Duration of surgical-orthodontic treatment.
To study the duration of surgical-orthodontic treatment with special reference to patients' age and the type of tooth movements, i.e. extraction vs. non-extraction and intrusion before or extrusion after surgery to level the curve of Spee. The material consisted files of 37 consecutive surgical-orthodontic patients. The files were reviewed and gender, diagnosis, type of malocclusion, age at the initiation of treatment, duration of treatment, type of tooth movements (extraction vs. non-extraction and levelling of the curve of Spee before or after operation) and type of operation were retrieved. For statistical analyses two sample t-test, Kruskal-Wallis and Spearman rank correlation tests were used. Mean treatment duration of the sample was 26.8 months, of which pre-surgical orthodontics took on average 17.5 months. Patients with extractions as part of the treatment had statistically and clinically significantly longer treatment duration, on average 8 months, than those without extractions. No other studied variable seemed to have an impact on the treatment time. The present small sample size prevents reliable conclusions to be made. However, the findings suggest, and patients should be informed, that extractions included in the treatment plan increase chances of longer duration of surgical-orthodontic treatment.


Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan.
Fifty-five gastric carcinoma tumors from Chinese patients in Taiwan, including 40 tubular type (one lymphoepthelioma-like carcinoma subtype), eight signet ring cell type, one papillary type, and six mucinous type gastric carcinomas, were investigated for the presence of Epstein-Barr virus (EBV) transcripts by in situ hybridization using fluorescein-conjugated EBV oligonucleotides for EBERs (Epstein-Barr virus early RNAs) expression and the polymerase chain reaction for viral DNA. Epstein-Barr virus was detected in six of 55 lesions (11%), a significantly lower proportion than has been observed in a North American series. Epstein-Barr virus involvement was more common among male patients. Epstein-Barr virus DNA and its EBERs were specifically present within gastric carcinoma and adjacent dysplastic cells but were absent in surrounding lymphocytes and normal gastric mucosa. Epstein-Barr virus DNA and EBERs were found in one sample of lymphoepithelioma-like carcinoma (LELC) and five specimens of typical gastric adenocarcinoma. Among the EBV-positive gastric adenocarcinomas, four were tubular type of varied differentiation and one was signet ring cell type. Furthermore, we evaluated the expression of the latent membrane protein (LMP) with monoclonal antibodies. We found that LMP was expressed in two EBV-positive samples. In addition, the presence of the EBV receptor was studied by probing samples with CD21 monoclonal antibody. Epstein-Barr virus receptor was not detected in any sample. Southern blot analysis indicated single clonal proliferation of tumor cells. These findings confirm and extend the results of Shibata et al. They also indicate that EBV infection might be related to oncogenesis not only in rare gastric cancers that resemble nasopharyngeal lymphoepithelioma but also in typical gastric adenocarcinoma.


Excited-state dynamics of an environment-sensitive push-pull diketopyrrolopyrrole: major differences between the bulk solution phase and the dodecane/water interface.
The excited-state dynamics of a diketopyrrolopyrrole (DPP) derivative with push-pull substituents has been investigated in a variety of solvents and at the dodecane/water and dodecane/heavy-water interfaces using a combination of ultrafast spectroscopic techniques, including transient electronic absorption and time-resolved surface second-harmonic generation. Whereas the photophysics of a nonpolar DPP analogue is mostly independent of the solvent, the fluorescence decay of the push-pull DPP accelerates strongly by going from aprotic to protic solvents. As this effect increases with the polarity and the hydrogen-bond-donating ability of the solvent, it is attributed to the occurrence of H-bond-assisted nonradiative deactivation induced by the charge-transfer character of the excited state that favors the coupling of the molecule to the H-bond network of the solvent. At the dodecane/water interface, the excited-state lifetime is longer by a factor of ca. 20 than that estimated in pure water and increases further by a factor of about 3 when going to the dodecane/heavy-water interface. This isotope effect, that is more than twice as strong as that measured in bulk solutions, and molecular dynamic simulations indicate that the slowing down of the dynamics at the interface cannot be solely ascribed to a reduced accessibility of the DPP molecule to the aqueous phase. The slower excited-state decay is rather assigned to the conjunction of several effects, such as the strengthening of the H-bond network formed by the interfacial water molecules and the lower local polarity of the interfacial region.


Laparoscopic right varicocelectomy for chronic scrotal pain.
Varicocele represents a common problem in young men with infertility or chronic scrotal pain and it is located on the left side in the vast majority of the cases. Right isolated varicocele is a quite rare entity, especially in middle-aged men and as the single pathology responsible for chronic pain. Further investigation might be needed to exclude other retroperitoneal or scrotal hidden lesions. Several surgical options are available for symptomatic patients with clinical varicocele including the laparoscopic approach of high ligation of the spermatic veins. We present a case of a 61-year-old patient treated with laparoscopic varicocelectomy for right chronic scrotal pain.


An Essential and Synergistic Role of Purinergic Signaling in Guided Migration of Corneal Epithelial Cells in Physiological Electric Fields.
Directional migration of corneal epithelial cells is essential for healing of corneal wounds, which is a robust response mediated by biochemical and bioelectrical cues. Naturally occurring electric fields at corneal wounds provide a powerful guidance cue for directional cell migration, as does extracellular ATP. Our recent large-scale siRNA library screening identified a role for purinergic signaling in the electric field-guided migration (galvanotaxis/electrotaxis) of human corneal epithelial (hTCEpi) cells. We examined the effect of extracellular ATP on galvanotaxis of hTCEpi cells. Galvanotactic cell migration was recorded by video microscopy, and directedness and migration speed was calculated. The role of purinergic receptors in galvanotaxis regulation was evaluated by pharmacological inhibition or knocking down of P2X and P2Y receptors. Addition of ATP enhanced galvanotaxis, and most remarkably sensitized galvanotaxis response to very low level of electric fields in the physiological range (10-30 mV/mm). The stimulatory effect of extracellular ATP was diminished by apyrase treatment. Importantly, cells stimulated with extracellular ATP migrated with significantly increased directedness and speed, which were diminished by knocking down or pharmacological inhibition of P2X and P2Y receptors. Inhibition of pannexin-1 (ATP permeable channel) significantly impaired galvanotaxis. Moreover, pharmacological inhibition of ectoATPase enhanced galvanotaxis. Extracellular ATP and physiological electric fields synergistically enhanced the galvanotaxis response of hTCEpi cells. hTCEpi cells are likely to secrete ATP actively, and purinergic signaling is down-regulated by ecto-ATPases. Both P2X and P2Y receptors coordinately play a role for galvanotaxis of hTCEpi cells.


Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists.
On the basis of the long-known prototypic pharmacophore 3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486, 2), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H2 receptor (H2R) agonists with various alkyl spacers were synthesized. Aiming at increased H2R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h/gp/rH2R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist (Emax = 88%) and 250 times more potent than histamine (pEC50: 8.56 vs 6.16, gpH2R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest hH2R affinities (pKi: 7.47, 7.33) in binding studies. Dimeric amino(methyl)thiazole derivatives, such as 58, generated an increased hH2R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H2R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH4R ligands.


Physical activity in relation to circulating hormone concentrations in 117,100 men in UK Biobank.
Physical activity may reduce the risk of some types of cancer in men. Biological mechanisms may involve changes in hormone concentrations; however, this relationship is not well established. Therefore, we aimed to investigate the associations of physical activity with circulating insulin-like growth factor-I (IGF-I), sex hormone-binding globulin (SHBG, which modifies sex hormone activity), and total and free testosterone concentrations, and the extent these associations might be mediated by body mass index (BMI). Circulating concentrations of these hormones and anthropometric measurements and self-reported physical activity data were available for 117,100 healthy male UK Biobank participants at recruitment. Objectively measured accelerometer physical activity levels were also collected on average 5.7 years after recruitment in 28,000 men. Geometric means of hormone concentrations were estimated using multivariable-adjusted analysis of variance, with and without adjustment for BMI. The associations between physical activity and hormones were modest and similar for objectively measured (accelerometer) and self-reported physical activity. Compared to men with the lowest objectively measured physical activity, men with high physical activity levels had 14% and 8% higher concentrations of SHBG and total testosterone, respectively, and these differences were attenuated to 6% and 3% following adjustment for BMI. Our results suggest that the associations of physical activity with the hormones investigated are, at most, modest; and following adjustment for BMI, the small associations with SHBG and total testosterone were largely attenuated. Therefore, it is unlikely that changes in these circulating hormones explain the associations of physical activity with risk of cancer either independently or via BMI.


Military traumatic brain and spinal column injury: a 5-year study of the impact blast and other military grade weaponry on the central nervous system.
During the past 5 years of Operation Iraqi Freedom (OIF), a significant majority of the severe closed and penetrating head trauma has presented for definitive care at the National Naval Medical Center (NNMC) in Bethesda, MD, and at the Walter Reed Army Medical Center (WRAMC) in Washington, DC. The purpose of this article is to review our experience with this population of patients. A retrospective review of all inpatient admissions from OIF was performed during a 5-year period (April 2003 to April 2008). Criteria for inclusion in this study included either a closed or penetrating head trauma suffered during combat operations in Iraq who subsequently received a neurosurgical evaluation at NNMC or WRAMC. Exclusion criteria included all patients for whom primary demographic data could not be verified. Primary outcome data included the type and mechanism of injury, Glasgow coma scale (GCS) and injury severity score at admission, and Glasgow outcome scale (GOS) at discharge, 6 months, and 1 to 2 years. Five hundred thirteen consultations were performed by the neurosurgery service on the aforementioned population. Four hundred eight patients met the inclusion criteria for this study (401:7, male: female; 228 penetrating brain injury, 139 closed head injury, 41 not specified). Explosive blast injury (229 patients; 56%) constituted the predominant mechanism of injury. The rates of pulmonary embolism (7%), cerebrospinal fluid leak (8.6%), meningitis (9.1%), spinal cord or column injury (9.8%), and cerebrovascular injury (27%) were characterized. Cerebrospinal fluid leak, vasospasm, penetrating head injury, and lower presenting GCS were statistically associated with longer intensive care unit stays and higher presenting injury severity scores (p < 0.05). While presenting GCS 3-5 correlated with worsened short-term and long-term GOS scores (p < 0.001), almost half of these patients achieved GOS >or=3 at 1- to 2-year follow-up. Total mortality after reaching NNMC/WRAMC was 4.4%. OIF has resulted in the highest concentration of severe closed and penetrating head trauma to return to NNMC and WRAMC since the Vietnam Conflict. Management scenarios were complex, incorporating principles designed to maximize outcomes in all body systems. Meaningful survival can potentially be achieved in a subset of patients with presenting GCS <or=5.


Postglacial range expansion and the role of ecological factors in driving adaptive evolution of Musa basjoo var. formosana.
Genetic variation evolves during postglacial range expansion of a species and is important for adapting to varied environmental conditions. It is crucial for the future survival of a species. We investigate the nuclear DNA sequence variation to provide evidence of postglacial range expansion of Musa basjoo var. formosana, a wild banana species, and test for adaptive evolution of amplified fragment length polymorphic (AFLP) loci underlying local adaptation in association with environmental variables. Postglacial range expansion was suggested by phylogeographical analyses based on sequence variation of the second intron of copper zinc superoxide dismutase 2 gene. Two glacial refugia were inferred by the average F ST parameter (mean F ST of a population against the remaining populations). Using variation partitioning by redundancy analysis, we found a significant amount of explained AFLP variation attributed to environmental and spatially-structured environmental effects. By combining genome scan methods and multiple univariate logistic regression, four AFLP loci were found to be strongly associated with environmental variables, including temperature, precipitation, soil moisture, wet days, and surface coverage activity representing vegetation greenness. These environmental variables may have played various roles as ecological drivers for adaptive evolution of M. basjoo var. formosana during range expansion after the last glacial maximum.


Diagnostic performance of gait speed, G8 and G8 modified indices to screen for vulnerability in older cancer patients: the prospective PF-EC cohort study.
The diagnostic performance of tools used to screen vulnerability in older cancer patients varies widely. We assessed the diagnostic performance of gait speed (GS) for assessing vulnerability in such patients. All consecutive outpatients 65 years and older were referred for geriatric oncology assessment (GA) before a therapeutic decision between November 2013 and April 2016 in a bicentric observational and prospective cohort study. Vulnerability was defined as impaired score on at least one of the 6 domains of the GA. GS and the G8 index and G8 modified index were assessed at the first geriatric oncology visit during the GA. Sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratio were estimated. The accuracy of the three tools was analysed by the area under the receiver operating characteristic curve (AUC). Among 269 included patients (mean [SD] age, 81.3 years [5.9]; 55% women, 94.4% solid tumors; 39.4% with metastasis), 252 (93.7%) had impaired GA. With the GS threshold of 1 m/s, sensitivity was 79.4% (95% CI, 73.8-84.2), specificity 64.7% (38.3-85.8), and AUC 82.0 (74.0-90.0). The corresponding values for the G8 index were 90.1% (85.7-93.5), 35.3% (14.2-61.7), and 79.0 (70.0-88.0) and G8 modified index were 89.3% (84.8-92.8), 64.7% (38.3-85.8), and 84.0 (74.0-92.0). GS < 1 m/s with a single measure could be used as a new screening tool for detecting vulnerability in older cancer outpatients. This first external validation of the G8 modified index was very good.


Attributing the burden of cancer at work: three areas of concern when examining the example of shift-work.
This commentary intends to instigate discussions about epidemiologic estimates and their interpretation of attributable fractions (AFs) and the burden of disease (BOD) of cancers due to factors at workplaces. By examining recent work that aims to estimate the number of cancers attributable to shift-work in Britain, we suggest that (i) causal, (ii) practical and (iii) methodological areas of concern may deter us from attributable caseload estimations of cancers at this point in time. Regarding (i), such calculations may have to be avoided as long as we lack established causality between shift-work and the development of internal cancers. Regarding (ii), such calculations may have to be avoided as long as we can neither abandon shift-work nor identify personnel that may be unaffected by shift-work factors. Regarding (iii), there are at least four methodological pitfalls which are likely to make AF calculations uninterpretable at this stage. The four pitfalls are: (1) The use of Levin's 1953 formula in case of adjusted relative risks; (2) The use of broad definitions of exposure in calculations of AFs; (3) The non-additivity of AFs across different levels of exposure and covariables; (4) The fact that excess mortality counts are misleading due to the fact that a human being dies exactly once - a death may occur earlier or later, but a death cannot occur more than once nor can it be avoided altogether for any given individual. Overall, causal, practical and methodological areas of concern should be diligently considered when performing and interpreting AF or BOD computations which - at least at the present time - may not be defensible.


Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma.
The signal transducer and activator of transcription 6 (STAT6) is a critical up-stream mediator of interleukin-13 (IL-13) and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT6 inhibition, we have identified the genes regulated by STAT6 in MF/SS tumors. We found that STAT6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell-cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT6 activation downregulates cytokine production and induces cell-cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT6 promotes the protumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced stage MF by upregulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the antitumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.


Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with serum lipid levels in the Guangxi Hei Yi Zhuang and Han populations.
Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. The present study was undertaken to compare the difference in the CETP TaqIB gene polymorphism and its association with serum lipid levels between the Guangxi Hei Yi Zhuang and Han populations. A total of 758 subjects of Hei Yi Zhuang and 778 participants of Han Chinese were surveyed. Genotyping of the CETP TaqIB was performed using polymerase chain reaction and restriction fragment length polymorphism and then confirmed using direct sequencing. The genotypic and allelic frequencies were significant differences between smokers and nonsmokers, or between hypertensives and normotensives in Hei Yi Zhuang, and between drinkers and nondrinkers in Han. The levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI in Hei Yi Zhuang but not in Han were higher in B2B2 genotype than in B1B1 genotype (P < 0.01 for each). Higher HDL-C levels in Hei Yi Zhuang were found only in females, nondrinkers, nonsmokers, subjects with a body mass index of 24 kg/m or lesser, or normotensives in B2B2 genotype. Higher HDL-C levels in Han were found only in females in B2B2 genotype and in subjects with a body mass index of 24 kg/m or lesser or normotensives in B1B2 genotype. The levels of HDL-C in B1B1 and B1B2 individuals in both ethnic groups were higher in drinkers than in nondrinkers. There were significant differences in the interactions between the CETP TaqIB genotypes and several environmental factors in the Hei Yi Zhuang and Han populations. The polymorphism predicted differences in HDL-C and ApoAI in the Hei Yi Zhuang but not in the Han Chinese, even after adjustment for confounding variables. This means that the gene may not be truly involved in regulation of high-density lipoprotein metabolism or that there is an ethnic-specific effect.


Impact of COVID-19 Pandemic on Rheumatology Practice in Latin America.
To describe the effect of the coronavirus disease 2019 (COVID-19) pandemic on Latin American rheumatologists from a professional, economic, and occupational point of view. We conducted an observational cross-sectional study using an online survey sent to rheumatologists of each non-English-speaking country member of the Pan American League of Rheumatology Associations (PANLAR). A specific questionnaire was developed. Our survey included 1097 rheumatologists from 19 Latin American countries. Median (IQR) age of respondents was 48 (40-59) years and 618 (56.3%) were female. Duration of practice since graduation as a rheumatologist was 17 years, and 585 (53.3%) were aged < 50 years. Most rheumatologists worked in private practice (81.8%) and almost half worked in institutional outpatient centers (55%) and inpatient care (49.9%). The median number of weekly hours (IQR) of face-to-face practice before the pandemic was 27 (15-40) hours, but was reduced to 10 (5-20) hours during the pandemic. Telehealth was used by 866 (78.9%) respondents during the pandemic. Most common methods of communication were video calls (555; 50.6%), telephone calls (499; 45.5%), and WhatsApp voice calls (423; 38.6%). A reduction in monthly wages was reported by 946 (86.2%) respondents. Consultation fees also were reduced and 88 (8%) rheumatologists stated they had lost their jobs. A reduction in patient adherence to medication was reported by nearly 50% of respondents. Eighty-one (7.4%) rheumatologists received a COVID-19 diagnosis and 7 (8.6%) of them were hospitalized. The COVID-19 pandemic has reshaped rheumatology practice in Latin America and has had a profound effect on rheumatologists' behaviors and clinical practice.


Polygenic risk score for embryo selection-not ready for prime time.
Numerous chronic diseases have a substantial hereditary component. Recent advances in human genetics have allowed the extent of this to be quantified via genome-wide association studies, producing polygenic risk scores (PRS), which can then be applied to individuals to estimate their risk of developing a disease in question. This technology has recently been applied to embryo selection in the setting of IVF and preimplantation genetic testing, with limited data to support its utility. Furthermore, there are concerns that the inherent limitations of PRS makes it ill-suited for use as a screening test in this setting. There are also serious ethical and moral questions associated with this technology that are yet to be addressed. We conclude that further research and ethical reflection are required before embryo selection based on PRS is offered to patients outside of the research setting.


Role of Male Sex Partners in HIV Risk of Adolescent Girls and Young Women in Mozambique.
Adolescent girls and young women (AGYW) ages 15-24 years are disproportionately affected by HIV/AIDS, particularly in East and Southern Africa. One strategy to reduce HIV among AGYW, proposed through the Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) Initiative, is to prevent and manage HIV among their male sexual partners. To implement this strategy and reach men, programs need information about AGYW's potential sexual partners at the local level. To support DREAMS programming in Mozambique, we undertook a study to characterize this population of men in 3 districts with ongoing DREAMS programming. In mid-2017 we conducted 15 focus group discussions with AGYW (N=102) and a venue-based intercept survey of men (N=1,140). Male sexual partners of AGYW who took the survey were diverse in age, education level, and socioeconomic status. Older AGYW focus group participants sought partners who could provide for them financially. Multiple sexual partnerships and inconsistent condom use were widely reported, with AGYW emphasizing that gender norms disempowered them from negotiating condom use. Reported condom use varied by AGYW and male-partner demographic characteristics, as well as by their relationship type. Condom use rates were much higher than national and regional estimates. AGYW who were less educated/not-in-school, were pregnant, or single mothers were particularly disempowered in sexual relationships. Less educated men were less likely to use condoms than educated men, and condom use was least likely in marriage. Study findings underscore the importance of reaching the diversity of male sexual partners of AGYW with HIV services as part of a strategy to reduce HIV risk among AGYW. They also support an enhanced focus on female-controlled HIV prevention methods that do not require negotiation with a male partner and special efforts to reach out-of-school/less educated AGYW, as well as pregnant AGYW and single mothers.


An improved permutation-diffusion type image cipher with a chaotic orbit perturbing mechanism.
During the past decades, chaos-based permutation-diffusion type image cipher has been widely investigated to meet the increasing demand for real-time secure image transmission over public networks. However, the existing researches almost exclusively focus on the improvements of the permutation and diffusion methods independently, without consideration of cooperation between the two processes. In this paper, an improved permutation-diffusion type image cipher with a chaotic orbit perturbing mechanism is proposed. In the permutation stage, pixels in the plain image are shuffled with a pixel-swapping mechanism, and the pseudorandom locations are generated by chaotic logistic map iteration. Furthermore, a plain pixel related chaotic orbit perturbing mechanism is introduced. As a result, a tiny change in plain image will be spread out during the confusion process, and hence an effective diffusion effect is introduced. By using a reverse direction diffusion method, the introduced diffusion effect will be further diffused to the whole cipher image within one overall encryption round. Simulation results and extensive cryptanalysis justify that the proposed scheme has a satisfactory security with a low computational complexity, which renders it a good candidate for real-time secure image storage and distribution applications.


Oral glucose and breast milk as a strategy for pain reduction during the heel lance procedure in newborns.
This paper presents the results of a study on pain reduction in newborns that undergo painful medical procedures. This research analyzed the reactions of babies before and after the heel lance procedure, a diagnostic test performed to detect phenylketonuria. This test involved the extraction of a capillary blood sample with a heel lance, a medical procedure that is painful for neonates. The main objective of this research was to evaluate the effectiveness of a 24% oral glucose solution and breastfeeding during heal lance. An experimental study was thus conducted on a sample of 93 newborns in the San Cecilio University Hospital in Granada in 2010. The babies in the sample were divided into three groups, depending on what they ingested during the heal lance. The results obtained showed that there was an association between the difference in HR and the time before the newborn's HR returned to normal after the heel lance (r = 0.562; p = 0.000). Moreover, a positive relation was found between the absolute difference in HR and the difference in oxygen saturation (OS) (r = 0.538; p = 0.000). The OS was found to be greater in the group of newborns that received breast milk.


Aberrant methylation of Reprimo in human malignancies.
Reprimo is a new candidate mediator of p53-mediated cell cycle arrest at the G2 phase. Loss of Reprimo gene expression accompanied by its promoter methylation was identified in pancreatic and lung cancers. Our aim was to examine the methylation status of Reprimo in a broad range of cancers. We examined Reprimo expression by RT-PCR and the DNA methylation status of the Reprimo promoter by MSP in 39 tumor cell lines. Loss or downregulation of Reprimo expression was frequent (62%), and we confirmed that transcriptional repression of Reprimo was caused by hypermethylation (overall concordance 92%). Treatment of expression-negative cells with 5-aza-2'-deoxycytidine restored Reprimo expression. We then examined aberrant methylation of Reprimo in 645 tumors representing 16 tumor types. Promoter methylation of Reprimo was found in 79% of gastric cancers, 62% of gallbladder cancers, 57% of lymphomas, 56% of colorectal cancers, 40% of esophageal adenocarcinomas, 37% of breast cancers and 31% of leukemias. Methylation frequencies in ovarian cancers, bladder cancers, cervical cancers, brain tumors, malignant mesotheliomas and pediatric tumors were lower (0-20%). Reprimo methylation was rarely detected in nonmalignant tissues (0-11%) except for gastric epithelia. While colorectal polyps were also frequently methylated (27%), chronic cholecystitis samples were infrequently methylated (4%). Furthermore, we failed to identify Reprimo mutation in colorectal and gastric cancer cell lines and 50 primary colorectal cancers. Aberrant methylation of Reprimo with loss of expression is a common event and may contribute to the pathogenesis of some types of human malignancy.


Implementation of a collaborative care model for the treatment of depression and anxiety in a community health center: results from a qualitative case study.
The collaborative care model is a systematic approach to the treatment of depression and anxiety in primary care settings that involves the integration of care managers and consultant psychiatrists, with primary care physician oversight, to more proactively manage mental disorders as chronic diseases, rather than treating acute symptoms. While collaborative care has been shown to be more effective than usual primary care in improving depression outcomes in a number of studies, less is known about the factors that support the translation of this evidence-based intervention to real-world program implementation. The purpose of this case study was to examine the implementation of a collaborative care model in a community based primary care clinic that primarily serves a low-income, uninsured Latino population, in order to better understand the interdisciplinary relationships and the specific elements that might facilitate broader implementation. An embedded single-case study design was chosen in order to thoroughly examine the components of one of several programs within a single organization. The main unit of analysis was semi-structured interviews that were conducted with seven clinical and administrative staff members. A grounded theory approach was used to analyze the interviews. Line-by-line initial coding resulted in over 150 initial codes, which were clustered together to rebuild the data into preliminary categories and then divided into four final categories, or main themes. FOUR UNIQUE THEMES ABOUT HOW THE IMPLEMENTATION OF A COLLABORATIVE CARE MODEL WORKED IN THIS SETTING EMERGED FROM THE INTERVIEWS: organizational change, communication, processes and outcomes of the program, and barriers to implementation. Each main theme had a number of subthemes that provided a detailed description of the implementation process and how it was unique in this setting. The results indicated that adequate training and preparation, acceptance and support from key personnel, communication barriers, tools for systematic follow-up and measurement, and organizational stability can significantly impact successful implementation. Further research is necessary to understand how organizational challenges may affect outcomes for patients.


Glu298Asp polymorphism influences the beneficial effects of fish oil fatty acids on postprandial vascular function.
Our objective was to determine whether the endothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism influences vascular response to raised NEFA enriched with saturated fatty acids (SFA) or long-chain (LC) n-3 polyunsaturated fatty acids (PUFA). Subjects were prospectively recruited for genotype (Glu298, n = 30 and Asp298, n = 29; balanced for age and gender) consumed SFA on two occasions, with and without the substitution of 0.07 g fat/kg body weight with LC n-3 PUFA, and with heparin infusion to elevate NEFA. Endothelial function was measured before and after NEFA elevation (240 min), with blood samples taken every 30 min. Flow-mediated dilation (FMD) decreased following SFA alone and increased following SFA+LC n-3 PUFA. There were 2-fold differences in the change in FMD response to the different fat loads between the Asp298 and Glu298 genotypes (P = 0.002) and between genders (P < 0.02). Sodium nitroprusside-induced reactivity, measured by laser Doppler imaging with iontophoresis, was significantly greater with SFA+LC n-3 PUFA in all female subjects (P < 0.001) but not in males. Elevated NEFA influences both endothelial-dependent and endothelial-independent vasodilation during the postprandial phase. Effects of fat composition appear to be genotype and gender dependent, with the greatest difference in vasodilatory response to the two fat loads seen in the Asp298 females.


Prolonged reduction of high blood pressure with an in vivo, nonpathogenic, adeno-associated viral vector delivery of AT1-R mRNA antisense.
To produce a prolonged decrease in blood pressure, we have developed a nonpathogenic adeno-associated viral vector (AAV) with the antisense DNA for AT1-R. AAV has many advantages over other viral vectors. AAV does not stimulate inflammation or immune reaction. AAV enters nondividing cells and does not replicate. Therefore, it is an appropriate choice for gene therapy. Recombinant AAV was prepared with a cassette containing a cytomegalovirus promoter and the cDNA for the AT1 receptor inserted in the antisense direction. The cassette was packaged in the virion. Stable transfection of NG108-15 cells with the PAAV-AS (plasmid AAV) antisense to AT1-R produced a significant reduction in AT1 receptors. A single injection of the rAAV-AS (viral vector) was made in adult spontaneously hypertensive rats, either directly in the hypothalamus (1 microL) or in the lateral ventricles (5 microL). The result shows that there is a significant decrease of blood pressure (approximately 23 +/- 2 mm Hg) for up to 9 weeks after injection. Control injections of mock vector produced no change in blood pressure during the same time period in age-matched controls. In young spontaneously hypertensive rats (3 weeks), a single intracardiac injection of recombinant rAAV-AS reduced blood pressure and slowed the development of hypertension compared with controls (P < .01). The results suggest that a prolonged reduction in high blood pressure can be achieved with AAV vectors delivering antisense to inhibit AT1 receptors with a single administration.


The tactile circumferential discriminator. A new, simple screening device to identify diabetic patients at risk of foot ulceration.
To evaluate the tactile circumferential discriminator (TCD) (Tacticon Medical Enterprises, West Chester, PA), a new, simple, handheld quantitative sensory testing device, in the identification of patients at potential risk of neuropathic ulceration. Patients with diabetes (n = 133) attending the Manchester Diabetes Centre or diabetic foot clinic seen within a 5-week period were assessed using the TCD, monofilaments, and vibration perception threshold (VPT) measured over the hallux. The sensitivity and specificity of each method in the identification of "high-risk" patients were compared. The TCD was easy to use, and there was a highly significant correlation between the results obtained compared with both filaments and VPT (P < 0.0001). Similarly, in the identification of patients at risk of ulceration, the TCD agreed with VPT in 75.2% of cases and with the monofilaments in 78.9%. In the identification of the 37 foot ulcer patients, TCD was highly sensitive (100%) but less specific (58.3%) than VPT (86.5%; 79.2%) and the monofilaments (91.9%; 76.0%). These data suggest that the TCD is a simple and reliable new technique for population screening for neuropathy and foot ulcer risk.


Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis.
Mechanisms responsible for energy management in the cell and in the whole organism require a complex network of transcription factors and cofactors. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a master regulator of mitochondrial biogenesis and function, thus becoming a crucial metabolic node. We present an overview of the mechanisms by which PGC-1α is regulated, including the transcriptional regulation of PGC-1α expression and the fine-tuning of its final activity via posttranslational modifications.


Underwater operational noise level emitted by a tidal current turbine and its potential impact on marine fauna.
Marine renewable energy development raised concerns over the impact of underwater noise. Here we assess the acoustic impacts of an operating tidal current turbine (Paimpol-Bréhat site, France) on marine fauna. Its source level (SL) has been measured in situ using 19 drifting transects at distances between 100 m to 2400 m from the turbine. SL ranged from 118 to 152 dB re1 μPa@1 m in third-octave bands at frequencies between 40 and 8192 Hz. It is comparable to the SL of a 19 m boat travelling at 10kt speed. This SL was used to estimate the impact of this noise type based on acoustic propagation simulations. The acoustic footprint of the device corresponds to a 1.5 km radius disk. Our results show that within this area of greatest potential impact, physiological injury of the hearing apparatus of invertebrates, fishes and marine mammals is improbable. Behavioral disturbance may occur up to 1 km around the device for harbor porpoises only. This is of little concern for a single turbine. However, greater concern on turbine noise impact, particularly on behavioral reactions has to be granted for a farm with up to 100 turbine. The lack of consolidated knowledge on behavioral disturbances identifies the needs for specific research programs.


Cryptotanshinone attenuates in vitro oxLDL-induced pre-lesional atherosclerotic events.
Development of early stage atherosclerosis involves the activation of endothelial cells by oxidized low-density lipoprotein (oxLDL) with subsequent increases in endothelial permeability and expression of adhesion molecules favoring the adherence of monocytes to the endothelium. Cryptotanshinone (CTS), a major compound derived from the Chinese herb Salvia miltiorrhiza, is known for its protective effects against cardiovascular diseases. The aim of this study was to determine whether CTS could prevent the oxLDL-induced early atherosclerotic events. OxLDL (100 µg/mL) was used to increase endothelial permeability and induce monocyte-endothelial cell adhesion in human umbilical vein endothelial cells (HUVECs). Endothelial nitric oxide (NO) concentrations, a permeability-regulating molecule, and expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. Results show that a) endothelial hyperpermeability was suppressed by 94 % (p < 0.005), b) monocyte adhesion by 105 % (p < 0.01), and c) ICAM-1 and VCAM-1 expressions by 90 % (p < 0.01) and 150 % (p < 0.005), respectively, when CTS was applied. In contrast, CTS increased NO levels by 129 % (p < 0.01) and was found to be noncytotoxic in the concentrations between 1-10 µM. These findings indicate that CTS suppresses an increase in endothelial permeability, likely due to the restoration of NO bioavailability in endothelial cells. They also indicate that CTS may attenuate monocyte adhesion to endothelial cells through the inhibition of adhesion molecules' expression. Thus, CTS may play an important role in the prevention of early or pre-lesional stage of atherosclerosis.


The pharmacological bases for repurposing statins in depression: a review of mechanistic studies.
Statins are commonly prescribed medications widely investigated for their potential actions on the brain and mental health. Pre-clinical and clinical evidence suggests that statins may play a role in the treatment of depressive disorders, but only the latter has been systematically assessed. Thus, the physiopathological mechanisms underlying statins' putative antidepressant or depressogenic effects have not been established. This review aims to gather available evidence from mechanistic studies to strengthen the pharmacological basis for repurposing statins in depression. We used a broad, well-validated search strategy over three major databases (Pubmed/MEDLINE, Embase, PsychINFO) to retrieve any mechanistic study investigating statins' effects on depression. The systematic search yielded 8068 records, which were narrowed down to 77 relevant papers. The selected studies (some dealing with more than one bodily system) described several neuropsychopharmacological (44 studies), endocrine-metabolic (17 studies), cardiovascular (6 studies) and immunological (15 studies) mechanisms potentially contributing to the effects of statins on mood. Numerous articles highlighted the beneficial effect of statins on depression, particularly through positive actions on serotonergic neurotransmission, neurogenesis and neuroplasticity, hypothalamic-pituitary axis regulation and modulation of inflammation. The role of other mechanisms, especially the association between statins, lipid metabolism and worsening of depressive symptoms, appears more controversial. Overall, most mechanistic evidence supports an antidepressant activity for statins, likely mediated by a variety of intertwined processes involving several bodily systems. Further research in this area can benefit from measuring relevant biomarkers to inform the selection of patients most likely to respond to statins' antidepressant effects while also improving our understanding of the physiopathological basis of depression.


ProSAAS-derived peptides are differentially processed and sorted in mouse brain and AtT-20 cells.
ProSAAS is the precursor for some of the most abundant peptides found in mouse brain and other tissues, including peptides named SAAS, PEN, and LEN. Both SAAS and LEN are found in big and little forms due to differential processing. Initial processing of proSAAS is mediated by furin (and/or furin-like enzymes) and carboxypeptidase D, while the smaller forms are generated by secretory granule prohormone convertases and carboxypeptidase E. In mouse hypothalamus, PEN and big LEN colocalize with neuropeptide Y. In the present study, little LEN and SAAS were detected in mouse hypothalamus but not in cell bodies of neuropeptide Y-expressing neurons. PEN and big LEN show substantial colocalization in hypothalamus, but big LEN and little LEN do not. An antiserum to SAAS that detects both big and little forms of this peptide did not show substantial colocalization with PEN or big LEN. To further study this, the AtT-20 cells mouse pituitary corticotrophic cell line was transfected with rat proSAAS and the distribution of peptides examined. As found in mouse hypothalamus, only some of the proSAAS-derived peptides colocalized with each other in AtT-20 cells. The two sites within proSAAS that are known to be efficiently cleaved by furin were altered by site-directed mutagenesis to convert the P4 Arg into Lys; this change converts the sequences from furin consensus sites into prohormone convertase consensus sites. Upon expression of the mutated form of proSAAS in AtT-20 cells, there was significantly more colocalization of proSAAS-derived peptides PEN and SAAS. Taken together, these results indicate that proSAAS is initially cleaved in the Golgi or trans-Golgi network by furin and/or furin-like enzymes and the resulting fragments are sorted into distinct vesicles and further processed by additional enzymes into the mature peptides.


PMT1 deficiency enhances basal UPR activity and extends replicative lifespan of Saccharomyces cerevisiae.
Pmt1p is an important member of the protein O-mannosyltransferase (PMT) family of enzymes, which participates in the endoplasmic reticulum (ER) unfolded protein response (UPR), an important pathway for alleviating ER stress. ER stress and the UPR have been implicated in aging and age-related diseases in several organisms; however, a possible role for PMT1 in determining lifespan has not been previously described. In this study, we report that deletion of PMT1 increases replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae, while overexpression of PMT1 (PMT1-OX) reduces RLS. Relative to wild-type and PMT1-OX strains, the pmt1Δ strain had enhanced HAC1 mRNA splicing and elevated expression levels of UPR target genes. Furthermore, the increased RLS of the pmt1Δ strain could be completely abolished by deletion of either IRE1 or HAC1, two upstream modulators of the UPR. The double deletion strains pmt1Δhac1Δ and pmt1Δire1Δ also displayed generally reduced transcription of UPR target genes. Collectively, our results suggest that PMT1 deficiency enhances basal activity of the ER UPR and extends the RLS of yeast mother cells through a mechanism that requires both IRE1 and HAC1.


Mothers matter! Maternal support, dominance status and mating success in male bonobos (Pan paniscus).
Variation in male mating success is often related to rank differences. Males who are unable to monopolize oestrous females alone may engage in coalitions, thus enhancing their mating success. While studies on chimpanzees and dolphins suggest that coalitions are independent of kinship, information from female philopatric species shows the importance of kin support, especially from mothers, on the reproductive success of females. Therefore, one might expect a similar effect on sons in male philopatric species. We evaluate mating success determinants in male bonobos using data from nine male individuals from a wild population. Results reveal a steep, linear male dominance hierarchy and a positive correlation between dominance status and mating success. In addition to rank, the presence of mothers enhances the mating success of sons and reduces the proportion of matings by the highest ranking male. Mothers and sons have high association rates and mothers provide agonistic aid to sons in conflicts with other males. As bonobos are male-philopatric and adult females occupy high dominance status, maternal support extends into adulthood and females have the leverage to intervene in male conflicts. The absence of female support to unrelated males suggests that mothers gain indirect fitness benefits by supporting their sons.


Standardized Assessment of Automatic Segmentation of White Matter Hyperintensities and Results of the WMH Segmentation Challenge.
Quantification of cerebral white matter hyperintensities (WMH) of presumed vascular origin is of key importance in many neurological research studies. Currently, measurements are often still obtained from manual segmentations on brain MR images, which is a laborious procedure. The automatic WMH segmentation methods exist, but a standardized comparison of the performance of such methods is lacking. We organized a scientific challenge, in which developers could evaluate their methods on a standardized multi-center/-scanner image dataset, giving an objective comparison: the WMH Segmentation Challenge. Sixty T1 + FLAIR images from three MR scanners were released with the manual WMH segmentations for training. A test set of 110 images from five MR scanners was used for evaluation. The segmentation methods had to be containerized and submitted to the challenge organizers. Five evaluation metrics were used to rank the methods: 1) Dice similarity coefficient; 2) modified Hausdorff distance (95th percentile); 3) absolute log-transformed volume difference; 4) sensitivity for detecting individual lesions; and 5) F1-score for individual lesions. In addition, the methods were ranked on their inter-scanner robustness; 20 participants submitted their methods for evaluation. This paper provides a detailed analysis of the results. In brief, there is a cluster of four methods that rank significantly better than the other methods, with one clear winner. The inter-scanner robustness ranking shows that not all the methods generalize to unseen scanners. The challenge remains open for future submissions and provides a public platform for method evaluation.


Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.
We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.


Catecholamine support at the initiation of epoprostenol therapy in pulmonary arterial hypertension.
Epoprostenol is a first-line therapy for patients with pulmonary arterial hypertension (PAH) in World Health Organization functional class IV who often have low cardiac output and hypotension. However, initiation of epoprostenol can cause hemodynamic collapse in these vulnerable patients. Inotropic agent support may prevent the hemodynamic instability caused by initiation of epoprostenol; however, a protocol for supportive therapy has not been established. To assess the reliability and prognostic effects of dobutamine and dopamine support at the initiation of epoprostenol therapy in patients with PAH. We initiated epoprostenol therapy in 71 patients with PAH. Hemodynamics at the initiation of epoprostenol were measured by right heart catheterization. We initiated dobutamine when a patient's mixed venous oxygen saturation was less than 60% or cardiac index was less than 2.0 L/min/m(2) or when right ventricular failure was clinically suspected. We initiated dopamine when a patient's systolic blood pressure was less than 90 mm Hg or urine volume was less than 20 ml/h. At the initiation of epoprostenol, dobutamine and/or dopamine were required to support 46 patients according to protocol. Eight patients died during the hospitalization and one patient received a living-donor lobar lung transplant after the initiation of epoprostenol therapy. Neither inotropic agent was an independent risk factor for short-term mortality (dobutamine: hazard ratio, 1.63; 95% confidence interval, 0.33-8.11; dopamine: hazard ratio, 0.22; 95% confidence interval, 0.03-1.70). Sixty-two patients were discharged for home infusion of epoprostenol. Transplant-free survival rates at 5 years were 80.0% for patients who did not require inotropic support at the start of epoprostenol and 76.6% for patients with who did require dopamine and/or dobutamine support (P = 0.45). Temporary use of dobutamine and dopamine appears to be safe for hemodynamic support at the initiation of epoprostenol therapy for selected patients with PAH with low cardiac output and hypotension. The protocol presented here requires validation at other centers.


Design of electrocatalysts for oxygen- and hydrogen-involving energy conversion reactions.
A fundamental change has been achieved in understanding surface electrochemistry due to the profound knowledge of the nature of electrocatalytic processes accumulated over the past several decades and to the recent technological advances in spectroscopy and high resolution imaging. Nowadays one can preferably design electrocatalysts based on the deep theoretical knowledge of electronic structures, via computer-guided engineering of the surface and (electro)chemical properties of materials, followed by the synthesis of practical materials with high performance for specific reactions. This review provides insights into both theoretical and experimental electrochemistry toward a better understanding of a series of key clean energy conversion reactions including oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction (HER). The emphasis of this review is on the origin of the electrocatalytic activity of nanostructured catalysts toward the aforementioned reactions by correlating the apparent electrode performance with their intrinsic electrochemical properties. Also, a rational design of electrocatalysts is proposed starting from the most fundamental aspects of the electronic structure engineering to a more practical level of nanotechnological fabrication.


Effect of inflammation stimulation on energy and nutrient utilization in piglets selected for low and high residual feed intake.
Selection of animals for improved feed efficiency can affect sustainability of animal production because the most efficient animals may face difficulties coping with challenges. The objective of this study was to determine the effects of an inflammatory challenge (using an intravenous injection of complete Freund's adjuvant - CFA) in piglets from two lines of pigs divergently selected during the fattening period for a low (RFI-) or a high (RFI+) residual feed intake (RFI; difference between actual feed intake and theoretical feed requirements). Nitrogen and energy balances (including heat production - HP - and its components: activity-related HP - AHP, thermic effect of feeding, and resting HP) were measured individually in thirteen 20-kg BW castrated male piglets (six and seven from RFI+ and RFI- line, respectively) fed at the same level (1.72 MJ ME/kg BW0.60 per day) from 3 days before to 3 days after CFA injection. Dynamics of dietary U-13C-glucose oxidation were estimated from measurements of 13CO2 production on the day before and 3 days after the CFA injection. Oxidation of dietary nutrients and lipogenesis were calculated based on HP and O2 consumption and CO2 production. The data were analyzed as repeated measurements within piglets in a mixed model. Before CFA injection, RFI- piglets had a lower resting energy expenditure than RFI+ piglets, which tended to increase energy retention because of a higher energy retention as fat. The CFA injection did not affect feed intake from the day following CFA injection onwards but it increased energy retention (P=0.04). Time to recover 50% of 13C from dietary glucose as expired 13CO2 was higher in RFI+ piglets before inducing inflammation but decreased after to the level of RFI- piglets (P<0.01). Oxidation of U-13C-glucose tended to slightly increased in RFI- piglets and to decreased in RFI+ piglets (P=0.10) because of CFA. Additionally, RFI- piglets had a lower respiratory quotient during the 1st day following the CFA injection whereas RFI+ piglets tended to have a higher respiratory quotient. In conclusion, selection for RFI during the fattening period also affected the energy metabolism of pigs during earlier stages of growth. The effects of CFA injection were moderated in both lines but the most efficient animals (RFI-) exhibited a marked re-orientation of nutrients only during the 1st day after CFA, and seemed to recover thereafter, whereas the less efficient piglets expressed a more prolonged alteration of their metabolism.


Temporal differentiation of optical signals using a phase-shifted fiber Bragg grating.
We propose and experimentally demonstrate an all-optical (all-fiber) temporal differentiator based on a simple pi-phase-shifted fiber Bragg grating operated in reflection. The proposed device can calculate the first time derivative of the complex field of an arbitrary narrowband optical waveform with a very high accuracy and efficiency. Specifically, the experimental fiber grating differentiator reported here offers an operation bandwidth of approximately 12 GHz. We demonstrate the high performance of this device by processing gigahertz-bandwidth phase and intensity optical temporal variations.


First Insights into the Subterranean Crustacean Bathynellacea Transcriptome: Transcriptionally Reduced Opsin Repertoire and Evidence of Conserved Homeostasis Regulatory Mechanisms.
Bathynellacea (Crustacea, Syncarida, Parabathynellidae) are subterranean aquatic crustaceans that typically inhabit freshwater interstitial spaces (e.g., groundwater) and are occasionally found in caves and even hot springs. In this study, we sequenced the whole transcriptome of Allobathynella bangokensis using RNA-seq. De novo sequence assembly produced 74,866 contigs including 28,934 BLAST hits. Overall, the gene sequences were most similar to those of the waterflea Daphnia pulex. In the A. bangokensis transcriptome, no opsin or related sequences were identified, and no contig aligned to the crustacean visual opsins and non-visual opsins (i.e. arthropsins, peropsins, and melaopsins), suggesting potential regressive adaptation to the dark environment. However, A. bangokensis expressed conserved gene family sets, such as heat shock proteins and those related to key innate immunity pathways and antioxidant defense systems, at the transcriptional level, suggesting that this species has evolved adaptations involving molecular mechanisms of homeostasis. The transcriptomic information of A. bangokensis will be useful for investigating molecular adaptations and response mechanisms to subterranean environmental conditions.


Automated screening for genomic imbalances using matrix-based comparative genomic hybridization.
Genome-wide screening for chromosomal imbalances using comparative genomic hybridization (CGH) revealed a wealth of data on previously unrecognized tumor-specific genomic alterations. CGH to microarrays of DNA, an approach termed matrix-CGH, allows detection of genomic imbalances at a much higher resolution. We show that matrix CGH is also feasible from small tissue samples requiring universal amplification of genomic DNA. Because widespread application of matrix-CGH experiments using large numbers of DNA targets demands a high degree of automation, we have developed a protocol for a fully automated procedure. The use of specialized instrumentation for the generation of DNA chips, their hybridization, scanning, and evaluation required numerous alterations and modifications of the initial protocol. We here present the elaboration and testing of automated matrix-CGH. A chip consisting of 188 different genomic DNA fragments, cloned in bacterial artificial chromosome (BAC) or P1-derived artificial chromosome (PAC) vectors and immobilized in replicas of 10, was used to assess the performance of the automated protocol in determining the gene dosage variations in tumor cell lines COLO320-HSR, HL60, and NGP. Although ratios of matrix-CGH were highly concordant with results of chromosomal CGH (85%), the dynamic range of the matrix-CGH ratios was highly superior. Investigation of the two amplicons on 8q24 in COLO320-HSR and HL60, containing the MYC gene, revealed a homogeneous amplicon in COLO320-HSR but a heterogeneous amplification pattern in HL60 cells. Although control clones for normalization of the signal ratios can be predicted in cases with defined chromosomal aberrations, in primary tumors such data are often not available, requiring alternative normalization algorithms. Testing such algorithms in a primary high-grade B-cell lymphoma, we show the feasibility of this approach. With the matrix-CGH protocol presented here, robust and reliable detection of genomic gains and losses is accomplished in an automated fashion, which provides the basis for widespread application in tumor and clinical genetics.


Epidemiology of multiple sclerosis: a critical overview.
The decisive conclusions to be drawn from the available epidemiological data, mostly geography and prevalence, of MS are: (1) a north-south (as well as west-east in the United States) gradient exists independent of genetic/racial factors; (2) major differences in prevalence occur in the absence of latitude differences; (3) individuals from the same ethnic derivation have either similar prevalence rates or very different prevalence rates in widely separated geographical areas and (4) specific resistant isolates are shown to exist regardless of latitude. Existing information leads to the almost inescapable conclusion that the epidemiology of MS cannot be explained by any single known environmental or genetic factor(s) in isolation. A combination of a heterogeneous distribution of both genetic and environmental factors appears to be required to explain the available data on MS.


What comorbidities accompany sarcoidosis? A large cohort (n=1779) patients analysis.
Sarcoidosis is a systemic granulomatous multiorgan disease with the most common manifestation is in the chest, although the granulomas can also involve all other organs causing variety of symptoms mimicking different diseases. To evaluate the incidence of comorbidity in a large group of patients with sarcoidosis diagnosed or followed in referral center for lung diseases in Poland. We performed a retrospective analysis in a group of 1779 patients discharged with the final diagnosis "sarcoidosis" (ICD-10: D86) from January 2008 to October 2011. The majority (79.2%) were diagnosed as pulmonary and/or lymph node sarcoidosis (D86.0, D86.1, D86.2). Sarcoidosis of other and combined sites (D86.8) were diagnosed in 15.8% and unspecified (D86.9) in 5.0% of patients. At least one comorbid condition was noted in 54% of the patients, most frequently arterial hypertension (22.4%), thyroid disorders (5.6%), diabetes mellitus (5.0%), COPD (4.3%) and obesity (3.3%). Using linear regression models, the associations between the number of comorbidities and age and extent of the disease were found (p<0.001). Patients with multiorgan sarcoidosis were more likely to have a comorbid condition. More than half of patients with sarcoidosis have a comorbid condition, which is more likely in older patients and those with multiorgan involvement.


A survey of sexual problems amongst psychiatric inpatients.
This paper reports the findings of a survey of 39 men and 17 women who had been admitted to the acute psychiatric wards of an inner London psychiatric unit. The patients were seen within 7 days of their admission and were interviewed about existing sexual and relationship problems. The admissions consisted largely of single men with schizophrenia and married or cohabiting women with affective disorders. Of the men, 62% of those with a diagnosis of schizophrenia, between 63 and 75% of those with affective disorders and 17% of those with other diagnoses reported current sexual or relationship problems. Of the women, 25% of those with a diagnosis of schizophrenia, 50-100% of those with affective disorders and 25% with other diagnoses reported a sexual or relationship problem. The high prevalence of such problems amongst inpatients indicates that such matters should be enquired after and therapeutic interventions considered at the time of admission. We examined the limitations of this work and proposed areas of potential research.


Do patents impede the provision of genetic tests in Australia?
Health policy and law reform agencies lack a sound evidence base of the impacts of patents on innovation and access to healthcare to assist them in their deliberations. This paper reports the results of a survey of managers of Australian genetic testing laboratories that asked a series of questions relating to the tests they perform, whether they pay to access patented inventions and whether they have received notifications from patent holders about patents associated with particular tests. Some diagnostics facilities are exposed to patent costs, but they are all located in the private sector. No public hospitals reported paying licence fees or royalties beyond those included in the price of commercial test kits. Some respondents reported having received enforcement notices from patent holders, but almost all related to the widely known breast cancer-associated patents. Respondents were also asked for their views on the most effective mechanisms to protect their ability to provide genetic tests now and in the future. Going to the media, paying licence fees, ignoring patent rights and relying on the government to take action were widely seen as most effective. Litigation and applications for compulsory licences were seen as some of the least effective mechanisms. These results provide an evidence base for development of health policy and law reform. What is known about the topic? The impact of patents on the delivery of genetic testing services remains unclear in Australia. What does this paper add? The survey reported in this paper suggests that, aside from well-known enforcement actions relating to the breast cancer associated patents, there is little evidence that providers of genetic testing services are being exposed to aggressive patent-enforcement practices. What are the implications for practitioners? Although patent-enforcement actions may increase in the future, a range of strategies are available to providers of testing services to protect them against adverse consequences of such actions. There are ongoing law reform activities aimed at improving these strategies.


Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.
To provide an evidence-based perspective on the prognostic value of novel markers in localised prostate cancer and to identify the best prognostic model including the three classical markers and investigate whether models incorporating novel markers are better. Eight electronic bibliographic databases were searched during March-April 2007. The reference lists of relevant articles were checked and various health services research-related resources consulted via the internet. The search was restricted to publications from 1970 onwards in the English language. Selected studies were assessed, data extracted using a standard template, and quality assessed using an adaptation of published criteria. Because of the heterogeneity regarding populations, outcomes and study type, meta-analyses were not undertaken and the results are presented in tabulated format with a narrative synthesis of the results. In total 30 papers met the inclusion criteria, of which 28 reported on prognostic novel markers and five on prognostic models. A total of 21 novel markers were identified from the 28 novel marker studies. There was considerable variability in the results reported, the quality of the studies was generally poor and there was a shortage of studies in some categories. The marker with the strongest evidence for its prognostic significance was prostate-specific antigen (PSA) velocity (or doubling time). There was a particularly strong association between PSA velocity and prostate cancer death in both clinical and pathological models. In the clinical model the hazard ratio for death from prostate cancer was 9.8 (95% CI 2.8-34.3, p < 0.001) in men with an annual PSA velocity of more than 2 ng/ml versus an annual PSA velocity of 2 ng/ml or less; similarly, the hazard ratio was 12.8 (95% CI 3.7-43.7, p < 0.001) in the pathological model. The quality of the prognostic model studies was adequate and overall better than the quality of the prognostic marker studies. Two issues were poorly dealt with in most or all of the prognostic model studies: inclusion of established markers and consideration of the possible biases from study attrition. Given the heterogeneity of the models, they cannot be considered comparable. Only two models did not include a novel marker, and one of these included several demographic and co-morbidity variables to predict all-cause mortality. Only two models reported a measure of model performance, the C-statistic, and for neither was it calculated in an external data set. It was not possible to assess whether the models that included novel markers performed better than those without. This review highlighted the poor quality and heterogeneity of studies, which render much of the results inconclusive. It also pinpointed the small proportion of models reported in the literature that are based on patient cohorts with a mean or median follow-up of at least 5 years, thus making long-term predictions unreliable. PSA velocity, however, stood out in terms of the strength of the evidence supporting its prognostic value and the relatively high hazard ratios. There is great interest in PSA velocity as a monitoring tool for active surveillance but there is as yet no consensus on how it should be used and, in particular, what threshold should indicate the need for radical treatment.


Structural basis of tubulin tyrosination by tubulin tyrosine ligase.
Tubulin tyrosine ligase (TTL) catalyzes the post-translational retyrosination of detyrosinated α-tubulin. Despite the indispensable role of TTL in cell and organism development, its molecular mechanism of action is poorly understood. By solving crystal structures of TTL in complex with tubulin, we here demonstrate that TTL binds to the α and β subunits of tubulin and recognizes the curved conformation of the dimer. Biochemical and cellular assays revealed that specific tubulin dimer recognition controls the activity of the enzyme, and as a consequence, neuronal development. The TTL-tubulin structure further illustrates how the enzyme binds the functionally crucial C-terminal tail sequence of α-tubulin and how this interaction catalyzes the tyrosination reaction. It also reveals how TTL discriminates between α- and β-tubulin, and between different post-translationally modified forms of α-tubulin. Together, our data suggest that TTL has specifically evolved to recognize and modify tubulin, thus highlighting a fundamental role of the evolutionary conserved tubulin tyrosination cycle in regulating the microtubule cytoskeleton.


Characterizing the S-layer structure and anti-S-layer antibody recognition on intact Tannerella forsythia cells by scanning probe microscopy and small angle X-ray scattering.
Tannerella forsythia is among the most potent triggers of periodontal diseases, and approaches to understand underlying mechanisms are currently intensively pursued. A ~22-nm-thick, 2D crystalline surface (S-) layer that completely covers Tannerella forsythia cells is crucially involved in the bacterium-host cross-talk. The S-layer is composed of two intercalating glycoproteins (TfsA-GP, TfsB-GP) that are aligned into a periodic lattice. To characterize this unique S-layer structure at the nanometer scale directly on intact T. forsythia cells, three complementary methods, i.e., small-angle X-ray scattering (SAXS), atomic force microscopy (AFM), and single-molecular force spectroscopy (SMFS), were applied. SAXS served as a difference method using signals from wild-type and S-layer-deficient cells for data evaluation, revealing two possible models for the assembly of the glycoproteins. Direct high-resolution imaging of the outer surface of T. forsythia wild-type cells by AFM revealed a p4 structure with a lattice constant of ~9.0 nm. In contrast, on mutant cells, no periodic lattice could be visualized. Additionally, SMFS was used to probe specific interaction forces between an anti-TfsA antibody coupled to the AFM tip and the S-layer as present on T. forsythia wild-type and mutant cells, displaying TfsA-GP alone. Unbinding forces between the antibody and wild-type cells were greater than with mutant cells. This indicated that the TfsA-GP is not so strongly attached to the mutant cell surface when the co-assembling TfsB-GP is missing. Altogether, the data gained from SAXS, AFM, and SMFS confirm the current model of the S-layer architecture with two intercalating S-layer glycoproteins and TfsA-GP being mainly outwardly oriented.


Visuospatial working memory in children with autism: the effect of a semantic global organization.
It has been reported that individuals with Autism Spectrum Disorders (ASD) perceive visual scenes as a sparse set of details rather than as a congruent and meaningful unit, failing in the extraction of the global configuration of the scene. In the present study, children with ASD were compared with typically developing (TD) children, in a visuospatial working memory task, the Visual Patterns Test (VPT). The VPT array was manipulated to vary the semantic affordance of the pattern, high semantic (global) vs. low semantic; temporal parameters were also manipulated within the change detection protocol. Overall, there was no main effect associated with Group, however there was a significant effect associated with Semantics, which was further qualified by an interaction between the Group and Semantic factors; there was only a significant effect of semantics in the TD group. The findings are discussed in light of the weak central coherence theory where the ASD group are unable to make use of long term memory semantics in order to construct global representations of the array.


Photometric flow injection determination of phosphate on a PDMS microchip using an optical detection system assembled with an organic light emitting diode and an organic photodiode.
A compact photometric detector was constructed from an organic light emitting diode (OLED) based on a europium complex, europium(diben-zoylmethanato)3(bathophenanthroline) (Eu(DBM)3bath), as the light source and an organic photodiode (OPD) fabricated from a hetero-junction of two layers of copper phthalocyanine (CuPc)/fullerene (C60) as the photo-detector on a microchip prepared from poly(dimethylsiloxan) (PDMS) and was applied to the determination of phosphate. The OLED and the OPD were fabricated by a vapor deposition method on an indium tin oxide (ITO) coated glass substrate with the following layered structure; Glass (0.7 mm)/ITO (110 nm)/4,4'-bis[N-(1-naphthyl)-N-phenyl amino]-biphenyl (α-NPD) (30 nm)/4,4'-di(N-carbazolyl)biphenyl (CBP): Eu(3+) (8 wt%, 30 nm)/bathocuproine (BCP) (30 nm)/aluminum tris(8-hydroxyquinoline) (Alq3) (25 nm)/magnesium and silver (MgAg) (100 nm)/Ag (10nm) and Glass (0.7 mm)/ITO (110 nm)/CuPc (35 nm)/C60 (50 nm)/BCP (10 nm)/Ag (50 nm), respectively. The OLED based on the europium complex emitted a sharp light at the wavelength of 612 nm with a full width at half maximum (FWHM) of 8 nm. The performance of the photometric detector assembled was evaluated based on measurements of the absorbance of different concentrations of malachite green (MG) solutions for a batch system with 1cm long path length. The molar absorptive coefficient of the MG solution, calculated from the photocurrent of the OPD, was in good agreement with the value reported in the literature. A microchip with two inlets and one outlet U-shaped channel was prepared by a conventional photolithograph method. The OLED and the OPD were configured so as to face each other through the PDMS microchip in parallel in order to align the light axis of the OLED and the OPD with the flow cell (optical path length of 5mm), which was located at the end of outlet. For the determination of phosphate, an ion-association reaction between MG and a molybdenum-phosphate complex was utilized and a good linear relationship between the concentration and absorbance was observed in the concentration range 0-0.2 ppm, with a detection limit (S/N=3) of 0.02 ppm. The assembled photometric detector was also applied to the determination of phosphate by the flow injection of river water samples using the reagent solution containing MG and molybdenum ammonium in sulfuric acid. A good recovery (97-99%) for the river water samples, which had been spiked with the standard 0.08 ppm, with an RSD of ca 5% (n=5) was obtained using the constructed system.


Genomic Contingencies and the Potential for Local Adaptation in a Hybrid Species.
Hybridization is increasingly recognized as a potent evolutionary force. Although additive genetic variation and novel combinations of parental genes theoretically increase the potential for hybrid species to adapt, few empirical studies have investigated the adaptive potential within a hybrid species. Here, we address whether genomic contingencies, adaptation to climate, or diet best explain divergence in beak morphology using genomically diverged island populations of the homoploid hybrid Italian sparrow Passer italiae from Crete, Corsica, and Sicily. Populations vary significantly in beak morphology both between and within islands of origin. Temperature seasonality best explains population divergence in beak size. Interestingly, beak shape along all significant dimensions of variation was best explained by annual precipitation, genomic composition, and their interaction, suggesting a role for contingencies. Moreover, beak shape similarity to a parent species correlates with proportion of the genome inherited from that species, consistent with the presence of contingencies. In conclusion, adaptation to local conditions and genomic contingencies arising from putatively independent hybridization events jointly explain beak morphology in the Italian sparrow. Hence, hybridization may induce contingencies and restrict evolution in certain directions dependent on the genetic background.


Systematic review and meta-analysis of surgical outcomes in Marfan patients undergoing aortic root surgery by composite-valve graft or valve sparing root replacement.
A major, life-limiting feature of Marfan syndrome (MFS) is the presence of aneurysmal disease. Cardiovascular intervention has dramatically improved the life expectancy of Marfan patients. Traditionally, the management of aortic root disease has been undertaken with composite-valve graft replacing the aortic valve and proximal aorta; more recently, valve sparing procedures have been developed to avoid the need for anticoagulation. This meta-analysis assesses the important surgical outcomes of the two surgical techniques. A systematic review and meta-analysis of 23 studies reporting the outcomes of aortic root surgery in Marfan patients with data extracted for outcomes of early and late mortality, thromboembolic events, late bleeding complications and surgical reintervention rates. The outcomes of 2,976 Marfan patients undergoing aortic root surgery were analysed, 1,624 patients were treated with composite valve graft (CVG) and 1,352 patients were treated with valve sparing root replacement (VSRR). When compared against CVG, VSRR was associated with reduced risk of thromboembolism (OR =0.32; 95% CI, 0.16-0.62, P=0.0008), late hemorrhagic complications (OR =0.18; 95% CI, 0.07-0.45; P=0.0003) and endocarditis (OR =0.27; 95% CI, 0.10-0.68; P=0.006). Importantly there was no significant difference in reintervention rates between VSRR and CVG (OR =0.89; 95% CI, 0.35-2.24; P=0.80). There is an increasing body of evidence that VSRR can be reliably performed in Marfan patients, resulting in a durable repair with no increased risk of re-operation compared to CVG, thus avoiding the need for systemic anticoagulation in selected patients.


Touchscreen Tablets: Coordinating Action and Perception for Mathematical Cognition.
Proportional reasoning is important and yet difficult for many students, who often use additive strategies, where multiplicative strategies are better suited. In our research we explore the potential of an interactive touchscreen tablet application to promote proportional reasoning by creating conditions that steer students toward multiplicative strategies. The design of this application (Mathematical Imagery Trainer) was inspired by arguments from embodied-cognition theory that mathematical understanding is grounded in sensorimotor schemes. This study draws on a corpus of previously treated data of 9-11 year-old students, who participated individually in semi-structured clinical interviews, in which they solved a manipulation task that required moving two vertical bars at a constant ratio of heights (1:2). Qualitative analyses revealed the frequent emergence of visual attention to the screen location halfway along the bar that was twice as high as the short bar. The hypothesis arose that students used so-called "attentional anchors" (AAs)-psychological constructions of new perceptual structures in the environment that people invent spontaneously as their heuristic means of guiding effective manual actions for managing an otherwise overwhelming task, in this case keeping vertical bars at the same proportion while moving them. We assumed that students' AAs on the mathematically relevant points were crucial in progressing from additive to multiplicative strategies. Here we seek farther to promote this line of research by reanalyzing data from 38 students (aged 9-11). We ask: (1) What quantitative evidence is there for the emergence of AAs?; and (2) How does the transition from additive to multiplicative reasoning take place when solving embodied proportions tasks in interaction with the touchscreen tablet app? We found that: (a) AAs appeared for all students; (b) the AA-types were few across the students; (c) the AAs were mathematically relevant (top of the bars and halfway along the tall bar); (d) interacting with the tablet was crucial for the AAs' emergence; and (e) the vast majority of students progressed from additive to multiplicative strategies (as corroborated with oral utterances). We conclude that touchscreen applications have the potential to create interaction conditions for coordinating action and perception into mathematical cognition.


CEBS: a comprehensive annotated database of toxicological data.
The Chemical Effects in Biological Systems database (CEBS) is a comprehensive and unique toxicology resource that compiles individual and summary animal data from the National Toxicology Program (NTP) testing program and other depositors into a single electronic repository. CEBS has undergone significant updates in recent years and currently contains over 11 000 test articles (exposure agents) and over 8000 studies including all available NTP carcinogenicity, short-term toxicity and genetic toxicity studies. Study data provided to CEBS are manually curated, accessioned and subject to quality assurance review prior to release to ensure high quality. The CEBS database has two main components: data collection and data delivery. To accommodate the breadth of data produced by NTP, the CEBS data collection component is an integrated relational design that allows the flexibility to capture any type of electronic data (to date). The data delivery component of the database comprises a series of dedicated user interface tables containing pre-processed data that support each component of the user interface. The user interface has been updated to include a series of nine Guided Search tools that allow access to NTP summary and conclusion data and larger non-NTP datasets. The CEBS database can be accessed online at http://www.niehs.nih.gov/research/resources/databases/cebs/.


GHTD-amide: a naturally occurring beta cell-derived peptide with hypoglycemic activity.
In the early 1970s, a peptide fraction with insulin potentiating activity was purified from human urine but the identity and origins of the active constituent remained unknown. Here we identify the active component and characterize its origins. The active peptide was identified as an alpha amidated tetrapeptide with the sequence GHTD-amide. The peptide was synthesized and tested for stimulation of glycogen synthesis and insulin potentiation by insulin tolerance testing in insulin-deficient rats, which confirmed GHTD-amide as the active peptide. Tissue localization using a peptide-specific anti-serum and epifluorescent and confocal microscopy showed decoration of pancreatic islets but not other tissues. Confocal microscopy revealed co-localization with insulin and immunogold and electron microscopy showed localization to dense core secretory granules. Consistent with these observations GHTD-amide was found in media conditioned by MIN6 islet beta cells. Sequence database searching found no annotated protein in the human proteome encoding a potential precursor for GHTD-amide. We conclude that the insulin potentiating activity originally described in human urine is attributable to the tetrapeptide GHTD-amide. GHTD-amide is a novel peptide produced by pancreatic beta cells and no precursor protein is present in the annotated human proteome. Stimulation of glycogen synthesis and co-localization with insulin in beta cells suggest that GHTD-amide may play a role in glucose homeostasis by enhancing insulin action and glucose storage in tissues.


Selective blockade of tumor necrosis factor receptor I inhibits proinflammatory cytokine and chemokine production in human rheumatoid arthritis synovial membrane cell cultures.
To determine whether selective blockade of tumor necrosis factor receptor I (TNFRI) affects spontaneous proinflammatory cytokine and chemokine production in ex vivo-cultured human rheumatoid arthritis synovial membrane mononuclear cells (MNCs) and to compare this response to that of TNF ligand blockade using etanercept. A bispecific, single variable-domain antibody (anti-TNFRI moiety plus an albumin binding moiety [TNFRI-AlbudAb]) was used to selectively block TNFRI. Inhibition of TNFα-mediated responses in cell lines expressing TNFRI/II confirmed TNFRI-AlbudAb potency, human rhabdomyosarcoma cell line KYM-1D4 cytotoxicity, and human umbilical vein endothelial cell (HUVEC) vascular cell adhesion molecule 1 (VCAM-1) upregulation. Eighteen RA synovial membrane MNC suspensions were cultured for 2 days or 5 days, either alone or in the presence of TNFRI-AlbudAb, control-AlbudAb, or etanercept. Proinflammatory cytokines and chemokines in culture supernatants were measured by enzyme-linked immunosorbent assays. A mixed-effects statistical analysis model was used to assess the extent of TNFRI selective blockade, where the results were expressed as the percentage change with 95% confidence intervals (95% CIs). TNFRI-AlbudAb inhibited TNFα-induced KYM-1D4 cell cytotoxicity (50% inhibition concentration [IC50 ] 4 nM) and HUVEC VCAM-1 up-regulation (IC50 12 nM) in a dose-dependent manner. In ex vivo-cultured RA synovial membrane MNCs, selective blockade of TNFRI inhibited the production of proinflammatory cytokines and chemokines to levels similar to those obtained with TNF ligand blockade, without inducing cellular toxicity. Changes in cytokine levels were as follows: -23.5% (95% CI -12.4, -33.2 [P = 0.004]) for granulocyte-macrophage colony-stimulating factor, -33.4% (95% CI -20.6, -44.2 [P ≤ 0.0001]) for interleukin-10 (IL-10), -17.6% (95% CI 3.2, -34.2 [P = 0.0880]) for IL-1β, and -19.0% (95% CI -3.4, -32.1 [P = 0.0207]) for IL-6. Changes in chemokine levels were as follows: -34.2% (-14.4, -49.4 [P = 0.0030]) for IL-8, -56.6% (-30.7, -72.9 [P = 0.0011]) for RANTES, and -24.9% (2, -44.8 [P = 0.0656]) for monocyte chemotactic protein 1. In ex vivo-cultured RA synovial membrane MNCs, although a limited role of TNFRII cannot be ruled out, TNFRI signaling was found to be the dominant pathway leading to proinflammatory cytokine and chemokine production. Thus, selective blockade of TNFRI could potentially be therapeutically beneficial over TNF ligand blockade by retaining the beneficial TNFRII signaling.


Tales from the Jazz ASH: highlights from the 2013 American Society of Haematology meeting.
The 55th annual ASH meeting was held in pleasant New Orleans and was the largest in its history, with 22,495 participants coming from 113 nations. A 'bench-to-bedside and back' attitude characterises haematology probably more than any other discipline in medicine and, as usual, this was reflected in the extremely wide breadth of the topics covered, including the last results from clinical trials and cutting-edge advancements in basic science. This year, the balance was arguably skewed: few truly clinical practice-changing results were presented. On the other hand, a great number of basic and translational studies significantly increased our understanding of the biology of numerous malignancies and heralded the coming of age of disruptive technologies. Namely, above all, next generation sequencing and T cell engineering-based cell therapy.


Elicitin-membrane interaction is driven by a positive charge on the protein surface: role of Lys13 residue in lipids loading and resistance induction.
Elicitins are family of small proteins secreted by species of the pathogenic fungus Phytophthora inducing a defence reaction in plants. They contain a hydrophobic cavity capable of binding sterols and fatty acids, and on the basis of their pI they are classified as either α-elicitins or more necrotising β-elicitins. The residue Lys13 was previously identified as a key determinant of the necrotising activity of basic elicitins. In the present study we describe changes in the ability of cryptogein, a β-elicitin inducing a hypersensitive response in tobacco, to transfer sterols and fatty acids between micelles and liposomes upon Lys13Val mutation. We propose that the change in activity is influenced by the elimination of positive charge on the surface of cryptogein, which is significant for correct positioning of the protein during lipid loading, without adversely affecting the binding of sterol to the cavity of the protein. Compared to wild type cryptogein, mutation Lys13Val resulted in lowered expression of defence-related genes and compromised resistance to Phytophthora parasitica. Furthermore, resistance induced by Lys13Val mutant was similar to that induced by acidic elicitin capsicein containing at amino position 13 valine Determined results sustained a crucial role of positive lysine residues on the surface of basic elicitins and suggested their significant role in correct protein-membrane interaction and thus on their biological activity.


Humans treat unreliable filled-in percepts as more real than veridical ones.
Humans often evaluate sensory signals according to their reliability for optimal decision-making. However, how do we evaluate percepts generated in the absence of direct input that are, therefore, completely unreliable? Here, we utilize the phenomenon of filling-in occurring at the physiological blind-spots to compare partially inferred and veridical percepts. Subjects chose between stimuli that elicit filling-in, and perceptually equivalent ones presented outside the blind-spots, looking for a Gabor stimulus without a small orthogonal inset. In ambiguous conditions, when the stimuli were physically identical and the inset was absent in both, subjects behaved opposite to optimal, preferring the blind-spot stimulus as the better example of a collinear stimulus, even though no relevant veridical information was available. Thus, a percept that is partially inferred is paradoxically considered more reliable than a percept based on external input. In other words: Humans treat filled-in inferred percepts as more real than veridical ones.


Heparin binding defect in a new antithrombin III variant: Rouen, 47 Arg to His.
Antithrombin III (AT-III) Rouen is a hereditary abnormal antithrombin with normal progressive inhibitory activity and reduced heparin cofactor activity. It was isolated from the plasma of a woman who suffered a sudden idiopathic sensorineural hearing loss and balance impairment. There was no familial history of thrombosis. By heparin-Sepharose chromatography, AT-III Rouen was separated from the normal antithrombin on elution with increasing concentrations of NaCl. AT-III Rouen eluted earlier than is normal at both pH 7.4 and pH 6.0. At the lower pH, the antithrombins bound more avidly to the column, with the abnormal AT-III eluting closer to the normal than at the higher pH. Two-dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests of carboxymethylated antithrombins was performed on thin-layer silica plates. The abnormal peptide was located by tryptophan staining, and amino acid analysis and sequence studies demonstrated a substitution of an arginine at residue 47 for a histidine. Results from this study suggest that replacement of arginine 47 by a partially positively charged histidine has less effect on the heparin binding affinity than dose replacing it with a neutral cysteine side chain as in AT-III Toyama, in which no heparin binding was observed. In addition, heparin binding per se is not a sufficient condition to activate AT-III.


[DNA polymerase I, Klenow fragment of Escherichia coli: hydrolysis and pyrophosphorolysis of DNA containing phosphothioate groups].
Reaction of DNA synthesis catalyzed by DNA polymerase I KF in the presence of 2'-deoxynucleoside 5'-alpha-thiotriphosphates (dNTP alpha S) was investigated. DNA with thiophosphate groups (DNA[P=S]) obtained by such a way was studied in reactions of hydrolysis and pyrophosphorolysis catalyzed by DNA polymerase I KF. It is shown that the rate of DNA elongation is decreased both on the step of incorporation of dNMP alpha S residues and on the step of incorporation of the next dNMP residue. The rate of pyrophosphorolysis of 3'-terminal dNMP alpha S was demonstrated to be one order of magnitude less in comparison with the corresponding reaction with the natural dNMP residue. Contrary, the rate of 3'----5'-exonuclease hydrolysis of both DNA[P=S] and DNA of the same structure revealed no distinguishable differences.


Model-based resolution: applying the theory in quantitative microscopy.
Model-based image processing techniques have been proposed as a way to increase the resolution of optical microscopes. Here a model based on the microscope's point-spread function is analyzed, and the resolution limits achieved with a proposed goodness-of-fit criterion are quantified. Several experiments were performed to evaluate the possibilities and limitations of this method: (a) experiments with an ideal (diffraction-limited) microscope, (b) experiments with simulated dots and a real microscope, and (c) experiments with real dots acquired with a real microscope. The results show that a threefold increase over classical resolution (e.g., Rayleigh) is possible. These results can be affected by model misspecifications, whereas model corruption, as seen in the effect of Poisson noise, seems to be unimportant. This research can be considered to be preliminary with the final goal being the accurate measurement of various cytogenetic properties, such as gene distributions, in labeled preparations.