Transcriptomic and functional screening of weapon formation genes implies significance of cell adhesion molecules and female-biased genes in broad-horned flour beetle.
For understanding the evolutionary mechanism of sexually selected exaggerated traits, it is essential to uncover its molecular basis. By using broad-horned flour beetle that has male-specific exaggerated structures (mandibular horn, head horn and gena enlargement), we investigated the transcriptomic and functional characters of sex-biased genes. Comparative transcriptome of male vs. female prepupal heads elucidated 673 sex-biased genes. Counter-intuitively, majority of them were female-biased (584 genes), and GO enrichment analysis showed cell-adhesion molecules were frequently female-biased. This pattern motivated us to hypothesize that female-biased transcripts (i.e. the transcripts diminished in males) may play a role in outgrowth formation. Potentially, female-biased genes may act as suppressors of weapon structure. In order to test the functionality of female-biased genes, we performed RNAi-mediated functional screening for top 20 female-biased genes and 3 genes in the most enriched GO term (cell-cell adhesion, fat1/2/3, fat4 and dachsous). Knockdown of one transcription factor, zinc finger protein 608 (zfp608) resulted in the formation of male-like gena in females, supporting the outgrowth suppression function of this gene. Similarly, knockdown of fat4 induced rudimental, abnormal mandibular horn in female. fat1/2/3RNAi, fat4RNAi and dachsousRNAi males exhibited thick and/or short mandibular horns and legs. These cell adhesion molecules are known to regulate tissue growth direction and known to be involved in the weapon formation in Scarabaeoidea beetles. Functional evidence in phylogenetically distant broad-horned flour beetle suggest that cell adhesion genes are repeatedly deployed in the acquisition of outgrowth. In conclusion, this study clarified the overlooked functions of female-biased genes in weapon development.


Reliability and validity of a tool to assess airway management skills in anesthesia trainees.
Gaining expertise in procedural skills is essential for achieving clinical competence during anesthesia training. Supervisors have the important responsibility of deciding when the trainee can be allowed to perform various procedures without direct supervision while ensuring patient safety. This requires robust and reliable assessment techniques. Airway management with bag-mask ventilation and tracheal intubation are routinely performed by anesthesia trainees at induction of anesthesia and to save lives during a cardiorespiratory arrest. The purpose of this study was to evaluate the construct validity, and inter-rater and test-retest reliability of a tool designed to assess competence in bag-mask ventilation followed by tracheal intubation in anesthesia trainees. Informed consent was obtained from all participants. Tracheal intubation and bag-mask ventilation skills in 10 junior and 10 senior anesthesia trainees were assessed by two investigators on two occasions at a 3-4 weeks interval, using a procedure-specific assessment tool. Average kappa value for inter-rater reliability was 0.91 and 0.99 for the first and second assessments, respectively, with an average agreement of 95%. The average agreement for test-retest reliability was 82% with a kappa value of 0.39. Senior trainees obtained higher scores compared to junior trainees in all areas of assessment, with a significant difference for patient positioning, preoxygenation, and laryngoscopy technique, depicting good construct validity. The tool designed to assess bag-mask ventilation and tracheal intubation skills in anesthesia trainees demonstrated excellent inter-rater reliability, fair test-retest reliability, and good construct validity. The authors recommend its use for formative and summative assessment of junior anesthesia trainees.


Structures of p63 DNA binding domain in complexes with half-site and with spacer-containing full response elements.
Transcription factor p63, a p53 family member, plays a role in epithelial cell development, cell cycle arrest, apoptosis, and tumorigenesis. Point mutations, primarily in the DNA binding domain (p63DBD), lead to malformation syndromes. To gain insight into differences between p63 and p53 and the impact of mutations on the structure, we have determined two crystal structures of p63DBD in complex with A/T-rich response elements. One complex contains a 10-bp DNA half-site response element (5'AAACATGTTT3') and the other contains a 22-bp DNA full response element with a 2-bp spacer between two half-sites (5'AAACATGTTTTAAAACATGTTT3'). In both structures, each half-site binds a p63DBD dimer. The two p63DBD dimers do not interact in the presence of the DNA spacer, whereas they interact with one another in the p63DBD/10-bp complex where the DNA simulates a full response element by packing end-to-end. A unique dimer-dimer interaction involves a variable loop region, which differs in length and sequence from the counterpart loop of p53DBD. The DNA trajectories in both structures assume superhelical conformations. Surface plasmon resonance studies of p63DBD/DNA binding yielded K(d) = 11.7 μM for a continuous full response element, whereas binding was undetectable with the 22-bp DNA, suggesting an important contribution of a p63DBD interdimer interface to binding and establishing that p63DBD affinity to the response element is approximately 1,000-fold lower than that of p53DBD. Analyses of the structural consequences of p63DBD mutations that cause developmental defects show that, although some mutations affect DNA binding directly, the majority affects protein stability.


A Tool That Assesses the Evidence, Transparency, and Usability of Online Health Information: Development and Reliability Assessment.
The internet is commonly used by older adults to obtain health information and this trend has markedly increased in the past decade. However, studies illustrate that much of the available online health information is not informed by good quality evidence, developed in a transparent way, or easy to use. Furthermore, studies highlight that the general public lacks the skills necessary to distinguish between online products that are credible and trustworthy and those that are not. A number of tools have been developed to assess the evidence, transparency, and usability of online health information; however, many have not been assessed for reliability or ease of use. The first objective of this study was to determine if a tool assessing the evidence, transparency, and usability of online health information exists that is easy and quick to use and has good reliability. No such tool was identified, so the second objective was to develop such a tool and assess it for reliability when used to assess online health information on topics of relevant to optimal aging. An electronic database search was conducted between 2002 and 2012 to identify published papers describing tools that assessed the evidence, transparency, and usability of online health information. Papers were retained if the tool described was assessed for reliability, assessed the quality of evidence used to create online health information, and was quick and easy to use. When no one tool met expectations, a new instrument was developed and tested for reliability. Reliability between two raters was assessed using the intraclass correlation coefficient (ICC) for each item at two time points. SPSS Statistics 22 software was used for statistical analyses and a one-way random effects model was used to report the results. The overall ICC was assessed for the instrument as a whole in July 2015. The threshold for retaining items was ICC>0.60 (ie, "good" reliability). All tools identified that evaluated online health information were either too complex, took a long time to complete, had poor reliability, or had not undergone reliability assessment. A new instrument was developed and assessed for reliability in April 2014. Three items had an ICC<0.60 (ie, "good" reliability). One of these items was removed ("minimal scrolling") and two were retained but reworded for clarity. Four new items were added that assessed the level of research evidence that informed the online health information and the tool was retested in July 2015. The total ICC score showed excellent agreement with both single measures (ICC=0.988; CI 0.982-0.992) and average measures (ICC=0.994; CI 0.991-0.996). The results of this study suggest that this new tool is reliable for assessing the evidence, transparency, and usability of online health information that is relevant to optimal aging.


Supportive parenting, Ecological Context, and Children's Adjustment: A seven-Year Longitudianl Study.
Two major questions regarding the possible impact of early supportive parenting (SP) on children's school adjustment were addressed:(1) Does SP assessed prekindergarten predict grade 6 adjustment after controlling for early barsh parenting (HP)? (2) Does SP moderate (buffer) the impact of early family adversity on grade 6 adjustment? Parenting and family adversity data were drawn from home-visit interviews with 585 mothers conducted prekindergarten. Four SP measure were derived: mother-to-child warmth, proactive teaching, inductive discipline, and positive involvement. HP was indexed as the use of harsh, physical disciple. Family adversity indicators were socioeconomic disadvantage, family stress, and single parenthood. Children 's adjustment (behavior problems, social skills, and academic performance) in kindergarten and grade 6 was assessedvia teacher ratings and school records. SP predicted adjustment in grade 6, even after controlling for kindergarten adjustment and HP. High levels of SP mitigated the effects of family adversity on later behavior problems. These findings implicate both direct (main effect)and indirect (moderator of adversity) processes in the linkage between positive and supportive aspects of parenting and children's school adjustment.


Histopathologic characteristics and short-term outcomes of colorectal cancer in young Tunisian patients: one center's experience.
Colorectal carcinoma (CRC) is generally a disease of persons older than 40 years. Concerning younger patients, controversies still exist regarding features and prognosis of CRC. We performed this study to characterise CRC in young patients (≤ 40 years) as well as to evaluate short-term outcome in comparison with older patients (>40 years) with CRC. Clinical and histopathological parameters of 40 patients aged 40 years or less were compared with 240 patients aged more than 40 years. In young patients, the minority suffered from hereditary cancer syndromes (0.4%). Furthermore, up to 87% of young patients denied any cancers in their families. Compared with older patients, young patients had more mucinous adenocarcinomas (32.5% vs. 11.5%; p=0.02), more venous invasion (p=0.021), more perineural invasion (p=0.028). For grading (p=0.42), lymphatic invasion (p=0.17) and tumor sites (p=0.46), no significant differences between young and older patients were found. Young patients had less post operative morbidity (p=0.039), less post operative mortality (0.029). Young and older patients had the same overall 1-year survival rates (p=0.24), and the same cancer-related 1-year survival rates (p=0.1). Tunisian patients present with colorectal cancer at a more advanced stage of the disease at younger ages compared to developed countries. The early detection of CRC followed by a sufficient oncologic treatment is crucial regardless of age. It is mandatory for all patients with suspicious symptoms to undergo early adequate diagnoses.


High-speed asynchronous optical sampling with sub-50fs time resolution.
We report an ultrafast time-domain spectroscopy system based on high-speed asynchronous optical sampling operating without mechanical scanner. The system uses two 1 GHz femtosecond oscillators that are offset-stabilized using high-bandwidth feedback electronics operating at the tenth repetition rate harmonics. Definition of the offset frequency, i.e. the time-delay scan rate, in the range of a few kilohertz is accomplished using direct-digital-synthesis electronics for the first time. The time-resolution of the system over the full available 1 ns time-delay window is determined by the laser pulse duration and is 45 fs. This represents a three-fold improvement compared to previous approaches where timing jitter was the limiting factor. Two showcase experiments are presented to verify the high time-resolution and sensitivity of the system.


[Evaluation of the National Vaccination Day in Bogota, D.C., 2001].
A national immunization day-NID, aimed at improving vaccination coverage, was carried out in Colombia in November 2001. The main objective of the study was to measure the proportion of children under 2 years either completing their immunization schedule or advancing through it by receiving doses during the NID. Besides, we also evaluated the proportion of lost opportunities for vaccination during the NID and the impact of the media (TV, ratio, newspapers, etc.) in advertising the NID. In order to evaluate the impact of immunization a cross sectional survey was carried out in Bogotá in the waiting rows of the 30 randomly selected vaccination posts; 623 participants were systematically chosen. The outcomes were analyzed by age, socioeconomic level and type of health insurance-SSS. Only children holding a vaccination card were considered eligible for the study. Most people become aware about NID through TV, 81%, followed by radio advertisements, 22%. After attending NID the proportion of fully vaccinated children, according to PAHO scheme, raised from 46% to 66%, a 43% increase. This increase was even higher among children aged less than 6 months (140% increment). There were no differences in the increment by social stratum or affiliation to the SSS. Among the children studied we identified a 24% of loss opportunities for vaccination that did not differ by socioeconomic level or SSS groups. Our results suggest that, despite its high costs, NID might be useful to transiently overcome barriers for adequate access to health services.


Evaluation of contact activation of citrated equine whole blood during storage and effects of contact activation on results of recalcification-initiated thromboelastometry.
To evaluate the degree of activation of the contact pathway in citrated equine whole blood over holding times ≤ 30 minutes and assess effects of contact activation on recalcification-initiated thromboelastometry. 11 healthy adult mixed-breed horses. Blood was collected by atraumatic jugular venipuncture into prewarmed evacuated siliconized glass tubes containing citrate anticoagulant and held at 37°C for ≤ 30 minutes. Thromboelastometry was performed with an in vitro viscoelasticity (thromboelastometry) monitoring system. Factor XII and factor XI procoagulant activities were determined in contemporaneously collected platelet-poor plasma samples by assessing changes in turbidity for 1 hour at approximately 25°C, with clotting times calculated by fitting a line to the steepest segment of the absorbance curve and determining its intersection with baseline. Effect of holding time on thromboelastometry parameters and plasma enzyme activity was evaluated by repeated-measures ANOVA on ranks. Association of procoagulant activities with coagulation time was determined by Spearman rank-order correlation analysis. Thromboelastometry parameters (coagulation time, clot formation time, α angle, and maximum clot firmness) reflected significant increases in coagulability during the holding period. Factor XII and factor XI procoagulant activities were significantly increased at 30 minutes, compared with 2 or 10 minutes (indicating contact activation of samples), and had significant negative correlation with coagulation time. Ex vivo activation of the contact system in equine whole blood was evident, suggesting that recalcification of blood in the absence of a trigger is not an acceptable method of assessing the hemostatic system in horses.


[Psychosis shared by 4 subjects].
Induced psychotic disorder is a very rare clinical picture. We describe here one occurrence which included four members of the same family. A brief review of the literature is made and several etiological factors are discussed.


Dermatology flow sheet.
This article presents an organized and relatively easy mechanism for the diagnosis of dermatologic problems by using an algorithmic flow sheet. Once this technique is understood, the practitioner may find it much easier to categorize, diagnose, and manage skin conditions of the lower extremities.


Outcomes and metrics: measuring the impact of a comprehensive adolescent and young adult cancer program.
Against a background of poorly coordinated provision of holistic care to the adolescent and young adult (AYA) cancer population, the Canadian National Task Force on Adolescent and Young Adult Oncology, which is supported by the Canadian Partnership Against Cancer and the C17 network, convened a workshop to formulate the components of a systematic approach to care for this age group. Because such a program will deflect scarce resources, it must be validated and justified by reproducible metrics. A subgroup of experts was convened, comprising attendees at the AYA workshop, including AYA cancer survivors. A substantial number of key, feasible, and consistent metrics were identified and are systematized, justified, and presented in this article. Prioritization from within this range will be necessary.


Urine desmosine as a marker of lung injury following total knee arthroplasty. A pilot study.
Lung injury following total knee arthroplasty (TKA) may occur secondary to embolization of bone debris, fat, and cement. Clinically relevant respiratory failure is rare and is therefore difficult to study. To facilitate future investigations on this subject, we evaluated the utility of the elastin breakdown product desmosine as a potential marker of lung injury during TKA surgery. The goals of this study were to answer (1) if desmosine levels would increase in response to the perioperative insults in patients undergoing TKA and (2) if this increase would differ among unilateral and bilateral TKA procedures. Twenty consecutive patients (ten unilateral and ten bilateral TKAs) were enrolled. Urine samples were collected before surgery and at 1 and 3 days postoperatively and analyzed for levels of desmosine using a validated radioimmunoassay. Baseline desmosine/creatinine ratios were higher in the unilateral as compared to the bilateral TKA group (p = 0.003). Tourniquet times, intraoperative estimated blood loss, and transfusion requirements among bilateral TKA patients were significantly higher than those of unilateral TKA recipients. Desmosine levels increased in both groups, but the rise was significant only in the bilateral group. We detected a significant increase in urine desmosine levels associated with bilateral but not unilateral TKA surgery. In the context of previous studies, our findings suggest that desmosine may be a marker of postoperative lung injury. Further research is warranted for validation and correlation of desmosine levels to clinical markers and various degrees of lung injury.


Active virological surveillance in backyard ducks in Bangladesh: detection of avian influenza and gammacoronaviruses.
Domestic waterfowl play an important role in the perpetuation and transmission of avian pathogens including avian influenza viruses (AIV) of low and high pathogenicity, which pose severe economic and public health concerns in Bangladesh. This study focused on active surveillance of several avian viral pathogens with a special reference to AIV in selected backyard duck populations in Bangladesh. A total of 500 pooled oropharyngeal and cloacal samples from individual ducks of four districts were tested by real time PCRs for the presence of AIV, avian avulavirus-1, anatid herpesvirus-1, avian parvovirus, avian bornavirus and avian coronavirus. The investigation identified 27 (5.4%) ducks positive for AIV and 12 (2.4%) positive for avian coronavirus. In 13 samples, RNA specific for AIV H4N6 was detected. Phylogenetic analysis of the AIV haemagglutinin H4 and neuraminidase N6 genes suggested a clustering of Bangladeshi AIV H4N6 in Eurasian lineage group 2. Other AIV positive samples had very low virus loads (Cq > 36) and were not subtyped. Coronaviral sequences of a fragment of the polymerase gene were related to Eurasian-Australian duck gamma-coronaviruses. Our current active surveillance in free-range domestic backyard ducks in Bangladesh failed to detect highly pathogenic (HP) AIV in contrast to our previous passive monitoring study. Nevertheless, active monitoring of domestic duck populations may be important to highlight presence and transmission dynamics of economically less important AIV that still may serve as reassortment partners for the generation of new HP and zoonotic AIV. RESEARCH HIGHLIGHTS Active surveillance for viral pathogens in domestic free-range backyard ducks. Detection of avian influenza virus subtype H4N6. First identification of avian gammacoronavirus in ducks in Bangladesh.


Harmonisation of variables names prior to conducting statistical analyses with multiple datasets: an automated approach.
Data requirements by governments, donors and the international community to measure health and development achievements have increased in the last decade. Datasets produced in surveys conducted in several countries and years are often combined to analyse time trends and geographical patterns of demographic and health related indicators. However, since not all datasets have the same structure, variables definitions and codes, they have to be harmonised prior to submitting them to the statistical analyses. Manually searching, renaming and recoding variables are extremely tedious and prone to errors tasks, overall when the number of datasets and variables are large. This article presents an automated approach to harmonise variables names across several datasets, which optimises the search of variables, minimises manual inputs and reduces the risk of error. Three consecutive algorithms are applied iteratively to search for each variable of interest for the analyses in all datasets. The first search (A) captures particular cases that could not be solved in an automated way in the search iterations; the second search (B) is run if search A produced no hits and identifies variables the labels of which contain certain key terms defined by the user. If this search produces no hits, a third one (C) is run to retrieve variables which have been identified in other surveys, as an illustration. For each variable of interest, the outputs of these engines can be (O1) a single best matching variable is found, (O2) more than one matching variable is found or (O3) not matching variables are found. Output O2 is solved by user judgement. Examples using four variables are presented showing that the searches have a 100% sensitivity and specificity after a second iteration. Efficient and tested automated algorithms should be used to support the harmonisation process needed to analyse multiple datasets. This is especially relevant when the numbers of datasets or variables to be included are large.


Long term control of hypercortisolism with fluconazole: case report and in vitro studies.
To evaluate the efficacy of fluconazole as an alternative treatment for controlling hypercortisolism in Cushing's syndrome and to determine its effect on glucocorticoid production in vitro. Case report and in vitro study in a University Clinic. An 83 year old patient presented with recurrence of Cushing's syndrome due to pulmonary metastases three years after unilateral adrenalectomy. During a near fatal episode of sepsis she was started on fluconazole 200 mg/day intravenously which normalised cortisol excretion. The therapy was continued orally for 18 months. Upon temporary discontinuation and reintroduction of treatment, cortisol levels increased and normalized, respectively. At month 16, fluconazole had to be increased to a dose of 400 mg/day to keep cortisol excretion in the normal range. Disease progression was slow and no side effects occurred. IN VITRO RESULTS: Fluconazole in a concentration of 500 microM nearly abolished corticosterone production over 24 h from the adrenal adenoma cell line Y-1 (8.6 +/- 0.5% compared with control, P < 0.0001) and significantly reduced corticosterone production in concentrations of 50 microM (48.3 +/- 1.9% vs. control, P < 0.0001) and 5 microM (80.5 +/- 8.5% vs. control, P < 0.05). These results demonstrate for the first time that fluconazole normalises cortisol concentrations in vivo in a patient with Cushing's syndrome with adrenal carcinoma and inhibit glucocorticoid production in vitro in a cell line. Thus, fluconazole might be useful in controlling glucocorticoid excess in Cushing's syndrome and because of its lower toxicity might be preferable to ketoconazole.


Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome.
Maternal immune activation during prenatal development, including treatment with the viral RNA mimic, polyriboinosinic-polyribocytidilic acid (poly IC), serves as a widely used animal model to induce behavioral deficits reminiscent of schizophrenia and related disease. Here, we report that massive cytokine activation after a single dose of poly IC in the prenatal period is associated with lasting working memory deficits in adult offspring. To explore whether dysregulated gene expression in cerebral cortex, contributes to cognitive dysfunction, we profiled the cortical transcriptome, and in addition, mapped the genome-wide distribution of trimethylated histone H3-lysine 4 (H3K4me3), an epigenetic mark sharply regulated at the 5' end of transcriptional units. However, deep sequencing-based H3K4me3 mapping and mRNA profiling by microarray did not reveal significant alterations in mature cerebral cortex after poly IC exposure at embryonic days E17.5 or E12.5. At a small set of genes (including suppressor of cytokine signaling Socs3), H3K4me3 was sensitive to activation of cytokine signaling in primary cultures from fetal forebrain but adult cortex of saline- and poly IC-exposed mice did not show significant differences. A limited set of transcription start sites (TSS), including Disrupted-in-Schizophrenia 1 (Disc1), a schizophrenia risk gene often implicated in gene-environment interaction models, showed altered H3K4me3 after prenatal poly IC but none of these differences survived after correcting for multiple comparisons. We conclude that prenatal poly IC is associated with cognitive deficits later in life, but without robust alterations in epigenetic regulation of gene expression in the cerebral cortex.


Radiosensitization, after a combined treatment of survivin siRNA and irradiation, is correlated with the activation of caspases 3 and 7 in a wt-p53 sarcoma cell line, but not in a mt-p53 sarcoma cell line.
Survivin, a member of the inhibitor-of-apoptosis family is an essential protein for regular mitosis and is involved in an anti-apoptotic pathway. In some studies, an association between survivin expression and radiosensitivity has been described for tumor cells, but the relationship between p53 and survivin regarding radioresistance remains to be clarified. In order to increase the effect of irradiation on two sarcoma cell lines, A-204 with wt-p53 and US 8-93 with mt-p53, siRNA was applied to knock down survivin expression. The effects of combined treatment of siRNA treatment and irradiation were investigated by clonogenic survival assay, measurement of activity of caspases 3 and 7, Western blot hybridization for survivin and p53, and morphological analysis of apoptosis. Survivin knock down caused radiosensitization in the cell line A-204 (wt-p53) with an enhancement factor of 1.8 at 2 Gy (p=0.05) and 2.5 at 4 Gy (p=0.02), respectively. No radiosensitization was found in the cell line US 8-93 (mt-p53), when clonogenic survival was analyzed. These findings were supported by an increase in activity (up to 5.2-fold) of caspases 3 and 7 in cell line A-204 (wt-p53), but not in cell line US 8-93 (mt-p53) after a combined treatment of siRNA and irradiation. Our findings suggest that the wt-p53-caspase pathway is of importance for the radiosensitization induced by targeting survivin, which may have an impact on future gene therapeutical treatments.


The role of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer.
The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology.


Identification of a mismatch-specific endonuclease in hyperthermophilic Archaea.
The common mismatch repair system processed by MutS and MutL and their homologs was identified in Bacteria and Eukarya. However, no evidence of a functional MutS/L homolog has been reported for archaeal organisms, and it is not known whether the mismatch repair system is conserved in Archaea. Here, we describe an endonuclease that cleaves double-stranded DNA containing a mismatched base pair, from the hyperthermophilic archaeon Pyrococcus furiosus The corresponding gene revealed that the activity originates from PF0012, and we named this enzyme Endonuclease MS (EndoMS) as the mismatch-specific Endonuclease. The sequence similarity suggested that EndoMS is the ortholog of NucS isolated from Pyrococcus abyssi, published previously. Biochemical characterizations of the EndoMS homolog from Thermococcus kodakarensis clearly showed that EndoMS specifically cleaves both strands of double-stranded DNA into 5'-protruding forms, with the mismatched base pair in the central position. EndoMS cleaves G/T, G/G, T/T, T/C and A/G mismatches, with a more preference for G/T, G/G and T/T, but has very little or no effect on C/C, A/C and A/A mismatches. The discovery of this endonuclease suggests the existence of a novel mismatch repair process, initiated by the double-strand break generated by the EndoMS endonuclease, in Archaea and some Bacteria.


Modelling approaches to compare sorption and degradation of metsulfuron-methyl in laboratory micro-lysimeter and batch experiments.
Results of laboratory batch studies often differ from those of outdoor lysimeter or field plot experiments--with respect to degradation as well as sorption. Laboratory micro-lysimeters are a useful device for closing the gap between laboratory and field by both including relevant transport processes in undisturbed soil columns and allowing controlled boundary conditions. In this study, sorption and degradation of the herbicide metsulfuron-methyl in a loamy silt soil were investigated by applying inverse modelling techniques to data sets from different experimental approaches under laboratory conditions at a temperature of 10 degrees C: first, batch-degradation studies and, second, column experiments with undisturbed soil cores (28 cm length x 21 cm diameter). The column experiments included leachate and soil profile analysis at two different run times. A sequential extraction method was applied in both study parts in order to determine different binding states of the test item within the soil. Data were modelled using ModelMaker and Hydrus-1D/2D. Metsulfuron-methyl half-life in the batch-experiments (t1/2 = 66 days) was shown to be about four times higher than in the micro-lysimeter studies (t1/2 about 17 days). Kinetic sorption was found to be a significant process both in batch and column experiments. Applying the one-rate-two-site kinetic sorption model to the sequential extraction data, it was possible to associate the stronger bonded fraction of metsulfuron-methyl with its kinetically sorbed fraction in the model. Although the columns exhibited strong significance of multi-domain flow (soil heterogeneity), the comparison between bromide and metsulfuron-methyl leaching and profile data showed clear evidence for kinetic sorption effects. The use of soil profile data had significant impact on parameter estimates concerning sorption and degradation. The simulated leaching of metsulfuron-methyl as it resulted from parameter estimation was shown to decrease when soil profile data were considered in the parameter estimation procedure. Moreover, it was shown that the significance of kinetic sorption can only be demonstrated by the additional use of soil profile data in parameter estimation. Thus, the exclusive use of efflux data from leaching experiments at any scale can lead to fundamental misunderstandings of the underlying processes.


Two cases of lichen striatus with prolonged active phase.
Lichen striatus is a localized, eczematous disorder distributed along the lines of Blaschko, primarily affecting children. In the literature, lesions have been described as having an active phase of inflamed lesions for 6 to 12 months followed by flattening and persistent pigmentary alteration. We describe two girls who had prolonged active-phase lesions for 2.5 and 3.5 years, respectively. Practitioners should be aware that lesions of lichen striatus may have a prolonged active phase.


Recent advances in antiplatelet agents.
Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.


The bile salt export pump (BSEP) in health and disease.
The bile salt export pump (BSEP) is the major transporter for the secretion of bile acids from hepatocytes into bile in humans. Mutations of BSEP are associated with cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 2 (PFIC-2), benign recurrent intrahepatic cholestasis type 2 (BRIC-2) and genetic polymorphisms are linked to intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). Detailed analysis of these diseases has considerably increased our knowledge about physiology and pathophysiology of bile secretion in humans. This review focuses on expression, localization, and function, short- and long-term regulation of BSEP as well as diseases association and treatment options for BSEP-associated diseases.


Modified single-sling myocutaneous island pedicle flap: series of 61 reconstructions.
Bilevel undermining above and below the transverse nasalis muscle in the construction of a myocutaneous island pedicle flap produces a bilateral or unilateral muscular sling with exceptional vascular supply for reconstruction of defects on the distal nose. We present further modification of the single-sling myocutaneous island pedicle flap that expands its application to a wide variety of nasal defects and further defines its usefulness in nasal reconstruction. A series of 61 consecutive myocutaneous island pedicle flap reconstructions performed after Mohs surgery between March 2005 and July 2006 are presented. Flap modifications are presented, and advantages and limitations are discussed. Flap modifications introduce additional reach and rotational mobility to the flap that permit extension of the flap to defects on the nasal tip and distal ala. Modifications of the bilevel approach to the single-sling nasalis myocutaneous island pedicle flap further define its practicality in nasal reconstruction and expand its application to a variety of nasal defects.


Waiting for care: effects of Ontario's 3-month waiting period for OHIP on landed immigrants.
To describe the experiences of a group of new immigrants and caregivers of new immigrants who were subject to the 3-month waiting period for the Ontario Health Insurance Plan and needed to access health care services during that time. Qualitative study using a phenomenologic framework. Participants were recruited through the Scarborough Community Volunteer Clinic in Toronto, Ont. Interviews were conducted in person at the clinic or by telephone. Seven participants were interviewed who themselves needed to access health care during the 3-month waiting period for the Ontario Health Insurance Plan or who were caring for someone who did. Seven semistructured, in-depth interviews were conducted using an interview guide; these were recorded and transcribed verbatim. Data were analyzed for themes to arrive at the essence of the participants' experiences. Participants believed that there was a lack of clear information and a lack of help from officials. Other common themes included poor social situations, financial loss or threat of financial loss related to health care, a choice to delay seeking care owing to cost, difficulty accessing alternative care, and appreciation for those who advocated on their behalf. Other themes that arose included emotional hardship, poor health outcomes or threat of poor health outcomes resulting from not seeking care, the importance and unpredictability of health, as well as negative impressions of Canada as a country as a result of the negative experience of seeking care. New immigrants to Ontario who need to access health care services during the 3-month waiting period for provincial health insurance and the caregivers of such newcomers can have potentially very negative experiences. They might be unable to access care without financial barriers and might, therefore, choose to delay seeking health care until the end of the waiting period; this can lead to emotional hardship for themselves and their caregivers as well as to potentially poor health outcomes. This potential for an overwhelmingly negative experience for some new immigrants to Ontario might lend support to the argument that this policy be eliminated.


New insights into donor directionality of mating-type switching in Schizosaccharomyces pombe.
Mating-type switching in Schizosaccharomyces pombe entails programmed gene conversion events regulated by DNA replication, heterochromatin, and the HP1-like chromodomain protein Swi6. The whole mechanism remains to be fully understood. Using a gene deletion library, we screened ~ 3400 mutants for defects in the donor selection step where a heterochromatic locus, mat2-P or mat3-M, is chosen to convert the expressed mat1 locus. By measuring the biases in mat1 content that result from faulty directionality, we identified in total 20 factors required for donor selection. Unexpectedly, these included the histone H3 lysine 4 (H3K4) methyltransferase complex subunits Set1, Swd1, Swd2, Swd3, Spf1 and Ash2, the BRE1-like ubiquitin ligase Brl2 and the Elongator complex subunit Elp6. The mutant defects were investigated in strains with reversed donor loci (mat2-M mat3-P) or when the SRE2 and SRE3 recombination enhancers, adjacent to the donors, were deleted or transposed. Mutants in Set1C, Brl2 or Elp6 altered balanced donor usage away from mat2 and the SRE2 enhancer, towards mat3 and the SRE3 enhancer. The defects in these mutants were qualitatively similar to heterochromatin mutants lacking Swi6, the NAD+-dependent histone deacetylase Sir2, or the Clr4, Raf1 or Rik1 subunits of the histone H3 lysine 9 (H3K9) methyltransferase complex, albeit not as extreme. Other mutants showed clonal biases in switching. This was the case for mutants in the NAD+-independent deacetylase complex subunits Clr1, Clr2 and Clr3, the casein kinase CK2 subunit Ckb1, the ubiquitin ligase component Pof3, and the CENP-B homologue Cbp1, as well as for double mutants lacking Swi6 and Brl2, Pof3, or Cbp1. Thus, we propose that Set1C cooperates with Swi6 and heterochromatin to direct donor choice to mat2-P in M cells, perhaps by inhibiting the SRE3 recombination enhancer, and that in the absence of Swi6 other factors are still capable of imposing biases to donor choice.


Selected contribution: role of spleen emptying in prolonging apneas in humans.
This study addressed the interaction between short-term adaptation to apneas with face immersion and erythrocyte release from the spleen. Twenty healthy volunteers, including ten splenectomized subjects, participated. After prone rest, they performed five maximal-duration apneas with face immersion in 10 degrees C water, with 2-min intervals. Cardiorespiratory parameters and venous blood samples were collected. In subjects with spleens, hematocrit and hemoglobin concentration increased by 6.4% and 3.3%, respectively, over the serial apneas and returned to baseline 10 min after the series. A delay of the physiological breaking point of apnea, by 30.5% (17 s), was seen only in this group. These parameters did not change in the splenectomized group. Plasma protein concentration, preapneic alveolar PCO2, inspired lung volume, and diving bradycardia remained unchanged throughout the series in both groups. Serial apneas thus triggered the hematological changes that have been previously observed after long apneic diving shifts; they were rapidly reversed and did not occur in splenectomized subjects. This suggests that splenic contraction occurs in humans as a part of the diving response and may prolong repeated apneas.


Validation of a hairy roots system to study soybean-soybean aphid interactions.
The soybean aphid (Aphis glycines) is one of the main insect pests of soybean (Glycine max) worldwide. Genomics approaches have provided important data on transcriptome changes, both in the insect and in the plant, in response to the plant-aphid interaction. However, the difficulties to transform soybean and to rear soybean aphid on artificial media have hindered our ability to systematically test the function of genes identified by those analyses as mediators of plant resistance to the insect. An efficient approach to produce transgenic soybean material is the production of transformed hairy roots using Agrobacterium rhizogenes; however, soybean aphids colonize leaves or stems and thus this approach has not been utilized. Here, we developed a hairy root system that allowed effective aphid feeding. We show that this system supports aphid performance similar to that observed in leaves. The use of hairy roots to study plant resistance is validated by experiments showing that roots generated from cotyledons of resistant lines carrying the Rag1 or Rag2 resistance genes are also resistant to aphid feeding, while related susceptible lines are not. Our results demonstrate that hairy roots are a good system to study soybean aphid-soybean interactions, providing a quick and effective method that could be used for functional analysis of the resistance response to this insect.


Fracture Toughness Comparison of Three Indirect Composite Resins Using 4-Point Flexural Strength Method.
The advantages of indirect composite restorations such as less crack formation during their computer-aided design/computer-aided manufacturing process, compared with ceramic restorations, have resulted in their growing popularity. However, restoration failure is a major concern with regard to the long-term clinical success of restorations and may occur as the result of propagation of a crack originated from an internal flaw in the restoration. This study aimed to compare the fracture toughness of three indirect composite resins. In this in vitro experimental study, 10 specimens measuring 3 × 3 × 18 mm were fabricated of Gradia, Crios, and high impact polymer composite indirect composites. A single edge notch with a diameter < 0.3 mm and 0.3 mm length was created in the 9 mm longitudinal dimension of specimens using a no. 11 surgical scalpel. The specimens were then subjected to 4-point flexural strength test in a universal testing machine with a crosshead speed of 0.1 mm/s until failure. Data were analyzed using IBM SPSS Statistics via one-way analysis of variance (ANOVA) and Tukey's HSD (honestly significant difference) test. The statistical power was set at p ˂ 0.05. One-way ANOVA showed a significant difference in fracture toughness of the three composite groups (p = 0.000). According to the Tukey HSD analysis, the fracture toughness of HIPC was significantly higher than that of the other two composites. The fracture toughness of Gradia was significantly lower among all. Within the limitations of this study, the results showed that high temperature-pressure polymerization can increase resistance to crack propagation and subsequently improve the clinical service of indirect composite restorations. Although we do not know the filler volume percentage of HIPC, it seems that filler volume percentage of the composite is inversely correlated with fracture toughness.


Expression of co-stimulatory molecules by tumor cells decreases tumorigenicity but may also reduce systemic antitumor immunity.
Many tumor cells do not express co-stimulatory molecules, and this may account, in part, for their poor ability to stimulate T cells directly. One strategy to enhance immune recognition would be to express such molecules on the tumor cell. Here, we show that expression of a member of the B7 family of co-stimulatory molecules by CMT93 murine colorectal tumor or 1735 murine melanoma cells resulted in a local antitumor response in immunocompetent mice. The antitumor effect was diminished in athymic nude mice, indicating that T cells played an important part in this response. The ability of the B7-expressing tumor cells to generate systemic protective immunity was investigated by excision of tumors that developed from the initial inoculation followed by rechallenge with parental tumor cells. CMT93 is a poorly immunogenic tumor and no significant systemic immunity was elicited by the expression of B7-1 in these cells. 1735 melanoma is a mildly immunogenic tumor. Unexpectedly, the systemic immunity obtained with 1735 tumors expressing B7-1 or B7-2 was weaker than that generated by parental 1735 cells (p < 0.001, stratified logrank test), even when coexpression of interferon-gamma in the B7-1 cells produced high levels of surface MHC class I expression. These results suggest that some caution is appropriate when considering the use of these molecules in the gene therapy of cancer.


White Matter Hyperintensities of Bilateral Lenticular Putamen in Patients with Proliferative Diabetic Retinopathy: A Voxel-based Morphometric Study.
To explore the changes in gray matter volume (GMV) and white matter volume (WMV) in proliferative diabetic retinopathy (PDR) patients using voxel-based morphometry (VBM). In total, 15 patients (10 males, 5 females) with PDR were enrolled to the patient group and 15 healthy controls (10 males, 5 females) to the control group, matched for age, sex, handedness, and education status. All individuals underwent voxel-based morphometry scans. GMV and WMV were compared between the two groups. GMV in bilateral superior temporal gyrus, sixth area of left cerebellum, left middle temporal gyrus, left orbital inferior frontal gyrus and left middle cingulum gyrus and WMV in left thalamus and left precuneus were significantly lower in patients than controls (P<0.01). Conversely, WMV was significantly higher in bilateral lenticular putamen of patients than controls (P<0.01). Abnormal GMV and WMV in many specific areas of the cerebrum provide new insights for exploration of the occurrence and development of DR and its pathophysiology.


Preoperative Nomograms Predict Patient-Specific Cervical Spine Surgery Clinical and Quality of Life Outcomes.
Clinical and quality of life (QOL) outcomes vary depending on the patient's demographics, comorbidities, presenting symptoms, pathology, and surgical treatment used. While there have been individual predictors identified, no comprehensive method incorporates a patient's complex clinical presentation to predict a specific individual postoperative outcome. To create tool that predicts patient-specific outcomes among those undergoing cervical spine surgery. A total of 952 patients at a single tertiary care institution who underwent anterior or posterior cervical decompression/fusion between 2007 and 2013 were retrospectively reviewed. Outcomes included postoperative emergency department visit or readmission within 30 d, reoperation within 90 d for infection, and changes in QOL outcomes. Nomograms were modeled based on patient demographics and surgical variables. Bootstrap was used for internal validation. Bias-corrected c-index for emergency department visits, readmission, and reoperation were 0.63, 0.78, and 0.91, respectively. For the QOL metrics, the bias-corrected adjusted R-squared was EQ-5D (EuroQOL): 0.43, for PHQ-9 (Patient Health Questionnaire-9): 0.35, and for PDQ (Pain/Disability Questionnaire): 0.47. Variables predicting the clinical outcomes varied, but included race and median income, body mass index, comorbidities, presenting symptoms, indication for surgery, surgery type, and levels. For the QOL nomograms, the predictors included similar variables, but were significantly more affected by the preoperative QOL of the patient. These prediction models enable referring physicians and spine surgeons to provide patients with personalized expectations regarding postoperative clinical and QOL outcomes following a cervical spine surgery. After appropriate validation, use of patient-specific prediction tools, such as nomograms, has the potential to lead to superior spine surgery outcomes and more cost effective care.


Large Cell Neuroendocrine Carcinoma of the Gallbladder: Where Survival Is a Rare Entity - Case Report and Review of the Literature.
Carcinoma of the gallbladder is extremely rare, papillary adenocarcinoma comprises 90% of these cases. Although neuroendocrine neoplasms (NENs) comprise 0.5% of the cases of gallbladder cancer, the incidence is rising. NEN is classified into a well-differentiated neuroendocrine tumor and poorly differentiated neuroendocrine cancer (NEC). Histologically, NEC is small-cell or large-cell carcinoma. We present the extremely rare case, 15th in the literature to be precise, of large cell neuroendocrine carcinoma of the gallbladder. A 72-year-old male presented to the emergency department with constipation and right upper quadrant pain for 3 months. Computed tomography scan of the abdomen demonstrated an ill-defined 7.2 × 4.9 cm hypodense lesion in the gallbladder fossa with extension into the liver. Histopathological and immunohistochemical analysis of the biopsy specimen confirmed the diagnosis of large cell neuroendocrine carcinoma of the gallbladder. He was started on palliative chemotherapy. The plethora of tumors present in the gallbladder necessitates a search for risk factors for gallbladder neoplasia, and underscores the need to more carefully examine the nature of "asymptomatic gallstones." Further studies may reveal subclasses of cholelithiasis, gallbladder morphology, or imaging to define which patients should be followed more carefully, and may clarify additional risk factors for cancer of the gallbladder.


Visuospatial processing bias in ADHD: A potential artifact in the Wechsler Adult Intelligence Scale and the Rorschach Inkblots Test.
Global processing bias is the automatic tendency to process the global picture before processing the local details. Recent studies suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) show a lack of global processing bias. In the current study, we examined whether lack of global processing bias affects performance on 2 psychological tests, Wechsler Adult Intelligence Scale IV (WAIS-IV) and the Rorschach inkblots test, which require the use of visuospatial processing while measuring different psychological constructs. Adult participants (30 ADHD and 30 typically developing controls) completed the subtests of the WAIS-IV, which rely on visuospatial components, and the Rorschach inkblots test. We found no indication of differences in general fluid intelligence between the groups. On the WAIS-IV test, ADHD participants consistently exhibited superior performance on tasks that relied on local processing and inferior performance on tasks that relied on global processing when compared with healthy controls. On the Rorschach inkblots test, ADHD participants exhibited more responses that referred to local aspects (part/s) of the stimulus and fewer responses that referred to global aspects (whole) of the stimulus. These findings imply that when patients with ADHD are given psychological tests that require visuospatial processing, a potential confound of visuospatial processing style needs to be considered. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The iron triangle and the chrome pentagon.
Like the arms race, the healthcare system is built on a framework of incentives driven by fear and finance--also like the arms race, it will not admit to piecemeal reform.


Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes.
Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.


Increased mitochondrial DNA copy number in occupations associated with low-dose benzene exposure.
Benzene is an established leukemogen at high exposure levels. Although low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses. Our goals were to determine in a large multicenter cross-sectional study whether low-level benzene is associated with increased blood mitochondrial DNA copy number (mtDNAcn, a biological oxidative response to mitochondrial DNA damage and dysfunction) and to explore potential links between mtDNAcn and leukemia-related epigenetic markers. We measured blood relative mtDNAcn by real-time polymerase chain reaction in 341 individuals selected from various occupational groups with low-level benzene exposures (> 100 times lower than the Occupational Safety and Health Administration/European Union standards) and 178 referents from three Italian cities (Genoa, Milan, Cagliari). In each city, benzene-exposed participants showed higher mtDNAcn than referents: mtDNAcn was 0.90 relative units in Genoa bus drivers and 0.75 in referents (p = 0.019); 0.90 in Milan gas station attendants, 1.10 in police officers, and 0.75 in referents (p-trend = 0.008); 1.63 in Cagliari petrochemical plant workers, 1.25 in referents close to the plant, and 0.90 in referents farther from the plant (p-trend = 0.046). Using covariate-adjusted regression models, we estimated that an interquartile range increase in personal airborne benzene was associated with percent increases in mtDNAcn equal to 10.5% in Genoa (p = 0.014), 8.2% (p = 0.008) in Milan, 7.5% in Cagliari (p = 0.22), and 10.3% in all cities combined (p < 0.001). Using methylation data available for the Milan participants, we found that mtDNAcn was associated with LINE-1 hypomethylation (-2.41%; p = 0.007) and p15 hypermethylation (+15.95%, p = 0.008). Blood MtDNAcn was increased in persons exposed to low benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.


Tissue engineering in cardiovascular surgery: new approach to develop completely human autologous tissue.
In cardiovascular tissue engineering, three-dimensional scaffolds serve as physical supports and templates for cell attachment and tissue development. Currently used scaffolds are still far from ideal, they are potentially immunogenic and they show toxic degradation and inflammatory reactions. The aim of this study is to develop a new method for a three-dimensional completely autologous human tissue without using any scaffold materials. Human aortic tissue is harvested from the ascending aorta in the operation room and worked up to pure human myofibroblasts cultures. These human aortic myofibroblasts cultures (1.5x10(6) cells, passage 3) were seeded into 15-cm culture dishes. Cells were cultured with Dulbecco' s modified Eagle's medium supplemented with 1 mM L-ascorbic acid 2-phosphate for 4 weeks to form myofibroblast sheets. The harvested cell sheets were folded to form four-layer sheets. The folded sheets were then framed up and cultured for another 4 weeks. Tissue development was evaluated by biochemical assay and light and electron microscopy. After 4 weeks of culture in ascorbic acid supplemented medium, myofibroblasts formed thin cell sheets in culture dishes. The cell sheets presented in a multi-layered pattern surrounded by extracellular matrices. Cultured for additional 4 weeks on the frames, the folded sheets further developed into more solid and flexible tissues. Light microscopy documented a structure resembling to a native tissue with confluent extracellular matrix. Under transmission electron microscope, viable cells and confluent bundles of striated mature collagen fibers were observed. Hydroxyproline assays showed significant increase of collagen content after culturing on the frames and were 80.5% of that of natural human pericardium. Improved cell culture technique may render human aortic myofibroblasts to a native tissue-like structure. A three-dimensional completely autologous human tissue may be further developed on the base of this structure with no show toxic degradation or inflammatory reactions.


Roles for chemokines in liver disease.
Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic versus antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets.


[Bilateral simultaneous LASIK. Pro and contra].
Until recently simultaneous bilateral laser in situ keratomileusis (LASIK) was regarded as contraindicated in Germany. However, the procedure was sporadically performed, because it offers patient comfort and is more cost effective than sequential LASIK. Even though the complication rate is below the calculated rate of 0.01%, bilateral complications may have catastrophic effects on the patient. In addition, there is the theoretical disadvantage that the results from the first eye cannot be used for the second eye. However, this effect has yet to be clinically proven.


Causal role for the subthalamic nucleus in interrupting behavior.
Stopping or pausing in response to threats, conflicting information, or surprise is fundamental to behavior. Evidence across species has shown that the subthalamic nucleus (STN) is activated by scenarios involving stopping or pausing, yet evidence that the STN causally implements stops or pauses is lacking. Here we used optogenetics to activate or inhibit mouse STN to test its putative causal role. We first demonstrated that optogenetic stimulation of the STN excited its major projection targets. Next we showed that brief activation of STN projection neurons was sufficient to interrupt or pause a self-initiated bout of licking. Finally, we developed an assay in which surprise was used to interrupt licking, and showed that STN inhibition reduced the disruptive effect of surprise. Thus STN activation interrupts behavior, and blocking the STN blunts the interruptive effect of surprise. These results provide strong evidence that the STN is both necessary and sufficient for such forms of behavioral response suppression.


Getting underneath the skin: A community engagement event for optimal vitamin D status in an 'easily overlooked' group.
Patient and public involvement and engagement (PPIE) is recognized as important for improved quality in health service provision and research. Vitamin D is one area where PPIE has potential to benefit public health initiatives, particularly for women and children with increased skin pigmentation (ie at high risk of deficiency) who are easily overlooked. We report findings from a community PPIE event that explored the knowledge, barriers and promoters for optimal vitamin D status amongst an exemplar high-risk and easily overlooked population group. Two researchers and one PPIE lead facilitated a single group discussion with twenty members of the Somali community from across west London. All attendees were women of reproductive age, or knew a mother and child that could benefit from a targeted initiative. The discussion was recorded, transcribed verbatim, organized and coded using NVivo 12 Pro to identify emergent themes underpinned by the Health Behaviour Model. Attendees thought community safety and competing demands of technology and education impacted on sun exposure and lifestyle activity. Language barriers impacted on access to health care. Attendees also felt the mother figure was 'the most important' influencer of both child and wider community health. Although further discourse is needed, this event emphasizes that it is important that the public voice is heard in informing, designing and evaluating appropriate public health interventions amongst specific ethnic groups. Insights from this Somali population have suggested benefit from using verbal health messages that are specifically targeted at mothers, compared with the general population.


Real-Time Stimulus Artifact Rejection Via Template Subtraction.
This paper presents an infinite impulse response (IIR) temporal filtering technique for real-time stimulus artifact rejection (SAR) based on template subtraction. A system architecture for the IIR SAR algorithm is developed, and the operation of the algorithm with fixed-point computation is analyzed to obtain the number of bits for the internal nodes of the system, considering dynamic range and fraction length requirements for optimum performance. Further, memory initialization with the first recorded stimulus artifact is proposed and shown to significantly decrease the IIR system response time, especially when artifacts are highly reproducible in consecutive stimulation cycles. The proposed system architecture is hardware-implemented on a field-programmable gate array (FPGA) and tested using two sets of prerecorded neural data from a rat and an Aplysia californica (a marine sea slug) obtained from two different laboratories. The measured results from the FPGA verify that the system can indeed remove the stimulus artifacts from the contaminated neural data in real time and recover the neural action potentials that occur on the tail end of the artifact (as close as within 0.5 ms after the artifact spike). The root-mean-square (rms) value of the pre-processed stimulus artifact is reduced on average by a factor of 17 (Aplysia californica) and 5.3 (rat) post-processing.


A new species of Andean frog of the genus Phrynopus (Anura: Strabomantidae) from southeastern Peru.
The Cordillera de los Andes is one of the most important regions for biodiversity. Among amphibians, many endemic species of terrestrial-breeding frogs have recently been discovered. Herein we describe Phrynopus sancristobali from the Andes of southeastern Peru based on molecular and morphological data. The new species is known from the ecotone between humid puna and montane forest at 3910 m a.s.l. on the left side of the Apurímac Valley in the Department of Ayacucho. The new species differs from congeners by having dorsum bearing pustules and light brown with dark brown reticulations surrounding the areolas, and coloration consisting of flanks golden brown with gray or dark brown marks, palms pale orange, soles deep orange, toes IV and V dark brown in dorsal and ventral view, belly cream to yellow with gray to light brown marks, and groin and throat deep orange. The snout-vent length (SVL) is 20.7 and 22.2 in two females, and 19.5 mm in one male. According to our phylogeny inferred using Maximum Likelihood with a concatenated dataset of three mitochondrial and two nuclear genes, P. sancristobali is sister taxon of P. apumantarum, recently described from Department Huancavelica. Our description extends the known geographic range of Phrynopus 73 km to the south, and P. sancristobali is the only species in the genus known to occur south of the Mantaro River, whose deep valley is hypothesized to be a biogeographic barrier for high-Andean organisms. The discovery of P. sancristobali confirms the high levels of endemism and beta diversity of Phrynopus in the moist puna grasslands and montane forests of the high Andes of Peru, and suggests that further work will reveal the presence of additional species in southern Peru.


Neonatal lead exposure impairs development of rodent barrel field cortex.
Childhood exposure to low-level lead can permanently reduce intelligence, but the neurobiologic mechanism for this effect is unknown. We examined the impact of lead exposure on the development of cortical columns, using the rodent barrel field as a model. In all areas of mammalian neocortex, cortical columns constitute a fundamental structural unit subserving information processing. Barrel field cortex contains columnar processing units with distinct clusters of layer IV neurons that receive sensory input from individual whiskers. In this study, rat pups were exposed to 0, 0.2, 1, 1.5, or 2 g/liter lead acetate in their dam's drinking water from birth through postnatal day 10. This treatment, which coincides with the development of segregated columns in the barrel field, produced blood lead concentrations from 1 to 31 microg/dl. On postnatal day 10, the area of the barrel field and of individual barrels was measured. A dose-related reduction in barrel field area was observed (Pearson correlation = -0.740; P < 0.001); mean barrel field area in the highest exposure group was decreased 12% versus controls. Individual barrels in the physiologically more active caudoventral group were affected preferentially. Total cortical area measured in the same sections was not altered significantly by lead exposure. These data support the hypothesis that lead exposure may impair the development of columnar processing units in immature neocortex. We demonstrate that low levels of blood lead, in the range seen in many impoverished inner-city children, cause structural alterations in a neocortical somatosensory map.


Steganalysis using image quality metrics.
We present techniques for steganalysis of images that have been potentially subjected to steganographic algorithms, both within the passive warden and active warden frameworks. Our hypothesis is that steganographic schemes leave statistical evidence that can be exploited for detection with the aid of image quality features and multivariate regression analysis. To this effect image quality metrics have been identified based on the analysis of variance (ANOVA) technique as feature sets to distinguish between cover-images and stego-images. The classifier between cover and stego-images is built using multivariate regression on the selected quality metrics and is trained based on an estimate of the original image. Simulation results with the chosen feature set and well-known watermarking and steganographic techniques indicate that our approach is able with reasonable accuracy to distinguish between cover and stego images.


Treatment of drainage water with industrial by-products to prevent phosphorus loss from tile-drained land.
Tile drained land with phosphorus (P)-rich topsoil is prone to P loss, which can impair surface water quality via eutrophication. We used by-products from steel and energy industries to mitigate P loss from tile drains. For each by-product, P sorption maximum (P(max)) and strength (k) were determined, while a fluvarium trial assessed P uptake with flow rate. Although two ash materials (fly ash and bottom ash) had high P(max) and k values, heavy metal concentrations negated their use in the field. The fluvarium experiment determined that P uptake with by-products was best at low flow, but decreased at higher flow in proportion to k. A mixture of melter slag (<10 mm) and basic slag (high P(max), 7250 mg kg(-1); and k, 0.508 L mg P(-1)) was installed as backfill in eight drains on a dairy farm. Four drains with greywacke as backfill were constructed for controls. The site (10 ha) had P-rich topsoil (Olsen P of 64 mg kg(-1)) and yielded a mean dissolved reactive P (DRP) and total P (TP) concentration from greywacke backfilled drains of 0.33 and 1.20 mg L(-1), respectively. In contrast, slag backfilled drains had DRP and TP concentrations of 0.09 and 0.36 mg L(-1), respectively. Loads of DRP and TP in greywacke drains (0.45 and 1.92, respectively) were significantly greater (P < 0.05) than those from slag drains (0.18 and 0.85, respectively). Data from a farm where melter slag was used as a backfill suggested that slag would have a life expectancy of about 25 yr. Thus, backfilling tile drains with melter slag and a small proportion of basic slag is recommended as an effective means of decreasing P loss from high P soils.


Metaplastic carcinoma of the breast with osteocartilaginous heterologous elements.
The clinicopathologic features of 32 metaplastic carcinomas with heterologous osteocartilaginous elements are reported. Each neoplasm consisted of invasive adenocarcinoma accompanied by a cartilaginous or osseous component. In 10 neoplasms, this consisted of cartilage and in 2 the heterologous element was osteoid or bone exclusively. The remaining 20 neoplasms contained a mixture of cartilaginous and osseous components. All patients were women; mean age was 56 years. Twenty-four patients were treated using mastectomy and eight by local excision. Twenty-six patients underwent axillary lymph node dissection. Lymph node metastases were detected in 6 of the 26 (23%) patients who underwent axillary dissection. Clinical follow-up was available for 29 of 32 patients (91%). Local recurrence or distant metastases developed in 6 patients (21%) within 2 years of initial treatment, and 4 of these patients died of metastatic carcinoma. The overall 5-year survival rate was 60%. When compared with control patients with infiltrating duct carcinoma, the group with metaplastic carcinoma tended to have a more favorable prognosis after adjustment for nodal status and tumor size. The prognosis of patients with metaplastic mammary carcinoma with heterologous osteocartilaginous elements is dependent on tumor stage at diagnosis. Immunohistochemical studies for 34BE12, p53, retinoblastoma protein, HER/2neu (polyclonal), epidermal growth factor receptor, and cyclin D1 were performed in 18 cases. Positive immunohistochemical staining was found as follows: 34BE12: n = 13 (72%); p53: n = 11 (61%); retinoblastoma protein: n = 12 (66%); HER2/neu: n = 2 (11%); epidermal growth factor receptor: n = 7 (38%); and cyclin Dm: n = 5 (28%). Positive staining for 34BE12 was observed in the carcinomatous component in 5 (38%) of the neoplasms, in the metaplastic component in 2 (15%), and in both elements in 6 (64%). A p53 staining was observed in the carcinomatous component exclusively in 4 (36%) of 11 p53-positive tumors. No disparity in p53 staining was noted between the epithelial and metaplastic elements in the other p53-positive tumors. Expression of these markers did not correlate with clinicopathologic features such as patient age, tumor size, tumor type, relative proportion of metaplastic elements, and axillary nodal status and was not predictive of disease-free survival.


Open Versus Laparoscopic Ventral Hernia Repair: A Randomized Clinical Trial.
Introduction With the advancement in technology as well as surgical techniques, laparoscopic ventral hernia repair (LVHR) is more commonly being performed as compared to open repair in various centres throughout the world. Our study aimed to compare the short-term operative outcomes between LVHR and open repair. Materials and methods Sixty patients diagnosed with noncomplicated ventral hernias were included in this prospective study and were randomly divided into the laparoscopic group and the open group. The two groups were compared to evaluate operative time, postoperative pain, length of hospital stay and time taken to return to normal activity. A p-value of less than 0.05 was considered to be statistically significant. Results Mean operative time was longer in LVHR (116 min) as compared to open repair (67 min)(p<0.01). Patients experienced more pain on the first and seventh postoperative days in the open group (p<0.01) and they also had a longer duration of hospital stay as compared to the laparoscopic group (6.23 ± 0.35 vs 2.17 ± 1.12 days, p = 0.02). Patients in the laparoscopic group returned to normal activity faster as compared to the open group (1.47 ± 0.11 vs 2.87 ± 0.34, p<0.01). Conclusion LVHR carries a significant advantage over open hernia repair, especially in terms of reduced postoperative pain, duration of hospital stay, and early resumption of normal activity.


Insights into Non-Proteolytic Inhibitory Mechanisms of Polymorphic Early-Stage Amyloid β Oligomers by Insulin Degrading Enzyme.
Insulin degrading enzyme (IDE) has been detected in the cerebrospinal fluid media and plays a role in encapsulating and degrading the amyloid β (Aβ) monomer, thus regulating the levels of Aβ monomers. The current work illustrates a first study by which IDE encapsulates polymorphic early-stage Aβ oligomers. The main goal of this study was to investigate the molecular mechanisms of IDE activity on the encapsulated early-stage Aβ dimers: fibril-like and random coil/α-helix dimers. Our work led to several findings. First, when the fibril-like Aβ dimer interacts with IDE-C domain, IDE does not impede the contact between the monomers, but plays a role as a 'dead-end' chaperone protein. Second, when the fibril-like Aβ dimer interacts with the IDE-N domain, IDE successfully impedes the contacts between monomers. Third, the inhibitory activity of IDE on random coil/α-helix dimers depends on the stability of the dimer. IDE could impede the contacts between monomers in relatively unstable random coil/α-helix dimers, but gets hard to impede in stable dimers. However, IDE encapsulates stable dimers and could serve as a 'dead-end' chaperone. Our results examine the molecular interactions between IDE and the dimers, and between the monomers within the dimers. Hence, this study provides insights into the inhibition mechanisms of the primary nucleation of Aβ aggregation and the basic knowledge for rational design to inhibit Aβ aggregation.


Cell cycle arrest in plants: what distinguishes quiescence, dormancy and differentiated G1?
Quiescence is a fundamental feature of plant life, which enables plasticity, renewal and fidelity of the somatic cell line. Cellular quiescence is defined by arrest in a particular phase of the cell cycle, typically G1 or G2; however, the regulation of quiescence and proliferation can also be considered across wider scales in space and time. As such, quiescence is a defining feature of plant development and phenology, from meristematic stem cell progenitors to terminally differentiated cells, as well as dormant or suppressed seeds and buds. While the physiology of each of these states differs considerably, each is referred to as 'cell cycle arrest' or 'G1 arrest'. Here the physiology and molecular regulation of (1) meristematic quiescence, (2) dormancy and (3) terminal differentiation (cell cycle exit) are considered in order to determine whether and how the molecular decisions guiding these nuclear states are distinct. A brief overview of the canonical cell cycle regulators is provided, and the genetic and genomic, as well as physiological, evidence is considered regarding two primary questions: (1) Are the canonical cell cycle regulators superior or subordinate in the regulation of quiescence? (2) Are these three modes of quiescence governed by distinct molecular controls? Meristematic quiescence, dormancy and terminal differentiation are each predominantly characterized by G1 arrest but regulated distinctly, at a level largely superior to the canonical cell cycle. Meristematic quiescence is intrinsically linked to non-cell-autonomous regulation of meristem cell identity, and particularly through the influence of ubiquitin-dependent proteolysis, in partnership with reactive oxygen species, abscisic acid and auxin. The regulation of terminal differentiation shares analogous features with meristematic quiescence, albeit with specific activators and a greater role for cytokinin signalling. Dormancy meanwhile appears to be regulated at the level of chromatin accessibility, by Polycomb group-type histone modifications of particular dormancy genes.


Most edges in Markov random fields for white matter hyperintensity segmentation are worthless.
The time and space complexities of Markov random field (MRF) algorithms for image segmentation increase with the number of edges that represent statistical dependencies between adjacent pixels. This has made MRFs too computationally complex for cutting-edge applications such as joint segmentation of longitudinal sequences of many high-resolution magnetic resonance images (MRIs). Here, we show that simply removing edges from full MRFs can reduce the computational complexity of MRF parameter estimation and inference with no notable decrease in segmentation performance. In particular, we show that for segmentation of white matter hyperintensities in 88 brain MRI scans of elderly individuals, as many as 66% of MRF edges can be removed without substantially degrading segmentation accuracy. We then show that removing edges from MRFs makes MRF parameter estimation and inference computationally tractable enough to enable modeling statistical dependencies within and across a larger number of brain MRI scans in a longitudinal series; this improves segmentation performance compared to separate segmentations of each individual scan in the series.


Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease.
There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R2 = 0.13, P < .05) and amyloid PET (R2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P < .005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P < .001) in Aβ-positive individuals with MCI. In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD.


Correlation of Technetium-99m scintigraphy, progressive acetabular osteolysis and acetabular component loosening in total hip arthroplasty.
In total hip arthroplasty (THA) Technetium scintigraphy can help to diagnose a loose implant by detecting elevated osteoblastic activity. It has been used for timing the revision of cemented implants. In uncemented cups progressive radiological acetabular osteolysis can be present before loosening accurs, but it is probably unwise to await cup loosening before embarking on revision. We explored the possible relationship between such osteolysis and positive findings on technetium scintigraphy, to see if the technique could predict the need for revision. Between 1990 and 1996 500 hydroxyapatite-coated hip prostheses were implanted (follow-up range: 9-15 years), and technetium scintigraphy and plain radiography were performed annually postoperatively. 32 cups were revised for progressive acetabular osteolysis. We compared the introperative findings at revision with the pre-operative scintigraphic and radiographic results. The sensitivity and specificity for diagnosing progressive acetabular osteolysis by technetium scintigraphy were 34% and 0% respectively. The sensitivity and specificity of the technique for detecting loosening were 38% and 73% respectively. The sensitivity and specificity of technetium scintigraphy for detection of a either loosening or progressive acetabular osteolysis are worse than reported for plain radiography. Despite negative scintigraphy, there may be progressive bone loss at a critical level. Scintigraphy has no additional value to plain radiography as a reliable indicator for timing cup revision in the process of progressive acetabular osteolysis.


Effect of external electric fields on the C-H bond activation reactivity of nonheme iron-oxo reagents.
The effect of external electric fields (EFs) on the reactivity of nonheme iron(IV)-oxo species toward alkanes is investigated computationally using density functional theory. It is shown that an external EF changes the energy landscape of the process and thereby impacts the mechanisms, rates, and selectivities of the reactions, in a manner dependent on the nature of the iron(IV)-oxo/alkane pair. When the iron-oxo species is a good electron acceptor, like N4PyFeO2+, and the alkane is a good electron donor, like toluene, the application of the EF changes the mechanism from hydrogen abstraction to electron transfer. With cyclohexane, which is a poorer electron donor than toluene, the EF promotes hydride transfer and generates a carbocation. However, in the reaction between a poorer electron acceptor TMC(SR)FeO+ and cyclohexane, the EF preserves the hydrogen abstraction/rebound mechanism but improves its features by lowering the barriers for both the C-H activation and rebound steps; larger effects were observed for the quintet-state reaction. In all cases, the EF effect obeys a selection rule; the largest effects are observed when the EF vector is aligned with the Fe=O axis (z) and directed along the molecular dipole. As such, an EF aligned in the direction of the electron flow from substrate to the iron-oxo center lowers the reaction barrier and affects both the reactivity and selectivity of the molecular catalysts.


Full characterization of the signal and idler noise figure spectra in single-pumped fiber optical parametric amplifiers.
For the first time, four different noise sources, which are amplified quantum noise, Raman phonon seeded excess noise, pump transferred noise (PTN), and pump residual noise, are considered simultaneously to model the wavelength-dependent noise figure in a single-pumped fiber optical parametric amplifier. An asymmetric signal NF spectrum induced by both Raman phonon seeded excess noise and Raman gain modified PTN is measured in the electrical domain. Theoretical results agree very well with the experimental data. The idler NF spectrum is also analyzed and measured, which shows a more symmetric profile.


Design and development of a temperature-compensated fiber optic polarimetric pressure sensor based on photonic crystal fiber at 1550 nm.
Use of photonic crystal fibers (PCFs) in the field of sensing is relatively new. We propose the application of a PCF for pressure sensing. The fiber analyzed is a polarization-maintaining PCF that has negligible sensitivity to temperature, making it an ideal candidate for pressure sensing in harsh environments. On the basis of theoretical and experimental analysis, PCF is proposed to be applied as a temperature-compensated pressure sensor. Detailed theoretical analysis and the experiment carried out are described to show the concept of the sensor.


Protective effects of astaxanthin on a combination of D-galactose and jet lag-induced aging model in mice.
Oxidative stress caused free radical and mitochondrial damage plays a critical role in the progression of aging and age-related damage at the cellular and tissue levels. Antioxidant supplementation has received growing attention and the effects of antioxidant on aging are increasingly assessed in both animal and human studies. However, additional and more promising treatments that contribute to the expansion of anti-aging therapies are needed. Astaxanthin, a super antioxidant carotenoid and free radical scavenger, inhibits lipid peroxidation more potently than vitamin E. In the present study, we investigated the preventative effects of astaxanthin on aging using an accelerated aging model: mice chronically treated with a combination of D-galactose and jet lag. After 6 weeks of treatment, astaxanthin administration tended to protect the liver weight loss in aged mice. It is probably by upregulating the mRNA expression of galactose-1-phosphate uridyltransferase, which contribute to the enhancement of D-galactose metabolism. Astaxanthin supplementation also improved muscle endurance of aged mice in a swimming test. These results were associated with reduced oxidative stress in serum and increased anti-oxidative enzymes activities and mRNA expression in vivo. Moreover, astaxanthin reversed the dysregulation of aging-related gene expression caused by the combination of D-galactose and jet lag in the liver and kidney of mice. In conclusion, astaxanthin prevents liver weight loss, ameliorates locomotive muscular function, exerts significant anti-aging effects by reducing oxidative stress and improving the expression of age-related genes in D-galactose and jet lag-induced aging model.


Aryl hydrocarbon (Ah) receptor levels are selectively modulated by hsp90-associated immunophilin homolog XAP2.
The aryl hydrocarbon receptor (AhR) is a ligand-inducible transcription factor that mediates biological responses to halogenated aromatic hydrocarbons. The unliganded AhR is a cytoplasmic, tetrameric complex consisting of the AhR ligand-binding subunit, a dimer of hsp90, and the hepatitis B virus X-associated protein 2 (XAP2). The role of XAP2 as a member of the AhR core complex is poorly understood. XAP2 shares significant homology with the immunophilins FKBP12 and FKBP52, including a highly conserved, C-terminal, tetratricopeptide repeat (TPR) domain. XAP2 forms a complex with hsp90 and the AhR but can also bind to both independently. This binding is mediated by the conserved TPR domain. Single-point mutations in this region are sufficient to disrupt the association of XAP2 with both the AhR and hsp90 in cells. Cotransfection of the AhR and XAP2 in COS-1 cells results in increased AhR levels compared with cells transfected with the AhR alone. In contrast, coexpression of the AhR with the TPR containing proteins FKBP52, protein phosphatase 5 (PP5), or XAP2 TPR-mutants deficient in binding to the AhR and hsp90 does not affect AhR levels and coexpression of the AhR with the TPR domain of PP5 results in AhR down-regulation. These results demonstrate that XAP2 is apparently unique among hsp90-binding proteins in its ability to enhance AhR levels. A yellow fluorescent protein (YFP)-XAP2-FLAG was constructed and biochemically characterized, and no loss of function was detected. YFP-XAP2-FLAG was transiently transfected into NIH 3T3 and was found to localize in both the nucleus and the cytoplasm when visualized by fluorescence microscopy. Treatment of Hepa-1 cells with the hsp90-binding benzoquinone ansamycin, geldanamycin, and the macrocyclic antifungal compound radicicol resulted in AhR but not XAP2 or FKBP52 turnover. Taken together, these results suggest that XAP2/hsp90 and FKBP52/hsp90 complexes are similar yet exhibit unique functional specificity.


Motorized actuation system to perform droplet operations on printed plastic sheets.
We developed an open microfluidic system to dispense and manipulate discrete droplets on planar plastic sheets. Here, a superhydrophobic material is spray-coated on commercially-available plastic sheets followed by the printing of hydrophilic symbols using an inkjet printer. The patterned plastic sheets are taped to a two-axis tilting platform, powered by stepper motors, that provides mechanical agitation for droplet transport. We demonstrate the following droplet operations: transport of droplets of different sizes, parallel transport of multiple droplets, merging and mixing of multiple droplets, dispensing of smaller droplets from a large droplet or a fluid reservoir, and one-directional transport of droplets. As a proof-of-concept, a colorimetric assay is implemented to measure the glucose concentration in sheep serum. Compared to silicon-based digital microfluidic devices, we believe that the presented system is appealing for various biological experiments because of the ease of altering design layouts of hydrophilic symbols, relatively faster turnaround time in printing plastic sheets, larger area to accommodate more tests, and lower operational costs by using off-the-shelf products.


Treatment for refractory pancreatic cancer. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.
While gemcitabine-based regimens are currently accepted as the standard first-line treatment of patients with locally advanced or metastatic pancreatic adenocarcinoma, there is no consensus regarding treatment in the second-line setting. This review is an update from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium regarding recent developments in the treatment of refractory pancreatic cancer, as these were presented in Abstracts #237 and #272 of the meeting.


Potential benefits versus hazards of herbal therapy during pregnancy; a systematic review of available literature.
The use of herbal medicine has considerably grown worldwide in the past two decades. Studies have shown that the prevalence of herbal diet therapy in pregnancy ranged from 1% to 60% in different societies. Many clinical reports have shown that some herbal medicines may have toxic effects on pregnant women and their fetuses because active ingredients of some medicinal plants can readily pass through the biological barriers (e.g., placental barrier). In the present study, we aimed to systematically review the literature to discover potential benefits versus the hazards of herbal therapy during pregnancy. For this purpose, a comprehensive literature review was performed, and after the literature search and selection of the appropriate documents, the desired data were extracted and reported. From 35 articles with a total of 39,950 study population, the results showed that some medicinal plants could cause severe toxicity on mothers and fetuses, in addition to abortion during pregnancy. It was also shown that some plants may lead to developmental abnormalities or fetal death. Findings of this survey showed that some herbal medicines have toxic, teratogenic, and abortive potential, particularly in the first trimester of pregnancy because active ingredients of some medicinal plants are able to pass through the placental barrier and reach the fetus.


Increased IL-12p70 and IL-8 Produced by Monocytes in Response to Streptococcus spp. and Actinomyces spp. Causals of Endodontic Primary Infections.
We sought to evaluate the effect of endodontic-causative microorganisms of primary infections on mononuclear cells such as CD14+, CD4+, CD8+, CD19+ and Tregs Foxp3+. Facultative anaerobic microorganisms were isolated from radicular conducts and peripheral blood samples, which were taken from patients with primary infections. Cellular cultures were performed with peripheral blood mononuclear cells (PBMC) with and without Actinomyces spp. and Streptococcus spp. during 48, 72, and 96 h of contact in culture (concentration 5 × 105 cells/well) in a round plate bound with 48 wells. Later, PBMC was collected for analysis by flow cytometry, with the monoclonal antibodies αCD14, αCD4, αCD8, αCD19 and αFoxp3, and acquired using an FACSCanto II cytometer. The supernatant of cellular cultures was analyzed for the quantification of inflammatory cytokines. Data analysis was performed in FlowJo v10.8.2 and FCAPArray software, and statistical analysis was performed using GraphPad v5.0. software. We observed an increase in the percentage of CD14+ cells in patients at different hours of cellular culture in the presence of both Actinomyces spp. and Streptococcus spp. microorganisms, compared to healthy controls. This study demonstrates the role played by the innate immune system in the pathogeny of endodontic primary infections, explaining the effects that generate the more common microorganisms in this oral pathology.