(2max), suggested an enhanced systolic capacity. This improvement is likely to be due to an enhanced inotropic contractility, which only becomes apparent during exercise.


Generalized friendship paradox in complex networks: the case of scientific collaboration.
The friendship paradox states that your friends have on average more friends than you have. Does the paradox "hold" for other individual characteristics like income or happiness? To address this question, we generalize the friendship paradox for arbitrary node characteristics in complex networks. By analyzing two coauthorship networks of Physical Review journals and Google Scholar profiles, we find that the generalized friendship paradox (GFP) holds at the individual and network levels for various characteristics, including the number of coauthors, the number of citations, and the number of publications. The origin of the GFP is shown to be rooted in positive correlations between degree and characteristics. As a fruitful application of the GFP, we suggest effective and efficient sampling methods for identifying high characteristic nodes in large-scale networks. Our study on the GFP can shed lights on understanding the interplay between network structure and node characteristics in complex networks.


A Daytime Nap Facilitates Generalization of Word Meanings in Young Toddlers.
One of the key processes in language development is generalization--the selection and extension of relevant features and information to similar objects and concepts. Little is known about how sleep influences generalization, and studies on the topic are inconclusive. Our aim was to investigate how a nap affects generalization in 16-mo-olds. We hypothesized that a nap is necessary for successful generalization of word meanings. Twenty-eight 16-mo-old, typically developing toddlers were randomly assigned to nap and wake groups. We trained toddlers with two novel object-word pairs and tested their initial ability to generalize. Toddlers took part in an intermodal preferential looking task, in which they were shown different colored versions of the original objects and heard one of the trained labels. If toddlers understand the label, they are expected to increase their looking time to the target. Looking behavior was measured with an automated eye tracker. Afterward, the nap group went to sleep, while the wake group stayed awake for approximately 2 h. We then repeated the test of their performance on the generalization task. A significant interaction of group and session was found in preferential looking. The performance of the nap group increased after the nap, whereas that of the wake group did not change. Our results suggest that napping improves generalization in toddlers.


Compositional syntax from cultural transmission.
A growing body of work demonstrates that syntactic structure can evolve in populations of genetically identical agents. Traditional explanations for the emergence of syntactic structure employ an argument based on genetic evolution: Syntactic structure is specified by an innate language acquisition device (LAD). Knowledge of language is complex, yet the data available to the language learner are sparse. This incongruous situation, termed the "poverty of the stimulus," is accounted for by placing much of the specification of language in the LAD. The assumption is that the characteristic structure of language is somehow coded genetically. The effect of language evolution on the cultural substrate, in the absence of genetic change, is not addressed by this explanation. We show that the poverty of the stimulus introduces a pressure for compositional language structure when we consider language evolution resulting from iterated observational learning. We use a mathematical model to map the space of parameters that result in compositional syntax. Our hypothesis is that compositional syntax cannot be explained by understanding the LAD alone: Compositionality is an emergent property of the dynamics resulting from sparse language exposure.


Summing up: lessons from a comprehensive community prevention trial.
This paper presents the findings and lessons from a community prevention trial involving three experimental communities in the United States to reduce alcohol-involved trauma. The paper provides recommendations for other community prevention efforts. Effectiveness was demonstrated by: (a) 78 fewer alcohol-involved traffic crashes as a result of the Drinking and Driving Component alone (approximately a 10% reduction); (b) a significant reduction in underage sales of alcohol, i.e. off-premise outlets sold to minors about one-half as often as in comparison communities; (c) increased implementation of responsible beverage service policies by bars and restaurants; and (d) increased adoption of local ordinances and regulations to reduce concentrations of alcohol outlets.


Interaural time difference processing in the mammalian medial superior olive: the role of glycinergic inhibition.
The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed.


Progression to unscheduled hospital admissions in people with diabetes: a qualitative interview study.
People with diabetes often have difficulty maintaining optimal blood glucose levels, risking progressive complications that can lead to unscheduled care. Unscheduled care can include attending emergency departments, ambulance callouts, out-of-hours care, and non-elective hospital admissions. A large proportion of non-elective hospital admissions involve people with diabetes, with significant health and economic burden. To identify precipitating factors influencing diabetes-related unscheduled hospital admissions, exploring potential preventive strategies to reduce admissions. Thirty-six people with type 1 (n = 11) or type 2 (n = 25) diabetes were interviewed. They were admitted to hospital for unscheduled diabetes-related care across three hospitals in Scotland, Northern Ireland, and the Republic of Ireland. Participants were admitted for peripheral limb complications (n = 17), hypoglycaemia (n = 5), hyperglycaemia (n = 6), or for comorbidities presenting with erratic blood glucose levels (n = 8). Factors precipitating admissions were examined using framework analysis. Three aspects of care influenced unscheduled admissions: perceived inadequate knowledge of diabetes complications; restricted provision of care; and complexities in engagement with self-care and help-seeking. Limited specialist professional knowledge of diabetes by staff in primary and community care, alongside inadequate patient self-management knowledge, led to inappropriate treatment and significant delays. This was compounded by restricted provision of care, characterised by poor access to services - in time and proximity - and poor continuity of care. Complexities in patient engagement, help-seeking, and illness beliefs further complicated the progression to unscheduled admissions. Dedicated investment in primary care is needed to enhance provision of and access to services. There should be increased promotion and earlier diabetes specialist team involvement, alongside training and use of technology and telemedicine, to enhance existing care.


Excited State Properties of Hybrid Perovskites.
Metal halide perovskites have come to the attention of the scientific community for the progress achieved in solar light conversion. Energy sustainability is one of the priorities of our society, and materials advancements resulting in low-cost but efficient solar cells and large-area lighting devices represent a major goal for applied research. From a basic point of view, perovskites are an exotic class of hybrid materials combining some merits of organic and inorganic semiconductors: large optical absorption, large mobilities, and tunable band gap together with the possibility to be processed in solution. When a novel class of promising semiconductors comes into the limelight, lively discussions ensue on the photophysics of band-edge excitations, because just the states close to the band edge are entailed in energy/charge transport and light emission. This was the case several decades ago for III-V semiconductors, it has been up to 10 years ago for organics, and it is currently the case for perovskites. Our aim in this Account is to rationalize the body of experimental evidence on perovskite photophysics in a coherent theoretical framework, borrowing from the knowledge acquired over the years in materials optoelectronics. A crucial question is whether photon absorption leads to a population of unbound, conductive free charges or instead excitons, neutral and insulating bound states created by Coulomb interaction just below the energy of the band gap. We first focus on the experimental estimates of the exciton binding energy (Eb): at room temperature, Eb is comparable to the thermal energy kBT in MAPbI3 and increases up to values 2-3kBT in wide band gap MAPbBr3 and MAPbCl3. Statistical considerations predict that these values, even though comparable to or larger than thermal energy, let free carriers prevail over bound excitons for all levels of excitation densities relevant for devices. The analysis of photophysics evidence confirms that all hybrid halide perovskites behave as free-charge semiconductors. Thanks to such property, in combination with band gap energies covering the entire solar spectrum, perovskites represent a promising materials platform for highly efficient, single and multijunction solar cells. Concerning the use of perovskites as color-tunable materials in light emitting devices, free-charges are not the preferred species, as they recombine radiatively through a bimolecular process that is inefficient at the charge-injection levels typical of LED operation. Strategies to overcome this limit, and thus extend the use of perovskite materials beyond solar energy conversion, could be borrowed from inorganic semiconductor optoelectronics and include the fabrication of nanostructures with reduced dimensionality to alter the electronic density of states, as well as engineering composite materials.


Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis.
We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk. We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women's Heart and Health Study (4,286 women aged 60-80) and the Caerphilly Cohort (2,398 men aged 45-59) using Cox regression and pooled our findings with previous prospective studies' in fixed and random effects meta-analyses. CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk. Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.


Effects of Pile Driving on the Residency and Movement of Tagged Reef Fish.
The potential effects of pile driving on fish populations and commercial fisheries have received significant attention given the prevalence of pile driving occurring in coastal habitats throughout the world. Behavioral impacts of sound generated from these activities on fish typically have a greater area of influence than physical injury, and may therefore adversely affect a greater portion of the local population. This study used acoustic telemetry to assess the movement, residency, and survival of 15 sheepshead (Archosargus probatocephalus) and 10 grey snapper (Lutjanus griseus) in Port Canaveral, Florida, USA, in response to 35 days of pile driving at a wharf complex. No obvious signs of mortality or injury to tagged fish were evident from the data. Received sound pressure levels from pile strikes on the interior of the wharf, where reef fish primarily occur, were on average 152-157 dB re 1 μPa (peak). No significant decrease in sheepshead daytime residency was observed during pile driving within the central portion of the wharf and area of highest sound exposure, and no major indicators of displacement from the exposure wharf with the onset of pile driving were observed. There was evidence of potential displacement from the exposure wharf that coincided with the start of pile driving observed for 2 out of 4 grey snapper, along with a decrease in daytime residency for a subset of this species with high site fidelity prior to the event. Results indicate that snapper may be more likely to depart an area of pile driving disturbance more readily than sheepshead, but were less at risk for behavioral impact given the lower site fidelity of this species.


Temporal folate status during lactation in mares and growth in foals.
To identify changes in folate status of mares and foals during lactation and growth, respectively. 20 Thoroughbred mares and foals. Pregnant mares, and following foaling the same mares with their foals, were maintained on mixed grass-legume pasture and fed either a traditional dietary supplement rich in sugar and starch (SS) or a dietary supplement high in fat and fiber (FF). Blood samples were collected monthly from mares and foals up to 6 months after foaling. Total folate concentration in feed and forage was determined. Analyses of plasma folate, RBC folate, plasma homocysteine (HCY), and milk folate concentrations were performed. Mare plasma folate concentrations declined moderately during 6 months of lactation. Mare RBC folate concentrations initially increased after foaling up to 3 months but declined toward the end of the study. Plasma HCY concentration was higher for mares fed the SS supplement, compared with mares fed the FF supplement from foaling to 6 months of lactation. Milk folate concentrations decreased during the first 3 months and then increased. Foal plasma folate initially declined but then increased. Stable concentrations of RBC folate were observed in foals. Plasma HCY concentrations in foals were unaffected by growth during the last 5 months. References range values for plasma folate, RBC folate, milk folate, and plasma HCY concentrations in healthy lactational mares and young growing foals were determined. Folate status was not impaired in lactating mares and growing foals under the conditions in our study. It appears that folate supplementation is not necessary.


Cryoprotection of lipid membranes for high-resolution solid-state NMR studies of membrane peptides and proteins at low temperature.
Solid-state NMR spectra of membrane proteins often show significant line broadening at cryogenic temperatures. Here we investigate the effects of several cryoprotectants to preserve the spectral resolution of lipid membranes and membrane peptides at temperatures down to ~200 K. Trehalose, glycerol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), and polyethylene glycol (PEG), were chosen. These compounds are commonly used in protein crystallography and cryobiology. 13C and 1H magic-angle-spinning spectra of several types of lipid membranes show that DMSO provides the best resolution enhancement over unprotected membranes and also best retards ice formation at low temperature. DMF and PEG-400 show slightly weaker cryoprotection, while glycerol and trehalose neither prevent membrane line broadening nor prevent ice formation under the conditions of our study. Neutral saturated-chain phospholipids are the most amenable to cryoprotection, whereas negatively charged and unsaturated lipids attenuate cryoprotection. 13C-1H dipolar couplings and 31P chemical shift anisotropies indicate that high spectral resolution at low temperature is correlated with stronger immobilization of the lipids at high temperature, indicating that line narrowing results from reduction of the conformational space sampled by the lipid molecules at high temperature. DMSO selectively narrowed the linewidths of the most disordered residues in the influenza M2 transmembrane peptide, while residues that exhibit narrow linewidths in the unprotected membrane are less impacted. A relatively rigid β-hairpin antimicrobial peptide, PG-1, showed a linewidth increase of ~0.5 ppm over a ~70 K temperature drop both with and without cryoprotection. Finally, a short-chain saturated lipid, DLPE, exhibits excellent linewidths, suggesting that it may be a good medium for membrane protein structure determination. The three best cryoprotectants found in this work-DMSO, PEG, and DMF-should be useful for low-temperature membrane-protein structural studies by SSNMR without compromising spectral resolution.


Can sub-Saharan Africa feed itself?
Although global food demand is expected to increase 60% by 2050 compared with 2005/2007, the rise will be much greater in sub-Saharan Africa (SSA). Indeed, SSA is the region at greatest food security risk because by 2050 its population will increase 2.5-fold and demand for cereals approximately triple, whereas current levels of cereal consumption already depend on substantial imports. At issue is whether SSA can meet this vast increase in cereal demand without greater reliance on cereal imports or major expansion of agricultural area and associated biodiversity loss and greenhouse gas emissions. Recent studies indicate that the global increase in food demand by 2050 can be met through closing the gap between current farm yield and yield potential on existing cropland. Here, however, we estimate it will not be feasible to meet future SSA cereal demand on existing production area by yield gap closure alone. Our agronomically robust yield gap analysis for 10 countries in SSA using location-specific data and a spatial upscaling approach reveals that, in addition to yield gap closure, other more complex and uncertain components of intensification are also needed, i.e., increasing cropping intensity (the number of crops grown per 12 mo on the same field) and sustainable expansion of irrigated production area. If intensification is not successful and massive cropland land expansion is to be avoided, SSA will depend much more on imports of cereals than it does today.


Plasmacytoid dendritic cells, interferon signaling, and FcγR contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia.
Immune thrombocytopenia (ITP) is an autoimmune disorder of childhood characterized by immune-mediated destruction of platelets. The mechanisms underlying the pathogenesis of ITP and the therapeutic efficacy of intravenous immunoglobulins (IVIG) in this disorder remain unclear. We show that monocytes from patients with ITP have a distinct gene expression profile, with increased expression of type I interferon response (IR) genes. Plasma from ITP patients had increased levels of several cytokines indicative of immune activation, including an increase in interferon-α. ITP patients also had an increase in plasmacytoid dendritic cells (pDCs) compared to healthy donors. Therapy-induced remission of ITP was associated with abrogation of the IR gene signature in monocytes without reduction in the levels of circulating interferon-α itself. IVIG altered the ratio of activating/inhibitory Fcγ receptors (FcγRs) in vivo primarily by reducing FcγRIII (CD16). The engagement of activating FcγRs was required for IVIG-mediated abrogation of monocyte response to exogenous interferon-α in culture. Moreover, plasma from ITP patients led to activation of monocytes and myeloid DCs in culture with an increase in T cell stimulatory capacity; this activation depended on the engagement of activating FcγRs and interferon-α receptor (IFNAR) and was inhibited by antibody-mediated blockade of these pathways. These data point to a central role of type I interferon in the pathogenesis of ITP and suggest targeting pDCs and blockade of IR as potential therapeutic approaches in this disorder. They also provide evidence for the capacity of IVIG to extinguish IR in vivo, which may contribute to its effects in autoimmunity.


Breast cancer screening: evidence of benefit depends on the method used.
In this article, we discuss the most common epidemiological methods used for evaluating the ability of mammography screening to decrease the risk of breast cancer death in general populations (effectiveness). Case-control studies usually find substantial effectiveness. However when breast cancer mortality decreases for reasons unrelated to screening, the case-control design may attribute to screening mortality reductions due to other causes. Studies based on incidence-based mortality have obtained contrasted results compatible with modest to considerable effectiveness, probably because of differences in study design and statistical analysis. In areas where screening has been widespread for a long time, the incidence of advanced breast cancer should be decreasing, which in turn would translate into reduced mortality. However, no or modest declines in the incidence of advanced breast cancer has been observed in these areas. Breast cancer mortality should decrease more rapidly in areas with early introduction of screening than in areas with late introduction of screening. Nonetheless, no difference in breast mortality trends has been observed between areas with early or late screening start. When effectiveness is assessed using incidence-based mortality studies, or the monitoring of advanced cancer incidence, or trends in mortality, the ecological bias is an inherent limitation that is not easy to control. Minimization of this bias requires data over long periods of time, careful selection of populations being compared and availability of data on major confounding factors. If case-control studies seem apparently more adequate for evaluating screening effectiveness, this design has its own limitations and results must be viewed with caution.See related Opinion article: http://www.biomedcentral.com/1741-7015/10/106 and Commentary http://www.biomedcentral.com/1741-7015/10/164.


BMP7-induced-Pten inhibits Akt and prevents renal fibrosis.
Bone morphogenetic protein-7 (BMP-7) counteracts pro-fibrotic effects of TGFβ1 in cultured renal cells and protects from fibrosis in acute and chronic renal injury models. Using the unilateral ureteral obstruction (UUO) model of chronic renal fibrosis, we investigated the effect of exogenous-rhBMP-7 on pro-fibrotic signaling pathways mediated by TGFβ1 and hypoxia. Mice undergoing UUO were treated with vehicle or rhBMP-7 (300μg/kg i.p.) every other day for eight days and kidneys analysed for markers of fibrosis and SMAD, MAPK, and PI3K signaling. In the kidney, collecting duct and tubular epithelial cells respond to BMP-7 via activation of SMAD1/5/8. Phosphorylation of SMAD1/5/8 was reduced in UUO kidneys from vehicle-treated animals yet maintained in UUO kidneys from BMP-7-treated animals, confirming renal bioactivity of exogenous rhBMP-7. BMP-7 inhibited Collagen Iα1 and Collagen IIIα1 gene expression and Collagen I protein accumulation, while increasing expression of Collagen IVα1 in UUO kidneys. Activation of SMAD2, SMAD3, ERK, p38 and PI3K/Akt signaling occurred during fibrogenesis and BMP-7 significantly attenuated SMAD3 and Akt signaling in vivo. Analysis of renal collecting duct (mIMCD) and tubular epithelial (HK-2) cells stimulated with TGFβ1 or hypoxia (1% oxygen) to activate Akt provided further evidence that BMP-7 specifically inhibited PI3K/Akt signaling. PTEN is a negative regulator of PI3K and BMP-7 increased PTEN expression in vivo and in vitro. These data demonstrate an important mechanism by which BMP-7 orchestrates renal protection through Akt inhibition and highlights Akt inhibitors as anti-fibrotic therapeutics.


Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
Photosynthesis of previtamin D3 can occur throughout the epidermis in the dermis when hypopigmented Caucasian skin is exposed to solar ultraviolet radiation. Once previtamin D3 is formed in the skin, it undergoes a temperature-dependent thermal isomerization that takes at least 3 days to complete. The vitamin D-binding protein preferentially translocates the thermal product, vitamin D3, into the circulation. These processes suggest a unique mechanism for the synthesis, storage, and slow, steady release of vitamin D3 from the skin into the circulation.


Assessment of the Association between Mean Hemoglobin A1c Levels for 5 Years and Coronary Artery Disease by Coronary Angiography in Nondiabetic Patients.
The effects of glucose on cardiovascular events or mortality in nondiabetic patients has been recently reported. However, since atherosclerosis can be formed over a long period of time, it is necessary to devote several years to unveil the relationship between the two factors. Here, we attempted to find out the relationship between the mean hemoglobin A1c (HbA1c) level and HbA1c variability for 5 years and coronary artery disease (CAD) by using coronary angiography (CAG) to assess nondiabetic patients. We reviewed patients who performed CAG who were followed up for at least 5 years after the initial diagnosis. The fasting blood test was performed annually for glucose and HbA1c level. CAD was defined as more than 50% of luminal narrowing. The severity of CAD was divided into two groups depending on whether no vessels were involved or one more vessel were involved (CAD(-) or CAD(+), respectively). The patients in CAD(+) group had higher mean HbA1c level for 5 years than CAD(-) group (5.71±0.40 vs. 5.86±0.68; P=0.04). Mean HbA1c was a significant predictor for CAD in multiple regression (odds ratio, 2.224; P=0.028). The percentage of patients with CAD was significantly higher in patients with >6.2% of mean HbA1c levels compared to patients with <6.2% of mean HbA1c levels (P<0.019). When the mean HbA1c levels were above 6.2%, the risk of CAD was higher. Also this study shows that HbA1c level can be one of the predictors for CAD even if the patients do not have diabetes.


Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain.
Kava, an intoxicating beverage prepared from the pepper plant Piper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAA binding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X-100, suggesting that lipid soluble components were involved. No effects were observed on GABAB binding sites in rat brain membranes in vitro. Kava resin and pyrones exerted some weak effects on benzodiazepine binding in vitro but this did not correlate with pharmacological activity. In addition, in ex vivo studies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by greater than 95%. Similar lack of activity was observed in in vivo binding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine-receptor ligand [3H]Ro15-1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding sites.


Nonenzymatic glycosylation, sulfhydryl oxidation, and aggregation of lens proteins in experimental sugar cataracts.
The formation of sugar-cataracts has been hypothesized to involve the nonenzymatic glycosylation, sulfhydryl oxidation, and aggregation of lens proteins. Cataractous lenses of diabetic and galactosemic rats were analyzed for glycosylated lysine residues in crystallins. A five- and a ten-fold increase in glycosylated lysine residues was measured in galactose and diabetic cataracts, respectively. The modification was predominant in the insoluble fraction of the lens homogenate. The proteins were further examined for the presence of disulfide bonds and high molecular weight aggregates. After careful disruption of the lens in a nitrogen environment, a cloudy solution was obtained from cataractous lenses whereas a clear solution was obtained from normal lenses. The absorbance at 550 nm of the solution of both the galactosemic and the diabetic cataracts could be decreased by approximately 50% with the addition of dithioerythritol (50 mM). The presence of high molecular weight aggregates was ascertained by sucrose gradient centrifugation and gel filtration chromatography. The proteins were heterogenous in size and showed a mol wt range of 36 to greater than 176 million daltons. Treatment with dithioerythritol induced a marked decrease in the amount of high molecular weight proteins. These data suggest that sugar cataracts of experimental animals have, in common with human cataracts, the presence of high molecular weight aggregates which are in part linked by disulfide bonds.


Randomized controlled trials of remdesivir in hospitalized coronavirus disease 2019 patients: A meta-analysis.
The first cases of the coronavirus disease 2019 (COVID-19) were reported in Wuhan, China. No antiviral treatment options are currently available with proven clinical efficacy. However, preliminary findings from phase III trials suggest that remdesivir is an effective and safe treatment option for COVID-19 patients with both moderate and severe disease. The aim of the present meta-analysis was to investigate whether remdesivir was effective for treating COVID-19 including reduced in-hospital adverse events, oxygen support, and mortality rates. According to the PRISMA reporting guidelines, a review was conducted from January 1, 2020, until August 25, 2020, with MeSH terms including COVID-19, COVID, coronavirus, SARS-CoV-2, remdesivir, adenosine nucleoside triphosphate analog, and Veklury using MEDLINE, Scopus, and CINAHL Plus. A modified Delphi process was utilized to include the studies and ensure that the objectives were addressed. Using dichotomous data for select values, the unadjusted odds ratios (ORs) were calculated applying Mantel-Haenszel random-effects method in Review Manager 5.4. Randomized controlled trials pooled in 3013 participants with 46.3% (n = 1395) in the remdesivir group and 53.7% (n = 1618) in the placebo group. The placebo group had a higher risk of mortality as compared to the intervention group with significant OR (0.61) (95% confidence interval of 0.45-0.82; P = 0.001). There was minimal heterogeneity among the studies (I 2 = 0%). Our findings suggest that remdesivir extends clinical benefits by reducing mortality, adverse events, and oxygen support in moderate to severely ill COVID-19 patients. Concerted efforts and further randomized placebo-controlled trials are warranted to examine the potency of antiviral drugs and immunopathological host responses contributing to the severity of COVID-19.


Betting Decision Under Break-Streak Pattern: Evidence from Casino Gaming.
Cognitive bias is prevalent among gamblers, especially those with gambling problems. Grounded in the heuristics theories, this study contributes to the literature by examining a cognitive bias triggered by the break streak pattern in the casino setting. We postulate that gamblers tend to bet on the latest outcome when there is a break-streak pattern. Moreover, three determinants of the betting decision under break-streak pattern, including the streak length of the alternative outcome, the frequency of the latest outcome, and gender, were identified and examined in this study. A non-participatory observational study was conducted among the Cussec gamblers in a casino in Macao. An analysis of 1229 bets confirms our postulation, particularly when the streak of the alternative outcome is long, the latest outcome is frequent, and the gamblers are females. The findings provide meaningful implications for casino management and public policymakers regarding the minimization of gambling harm.


An essential role of PDCD4 in vascular smooth muscle cell apoptosis and proliferation: implications for vascular disease.
It is well established that vascular smooth muscle cell (VSMC) apoptosis and proliferation are critical cellular events in a variety of human vascular diseases. However, the molecular mechanisms involved in controlling VSMC apoptosis and proliferation are still unclear. In the current study, we have found that programmed cell death 4 (PDCD4) is significantly downregulated in balloon-injured rat carotid arteries in vivo and in platelet-derived growth factor-stimulated VSMCs in vitro. Overexpression of PDCD4 via adenovirus (Ad-PDCD4) increases VSMC apoptosis in an apoptotic model induced by serum deprivation. In contrast, VSMC apoptosis is significantly decreased by knockdown of PDCD4 via its small interfering RNA. In the rat carotid arteries in vivo, VSMC apoptosis is increased by Ad-PDCD4. We have further identified that activator protein 1 is a downstream signaling molecule of PDCD4 that is associated with PDCD4-mediated effects on VSMC apoptosis. In addition, VSMC proliferation was inhibited by overexpression of PDCD4. The current study has identified, for the first time, that PDCD4 is an essential regulator of VSMC apoptosis and proliferation. The downregulation of PDCD4 expression in diseased vascular walls may be responsible for the imbalance of VSMC proliferation and apoptosis. The results indicate that PDCD4 may be a new therapeutic target in proliferative vascular diseases.


Validation of the Daily Living Tasks Dependent on Vision (DLTV) questionnaire in a U.S. population with age-related macular degeneration.
The Daily Living Tasks Dependent on Vision questionnaire (DLTV) has been used to assess functional impairment among patients with age-related macular degeneration (AMD). This study evaluated the psychometric properties of the DLTV using patient-reported rates of use of services and devices in an outpatient population. The DLTV was included in a survey mailed to members of an AMD advocacy organization. Included in the survey were questions about demographic and clinical characteristics as well as questions about use of low vision aids and care-giving. Respondents provided informed consent. Data were analyzed in SAS. Four respondents of 803 did not complete the DLTV; missing data were uncommon. Most (56%) respondents were male; the mean age was 73 years. Internal consistency reliability of the DLTV was 0.9699. Construct validity was demonstrated with moderate to high correlations between the DLTV and use of services and devices. The DLTV demonstrated discriminant validity and could distinguish between respondents with different levels of impairment, i.e., those who reported regular care-giving compared to those without regular care-giving. In this outpatient population, the DLTV demonstrated reliability and validity. This analysis complements existing research and supports the use of the DLTV in AMD patients.


Overweight among Four-Year-Old Children in Relation to Early Growth Characteristics and Socioeconomic Factors.
Objectives. To assess early growth characteristics and socioeconomic factors of children in relation to body mass index (BMI) and presence of overweight among four-year-old children. Methods. Two Child Health Centres (CHC) participated in the study. They were selected to obtain two populations of children featuring divergent socio-economic characteristics. Growth data registered at the CHCs from birth to the 4-year check-up were recovered. Overweight was defined by the BMI cut-offs established by IOTF. BMI values expressed as BMI standard deviation score (BMISDS) were used for analysis. Results. At the 4-year check-up, the BMISDS and the proportion of children with overweight (including the obese) were significantly higher in the district with lower socio-economic status. High BMI at birth and low socio-economic status of the population in the CHC-district were shown to be independent determinants for overweight and BMISDS at four years of age. Conclusions. More research is needed to understand the mechanisms and how intervention programs should be designed in order to prevent the development of overweight and obesity in children.


Early gastric cancer: the case for long term surveillance.
Thirty five patients with early gastric cancer have been treated at the Bristol Royal Infirmary since 1965. The number of cases diagnosed has doubled in the last 10 years. Epigastric pain (74%), loss of weight (63%), and gastrointestinal bleeding (43%) were the most common presenting symptoms, with a median length of history of 12 months (range five days to 72 months). Life table survival curves showed a crude five year survival of 71% (age adjusted 92%) and a crude 10 year survival of 63% (age adjusted 85%). Sixteen patients have been followed up clinically, endoscopically, and by scintigraphy with technetium-99m p-butyl iminodiacetic acid to assess the risk of recurrent disease. Of seven patients with pronounced bile reflux, two had moderate dysplasia of the gastric remnant, and one patient was found to have developed a metachronous tumour nine years after surgery. Partial resection seems to be the best choice of treatment for early gastric cancer, giving good functional results. Consideration should, however, be given to Roux en Y diversion, and long term surveillance of the gastric remnant is recommended.


Soluble interleukin 2 receptor levels and cervical neoplasia: results from a population-based case-control study in Costa Rica.
Progression from infection with human papillomavirus (HPV) to cervical cancer in some women is thought to involve a permissive host environment, one in which immune response is mobilized in an inappropriate manner. In a previous study (A. Hildesheim et al., Cancer Epidemiol. Biomark. Prev., 6: 807-813, 1997), increasing levels of soluble interleukin 2 receptor (sIL-2R), a known proxy for general immune activation, was found to be positively associated with increasing levels of cervical neoplasia. We attempted to confirm this finding by conducting a nested case-control study of 478 women within a 10,000-woman population-based cohort in Costa Rica. We selected for the study all of the women diagnosed (at enrollment into the cohort) with: (a) low-grade squamous intraepithelial lesions (LSIL, n = 191); (b) high-grade squamous intraepithelial lesions (HSIL, n = 130); or (c) cancer (n = 37). Controls were 120 cytologically normal, HPV-negative women selected from a random sample of the entire cohort. A questionnaire was administered to participants to elicit information on cervical cancer risk factors. All of the women received a pelvic examination during which cervical cells were collected and used for HPV DNA testing by PCR. Blood samples were also collected. Plasma obtained from the blood samples was tested for sIL-2R levels by ELISA. Results indicated that sIL-2R levels increased with age. Among controls, we observed that 44.3% of women over the age of 50 had high levels of sIL-2R (defined as >735 units/ml) compared with 15.8% of women <30 years of age (P = 0.008). When women with cervical disease (LSIL+) were compared with controls, women in the upper quartile of the sIL-2R distribution had an age-adjusted odds ratio (OR) of 2.1 [95% confidence interval (CI), 1.1-4.1]. Comparing each advancing state of neoplasia with its precursor, we found that women with LSIL had higher sIL-2R levels than controls (OR for upper quartile of sIL-2R, 2.3; 95% CI, 1.1-5.2; comparing LSIL cases with controls); women diagnosed with HSIL were similar to the LSIL group (OR for upper quartile of sIL-2R, 1.1; 95% CI, 0.5-2.4; comparing HSIL cases with LSIL cases); and those with cancer had higher sIL-2R levels than subjects with an HSIL diagnosis (OR for upper quartile of sIL-2R = 1.8; 95% CI, 0.5-7.1; comparing cancer cases with HSIL cases). These data suggest that among our study subjects, sIL-2R levels most likely rise as a response to the events of infection and cancerous invasion, but that sIL-2R levels are unlikely to be predictive of disease progression among women with LSIL.


Therapeutic angiogenesis.
We have proposed the term "therapeutic angiogenesis" to describe the induction or stimulation of neovascularization for the treatment or prevention of pathological clinical situations characterized by local hypovascularity. Evidence also shows that "clinically normal" healing and tissue regeneration can be improved or accelerated by therapeutic angiogenesis. Traditionally, therapeutic angiogenesis has been achieved by surgical methods, ie, the transposition of autologous tissues with uncompromised vasculature and high angiogenic potential such as omentum majus flaps and muscle flaps. Recent advances in the understanding of the biological process of neovascularization as well as the discovery and cloning of angiogenic cytokines may add a new clinical tool: therapeutic angiogenesis by pharmaceutical methods. Based on the results of animal studies and preliminary clinical trials, this review is aimed to give a state-of-the-art compilation of (1) those angiogenesis factors that appear promising in clinical application for therapeutic angiogenesis and (2) the surgical indication fields with near-term potential for therapeutic angiogenesis by use of angiogenic cytokines.


Can subtle changes in gene expression be consistently detected with different microarray platforms?
The comparability of gene expression data generated with different microarray platforms is still a matter of concern. Here we address the performance and the overlap in the detection of differentially expressed genes for five different microarray platforms in a challenging biological context where differences in gene expression are few and subtle. Gene expression profiles in the hippocampus of five wild-type and five transgenic deltaC-doublecortin-like kinase mice were evaluated with five microarray platforms: Applied Biosystems, Affymetrix, Agilent, Illumina, LGTC home-spotted arrays. Using a fixed false discovery rate of 10% we detected surprising differences between the number of differentially expressed genes per platform. Four genes were selected by ABI, 130 by Affymetrix, 3,051 by Agilent, 54 by Illumina, and 13 by LGTC. Two genes were found significantly differentially expressed by all platforms and the four genes identified by the ABI platform were found by at least three other platforms. Quantitative RT-PCR analysis confirmed 20 out of 28 of the genes detected by two or more platforms and 8 out of 15 of the genes detected by Agilent only. We observed improved correlations between platforms when ranking the genes based on the significance level than with a fixed statistical cut-off. We demonstrate significant overlap in the affected gene sets identified by the different platforms, although biological processes were represented by only partially overlapping sets of genes. Aberrances in GABA-ergic signalling in the transgenic mice were consistently found by all platforms. The different microarray platforms give partially complementary views on biological processes affected. Our data indicate that when analyzing samples with only subtle differences in gene expression the use of two different platforms might be more attractive than increasing the number of replicates. Commercial two-color platforms seem to have higher power for finding differentially expressed genes between groups with small differences in expression.


Impact of hydrogel nanoparticle size and functionalization on in vivo behavior for lung imaging and therapeutics.
Polymer chemistry offers the possibility of synthesizing multifunctional nanoparticles which incorporate moieties that enhance diagnostic and therapeutic targeting of cargo delivery to the lung. However, since rules for predicting particle behavior following modification are not well-defined, it is essential that probes for tracking fate in vivo are also included. Accordingly, we designed polyacrylamide-based hydrogel particles of differing sizes, functionalized with a nona-arginine cell-penetrating peptide (Arg(9)), and labeled with imaging components to assess lung retention and cellular uptake after intratracheal administration. Radiolabeled microparticles (1-5 microm diameter) and nanoparticles (20-40 nm diameter) without and with Arg(9) showed diffuse airspace distribution by positron emission tomography imaging. Biodistribution studies revealed that particle clearance and extrapulmonary distribution was, in part, size dependent. Microparticles were rapidly cleared by mucociliary routes but, unexpectedly, also through the circulation. In contrast, nanoparticles had prolonged lung retention enhanced by Arg(9) and were significantly restricted to the lung. For all particle types, uptake was predominant in alveolar macrophages and, to a lesser extent, lung epithelial cells. In general, particles did not induce local inflammatory responses, with the exception of microparticles bearing Arg(9). Whereas microparticles may be advantageous for short-term applications, nanosized particles constitute an efficient high-retention and non-inflammatory vehicle for the delivery of diagnostic imaging agents and therapeutics to lung airspaces and alveolar macrophages that can be enhanced by Arg(9). Importantly, our results show that minor particle modifications may significantly impact in vivo behavior within the complex environments of the lung, underscoring the need for animal modeling.


Contrasting effects of plant richness and composition on insect communities: a field experiment.
We experimentally separated the effects of two components of plant diversity-plant species richness and plant functional group richness-on insect communities. Plant species richness and plant functional group richness had contrasting effects on insect abundances, a result we attributed to three factors. First, lower insect abundances at higher plant functional group richness were explained by a sampling effect, which was caused by the increasing likelihood that one low-quality group, C4 grasses, would be present and reduce average insect abundances by 25%. Second, plant biomass, which was positively related to plant functional group richness, had a strong, positive effect on insect abundances. Third, a positive effect of plant species richness on insect abundances may have been caused by greater availability of alternate plant resources or greater vegetational structure. In addition, a greater diversity of insect species, whose individual abundances were often unaffected by changes in plant species richness, may have generated higher total community abundances. After controlling for the strong, positive influence of insect abundance on insect diversity through rarefaction, insect species richness increased as plant species richness and plant functional group richness increased. Although these variables did not explain a high proportion of variation individually, plant species richness and plant functional group richness had similar effects on insect diversity and opposing effects on insect abundances, and both factors may explain how the loss of plant diversity influences higher trophic levels.


Cost effectiveness of using surgery versus skeletal traction in management of femoral shaft fractures at Thika level 5 hospital, Kenya.
A prospective quasi experimental study was undertaken at the Thika level 5 hospital. The study aimed to compare the costs of managing femoral shaft fracture by surgery as compared to skeletal traction. Sixty nine (46.6%) patients were enrolled in group A and managed surgically by intramedullary nailing while 79 (53.4%) patients were enrolled in group B and managed by skeletal traction. Exclusion criteria included patients with pathological fractures and previous femoral fractures. Data was collected by evaluation of patients in patient bills using a standardized questionnaire. The questionnaire included cost of haematological and radiological tests, bed fees, theatre fees and physiotherapy costs. The data was compiled and analyzed using SPSS version 16. Person's chi square and odds ratios were used to measure associations and risk analysis respectively. A higher proportion of patients (88.4%) in group A were hospitalized for less than one month compared to 20 patients (30.4%) in group B (p, 0.001).Total cost of treatment in group A was significantly lower than in group B. Nineteen (27.9%) patients who underwent surgery paid a total bill of Ksh 5000-7500 compared to 7(10.4%) who were treated by traction. The financial cost benefit of surgery was further complimented by better functional outcomes. The data indicates a cost advantage of managing femoral shaft fracture by surgery compared to traction. Furthermore the longer hospital stay in the traction group is associated with more malunion, limb deformity and shortening.


Assessing posttraumatic stress disorder's latent structure in elderly bereaved European trauma survivors: evidence for a five-factor dysphoric and anxious arousal model.
The three-factor structure of posttraumatic stress disorder (PTSD) specified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, is not supported in the empirical literature. Two alternative four-factor models have received a wealth of empirical support. However, a consensus regarding which is superior has not been reached. A recent five-factor model has been shown to provide superior fit over the existing four-factor models. The present study investigated the fit of the five-factor model against the existing four-factor models and assessed the resultant factors' association with depression in a bereaved European trauma sample (N = 325). The participants were assessed for PTSD via the Harvard Trauma Questionnaire and depression via the Beck Depression Inventory. The five-factor model provided superior fit to the data compared with the existing four-factor models. In the dysphoric arousal model, depression was equally related to both dysphoric arousal and emotional numbing, whereas depression was more related to dysphoric arousal than to anxious arousal.