Estrogen Receptor Status by Immunohistochemistry Is Superior to the Ligand-Binding Assay for Predicting Response to Adjuvant Endocrine Therapy in Breast Cancer.
Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.


Combinatorial Action of MicroRNAs let-7 and miR-34 Effectively Synergizes with Erlotinib to Suppress Non-small Cell Lung Cancer Cell Proliferation.
Lung cancer represents the leading cause of cancer-related deaths in men and women worldwide. Targeted therapeutics, including the epidermal growth factor receptor (EGFR) inhibitor erlotinib, have recently emerged as clinical alternatives for the treatment of non-small cell lung cancer (NSCLC). However, the development of therapeutic resistance is a major challenge, resulting in low 5-year survival rates. Due to their ability to act as tumor suppressors, microRNAs (miRNAs) are attractive candidates as adjuvant therapeutics for the treatment of NSCLC. In this study, we examine the ability of 2 tumor suppressor miRNAs, let-7b and miR-34a to sensitize KRAS;TP53 mutant non-small cell lung cancer cells to the action of erlotinib. Treatment with these miRNAs, individually or in combination, resulted in synergistic potentiation of the anti-proliferative effects of erlotinib. This effect was observed over a wide range of miRNA and erlotinib interactions, suggesting that let-7b and miR-34a target oncogenic pathways beyond those inhibited by EGFR. Combinatorial treatment with let-7b and miR-34a resulted in the strongest synergy with erlotinib, indicating that these miRNAs can effectively target multiple cellular pathways involved in cancer cell proliferation and resistance to erlotinib. Together, our findings indicate that NSCLC cells can be effectively sensitized to erlotinib by supplementation with tumor suppressor miRNAs, and suggest that the use of combinations of miRNAs as adjuvant therapeutics for the treatment of lung cancer is a viable clinical strategy.


Porous copper-graphene heterostructures for cooling of electronic devices.
Recently, research on micro-electronic and optoelectronic devices has been rapidly increasing. Parts and products related to these devices are becoming smaller and more integrated within circuits. As a result, the heat generated in devices has increased greatly. When excess heat is generated, important properties are affected such as efficiency and lifetime and, in severe cases, this can result in the failure of devices. Therefore, efficient cooling is required and it becomes necessary to study the heat dissipation properties of device materials. Research on heat-dissipating materials with high thermal conductivities and large surface areas, and which can transfer heat rapidly to facilitate progressive heat-release, is being actively pursued. In this study, a porous copper with reduced graphene oxide (pCu-rGO) heterostructure was fabricated by thermal annealing using Cu powder and GO. The thermal properties were then investigated and the results indicated that the pCu-rGO heterostructure exhibits a higher thermal conductivity than porous Cu. In addition, the thermal resistance of the sample was measured by applying it as a heat sink of a light emitting diode (LED). The result was 18.33% lower than that of bulk Cu. Also, when an overcurrent of 750 mA was applied for 144 hours, the luminance of bulk Cu decreased from 100% to 86.07%. On the other hand, the pCu-rGO showed that the luminance was maintained at 95.64%. Therefore, it is expected to resolve the existing problem of heat generation in electronic and optical devices.


Burden of pelvis fracture: a population-based study of incidence, hospitalisation and mortality.
The objective of this study was to describe the incidence and consequences of pelvic fractures in a community cohort. The incidence of pelvic fractures increases with age with a protective effect of higher body mass index. Almost 60% of those with a pelvic fracture required an inpatient stay, with a median of 9 days. There was a higher 3-year mortality in those admitted (17%) vs. those not admitted (6.3%). Given the substantial health burden, further work is required to identify the optimal post-fracture therapeutic strategy to improve outcomes. The burden of pelvis fractures is projected to increase, but there is a paucity of community-based studies describing rates, mortality and future fracture risk. We therefore estimated the age, gender and BMI-specific incidence of pelvis fracture in Catalonia (North-East Spain), and assessed hospital stay and mortality following fracture. The SIDIAP(Q) database contains validated clinical information from computerised medical records of a representative sample of 30% of the population of Catalonia. We conducted a retrospective cohort study including all subjects aged ≥ 40 in SIDIAP(Q) and linked to the regional Hospital Admissions Database from 2007 to 2009. Pelvis fractures were ascertained using ICD-10 codes. Incidence and mortality rates were calculated. A total of 1,118,173 patients (582,820 women) were observed for 3 years and 1,356 had a pelvic fracture. The rate for pelvic fracture was 4.35/10,000 person-years (pyar) [95% CI 4.13-4.59] (men-2.73 [2.48-3.01]; women-5.82 [5.46-6.20]). This increased with age, peaking in those over 90 years: 29.41 [25.74-33.59]. Higher BMI was protective (HR 0.75 per SD BMI; [0.69-0.82]). Moreover, 59.1% of fractured patients were hospitalised with a median (IQR) stay of 9 (5-16) days, and after the 3-year follow-up 13.9% died (mortality rate 10.7/100 pyar [9.3-12.3]) with higher rates in those hospitalised (17.0%). Pelvic fractures are associated with high rates of hospitalisation and mortality. Given this, further work is required to identify the optimal post-fracture therapeutic strategy to improve outcomes in this elderly patient group.


Paratonia: a Delphi procedure for consensus definition.
Paratonia is a motor problem that develops during the course of dementia. Definitions of paratonia used in the literature differ considerably, which has clinical implications and may lead to an undesirable heterogeneity in study populations. For this reason, we initiated a Delphi procedure with known experts in the field to establish an operational consensus definition of paratonia. The Delphi procedure involved an anonymous and multistage approach presented as a questionnaire, with each stage building on the results of the previous one in order to reach consensus on the definition of paratonia. Eight of 17 experts agreed to participate in the study. After 4 rounds, the participants reached consensus on the following definition: paratonia is a form of hypertonia with an involuntary variable resistance during passive movement. The nature of paratonia may change with progression of dementia (eg, from active assistance (aka Mitgehen) to active resistance). The degree of resistance depends on the speed of movement (eg, slow > low resistance, fast > high resistance). The degree of paratonia is proportional to the amount of force applied and increases with progression of dementia. The resistance to passive movement is in any direction and there is no clasp-knife phenomenon. The Delphi procedure resulted in a comprehensive, operational definition of paratonia. Future research should focus on the reliability and validity of this definition.


Bevacizumab preconditioning followed by Etoposide and Cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy.
We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC). A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m(2)/day; days 2-4) and cisplatin (70 mg/m(2); day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)-objective response rate according to volumetric response criteria. A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9-89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%). By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted.


Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.
Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p < 0.001). Moreover, we observed a significant decrease in cell proliferation as well as significant decrease in IC50 of ibrutinib in combination with dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001). In-vivo studies demonstrated ibrutinib treated mice had a significantly prolonged survival with median survival of mice following ibrutinib treatment (32 days) (24 days) (p < 0.02). In conclusion, our findings demonstrate the significant in-vitro and preclinical in-vivo effects of ibrutinib in BL. Based on our preclinical results in this investigation, there is an on-going clinical trial comparing overall survival in children and adolescents with relapsed/refractory BL treated with chemoimmunotherapy with or without ibrutinib (NCT02703272).


Dissipation of PAHs in saturated, dredged sediments: a field trial.
Sediments dredged from navigable rivers often contain elevated concentrations of recalcitrant, potentially toxic organic compounds such as polychlorinated biphenyls (PCBs) and polyaromatic hydrocarbons (PAHs). The presence of these compounds often requires that the sediments be stored in fully contained disposal facilities. A 3-year field study was conducted at the Jones Island disposal facility in Milwaukee, Wisconsin, to compare bioremediation of PAHs in contaminated dredged sediments in the absence of plants to phytoremediation with Salix nigra (black willow) (SX61), Spartina pectinata (prairie cord grass), Carex aquatalis (lake sedge), Lolium multiflorum (annual rye), and Scirpus fluviatilis (bulrush). Nine PAHs were detected initially in the sediments. Over the 3-year experiment, acenaphthene dissipation ranged from 94% to 100%, whereas anthracene, benzo[a]pyrene and indo[1,2,3-cd]pyrene generally had modest decreases in concentration (0-30% decrease). The remaining five PAHs ranged in degree of disappearance from 23% to 82%. Planted treatments did not enhance PAH dissipation relative to those without plants, but treatments with high biomass yield and high transpiration plant species had significantly less removal of PAHs than unplanted controls. Significant, negative correlations between nitrogen removal and decreases in PAH concentration suggest that competition for nutrients between plants and microorganisms may have impeded the microbial degradation of PAHs in the rhizosphere of the more rapidly growing plant species.


Risk of dementia in adults with cerebral palsy: a matched cohort study using general practice data.
Determine the risk of incident dementia in adults with cerebral palsy (CP) compared with age, sex and general practice (GP) matched controls. Retrospective cohort study. UK GPs linked into the Clinical Practice Research Datalink (CPRD). CPRD data were used to identify adults aged 18 or older with a diagnosis of CP. Each adult with CP was matched to three controls who were matched for age, sex and GP. In total, 1703 adults with CP and 5109 matched controls were included in the analysis. The mean baseline age of participants was 33.30 years (SD: 15.48 years) and 46.8% of the sample were female. New diagnosis of dementia during the follow-up period (earliest date of 1987 to latest date of 2015). During the follow-up, 72 people were identified with a new diagnosis of dementia. The overall proportion of people with and without CP who developed dementia was similar (CP: n=19, 1.1%; matched controls n=54, 10.0%). The unadjusted HR suggested that people with CP had an increased hazard of being diagnosed with dementia when compared with matched controls (HR 2.69, 95% CI 1.44 to 5.00). This association was attenuated when CP comorbidities (sensory impairment, intellectual disability and epilepsy) were accounted for (HR 1.92, 95% CI 0.92 to 4.02). There was no difference in the proportion of people with CP and matched controls who were diagnosed with dementia during the follow-up. Furthermore, while there was evidence for an increased hazard of dementia among people with CP, the fact that this association was attenuated after controlling for comorbidities indicates that this association may be explained by comorbidities rather than being a direct result of CP. Findings should be interpreted with caution due to the low number of incident cases of dementia.


Renal function of chloralkali workers after the cessation of exposure to mercury vapor.
The aims of the study were to assess renal function in chloralkali workers previously exposed to mercury vapor and to assess the impact of selenium status on the biomarkers of kidney function. Forty-nine chloralkali workers previously exposed to mercury vapor were compared with 49 age-matched referents in a cross-sectional study. Selected biomarkers of kidney function and biomarkers of selenium status were measured. The index group had been exposed for 13.1 (range 2.8-34.5) years on the average at a mean urinary mercury excretion of 9.3 (range 4.0-25.4) nmol/mmol creatinine a year. The exposure had ceased on an average of 4.8 (range 4.2-10.0) years prior to the examinations. No statistically significant differences were found between the groups for the measured biomarkers of kidney function. The serum selenium concentration and serum glutathione peroxidase activity were associated with the activity of N-acetyl-beta-D-glucosaminidase in urine (U-NAG). The results indicate that having higher glutathione peroxidase activity or a higher serum selenium concentration results in a lower excretion of U-NAG. This effect was the most pronounced in the oldest third of the participants. Apparently the well-known association between U-NAG and age could only be found for the participants with a lower selenium status. Increased activities of U-NAG during ongoing exposure to mercury vapor appear to be reversible upon cessation of exposure. Selenium status has a substantial impact on U-NAG activity and should be considered in studies of U-NAG excretion.


A comparison of the minimum data sets for primary shoulder arthroplasty between national shoulder arthroplasty registries. Is international harmonization feasible?
The aims of this study were to identify the common components of the Minimum Data Set (MDS) of current national shoulder arthroplasty registries that could be pooled for analysis; and to determine whether further harmonisation of data collection across these registries would be feasible. Copies of primary shoulder arthroplasty MDS forms, annual reports, and other publications from national shoulder arthroplasty registries were identified using internet search engines up to November 2016. Data relating to local or regional registries was excluded. There were nine national shoulder arthroplasty registries reporting a total of 97,388 primary shoulder replacements. All minimum data sets included patient identifiers, date of surgery, implant identification, laterality of surgery, indication and mode of implant fixation. At least 6 registries had common options within the categories of indication, implant fixation and previous operations. Most discrepancies were seen in categories for additional interventions, outcome measures, and intra-operative complications. As numbers within individual registries are relatively small, international collaboration would harness the global strength of knowledge and experience in shoulder replacement. Several similarities were identified between the current national registries that could become unified with only minor changes by a few registries, highlighting the potential feasibility of MDS harmonisat.


TNF Block Gene Variants Associate With Pain Intensity in Black Southern Africans With HIV-associated Sensory Neuropathy.
HIV-associated sensory neuropathy (HIV-SN) is a common neurological complication of HIV infection, and it is often painful. Tumor necrosis factor (TNF)-α is implicated in neuropathic pain, but associations between neuropathic pain and polymorphisms in the TNFA gene have not been identified. The "TNF block" is a region of high linkage disequilibrium within the central major histocompatability complex that contains several genes involved in the regulation of inflammation, including TNFA. Polymorphisms in the block have been associated with an altered risk of HIV-SN, but no investigations into whether this region is associated with the painful symptoms of neuropathy have been undertaken. Therefore, we investigated whether polymorphisms in the TNF block are associated with pain intensity in black Southern Africans with HIV-SN. Single-nucleotide polymorphisms (SNPs) defining TNF block haplotypes and African-specific tagSNPs were genotyped in samples from 150 black Southern Africans with HIV-SN. One SNP allele, rs28445017*A, was significantly associated with an increased pain intensity after correction for age, sex, and the CD4 T-cell count. A common 3-SNP haplotype containing rs28445017*G remained associated with a reduced pain intensity after correction for covariates and multiple comparisons. We identified a novel genetic association between polymorphisms in the TNF block and the pain intensity in black Southern Africans with HIV-SN. Our study implicates rs28445017 in painful HIV-SN, although its precise role and whether it may be causative is unclear. rs28445017 was not associated with the risk for HIV-SN as such, highlighting potential differences between the pathophysiology of the neuropathy and the painful features of the neuropathy.


Beneficial effects of different Polygonum multiflorum Thunb. extracts on memory and hippocampus morphology.
Four groups of 1-mo-old male senescence-accelerated mice (SAMP8) were fed Polygonum multiflorum Thunb. (PM) extract for 18 wk to determine the effect of PM on memory ability and histopathological changes in mice. The baseline diet consisted of a casein diet group, and the three test diets were supplemented with 50% ethanol, 95% ethanol, or water extracts of PM. It was found that the mice fed with PM extracts had better active shuttle avoidance response, fewer vacuole numbers, less lipofuscin in the hippocampus, and lower MDA concentrations in the brain. Our data showed that the ethanol PM extract groups (both 50% and 95% groups) had lower lipofuscin percentages and MDA concentrations, and higher total thiol concentrations than the water PM extract group. The 50% ethanol PM extract group showed significantly lower total cholesterol and triglyceride values than the other groups, but the HDL cholesterol level was the same. These results suggest that dietary supplementation with either ethanol or water extracts can reduce brain pathological changes and promote learning and memory ability. The performance of PM extracts depended on the extraction method, with ethanol extraction tending to obtain better results.


A Randomized, Double-Blind, Placebo-Controlled Trial on Clinical Efficacy of Topical Agents in Reducing Pain and Frequency of Recurrent Aphthous Ulcers.
Recurrent Aphthous Ulcers (RAU) is one of the most common oral ulcerative Disease of the oral mucosa with high recurrence rate. Standard topical treatment options provide symptomatic relief with few have been found to be effective in treating or relieving the symptoms. The study aimed to evaluate the clinical efficacy of various topical agents in order to find the better treatment modality so as to decrease the number, size, exudate level and discomfort associated with pain with RAU. The patients diagnosed with minor recurrent aphthous ulcers fulfilling the inclusion and exclusion criteria were enrolled. All the baseline parameters were measured by the principal investigator. The treatment modality was assigned by generating a randomization list by computer software, double-blinded in consecutively numbered sealed envelopes. The topical treatment modalities that were included: 5% Amlexanox, 0.1% Triamcinolone Acetonide, 20% Benzocaine gel, 100 mg Doxycycline hyclatemixed with denture adhesive and normal saline (20:2:1); The study was placebo controlled in which placebo gel 10 gm was used. The size, no of ulcers, pain, erythema and exudate level were measured by the principal investigator at days 1, 4, 8 and 10. All quantitative variables were estimated using measures of central tendency (mean, median) and measures of dispersion (standard deviation). Qualitative or categorical variables were described as frequencies or proportions. Proportions were compared using Post Hoc Test and N Par Tests. Effectiveness was checked using p-value (< 0.005). It was observed that 0.1% Triamcinolone Acetonide and 5% Amlexanox proven to be more efficacious in the reduction of size, Number, Pain, Erythema and Exudate Levels at day 8, (p = .000*) and at day 10 (p =. 000*) as compared to single application of 100 mg Doxycycline Hyclate, 20% Benzocaine gel and the placebo, which was statistically significant. VAS scale was significant for 100 mg Doxycycline Hyclate and 20% Benzocaine gel. The selected topical treatment modality can deliver cheap, effective and safe drug therapy which benefits the patient in refining their regular activities and everyday events of life.


Fetal health stagnation: Have health conditions in utero improved in the United States and Western and Northern Europe over the past 150 years?
Many empirical studies have shown that health conditions in utero can have long lasting consequences for health across the life course. However, despite this evidence, there is no clear consensus about how fetal health has changed in the very long run. This paper analyses historical birth weights and perinatal mortality rates to construct a coherent picture of how health conditions in utero have changed over the past 150 years. In short, the evidence suggests that fetal health has been relatively stagnant. Limited evidence on birth weights shows that they had already reached their current levels in North America and Northern and Western Europe by the late nineteenth century, and they have changed very little in between. Perinatal mortality rates have fallen dramatically since the late 1930s, but this decline was mainly caused by improvements in intrapartum treatments after the introduction of Sulfa drugs and antibiotics. Thus, the health benefits associated with the perinatal mortality decline were concentrated among those at risk and did not influence the population at large. Finding stagnant fetal health during a period when many other indicators of health improved dramatically is provocative and suggests two conclusions: either fetal health did not improve or the indicators used to measure fetal health, indicators still widely used today, may not accurately capture all aspects of health in utero. If fetal health has been stagnant, then better conditions in utero cannot explain cohort improvements in life expectancy over the twentieth century. If the indicators of fetal health are problematic, then researchers must move beyond birth weight and perinatal mortality to understand how developmental plasticity based on the prenatal environment influences later life health.


Role of cells in freezing-induced cell-fluid-matrix interactions within engineered tissues.
During cryopreservation, ice forms in the extracellular space resulting in freezing-induced deformation of the tissue, which can be detrimental to the extracellular matrix (ECM) microstructure. Meanwhile, cells dehydrate through an osmotically driven process as the intracellular water is transported to the extracellular space, increasing the volume of fluid for freezing. Therefore, this study examines the effects of cellular presence on tissue deformation and investigates the significance of intracellular water transport and cell-ECM interactions in freezing-induced cell-fluid-matrix interactions. Freezing-induced deformation characteristics were examined through cell image deformetry (CID) measurements of collagenous engineered tissues embedded with different concentrations of MCF7 breast cancer cells versus microspheres as their osmotically inactive counterparts. Additionally, the development of a biophysical model relates the freezing-induced expansion of the tissue due to the cellular water transport and the extracellular freezing thermodynamics for further verification. The magnitude of the freezing-induced dilatation was found to be not affected by the cellular water transport for the cell concentrations considered; however, the deformation patterns for different cell concentrations were different suggesting that cell-matrix interactions may have an effect. It was, therefore, determined that intracellular water transport during freezing was insignificant at the current experimental cell concentrations; however, it may be significant at concentrations similar to native tissue. Finally, the cell-matrix interactions provided mechanical support on the ECM to minimize the expansion regions in the tissues during freezing.


The Potential Therapeutic Effects of Artesunate on Stroke and Other Central Nervous System Diseases.
Artesunate is an important agent for cerebral malaria and all kinds of other severe malaria because it is highly efficient, lowly toxic, and well-tolerated. Loads of research pointed out that it had widespread pharmacological activities such as antiparasites, antitumor, anti-inflammation, antimicrobes activities. As we know, the occurrence and development of neurological disorders usually refer to intricate pathophysiologic mechanisms and multiple etiopathogenesis. Recent progress has also demonstrated that drugs with single mechanism and serious side-effects are not likely the candidates for treatment of the neurological disorders. Therefore, the pluripotent action of artesunate may result in it playing an important role in the prevention and treatment of these neurological disorders. This review provides an overview of primary pharmacological mechanism of artesunate and its potential therapeutic effects on neurological disorders. Meanwhile, we also briefly summarize the primary mechanisms of artemisinin and its derivatives. We hope that, with the evidence presented in this review, the effect of artesunate in prevention and curing for neurological disorders can be further explored and studied in the foreseeable future.


Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies.
Bromelain, an extract from the pineapple plant, has been demonstrated to show anti-inflammatory and analgesic properties and may provide a safer alternative or adjunctive treatment for osteoarthritis. All previous trials, which have been uncontrolled or comparative studies, indicate its potential use for the treatment of osteoarthritis. This paper reviews the mechanism of its putative therapeutic actions, those clinical trials that have assessed its use in osteoarthritis to date, as well as considering the safety implications of this supplement for osteoarthritis and reviewing the evidence to date regarding the dosage for treating this condition. The data available at present indicate the need for trials to establish the efficacy and optimum dosage for bromelain and the need for adequate prospective adverse event monitoring in such chronic conditions as osteoarthritis.


Single-shot, simultaneous incoherent and holographic microscopy.
In this work, we demonstrate single-shot, simultaneous recording and subsequent retrieval of one incoherent and two holographic (intensity and phase) images from the same camera frame. Demultiplexing of incoherent and holographic signals in the spatial frequency domain is made possible by carrier frequency modulation and spatial oversampling intrinsic to the off-axis digital holographic configuration. In particular, we show applications to combined fluorescence and digital holographic microscopy, as well as combined bright field and holographic second harmonic generation microscopy.


Beyond bilateral symmetry: geometric morphometric methods for any type of symmetry.
Studies of symmetric structures have made important contributions to evolutionary biology, for example, by using fluctuating asymmetry as a measure of developmental instability or for investigating the mechanisms of morphological integration. Most analyses of symmetry and asymmetry have focused on organisms or parts with bilateral symmetry. This is not the only type of symmetry in biological shapes, however, because a multitude of other types of symmetry exists in plants and animals. For instance, some organisms have two axes of reflection symmetry (biradial symmetry; e.g. many algae, corals and flowers) or rotational symmetry (e.g. sea urchins and many flowers). So far, there is no general method for the shape analysis of these types of symmetry. We generalize the morphometric methods currently used for the shape analysis of bilaterally symmetric objects so that they can be used for analyzing any type of symmetry. Our framework uses a mathematical definition of symmetry based on the theory of symmetry groups. This approach can be used to divide shape variation into a component of symmetric variation among individuals and one or more components of asymmetry. We illustrate this approach with data from a colonial coral that has ambiguous symmetry and thus can be analyzed in multiple ways. Our results demonstrate that asymmetric variation predominates in this dataset and that its amount depends on the type of symmetry considered in the analysis. The framework for analyzing symmetry and asymmetry is suitable for studying structures with any type of symmetry in two or three dimensions. Studies of complex symmetries are promising for many contexts in evolutionary biology, such as fluctuating asymmetry, because these structures can potentially provide more information than structures with bilateral symmetry.


Opportunities for mobilizing recalcitrant phosphorus from agricultural soils: a review.
Phosphorus (P) fertilizer is usually applied in excess of plant requirement and accumulates in soils due to its strong adsorption, rapid precipitation and immobilisation into unavailable forms including organic moieties. As soils are complex and diverse chemical, biochemical and biological systems, strategies to access recalcitrant soil P are often inefficient, case specific and inconsistently applicable in different soils. Finding a near-universal or at least widely applicable solution to the inefficiency in agricultural P use by plants is an important unsolved problem that has been under investigation for more than half a century. In this paper we critically review the strategies proposed for the remobilization of recalcitrant soil phosphorus for crops and pastures worldwide. We have additionally performed a meta-analysis of available soil 31P-NMR data to establish the potential agronomic value of different stored P forms in agricultural soils. Soil inorganic P stocks accounted on average for 1006 ± 115 kg ha-1 (57 ± 7%), while the monoester P pool accounted for 587 ± 32 kg ha-1 (33 ± 2%), indicating the huge potential for the future agronomic use of the soil legacy P. New impact driven research is needed in order to create solutions for the sustainable management of soil P stocks.


Beneficial effects of breast milk in the neonatal intensive care unit on the developmental outcome of extremely low birth weight infants at 18 months of age.
Beneficial effects of breast milk on cognitive skills and behavior ratings have been demonstrated previously in term and very low birth weight infants. Extremely low birth weight infants are known to be at increased risk for developmental and behavior morbidities. The benefits of breast milk that is ingested in the NICU by extremely low birth weight infants on development and behavior have not been evaluated previously. Nutrition data including enteral and parenteral feeds were collected prospectively, and follow-up assessments of 1035 extremely low birth weight infants at 18 months' corrected age were completed at 15 sites that were participants in the National Institute of Child Health and Human Development Neonatal Research Network Glutamine Trial between October 14, 1999, and June 25, 2001. Total volume of breast milk feeds (mL/kg per day) during hospitalization was calculated. Neonatal characteristics and morbidities, interim history, and neurodevelopmental and growth outcomes at 18 to 22 months' corrected age were assessed. There were 775 (74.9%) infants in the breast milk and 260 (25.1%) infants in the no breast milk group. Infants in the breast milk group were similar to those in the no breast milk group in every neonatal characteristic and morbidity, including number of days of hospitalization. Mean age of first day of breast milk for the breast milk infants was 9.3 +/- 9 days. Infants in the breast milk group began to ingest non-breast milk formula later (22.8 vs 7.3 days) compared with the non-breast milk group. Age at achieving full enteral feeds was similar between the breast milk and non-breast milk groups (29.0 +/- 18 vs 27.4 +/- 15). Energy intakes of 107.5 kg/day and 105.9 kg/day during the hospitalization did not differ between the breast milk and non-breast milk groups, respectively. At discharge, 30.6% of infants in the breast milk group still were receiving breast milk. Mothers in the breast milk group were significantly more likely to be white (42% vs 27%), be married (50% vs 30%), have a college degree (22% vs 6%), and have private health insurance (34% vs 18%) compared with the no breast milk group. Mothers who were black, had a low household income (< or = dollar 20000), or had higher parity were less likely to provide breast milk feeds. The analysis of outcomes between the any human milk and no human milk groups were adjusted for maternal age, maternal education, marital status, race/ethnicity, and the other standard covariates. Children in the breast milk group were more likely to have a Bayley Mental Development Index > or = 85, higher mean Bayley Psychomotor Development Index, and higher Bayley Behavior Rating Scale percentile scores for orientation/engagement, motor regulation, and total score. There were no differences in the rates of moderate to severe cerebral palsy or blindness or hearing impairment between the 2 study groups. There were no differences in the mean weight (10.4 kg vs 10.4 kg), length (80.5 cm vs 80.5 cm), or head circumference (46.8 cm vs 46.6 cm) for the breast milk and no breast milk groups, respectively, at 18 months. Multivariate analyses, adjusting for confounders, confirmed a significant independent association of breast milk on all 4 primary outcomes: the mean Bayley (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and incidence of rehospitalization). For every 10-mL/kg per day increase in breast milk ingestion, the Mental Development Index increased by 0.53 points, the Psychomotor Development Index increased by 0.63 points, the Behavior Rating Scale percentile score increased by 0.82 points, and the likelihood of rehospitalization decreased by 6%. In an effort to identify a threshold effect of breast milk on Bayley Mental Development Index and Psychomotor Development Index scores and Behavior Rating Scale percentile scores, the mean volume of breast milk per kilogram per day during the hospitalization was calculated, and infants in the breast milk group were divided into quintiles of breast milk ingestion adjusted for confounders. Overall, the differences across the feeding quintiles of Mental Development Index and Psychomotor Development Index were significant. There was a 14.0% difference in Behavior Rating Scale scores between the lowest and highest quintiles. For the outcomes (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and Rehospitalization <1 year), only the values for the >80th percentile quintile of breast milk feeding were significantly different from the no breast milk values. In our adjusted regression analyses, every 10 mL/kg per day breast milk contributed 0.53 points to the Bayley Mental Development Index; therefore, the impact of breast milk ingestion during the hospitalization for infants in the highest quintile (110 mL/kg per day) on the Bayley Mental Development Index would be 10 x 0.53, or 5.3 points. An increase of 5 points potentially would optimize outcomes and decrease costs by decreasing the number of very low birth weight children who require special education services. The societal implications of a 5-point potential difference (one third of an SD) in IQ are substantial. The potential long-term benefit of receiving breast milk in the NICU for extremely low birth weight infants may be to optimize cognitive potential and reduce the need for early intervention and special education services.


Hierarchy is Detrimental for Human Cooperation.
Studies of animal behavior consistently demonstrate that the social environment impacts cooperation, yet the effect of social dynamics has been largely excluded from studies of human cooperation. Here, we introduce a novel approach inspired by nonhuman primate research to address how social hierarchies impact human cooperation. Participants competed to earn hierarchy positions and then could cooperate with another individual in the hierarchy by investing in a common effort. Cooperation was achieved if the combined investments exceeded a threshold, and the higher ranked individual distributed the spoils unless control was contested by the partner. Compared to a condition lacking hierarchy, cooperation declined in the presence of a hierarchy due to a decrease in investment by lower ranked individuals. Furthermore, hierarchy was detrimental to cooperation regardless of whether it was earned or arbitrary. These findings mirror results from nonhuman primates and demonstrate that hierarchies are detrimental to cooperation. However, these results deviate from nonhuman primate findings by demonstrating that human behavior is responsive to changing hierarchical structures and suggests partnership dynamics that may improve cooperation. This work introduces a controlled way to investigate the social influences on human behavior, and demonstrates the evolutionary continuity of human behavior with other primate species.


Impact of sedentary behavior and emotional support on prenatal psychological distress and birth outcomes during the COVID-19 pandemic.
Abstract. Studies have reported mixed findings regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women and birth outcomes. This study used a quasi-experimental design to account for potential confounding by sociodemographic characteristics. Data were drawn from 16 prenatal cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) program. Women exposed to the pandemic (delivered between 12 March 2020 and 30 May 2021) (n = 501) were propensity-score matched on maternal age, race and ethnicity, and child assigned sex at birth with 501 women who delivered before 11 March 2020. Participants reported on perceived stress, depressive symptoms, sedentary behavior, and emotional support during pregnancy. Infant gestational age (GA) at birth and birthweight were gathered from medical record abstraction or maternal report. After adjusting for propensity matching and covariates (maternal education, public assistance, employment status, prepregnancy body mass index), results showed a small effect of pandemic exposure on shorter GA at birth, but no effect on birthweight adjusted for GA. Women who were pregnant during the pandemic reported higher levels of prenatal stress and depressive symptoms, but neither mediated the association between pandemic exposure and GA. Sedentary behavior and emotional support were each associated with prenatal stress and depressive symptoms in opposite directions, but no moderation effects were revealed. There was no strong evidence for an association between pandemic exposure and adverse birth outcomes. Furthermore, results highlight the importance of reducing maternal sedentary behavior and encouraging emotional support for optimizing maternal health regardless of pandemic conditions.


Global molecular epidemiology of the O15:K52:H1 extraintestinal pathogenic Escherichia coli clonal group: evidence of distribution beyond Europe.
Escherichia coli O15:K52:H1 is a significant extraintestinal pathogen in Europe (G. Prats et al., J. Clin. Microbiol. 38:201-209, 2000). To search for evidence of this clonal group outside of Europe, 75 non-European E. coli isolates of serogroup O15 were compared with five members of the O15:K52:H1 clonal group from Barcelona, Spain, according to genomic background, virulence genotypes, and antimicrobial resistance profiles. Amplification phylotyping showed that 16 (21%) of the 75 non-European O15 isolates corresponded with the O15:K52:H1 clonal group. The 16 non-European O15:K52:H1 clonal group members represented diverse geographic locales. They were isolated almost exclusively from humans with extraintestinal infections and accounted for 50% of all O15 isolates from five human clinical collections studied. Most non-European clonal group members exhibited a consensus virulence factor profile that included the F16 or F7-2 papA alleles (P fimbrial structural subunit), papG allele II (P fimbrial adhesin), iha (putative adhesin siderophore), and iutA (aerobactin receptor). This resembles the virulence profiles of (i) European representatives of the O15:K52:H1 clonal group and (ii) phylogenetically related "clonal group A," a recently recognized significant contributor to trimethoprim-sulfamethoxazole resistance in the United States (A. R. Manges et al., N. Engl. J. Med. 345:1007-1013, 2001). Antimicrobial resistance profiles were variable, and resistance was inconsistently transferred by conjugation. These findings indicate that the O15:K52:H1 clonal group is broadly distributed beyond Europe, exhibits previously unrecognized phenotypic and genotypic diversity, and contributes significantly to extraintestinal infections in humans.


Two-dimensional wavelet transform achieved by computer-generated multireference matched filter and Dammann grating.
A two-dimensional wavelet transform is optically performed in real time by use of a new multichannel system that processes the different daughter wavelets separately. The system, which is able to handle every wavelet function, relies on a Dammann grating for generating a multichannel array. All channels are processed in parallel by a conventional two-dimensional correlator. Experimental results applying Morlet-wavelet decomposition are presented.


High prevalence of human T-cell leukemia virus type-1b genotype among blood donors in Gabon, Central Africa.
The African continent is considered to be the largest endemic area of HTLV-1 infection, with at least several million infected individuals. Systematic screening of blood donors can prevent the transmission of HTLV-1 in blood. Gabon is one of the countries with the highest prevalence of HTLV-1 worldwide, and yet the routine testing of blood donors has still not been introduced. All blood donations collected between April and July 2017 at the Centre National de Transfusion Sanguine of Gabon were studied. Plasma samples were screened by ELISA for the presence of HTLV-1/2 antibodies. Western blot (WB) and polymerase chain reaction (PCR) tests were used for confirmation. In total, 3123 blood donors were tested, including 1740 repeat and 1378 first-time blood donors (FTBDs). Of them, 132 samples tested positive for HTLV-1/2 by ELISA (4.2%). WB and PCR confirmed HTLV-1 infection for 23 individuals. The overall prevalence of HTLV-1 was 0.74% [95% CI 0.47%-1.10%], 1% in FTBD, and 0.5% in repeat donors. Age and sex-adjusted prevalence was five-fold lower in FTBD than in the general adult population of rural areas of Gabon. All detected HTLV-1 strains belonged to the central African HTLV-1b genotype but were highly diverse. We report an overall prevalence of HTLV-1 of 0.74%, one of the highest values reported for blood donors in Africa. Given the high risk of HTLV-1 transmission in blood, it is necessary to conduct cost-effectiveness studies to determine the need and feasibility of implementing screening of HTLV-1 in blood donors in Gabon.


New airborne scanning lidar system: applications for atmospheric remote sensing.
A new scanning airborne-aerosol lidar system that has the potential to be a valuable atmospheric remote-sensing tool has been developed. The system has the ability to scan both parallel and perpendicular to an aircraft's flight path, and this ability permits both the three-dimensional rendering of the aerosol structure below the aircraft and the measurement of aerosol extinction and optical depth. The system has been integrated into a NASA P-3 aircraft and during a recent flight was used to acquire excellent data with both scanning modes. The system design, the application of the across-track scanning data to the study of the atmospheric boundary layer, and the computation of optical depth derived from along-track scan data are reported.


Computational imaging with the logarithmic asphere: theory.
A theory for an integrated system is described that combines a logarithmic aspheric imaging lens with maximum-entropy digital processing to extend the depth of field ten times over that of a conventional lens and to provide near-diffraction-limited resolution. Two types of logarithmic aspheres are derived that are circularly symmetric lenses with controlled continuous radial variation of focal length. The details of an iterative maximum-entropy algorithm are also presented. The properties of convergence and speed of the algorithm are greatly improved by introducing a metric parameter to adjust the weight of different pixel values of the recovered picture in each loop properly.


Crystal structure of PAV1-137: a protein from the virus PAV1 that infects Pyrococcus abyssi.
Pyrococcus abyssi virus 1 (PAV1) was the first virus particle infecting a hyperthermophilic Euryarchaeota (Pyrococcus abyssi strain GE23) that has been isolated and characterized. It is lemon shaped and is decorated with a short fibered tail. PAV1 morphologically resembles the fusiform members of the family Fuselloviridae or the genus Salterprovirus. The 18 kb dsDNA genome of PAV1 contains 25 predicted genes, most of them of unknown function. To help assigning functions to these proteins, we have initiated structural studies of the PAV1 proteome. We determined the crystal structure of a putative protein of 137 residues (PAV1-137) at a resolution of 2.2 Å. The protein forms dimers both in solution and in the crystal. The fold of PAV1-137 is a four- α -helical bundle analogous to those found in some eukaryotic adhesion proteins such as focal adhesion kinase, suggesting that PAV1-137 is involved in protein-protein interactions.


Frequency of NY-ESO-1 and LAGE-1 expression in bladder cancer and evidence of a new NY-ESO-1 T-cell epitope in a patient with bladder cancer.
Cancer-testis (CT) antigens are ideal vaccine targets since their expression is restricted in adult tissues to testicular germ cells and a subset of cancers. The frequency of expression in transitional cell carcinomas (TCCs) of NY-ESO-1, the most immunogenic CT antigen to date, and its closely related gene LAGE-1 was studied. NY-ESO-1 and LAGE-1 antigen expression were found to occur frequently in high-grade TCC tumors. On an MSKCC IRB-approved protocol, 68 patient specimens were collected prospectively at the time of transurethral resection or cystectomy, of which 43 were read pathologically as high-grade tumors (pCIS, pTaG3, pT1, pT2, pT3, and pT4), 8 as low-grade tumors (pTaG1, pTaG2), and 17 as disease-free samples. These 68 samples were analyzed by immunohistochemistry (IHC) and/or RT-PCR. There were also an additional 53 paraffin-embedded specimens studied retrospectively by IHC, of which 39 were high-grade tumors and 14 were low-grade tumors. Cumulatively, our data indicate that NY-ESO-1 and/or LAGE-1 are expressed in 39/82 (48%) high-grade TCC and 3/22 (14%) low-grade TCC samples when analyzed by RT-PCR and/or IHC. Immunological assessment of these patients' sera identified one patient, whose tumor homogeneously expressed NY-ESO-1, which had detectable antibodies against NY-ESO-1 and LAGE-1. Further analysis of this patient, who remains clinically without evidence of disease 24 months after cystectomy for high-grade pT4 disease, revealed T-cell immunity against NY-ESO-1. This patient's T-cell response was determined to be specific for a new NY-ESO-1 epitope, p94-102, in the context of HLA-B35.


Noninvasive ultrasonic induction of cerebrospinal fluid flow enhances intrathecal drug delivery.
Intrathecal drug delivery is routinely used in the treatment and prophylaxis of varied central nervous system conditions, as doing so allows drugs to directly bypass the blood-brain barrier. However, the utility of this route of administration is limited by poor brain and spinal cord parenchymal drug uptake from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol can significantly increase influx of cerebrospinal fluid into the perivascular spaces of the brain, to enhance the uptake of intrathecally administered drugs. Specifically, we administered small (~1 kDa) and large (~155 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of small molecule agents into the brain parenchyma, and of both small and large molecule agents into the perivascular space from the cerebrospinal fluid. Notably, there was no evidence of brain parenchymal damage following this intervention. The low intensity and noninvasive approach of transcranial ultrasound in this protocol underscores the ready path to clinical translation of this technique. In this manner, this protocol can be used to directly bypass the blood-brain barrier for whole-brain delivery of a variety of agents. Additionally, this technique can potentially be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated.


Diagnostic transgastric endoscopic peritoneoscopy: extension of the initial human trial for staging of pancreatic head masses.
The validity of natural orifice transluminal endoscopic surgery (NOTES) was confirmed in a human trial of 10 patients undergoing diagnostic transgastric endoscopic peritoneoscopy (DTEP) for staging of pancreatic head masses. This report is an update with 10 additional patients in the series and includes bacterial contamination data. The patients in this human trial were scheduled to undergo diagnostic laparoscopy for abdominal staging of a pancreatic head mass. A second surgeon, blinded to the laparoscopic findings, performed a transgastric endoscopic peritoneoscopy (TEP). The findings of laparoscopic exploration were compared with that those of the TEP. Diagnostic findings, operative times, and clinical course were recorded. Bacterial contamination data were collected for the second cohort of 10 patients. Bacterial samples were collected from the scope before use and the abdominal cavity before and after creation of the gastrotomy. Samples were assessed for bacterial counts and species identification. Definitive care was rendered based on the findings from laparoscopy. In this study, 20 patients underwent diagnostic laparoscopy followed by DTEP. The average time for completion of diagnostic laparoscopy was 10 min compared with 21 min for TEP. The experience acquired during the initial 10 procedures translated to a 7-min decrease in TEP time for the second 10 cases. For 19 of the 20 patients, DTEP corroborated laparoscopic findings for surgical decision making. One endoscopic and five laparoscopic biopsies were performed. Pancreaticoduodenectomy was performed for 14 patients and palliative gastrojejunostomy for 6 patients. No cross-contamination of the peritoneum or infectious complications were noted. No significant complications related to either the endoscopic or laparoscopic approach occurred. This study supports the authors' previous conclusions that the transgastric approach to diagnostic peritoneoscopy is feasible, safe, and accurate. The lack of documented bacterial contamination further supports the use of this technique. Technical issues, including intraabdominal manipulation and gastric closure, require further investigation.


The characterization of the invasion phenotype of uveal melanoma tumour cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker.
Uveal malignant melanoma (UM) is the most frequent primary intraocular tumour in adult humans. Because the survival rate of patients with UM has changed little in the past few decades, a better understanding of the molecular events governing UM development and the identification of markers indicating the potential for metastasis at the time of diagnosis are necessary to design improved and more specific treatments. In this study, we investigated UM tumour development by comparing two recently established UM cultures with different invasion potential by two-dimensional gel electrophoresis. Protein features expressed differentially were identified by mass spectrometric analysis. Potential markers were assayed in both cultures and in long-term established UM cell lines (UW-1, OCM-1, SP6.5 and 92.1) by Western blotting and their role in invasion analysed using Matrigel membranes. Comparative analysis revealed that UM cultures with low- and high-grade invasion potential differ in their cellular metabolism and, more interestingly, in several cancer-associated proteins, including those implicated in cell adhesion and migration, proliferation and various oncogenes. Our data indicate a correlation between MUC18 and HMG-1 expression and the invasiveness of UM cells. We also demonstrate the expression and secretion of DJ-1 oncoprotein by UM cells. We suggest a possible role for MUC18 and HMG-1 proteins in UM cell invasion. The secretion of DJ-1 by UM cells, and the ability to detect this protein in UM patients' sera implicate it as a potential noninvasive biomarker for this malignancy.


Bicarbonate enhances expression of the endocarditis and biofilm associated pilus locus, ebpR-ebpABC, in Enterococcus faecalis.
We previously identified ebpR, encoding a potential member of the AtxA/Mga transcriptional regulator family, and showed that it is important for transcriptional activation of the Enterococcus faecalis endocarditis and biofilm associated pilus operon, ebpABC. Although ebpR is not absolutely essential for ebpABC expression (100-fold reduction), its deletion led to phenotypes similar to those of an ebpABC mutant such as absence of pili at the cell surface and, consequently, reduced biofilm formation. A non-piliated ebpABC mutant has been shown to be attenuated in a rat model of endocarditis and in a murine urinary tract infection model, indicating an important participation of the ebpR-ebpABC locus in virulence. However, there is no report relating to the environmental conditions that affect expression of the ebpR-ebpABC locus. In this study, we examined the effect of CO2/HCO3(-), pH, and the Fsr system on the ebpR-ebpABC locus expression. The presence of 5% CO2/0.1 M HCO3(-) increased ebpR-ebpABC expression, while the Fsr system was confirmed to be a weak repressor of this locus. The mechanism by which the Fsr system repressed the ebpR-ebpABC locus expression appears independent of the effects of CO2(-) bicarbonate. Furthermore, by using an ebpA::lacZ fusion as a reporter, we showed that addition of 0.1 M sodium bicarbonate to TSBG (buffered at pH 7.5), but not the presence of 5% CO2, induced ebpA expression in TSBG broth. In addition, using microarray analysis, we found 73 genes affected by the presence of sodium bicarbonate (abs(fold) > 2, P < 0.05), the majority of which belong to the PTS system and ABC transporter families. Finally, pilus production correlated with ebpA mRNA levels under the conditions tested. This study reports that the ebp locus expression is enhanced by the presence of bicarbonate with a consequential increase in the number of cells producing pili. Although the molecular basis of the bicarbonate effect remains unclear, the pathway is independent of the Fsr system. In conclusion, E. faecalis joins the growing family of pathogens that regulates virulence gene expression in response to bicarbonate and/or CO2.


Use of in-line near-infrared spectroscopy in combination with chemometrics for improved understanding of pharmaceutical processes.
High shear granulation is a complex unit operation with several interacting process parameters. No generally accepted real-time in-line tools are available to gain insight into this process, and in practice, a highly experienced process formulator and operator are needed to develop a wet granulated solid dosage form. In this study, the use of in-line near-infrared (NIR) spectroscopy as a process analytical tool for high shear granulation was investigated. In combination with principal component-based methods, process analysis of three separate phases of high shear wet granulation (mixing, spraying, and wet massing) was facilitated. Critical information, both chemical and physical, was collected during processing. Chemical information included the homogeneity of the formulation and the amount of water in wet mass. In addition, physical information related to the particle size of granules was extracted. Principal component loadings were fully interpreted to validate the conclusions drawn from scores and predictions. Thus NIR spectroscopy could be used to determine the end points of the three subphases of high shear wet granulation and, as such, provide a fast in-line quality control tool.


Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells.
CD154 is an important regulator of chronic lymphocytic leukaemia (CLL)-cell survival. In CLL, high serum levels of VEGF are a feature of advanced disease, and we and others have previously shown that CLL cells produce and secrete this growth factor. Since CD154 stimulates VEGF production in other cell types, and VEGF is known to promote cell survival, we examined whether the cytoprotection of CLL cells by CD154 involves VEGF. We report for the first time that treatment of CLL cells with CD154 results in increased VEGF production and demonstrate involvement of NF-kappaB in this process. Moreover, we show that CD154-induced CLL-cell survival is reduced by anti-VEGF-neutralising antibody and by inhibiting VEGF receptor (VEGFR) signalling with SU5416. However, addition of exogenous VEGF alone or blocking secreted autocrine VEGF had little or no effect on CLL-cell survival. We therefore conclude that CLL-cell cytoprotection in the presence of CD154 requires combined signalling by both CD40 and VEGFR. This combined signalling and resulting cytoprotection were shown to involve NF-kappaB activation and increased survivin production. In conclusion, our findings identify autocrine VEGF as an important mediator of the antiapoptotic effect of CD40 ligation, and thus provide new insights into CLL-cell rescue by CD154 in lymphoreticular tissues.


Fundamental aspects of electrochemically controlled wetting of nanoscale composite materials.
Electroactive films based on conducting polymers have numerous potential applications, but practical devices frequently require a combination of properties not met by a single component. This has prompted an extension to composite materials, notably those in which particulates are immobilised within a polymer film. Irrespective of the polymer and the intended application, film wetting is important: by various means, it facilitates transport processes - of electronic charge, charge-balancing counter ions ("dopant") and analyte/reactant molecules - and motion of polymer segments. While film solvent content and transfer have been widely studied for pristine polymer films exposed to molecular solvents, extension to non-conventional solvents (such as ionic liquids) or to composite films has been given much less attention. Here we consider such cases based on polyaniline films. We explore two factors, the nature of the electrolyte (solvent and film-permeating ions) and the effect of introducing particulate species into the film. In the first instance, we compare film behaviours when exposed to a conventional protic solvent (water) with an aprotic ionic liquid (Ethaline) and the intermediate case of a protic ionic liquid (Oxaline). Secondly, we explore the effect of inclusion of physically diverse particulates: multi-walled carbon nanotubes, graphite or molybdenum dioxide. We use electrochemistry to control and monitor the film redox state and change therein, and acoustic wave measurements to diagnose rheologically vs. gravimetrically determined response. The outcomes provide insights of relevance to future practical applications, including charge/discharge rates and cycle life for energy storage devices, "salt" transfer in water purification technologies, and the extent of film "memory" of previous environments when sequentially exposed to different media.


Complex Sociality of Wild Chimpanzees Can Emerge from Laterality of Manual Gestures.
Humans are strongly lateralized for manual gestures at both individual and population levels. In contrast, the laterality bias in primates is less strong, leading some to suggest that lateralization evolved after the Pan and Homo lineages diverged. However, laterality in humans is also context-dependent, suggesting that observed differences in lateralization between primates and humans may be related to external factors such as the complexity of the social environment. Here we address this question in wild chimpanzees and examine the extent to which the laterality of manual gestures is associated with social complexity. Right-handed gestures were more strongly associated with goal-directed communication such as repair through elaboration in response to communication failure than left-handed gestures. Right-handed gestures occurred in evolutionarily urgent contexts such as in interactions with central individuals in the network, including grooming reciprocity and mating, whereas left-handed gestures occurred in less-urgent contexts, such as travel and play. Right-handed gestures occurred in smaller parties and in the absence of social competition relative to left-handed gestures. Right-handed gestures increased the rate of activities indicating high physiological arousal in the recipient, whereas left-handed gestures reduced it. This shows that right- and left-handed gestures differ in cognitive and social complexity, with right-handed gestures facilitating more complex interactions in simpler social settings, whereas left-handed gestures facilitate more rewarding interactions in complex social settings. Differences in laterality between other primates and humans are likely to be driven by differences in the complexity of both the cognitive skills underpinning social interactions and the social environment.


Asymmetric syntheses of nakinadine D, nakinadine E, and nakinadine F: confirmation of their relative (RS,SR)-configurations and proposal of their absolute (2S,3R)-configurations.
The syn- and anti-diastereoisomeric forms of the reported structures of the marine alkaloids nakinadines D-F have been synthesized, for the first time in all cases, via an approach involving asymmetric Mannich-type (imino-aldol) reactions of methyl phenylacetate with N-tert-butylsulfinyl imines as the key steps to control the stereochemistry. Comparison of the (1)H and (13)C NMR spectroscopic data reported for the natural materials with those acquired for these synthetic samples confirms the initially assigned relative (RS,SR)-configurations of these three alkaloids. In the absence of specific rotation (or other diagnostic) data for the natural materials, it is not possible to unambiguously assign their absolute configurations, although given the absolute (2S)-configurations assigned to nakinadines B and C, and the absolute (2S,3R)-configuration previously established for nakinadine A, the data herein uphold our proposal that nakinadines D-F share the absolute (2S,3R)-configuration.


Evaluation of transient elastography for fibrosis assessment compared with large biopsies in chronic hepatitis B and C.
Fibrosis determines prognosis and management in patients with chronic hepatitis B and C (CHB and CHC). Transient elastography (TE) is a promising non-invasive method to assess fibrosis. We prospectively studied the performance of TE compared to histology and also whether there are differences between CHB and CHC. Only large biopsies (≥ 25 mm) were used. We included 241 patients with CHB (n = 125) and CHC (n = 116), of whom we acquired 257 liver biopsies, all preceded by elastography. We correlated liver stiffness with fibrosis stage according to the METAVIR system, inflammation (Histology Activity Index), steatosis and iron. The impact of gender, age, body mass index, alcohol, alanine aminotransferase levels, platelet count, viral load and genotype on liver stiffness was evaluated. The AUROC's for F ≥ 2 were 0.85 for CHB and 0.76 for CHC. AUROC's for F ≥ 3 were 0.91 for CHB and 0.87 for CHC and 0.90 and 0.91 for F4 for CHB and CHC respectively. For F ≥ 2 the cut-off value was 6.0 kPa for CHB and 5.0 kPa for CHC. The cut-off values for ≥ F3 were 9.0 and 8.0 kPa for CHB and CHC, respectively, and 13.0 kPa for F4 in both CHB and CHC patients. Besides inflammation, all other remaining factors do not influence liver stiffness. For the diagnosis of fibrosis stages F ≤ 2 TE is suboptimal, and inflammation may induce higher values. For stages F ≥ 3 TE performance is good and equal in both CHB and CHC patients.


Synaptogenesis on mature hippocampal dendrites occurs via filopodia and immature spines during blocked synaptic transmission.
During development, dendritic spines emerge as stubby protrusions from single synapses on dendritic shafts or from retracting filopodia, many of which have more than one synapse. These structures are rarely encountered in the mature brain. Recently, confocal and two-photon microscopy have revealed a proliferation of new filopodia-like protrusions in mature hippocampal slices, especially when synaptic transmission was blocked. It was not known whether these protrusions have synapses nor whether they are accompanied by the other immature spine forms. Here, reconstruction from serial section electron microscopy (ssEM) was used to answer these questions. Acute hippocampal slices from mature male rats, ages 56 and 63 days, were maintained in vitro in control medium or in a nominally calcium-free medium with high magnesium, glutamate receptor antagonists, and sodium and calcium channel blockers. At the end of each 8-hour experiment, all slices were fixed, coded, and processed for ssEM. In agreement with light microscopy, there were more filopodia along dendrites in slices with blocked synaptic transmission. These filopodia were identified by their pointy tips and either the absence of synapses or presence of multiple synapses along them. There was also a proliferation of stubby spines. Filopodia along mature dendrites were typically shorter than developmental filopodia, with outgrowth likely being constrained by reduced extracellular space and compact neuropil, providing numerous candidate presynaptic partners in the vicinity of the mature dendrites. These findings suggest that synaptogenesis and spine formation are readily initiated under conditions of reduced activity in the mature brain.


Fermented Red Ginseng Alleviates Cyclophosphamide-Induced Immunosuppression and 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis in Mice by Regulating Macrophage Activation and T Cell Differentiation.
A variety of products have been developed with red ginseng (RG, the steamed roots of Panax ginseng Meyer). To clarify the immunomodulating effects of water-extracted RG (wRG), 50% ethanol-extracted RG (eRG), enzyme-treated eRG (ERG) and probiotic-fermented eRG (FRG), we examined their immunopotentiating and immunosuppressive effects in mice with cyclophosphamide (CP)-induced immunosuppression (CI) or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis (TC). Oral administration of RG in CI mice significantly increased blood IFN- γ levels. Treatment with RG also increased the tumoricidal effects of CI mouse splenic cytotoxic T (Tc) and NK cells against YAC-1 cells. Treatment with RGs, in particular FRG and wRG, significantly increased Th1 cell differentiation. Treatment with RG except wRG increased Treg cell differentiation. However, wRG alone increased IL-6 and IL-17 expression in the colon of CI mice. Furthermore, RG alleviated colitis in TC mice. FRG most potently suppressed TNBS-induced colon shortening, NF- κ B activation and TNF- α and IL-17 expression and increased IL-10 expression. RGs inhibited TNF- α expression and increased IL-10 expression in lipopolysaccharide-stimulated primary macrophages in vitro while the differentiation of splenic T cells into type 1 T (Th1) and regulatory T (Treg) cells was increased by FRG in vitro. In conclusion, FRG can alleviate immunosuppression and inflammation by inhibiting macrophage activation and regulating Th1 and Treg cell differentiation.


The tumor suppressor Scrib interacts with the zyxin-related protein LPP, which shuttles between cell adhesion sites and the nucleus.
At sites of cell adhesion, proteins exist that not only perform structural tasks but also have a signaling function. Previously, we found that the Lipoma Preferred Partner (LPP) protein is localized at sites of cell adhesion such as focal adhesions and cell-cell contacts, and shuttles to the nucleus where it has transcriptional activation capacity. LPP is a member of the zyxin family of proteins, which contains five members: ajuba, LIMD1, LPP, TRIP6 and zyxin. LPP has three LIM domains (zinc-finger protein interaction domains) at its carboxy-terminus, which are preceded by a proline-rich pre-LIM region containing a number of protein interaction domains. To catch the role of LPP at sites of cell adhesion, we made an effort to identify binding partners of LPP. We found the tumor suppressor protein Scrib, which is a component of cell-cell contacts, as interaction partner of LPP. Human Scrib, which is a functional homologue of Drosophila scribble, is a member of the leucine-rich repeat and PDZ (LAP) family of proteins that is involved in the regulation of cell adhesion, cell shape and polarity. In addition, Scrib displays tumor suppressor activity. The binding between Scrib and LPP is mediated by the PDZ domains of Scrib and the carboxy-terminus of LPP. Both proteins localize in cell-cell contacts. Whereas LPP is also localized in focal adhesions and in the nucleus, Scrib could not be detected at these locations in MDCKII and CV-1 cells. Furthermore, our investigations indicate that Scrib is dispensable for targeting LPP to focal adhesions and to cell-cell contacts, and that LPP is not necessary for localizing Scrib in cell-cell contacts. We show that all four PDZ domains of Scrib are dispensable for localizing this protein in cell-cell contacts. Here, we identified an interaction between one of zyxin's family members, LPP, and the tumor suppressor protein Scrib. Both proteins localize in cell-cell contacts. This interaction links Scrib to a communication pathway between cell-cell contacts and the nucleus, and implicates LPP in Scrib-associated functions.


Mid- and long-term outcomes of carotid-cavernous fistula endovascular management with Onyx and n-BCA: experience of a single tertiary center.
Endovascular therapy is the preferred treatment for most carotid-cavernous fistulas (CCFs). Early reports have documented excellent initial clinical and radiographic outcomes after embolization of CCFs with Onyx or n-butyl cyanoacrylate (n-BCA), but little evidence is available about the long-term durability of this technique. To characterize the long-term durability of CCF liquid embolization. The authors retrospectively reviewed a database of 24 CCFs in 21 consecutive patients who underwent Onyx or n-BCA embolization of a CCF from 2006 to 2013 at our institution. A total of 25 Onyx or n-BCA embolization procedures were attempted and 24 successfully completed during the study, resulting in complete or near-complete occlusion by the end of the study in all 24 CCFs (obliteration success, 100%). Attempted embolization in a single CCF failed initially, but was performed successfully at a later date by a different approach. None of the 24 CCFs recanalized, regrew, or required any further treatment subsequent to Onyx or n-BCA embolization throughout a mean 12.4 months of angiographic follow-up (range 1-36 months). Clinically significant complications were seen in three embolization procedures, including cranial nerve palsies (n=1), embolic infarct (n=1), and intraperitoneal hemorrhage (n=1). Early evidence has indicated that endovascular embolization with Onyx is relatively safe and effective at achieving an initial angiographic cure for CCFs. Results of our series suggest that angiographic and clinical outcomes of Onyx and n-BCA embolization remain stable at mid- and long-term follow-up.


[The life quality of the people with tuberculosis in observed taking administration].
The World Health Organization assumed, since 1993, Tuberculosis, as a world emergency. The control of the disease is implemented by the strategy DOTS (Direct Observed Therapy Short Course) through standardized treatments, in administration of observed taking (TOD) in order to maximize the success of the treatment and to avoid the multi resistance. The monitorization of the problems lived by these patients is still little known. The present study is a descriptive and cross-sectional study. The sample consisted of a 151 users of five Pneumologics Diagnostics Centres of the Oporto district (Portugal). The purposes of this study was to investigate the life quality of the people with Pulmonary Tuberculosis in administration of observed taking and its relation with the descriptive variables, socio-economic and clinic variables. The data was collected by: i) a bio and a clinical questionnaire, ii) the SF-36. The mean values of the life quality swing between 31.3 in the Vitality domain and 68.4 in the Physical Pain domain. The younger persons present better levels of life quality in Health in General and in the Performance Physical, occurring the inverse in the Social Performance. The data suggest a fragile life quality in what concerns the Vitality level (31.3), Mental Health (36.7) and Physic Performance (39.7). This study makes possible the future focus in the adjustment of the health services to the users' necessities, being able to optimize the approval to the treatment, increasing the therapeutic success, contributing this way to the disease control.


Characterization of putative stem cell populations in the cornea using synchrotron infrared microspectroscopy.
High-resolution synchrotron radiation-based Fourier transform infrared (SR-FTIR) microspectroscopy coupled with multivariate analysis was used to investigate the characteristics of putative adult stem cell (SC), transiently amplified (TA) cell, and terminally differentiated (TD) cell populations of the corneal epithelium. Spectra of individual cells in situ in cryosections of bovine cornea were collected by using a synchrotron microspectroscopy facility at Daresbury Laboratory (United Kingdom). The resultant spectra were analyzed by multivariate analysis. The median spectra of the three different cell populations showed marked differences, which correlated with their degree of differentiation and proliferative capacity. Multivariate (principal component) analysis (PCA) showed that the three cell populations could be segregated into discrete clusters, with only a slight overlap between the SC and TA cell populations. Further analysis (Mann-Whitney test) indicated that the most significant (P<0.001) spectral differences between the SC and TA cell populations were chiefly associated with changes in nucleic acid conformation. SR-FTIR microspectroscopy coupled with PCA appears to enable the identification of SC, TA cell, and TD cell populations. The results also suggest that a small subpopulation of cells in the corneal epithelial SC niche possess TA cell-like characteristics. The most significant spectral characteristics associated with the SCs appear to relate to differences in nucleic acid conformation. This finding is consistent with recent theories suggesting that the control of differentiation is related to major changes in chromatin structure.


Occupational and recreational noise exposure from indoor arena hockey games.
Occupational and recreational noise exposures were evaluated at two sporting arenas hosting collegiate hockey games (Venue 1) and semi-professional hockey (Venue 2). A total of 54 personal noise dosimetry samples were taken over the course of seven home hockey games: 15 workers and 9 fans at Venue 1, and 19 workers and 11 fans at Venue 2. None of the sampled workers were overexposed to noise based on Occupational Safety and Health Administration criteria. However, 40% and 57% of workers at Venue 1 and 33% and 91% of fans at Venue 2 were overexposed based on ACGIH noise exposure criteria. Noise exposures for fans were significantly different between venues, but worker noise exposures between venues were not significantly different. In addition, extensive area noise monitoring was conducted at each venue to further characterize the stadium noise on a location-by-location basis. Mean equivalent sound pressure levels ranged from 81 to 96 dBA at Venue 1 and from 85 to 97 dBA at Venue 2. Mean noise peak levels ranged from 105 to 124 dBA at Venue 1, and from 110 to 117 dBA at Venue 2. These data reflect the potential for overexposure at indoor hockey events and are useful in characterizing occupational noise exposure of indoor arena support staff and may also provide a foundation for future noise control research in indoor sports arenas.


Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-gamma-dependent mechanism.
In the mucosal immune system, resident dendritic cells are specialized for priming Th2-polarized immunity, whereas the Ag-presenting activity of macrophages has been linked with the development of Th1 phenotype. As an immune switch toward Th1 can protect against Th2-mediated allergic response, this study investigated the capacity of lung macrophages to stimulate Th1 responses during the secondary exposure to inhaled allergen, thereby suppressing Th2-mediated allergic airway inflammation in a murine model of allergic asthma. Following airway macrophage depletion in OVA-sensitized mice, lung T cells defaulted to a phenotype that produced less Th1 (IFN-gamma) and more Th2 (IL-4 and IL-5) cytokines, leading to more severe airway hyperreactivity and inflammation after intranasal Ag challenge. After OVA pulsing and adoptive transfer, lung macrophages selectively promoted a Th1 response in Ag-sensitized recipients and did not induce pulmonary eosinophilia. By contrast, OVA pulsing and adoptive transfer of a lung cell preparation, consisting of dendritic cells, B cells, and macrophages, promoted a Th2 response with an associated inflammatory response that was suppressed when macrophages were present and pretreated with IFN-gamma, but exacerbated when macrophages were depleted before IFN-gamma treatment. In addition, Th1-promoting activity of lung macrophages was not related to the autocrine production of IL-12p40. These results suggest that the Th1-promoting APC activity may be an inherent property of the lung macrophage population, and may play an important role, upon stimulation by IFN-gamma, in antagonizing an ongoing Th2 immunity and Th2-dependent allergic responses.


Bioenhancers from mother nature and their applicability in modern medicine.
Concept of bioenhancers or biopotentiators was first time reported in 1929 by Bose. A bioenhancer is an agent capable of enhancing bioavailability and efficacy of a drug with which it is co-administered, without any pharmacological activity of its own at therapeutic dose used. Development and consequent isolation of these molecules, such as piperine and quercetin, is considered as scientific breakthrough. A fixed drug combination (Risorine) of rifampicin, isoniazid, and piperine is the result of this research. It contains almost 60% less dose of rifampicin because of its increased bioavailability and it also prevents resistance. This concept is mentioned as yogvahi in ayurveda and was used to increase the effect of medicines by increasing oral bioavailability, decreasing adverse effects and to circumvent parenteral routes of drug administration. More such useful and economically viable drug combinations can be developed by integrating knowledge of time tested ayurveda with modern methods of research. This review is an account of these bioenhancers, available from the natural resources.


Heparin-induced platelet aggregation vs platelet factor 4 enzyme-linked immunosorbent assay in the diagnosis of heparin-induced thrombocytopenia-thrombosis.
Thrombosis occurs in an unpredictable subset of patients with heparin-induced thrombocytopenia (HIT). The diagnosis of HIT requires clinical suspicion and laboratory confirmation. Although the "gold-standard" diagnostic test is considered to be the serotonin release assay (SRA), most laboratories use heparin-induced platelet aggregation (HIPA), which is highly specific but reported to be less sensitive than the SRA. Recently, the heparin-platelet factor 4 (PF4) enzyme-linked immunosorbent assay (ELISA) has been reported to have comparable sensitivity to the SRA. We compared the HIPA and PF4 ELISA in serum samples from 146 patients examined for HIT and assessed whether either test predicted thrombotic risk. Results for 81 patients were positive for HIPA, PF4 ELISA, or both. Of these, 91% were HIPA-positive, while only 60% were PF4 ELISA-positive. Clinical information was available on 63 patients, 17 of whom had thrombotic events (10 venous, 6 arterial, and 1 both). Neither the HIPA nor the PF4 ELISA predicted thrombotic risk, but the HIPA proved to be a more sensitive test for laboratory confirmation.


The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors.
To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.


The use of climate information to estimate future mortality from high ambient temperature: A systematic literature review.
Heat related mortality is of great concern for public health, and estimates of future mortality under a warming climate are important for planning of resources and possible adaptation measures. Papers providing projections of future heat-related mortality were critically reviewed with a focus on the use of climate model data. Some best practice guidelines are proposed for future research. The electronic databases Web of Science and PubMed/Medline were searched for papers containing a quantitative estimate of future heat-related mortality. The search was limited to papers published in English in peer-reviewed journals up to the end of March 2017. Reference lists of relevant papers and the citing literature were also examined. The wide range of locations studied and climate data used prevented a meta-analysis. A total of 608 articles were identified after removal of duplicate entries, of which 63 were found to contain a quantitative estimate of future mortality from hot days or heat waves. A wide range of mortality models and climate model data have been used to estimate future mortality. Temperatures in the climate simulations used in these studies were projected to increase. Consequently, all the papers indicated that mortality from high temperatures would increase under a warming climate. The spread in projections of future climate by models adds substantial uncertainty to estimates of future heat-related mortality. However, many studies either did not consider this source of uncertainty, or only used results from a small number of climate models. Other studies showed that uncertainty from changes in populations and demographics, and the methods for adaptation to warmer temperatures were at least as important as climate model uncertainty. Some inconsistencies in the use of climate data (for example, using global mean temperature changes instead of changes for specific locations) and interpretation of the effects on mortality were apparent. Some factors which have not been considered when estimating future mortality are summarised. Most studies have used climate data generated using scenarios with medium and high emissions of greenhouse gases. More estimates of future mortality using climate information from the mitigation scenario RCP2.6 are needed, as this scenario is the only one under which the Paris Agreement to limit global warming to 2°C or less could be realised. Many of the methods used to combine modelled data with local climate observations are simplistic. Quantile-based methods might offer an improved approach, especially for temperatures at the ends of the distributions. The modelling of adaptation to warmer temperatures in mortality models is generally arbitrary and simplistic, and more research is needed to better quantify adaptation. Only a small number of studies included possible changes in population and demographics in their estimates of future mortality, meaning many estimates of mortality could be biased low. Uncertainty originating from establishing a mortality baseline, climate projections, adaptation and population changes is important and should be considered when estimating future mortality.


Limited interaction between translation and visual motion aftereffects in humans.
After exposure to a moving sensory stimulus, subsequent perception is often biased in the opposite direction. This phenomenon, known as an aftereffect, has been extensively studied for optic flow stimuli where it is known as the visual motion aftereffect (MAE). Such visual motion can also generate the sensation of self-motion or vection. It has recently been demonstrated that fore-aft translation in darkness also produces an aftereffect. The current study examines the interaction between visual MAE and vestibular translation aftereffects. Human subjects participated in a two-interval experiment in which the first interval (adapter) was visual, translation, or both combined congruently or in conflict. Subjects identified the direction of the second (test) interval of either visual or translation using a forced-choice technique. The translation adapter had no influence on visual test stimulus perception, and the visual adapter did not influence vestibular test stimulus perception in any subjects. However, congruent visual and translation induced a significantly larger perceptual bias on the translation test stimulus than was observed for a translation only adapter. The congruent adapter caused the MAE to be diminished relative to a visual only adapter. Conflicting visual and vestibular adapters produced an aftereffect similar to that seen when the single adapting stimulus was the same modality as the test stimulus. These results suggest that unlike visual and translation stimuli whose combined influence on perception can be predicted based on the effects of each stimulus individually, the effects of combined visual and translation stimuli on aftereffects cannot be predicted from the influences of each stimulus individually.


Survival of cultured allogeneic limbal epithelial cells following corneal repair.
In this study a technique for determining donor cell fate following corneal grafting was evaluated. Patients treated for limbal deficiency with allogeneic cultured corneal epithelial cells were studied to determine the fate of the grafted cells. The technique was evaluated initially through the use of donor eyes and then applied to the clinical analysis of 7 patients who had received a cultured corneal epithelial allograft. Cells removed from the cornea and any retrieved tissue were analyzed via polymerase chain reaction (PCR) genotyping to determine the origin of the cells populating the patients' healed cornea. A mixture of genotypes was detected in a cornea retrieved from a patient following a fully penetrating keratoplasty who had received a mixture of allogeneic tissue. Donor cells were no longer detected on the corneal surface of all 7 cases beyond 28 weeks postgraft. At these later time points, only patient genotype could be detected. These results demonstrate that PCR genotyping can be used to determine the origin of cells populating the surface of the cornea following the grafting of cultured allogeneic cells and demonstrates that transplanted cultured limbal epithelial cells do not persist on the surface of the host cornea for more than 28 weeks.


Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes.
Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.


Phase IV, open-label assessment of the treatment of actinic keratosis with 3.0% diclofenac sodium topical gel (Solaraze).
A clearance rate of all occurrences > or = 75% for actinic keratoses (AK) lesions is an accepted efficacy endpoint for topical agents. This efficacy endpoint has not been assessed for 3.0% diclofenac sodium gel (Solaraze). We evaluated the efficacy and tolerability of 3.0% diclofenac sodium gel in the treatment of AK for a treatment period of 90 days and a 30-day follow-up period. This is a multicenter, single-arm, open-label study in patients diagnosed with five or more AK lesions contained in 1 to 3 blocks (5 cm2) on the forehead, central face, or scalp. Patients were treated twice daily with a topical application of 3.0% diclofenac sodium gel for a period of 90 days with a follow-up assessment at 30 days post-treatment. The presence or absence of target lesions and new lesions was assessed at each visit a long with a global improvement index score. Of the 76 patients who entered the study, 67 (88%) patients completed the study. At Day 90 of treatment, 78% of patients had > or = 75% AK lesion clearance based on the target lesion number score (TLNS). Improving to 85% of patients demonstrating > or = 75% AK lesion clearance at Day 120 (follow-up). Improvement was also demonstrated by 100% AK lesion clearance based on the TLNS clearance (Day 90 of treatment: 41%; Day 120 [follow-up]: 58%). Similar improvements were shown in cumulative lesion number score (CLNS), which included new as well as targeted AK lesions within the designated treatment areas, at Day 90 and Day 120 (follow-up). Investigators' assessment based on Investigator Global Improvement Index (IGII) confirmed the efficacy of 3.0% diclofenac gel in the clearance of AK lesions. A total of 39 patients (51%) experienced at least 1 adverse event considered to be related to 3.0% diclofenac sodium gel during the study. Dry skin and rash at the application site were most common reported adverse events, and most of these adverse events were mild or moderate in severity. The topical application of 3.0% diclofenac sodium gel provides a safe and effective approach for the treatment of AK.