Changes in dental pulp blood flow of different maxillary tooth types after Le Fort I osteotomy.
This study examined the effects of Le Fort I (LF-I) osteotomy on pulpal blood flow (PBF) in maxillary teeth during a 12-month postsurgical period. A laser Doppler flowmeter was used to measure PBF in maxillary incisors, canines, and first premolars of 14 patients undergoing LF-I osteotomy (study group), 7 patients undergoing mandibular osteotomy (surgical control group), and 7 nonsurgical controls. The PBF was measured at baseline (preoperatively) and at 1 week and 1, 3, 6, and 12 months postoperatively and at similar intervals in nonsurgical control subjects. Data were evaluated using Kruskal-Wallis and post hoc Mann-Whitney tests. Changes in PBF over time for each tooth type were evaluated using the Wilcoxon signed-rank test. The level of significance was set at P < 0.05. Study findings showed that baseline PBF values did not differ significantly between groups. Maxillary PBF in the control group did not vary over time; however, an initial decrease in PBF was observed in all tooth types immediately after surgery in the study group. A gradual increase to near-preoperative levels was then observed during a 12-month healing period. Although dramatic reductions in maxillary perfusion of the first premolar and canine pulps were observed at 1 week and 1 month after LF-I osteotomy when compared with baseline (P < 0.001), PBF significantly recovered over time. Moreover, hyperemia was observed in lateral incisors 3 months postoperatively, demonstrating a tooth type-specific effect of LF-I osteotomy on PBF.


Mycobacterium fortuitum mastitis following augmentation mammaplasty: report of a case.
A 26-year-old woman was admitted to the Veterans General Hospital with the chief problem of recurrent abscess formation over the right breast one month after augmentation mammaplasty. Pus aspirated from the right breast grew Mycobacterium fortuitum, a rapidly growing atypical Mycobacterium, in 4 consecutive cultures. The infected mammanoplastic prosthesis was surgically removed. Acid-fast bacilli were found on pathologic examination of the surgical specimen. Amikacin, doxycycline and ethambutol were given for two weeks according to the sensitivity test. The patient underwent reconstructive surgery of her right breast 10 months later. A specimen obtained from that surgery showed no more acid-fast bacilli on pathological examination. To date there are no signs of recurrence. We suggest that the possibility of mycobacterial infection should be kept in mind when the pus is reported as being "sterile" on an ordinary bacterial culture.


Dendrimers as Competitors of Protein-Protein Interactions of the Intrinsically Disordered Nuclear Chromatin Protein NUPR1.
NUPR1 is a protumoral multifunctional intrinsically disordered protein, which is activated during the acute phases of pancreatitis, interacting with several biomolecules through residues around Ala33 and Thr68. Because of the large size of this hot-spot, designed small molecules could be insufficient to modulate all NUPR1 functions. In this work, we studied NUPR1 interactions with dendrimers by using biophysical techniques and in silico methods. Our results, obtained with different functionalized dendrimers (anionic, cationic and neutral) and several of their generations, indicate that NUPR1 was bound to the dendrimers. Functionalities at the dendrimer periphery modulated the affinity for NUPR1, and for any dendrimer, the affinity increased with generation. The affinities of most of the dendrimers were in the range 4-40 × 103 M-1, and those of the [Gn]-PhCO2Na dendrimers were similar to those of NUPR1 for its natural partners (0.1-1 × 106 M-1). In all dendrimers, the residues of NUPR1 first affected upon binding were located around Ala33, indicating that NUPR1 employs the same hot-spot to recognize any natural or synthetic molecule.


Towards quality, comprehensiveness and excellence. The accreditation project of the Organisation of European Cancer Institutes (OECI).
There are important gaps in the health status of citizens across Europe, as measured by life expectancy, mortality or morbidity data (Report for the European Commission on the health status of the European Union, 2003). Among the main determinants of the major causes of mortality and morbidity, stated in this report, stands recurrently access to quality healthcare. There is a fundamental need to define quality indicators and set minimal levels of performance quality criteria for healthcare. There is a need to integrate research into healthcare and to provide patients with equity of access to such high quality care. Oncology is a specialty particularly suited to experimenting a first application of accreditation at European level. The Organisation of European Cancer Institutes is a growing network of cancer Centres in Europe. The focus of the OECI is to work with professionals and organisations with regard to prevention, care, research, development, patient's role and education. In order to fulfil its mission, the OECI initiated in 2002 an accreditation project with three objectives: * to develop a comprehensive accreditation system for oncology care, taking into account prevention, care, research, education and networking. * to set an updated database of cancer centres in Europe, with exhaustive information on their resources and activities (in care, research, education and management) * to develop a global labelling tool dedicated to comprehensive cancer centres in Europe, designating the various types of cancer structures, and the comprehensive cancer centres of reference and Excellence. An accreditation tool has been established, defining standards and criteria for prevention, care, research, education and follow-up activities. A quantitative database of cancer centres is integrated in the tool, with a questionnaire, that provides an overall view of the oncological landscape in OECI cancer centres in Europe. Data on infrastructures, resources and activities have been collected. This OECI accreditation tool will be launched in autumn 2008 for all cancer centres in Europe. It serves as a basis for the development of the labelling tool for cancer structures in Europe, with a focus on Comprehensiveness and Excellence labels. Quality assessment and improvement is a critical need in Europe and is addressed by the OECI for cancer care in Europe. Accreditation is a well accepted process and is feasible. Standards and criteria as well as an accreditation tool have been developed. The OECI questionnaire gives an accurate vision of cancer institutions throughout Europe, helping assessing the needs and providing standards. The accreditation project is a long-term complete and voluntary process with external and internal added value, an active process of sharing information and experience that should help the whole cancer community reach comprehensiveness and excellence.


The contribution made by cells from a single somite to tissues within a body segment and assessment of their integration with similar cells from adjacent segments.
Somites represent the first visual evidence of segmentation in the developing vertebrate embryo and it is becoming clear that this segmental pattern of the somites is used in the initial stages of development of other segmented systems such as the peripheral nervous system. However, it is not known whether the somites continue to contribute to the maintenance of the segmental pattern after the dispersal of the somitic cells. In particular, the extent to which cells from a single somite contribute to all of the tissues of a single body segment and the extent to which they mix with cells from adjacent segments during their migration is not known. In this study, we have replaced single somites in the future cervical region of 2-day-old chick embryos with equivalent, similarly staged quail somites. The chimerae were then allowed to develop for a further 6 days when they were killed. The cervical region was dissected and serially sectioned. The sections were stained with the Feulgen reaction for DNA to differentiate between the chick and quail cells. The results showed that the cells from a single somite remained as a clearly delimited group throughout their migration. Furthermore, the sclerotome, dermatome and myotome portions from the single somites could always be recognised as being separate from similar cells from other somites. The somitic cells formed all of the tissues within a body segment excluding the epidermis, notochord and neural tissue. There was very little mixing of the somitic cells between adjacent segments. The segmental pattern of the somites is therefore maintained during the migration of the somitic cells and this might be fundamental to a mechanism whereby the segmentation of structures, such as the peripheral nervous system, is also maintained during development.


Defective pollen wall is required for anther and microspore development in rice and encodes a fatty acyl carrier protein reductase.
Aliphatic alcohols naturally exist in many organisms as important cellular components; however, their roles in extracellular polymer biosynthesis are poorly defined. We report here the isolation and characterization of a rice (Oryza sativa) male-sterile mutant, defective pollen wall (dpw), which displays defective anther development and degenerated pollen grains with an irregular exine. Chemical analysis revealed that dpw anthers had a dramatic reduction in cutin monomers and an altered composition of cuticular wax, as well as soluble fatty acids and alcohols. Using map-based cloning, we identified the DPW gene, which is expressed in both tapetal cells and microspores during anther development. Biochemical analysis of the recombinant DPW enzyme shows that it is a novel fatty acid reductase that produces 1-hexadecanol and exhibits >270-fold higher specificity for palmiltoyl-acyl carrier protein than for C16:0 CoA substrates. DPW was predominantly targeted to plastids mediated by its N-terminal transit peptide. Moreover, we demonstrate that the monocot DPW from rice complements the dicot Arabidopsis thaliana male sterile2 (ms2) mutant and is the probable ortholog of MS2. These data suggest that DPWs participate in a conserved step in primary fatty alcohol synthesis for anther cuticle and pollen sporopollenin biosynthesis in monocots and dicots.


Ecdysteroid biosynthesis in workers of the European honeybee Apis mellifera L.
We previously reported preferential expression of genes for ecdysteroid signaling in the mushroom bodies of honeybee workers, suggesting a role of ecdysteroid signaling in regulating honeybee behaviors. The organs that produce ecdysteroids in worker honeybees, however, remain unknown. We show here that the expression of neverland and Non-molting glossy/shroud, which are involved in early steps of ecdysteroid synthesis, was enhanced in the ovary, while the expression of CYP306A1 and CYP302A1, which are involved in later steps of ecdysone synthesis, was enhanced in the brain, and the expression of CYP314A1, which is involved in converting ecdysone into active 20-hydroxyecdysone (20E), was enhanced in the brain, fat body, and ovary. In in vitro organ culture, a significant amount of ecdysteroids was detected in the culture medium of the brain, fat body, and hypopharyngeal glands. The ecdysteroids detected in the culture medium of the fat body were identified as ecdysone and 20E. These findings suggest that, in worker honeybees, cholesterol is converted into intermediate ecdysteroids in the ovary, whereas ecdysone is synthesized and secreted mainly by the brain and converted into 20E in the brain and fat body.


Functional and evolutionary consequences of cranial fenestration in birds.
Ostrich-like birds (Palaeognathae) show very little taxonomic diversity while their sister taxon (Neognathae) contains roughly 10,000 species. The main anatomical differences between the two taxa are in the crania. Palaeognaths lack an element in the bill called the lateral bar that is present in both ancestral theropods and modern neognaths, and have thin zones in the bones of the bill, and robust bony elements on the ventral surface of their crania. Here we use a combination of modeling and developmental experiments to investigate the processes that might have led to these differences. Engineering-based finite element analyses indicate that removing the lateral bars from a neognath increases mechanical stress in the upper bill and the ventral elements of the skull, regions that are either more robust or more flexible in palaeognaths. Surgically removing the lateral bar from neognath hatchlings led to similar changes. These results indicate that the lateral bar is load-bearing and suggest that this function was transferred to other bony elements when it was lost in palaeognaths. It is possible that the loss of the load-bearing lateral bar might have constrained diversification of skull morphology in palaeognaths and thus limited taxonomic diversity within the group.


CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022.
This guideline provides recommendations for clinicians providing pain care, including those prescribing opioids, for outpatients aged ≥18 years. It updates the CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016 (MMWR Recomm Rep 2016;65[No. RR-1]:1-49) and includes recommendations for managing acute (duration of <1 month), subacute (duration of 1-3 months), and chronic (duration of >3 months) pain. The recommendations do not apply to pain related to sickle cell disease or cancer or to patients receiving palliative or end-of-life care. The guideline addresses the following four areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Recommendations are based on systematic reviews of the scientific evidence and reflect considerations of benefits and harms, patient and clinician values and preferences, and resource allocation. CDC obtained input from the Board of Scientific Counselors of the National Center for Injury Prevention and Control (a federally chartered advisory committee), the public, and peer reviewers. CDC recommends that persons with pain receive appropriate pain treatment, with careful consideration of the benefits and risks of all treatment options in the context of the patient's circumstances. Recommendations should not be applied as inflexible standards of care across patient populations. This clinical practice guideline is intended to improve communication between clinicians and patients about the benefits and risks of pain treatments, including opioid therapy; improve the effectiveness and safety of pain treatment; mitigate pain; improve function and quality of life for patients with pain; and reduce risks associated with opioid pain therapy, including opioid use disorder, overdose, and death.


"Just in time" decision making for ICU care after carotid endarterectomy.
Many patients undergoing carotid endarterectomy (CE) do not require active intensive care unit (ICU) care (AIC). Until recently, all patients spent 24 hours postoperatively in an ICU, but many of these patients were simply monitored and did not need unique ICU services. To aid in developing a selective policy for ICU admission following CE, we reviewed preoperative risk factors, recovery room course, and total hospital stay of 126 patients for 2 years when postoperative ICU admission was routine. Preoperative assessment included presence or absence of cardiac disease, hypertension, severe respiratory disease, diabetes, arrhythmia, renal failure, and a Goldman cardiac risk score. The operative, recovery room, and ward records were reviewed for conditions requiring AIC. Requirement for AIC was defined as need for infusion of vasoactive, bronchodilator, or antiarrhythmic medication beyond the recovery room period. In addition, treatment for coronary ischemia or MI, need for active diuresis, perioperative neurological event, or requirement for mechanical ventilation were indications for AIC. There were 132 CEs in 126 patients; 37% required AIC as defined above. When patients who required AIC were compared with patients not requiring AIC, the only significant difference was the number of risk factors per patient. Goldman cardiac risk class I patients were at less risk for cardiac morbidity than the combined Class II and III patients. In an individual patient, preoperative risk assessment does not aid in predicting the need for AIC following CE. Selection of patients for ICU admission following CE can be accurately determined by a short period of recovery room observation.


Temporal course of gene expression during motor memory formation in primary motor cortex of rats.
Motor learning is associated with plastic reorganization of neural networks in primary motor cortex (M1) that depends on changes in gene expression. Here, we investigate the temporal profile of these changes during motor memory formation in response to a skilled reaching task in rats. mRNA-levels were measured 1h, 7h and 24h after the end of a training session using microarray technique. To assure learning specificity, trained animals were compared to a control group. In response to motor learning, genes are sequentially regulated with high time-point specificity and a shift from initial suppression to later activation. The majority of regulated genes can be linked to learning-related plasticity. In the gene-expression cascade following motor learning, three different steps can be defined: (1) an initial suppression of genes influencing gene transcription. (2) Expression of genes that support translation of mRNA in defined compartments. (3) Expression of genes that immediately mediates plastic changes. Gene expression peaks after 24h - this is a much slower time-course when compared to hippocampus-dependent learning, where peaks of gene-expression can be observed 6-12h after training ended.


Targeting dendritic cells to treat multiple sclerosis.
Multiple sclerosis (MS) is considered to be a predominantly T-cell-mediated disease, and emerging evidence indicates that dendritic cells have a critical role in the initiation and progression of this debilitating condition. Dendritic cells are specialized antigen-presenting cells that can prime naive T cells and modulate adaptive immune responses. Their powerful biological functions indicate that these cells can be exploited by immunotherapeutic approaches. Therapies that inhibit the immunogenic actions of dendritic cells through the blockade of proinflammatory cytokine production and T cell co-stimulatory pathways are currently being pursued. Furthermore, novel strategies that can regulate dendritic cell development and differentiation and harness the tolerogenic capacity of these cells are also being developed. Here, we evaluate the prospects of these future therapeutic strategies, which focus on dendritic cells and dendritic cell-related targets to treat MS.


Temperature-dependent terahertz imaging of excised oral malignant melanoma.
We imaged a single case of oral malignant melanoma using terahertz (THz) reflection imaging at room temperature (20 °C) and below freezing (-20 °C). A malignant nodule beneath the oral tissue surface was visualized using 2-D and B-scan THz imaging techniques. The THz images were well correlated with the histological findings. The nodule was found to have lower water content than that of normal cells, and this water effect may have influenced the THz refractive index and absorption coefficient at 20 °C. The THz spectroscopic image of the frozen tissue at -20 °C showed better contrast because of the lack of liquid water; this implies that there are significant structural differences between malignant oral melanoma cells and normal mucosal cells. The better contrast in the frozen tissue images was due to the greater penetration of THz radiation into the sample. This temperature-dependent THz imaging approach demonstrated the feasibility of accurate imaging of the oral tumor tissue.


Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.
Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.


Comprehensive analyses of prostate gene expression: convergence of expressed sequence tag databases, transcript profiling and proteomics.
Several methods have been developed for the comprehensive analysis of gene expression in complex biological systems. Generally these procedures assess either a portion of the cellular transcriptome or a portion of the cellular proteome. Each approach has distinct conceptual and methodological advantages and disadvantages. We have investigated the application of both methods to characterize the gene expression pathway mediated by androgens and the androgen receptor in prostate cancer cells. This pathway is of critical importance for the development and progression of prostate cancer. Of clinical importance, modulation of androgens remains the mainstay of treatment for patients with advanced disease. To facilitate global gene expression studies we have first sought to define the prostate transcriptome by assembling and annotating prostate-derived expressed sequence tags (ESTs). A total of 55000 prostate ESTs were assembled into a set of 15953 clusters putatively representing 15953 distinct transcripts. These clusters were used to construct cDNA microarrays suitable for examining the androgen-response pathway at the level of transcription. The expression of 20 genes was found to be induced by androgens. This cohort included known androgen-regulated genes such as prostate-specific antigen (PSA) and several novel complementary DNAs (cDNAs). Protein expression profiles of androgen-stimulated prostate cancer cells were generated by two-dimensional electrophoresis (2-DE). Mass spectrometric analysis of androgen-regulated proteins in these cells identified the metastasis-suppressor gene NDKA/nm23, a finding that may explain a marked reduction in metastatic potential when these cells express a functional androgen receptor pathway.


Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation.
Declined skeletal muscle mass and function are inevitable consequences of long-term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia. Wild-type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms. STING was abnormally activated in diabetic muscles and in PA-treated myotubes (P < 0.01 for all parameters). The diabetic mice demonstrated decreased forelimb grip strength, lean mass, muscle weight and hanging impulse, which were improved by STING deficiency due to alleviated muscle fibre atrophy and interstitial fibrosis (P < 0.05 for all parameters). STING deficiency alleviated muscle fibre atrophy through the following mechanisms. Firstly, STING deficiency or inhibition increased the contents of pDRP1Ser616 , PINK1, Parkin and LC3-II, decreased p62 content, and increased the amount of mito-Keima fluorescent dots at 578 nm in diabetic state (P < 0.05 for all parameters), suggesting improved mitofission and mitophagy. Secondly, STING deficiency or inhibition increased the expression of pAKTSer473 and GLUT4 post-insulin change in diabetic state (P < 0.05 for all), indicating alleviated insulin resistance (IR). Mechanically, STING deficiency or inhibition increased peroxisome proliferator activated receptors γ (PPARγ) protein content by reducing the degradation of ubiquitinated PPARγ through the proteasome pathway and thus increased the expression of fatty acid oxidation (FAO)-related proteins in diabetic state (P < 0.05 for all parameters). Decreased expression of FAO-related proteins caused by PPARγ inhibition abolished the improvements in mitofission, mitophagy and IR achieved by STING inhibition in PA-treated myotubes and thus promoted muscle fibre atrophy (P < 0.05 for all parameters). STING deficiency alleviated interstitial fibrosis by decreasing TGFβ1 expression in diabetic state and TGFβ1 promoted the fibrogenic differentiation of fibro-adipogenic progenitors (P < 0.05 for all parameters). PPARγ inhibition abolished the effect of STING inhibition on reducing TGFβ1 content in PA-treated myotubes (P < 0.01). STING deficiency exerted protective effects in diabetic sarcopenia by inhibiting the degradation of ubiquitinated PPARγ through the proteasome pathway and enhancing PPARγ-mediated FAO, which alleviated muscle fibre atrophy by promoting mitophagy and ameliorating IR, and alleviated interstitial fibrosis by reducing TGFβ1 production and suppressing the fibrogenic differentiation of fibro-adipogenic progenitors.


Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites.
Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction. Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥ 2 years before and ≥ 1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0.55, 95% CI 0.46-0.65) and remained relatively stable through year 7 (RR 0.49, 95% CI 0.35-0.68). Point estimates for VT IPD decreased annually through year 7 (RR 0.03, 95% CI 0.01-0.10), while NVT IPD increased (year 7 RR 2.81, 95% CI 2.12-3.71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18-49 year-olds [RR 0.52, 95% CI 0.29-0.91], 50-64 year-olds [RR 0.84, 95% CI 0.77-0.93], and ≥ 65 year-olds [RR 0.74, 95% CI 0.58-0.95]). Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used. Please see later in the article for the Editors' Summary.


Anaerobic oxidation of methane at different temperature regimes in Guaymas Basin hydrothermal sediments.
Anaerobic oxidation of methane (AOM) was investigated in hydrothermal sediments of Guaymas Basin based on δ(13)C signatures of CH(4), dissolved inorganic carbon and porewater concentration profiles of CH(4) and sulfate. Cool, warm and hot in-situ temperature regimes (15-20 °C, 30-35 °C and 70-95 °C) were selected from hydrothermal locations in Guaymas Basin to compare AOM geochemistry and 16S ribosomal RNA (rRNA), mcrA and dsrAB genes of the microbial communities. 16S rRNA gene clone libraries from the cool and hot AOM cores yielded similar archaeal types such as Miscellaneous Crenarchaeotal Group, Thermoproteales and anaerobic methane-oxidizing archaea (ANME)-1; some of the ANME-1 archaea formed a separate 16S rRNA lineage that at present seems to be limited to Guaymas Basin. Congruent results were obtained by mcrA gene analysis. The warm AOM core, chemically distinct by lower porewater sulfide concentrations, hosted a different archaeal community dominated by the two deep subsurface archaeal lineages Marine Benthic Group D and Marine Benthic Group B, and by members of the Methanosarcinales including ANME-2 archaea. This distinct composition of the methane-cycling archaeal community in the warm AOM core was confirmed by mcrA gene analysis. Functional genes of sulfate-reducing bacteria and archaea, dsrAB, showed more overlap between all cores, regardless of the core temperature. 16S rRNA gene clone libraries with Euryarchaeota-specific primers detected members of the Archaeoglobus clade in the cool and hot cores. A V6-tag high-throughput sequencing survey generally supported the clone library results while providing high-resolution detail on archaeal and bacterial community structure. These results indicate that AOM and the responsible archaeal communities persist over a wide temperature range.


Movement-induced gain modulation of somatosensory potentials and soleus H-reflexes evoked from the leg. II. Correlation with rate of stretch of extensor muscles of the leg.
Attenuation of initial somatosensory evoked potential (SEP) gain becomes more pronounced with increased rates of movement. Manipulation of the range of movement also might alter the SEP gain. It could alter joint receptor discharge; it should alter the discharge of muscle stretch receptors. We hypothesized that: (1) SEP gain reduction correlates with both the range and the rate of movement, and (2) manipulation of range and rate of movement to achieve similar estimated rates of stretch of a leg extensor muscle group (the vasti) results in similar decreases in SEP gain. SEPs from Cz', referenced to Fpz' (2 cm caudal to Cz and Fpz, respectively, according to the International 10-20 System), along with soleus H-reflexes were elicited by electrical stimulation of the tibial nerve at the popliteal fossa. Stable magnitudes of small M-waves indicated stability of stimulation. A modified cycle ergometer with an adjustable pedal crank and electric motor was used to passively rotate the right leg over three ranges (producing estimated vasti stretch of 12, 24 and 48 mm) and four rates (0, 20, 40 and 80 rpm) of movement. Two experiments were conducted. Ranges and rates of pedalling movement were combined to produce two or three equivalent estimated rates of tissue stretch of the vasti muscles at each of 4, 16, 32 and 64 mm/s. Tibial nerve stimuli were delivered when the knee was moved through its most flexed position and the hip was nearing its most flexed position. Means of SEP, H-reflex and M-wave magnitudes were tested for rate and range effects (ANOVA). A priori contrasts compared means produced by equivalent estimated rates of vasti stretch. Increasing the rate of movement significantly increased the attenuation of SEP and H-reflex gain (P<0.05). Increasing the range of movement also significantly increased these gain attenuations (P<0.05). Combining these to achieve equivalent rates of stretch, through different combinations of rate and range, resulted in equivalent depressions of SEP gain. H-reflex gains were similarly conditioned. These results suggest that muscle stretch receptors play a more important role than joint or cutaneous receptors in regulating SEP gain consequent to movement. We note that the present calculation only considers the knee extensors; however, the biomechanical model of stretch applies also to receptors in the hip extensors. This paper and the companion one show that primary factors in the kinaesthetic components of the movement regulate activity-induced gain attenuation of SEPs.


Ivermectin treatment of onchocercal skin lesions: observations from a placebo-controlled, double-blind trial in Malawi.
To determine effects of ivermectin on skin lesions of onchocerciasis, a placebo-controlled, double-blind trial was carried out in the Thyolo highlands of Malawi involving 70 persons over a 32-month period. Assessment was made using both a clinical numeric grading system and sequential photographs. Among both ivermectin and placebo recipients, there was a significant reduction in both the severity and extent of papular skin lesions. Persons with edematous or lichenified skin lesions of onchocerciasis who received ivermectin showed significantly more improvement than those receiving placebo. Twelve months after the placebo group received ivermectin, their skin lesions were similar to those of the ivermectin group. Changes were most evident for those persons with more severe skin disease in both the ivermectin and placebo groups. Annual ivermectin treatment for onchocercal skin lesions is probably inadequate, and treatment three or four times a year may be required, although the optimum regimen has not been established.


Experimental methods of ethanol administration.
Techniques are reviewed for the experimental feeding of alcohol, including a liquid diet procedure invented 25 years ago. This technique results in much higher ethanol intake than with other approaches. As a consequence, various complications observed in alcoholics can be reproduced in animal models. These include fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared, and adequacy of nutrition in terms of minerals, vitamins, lipotropes, carbohydrates and proteins is discussed. The importance of selecting proper controls is emphasized. The respective advantages of three standardized basic rat formulas are reviewed: (i) an all-purpose (35% fat) diet, comparable to the diet previously referred to as the "Lieber-DeCarli formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of hepatic changes characterized by a fatty liver; (ii) a low-fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes, and (iii) a high-protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e. pregnancy). Variations of this technique, including continuous intragastric infusion, are also discussed. It is concluded that, for most experimental studies of chronic alcohol consumption, the liquid diet technique provides one of the most efficient tools to study the effects of ethanol under controlled nutritional conditions because it allows for alcohol consumption of clinical relevance and offers flexibility to adjust to special experimental or physiologic needs by allowing for various substitutions required for a particular experimental design, including changes in lipids, proteins or other dietary constituents. The technique also facilitates the comparison with controls by simplifying the pair feeding and is the best procedure available for the study of the toxic effects of alcohol and their interactions with deficiency or excess of various nutrients.


I'll Show You the Way: Risky Driver Behavior When "Following a Friend".
Previous research examining social influences on driving behavior has primarily focused on the effects of passengers and surrounding vehicles (e.g., speed contagion). Of current interest was the interaction between drivers that occurs in a "following a friend" scenario, i.e., the driver of one vehicle (the leader) knows how to get to the desired destination while the driver of a second vehicle (the follower) does not. Sixteen participants drove through a simulated city in a driving simulator under three conditions: (i) a baseline condition in which they could choose their own route, (ii) a navigation system condition in which they were given audible route instructions, and (iii) a "follow a friend" condition in which they required to follow a simulated vehicle. In the follow a friend condition, drivers engaged in significantly more risky behaviors (in comparison to the other conditions) such as making more erratic and higher speed turns and lane changes, maintaining overall higher speed, as well as maintaining a shorter time headway when following a lead vehicle. These effects suggest a relationship to time pressure caused by a fear of getting lost.


Diversity and evolution of the class A chromosomal beta-lactamase gene in Klebsiella pneumoniae.
We investigated the diversity of the chromosomal class A beta-lactamase gene in Klebsiella pneumoniae in order to study the evolution of the gene. A 789-bp portion was sequenced in a panel of 28 strains, representative of three phylogenetic groups, KpI, KpII, and KpIII, recently identified in K. pneumoniae and of different chromosomal beta-lactamase variants previously identified. Three groups of sequences were found, two of them corresponding to the families SHV (pI 7.6) and LEN (pI 7.1), respectively, and one, more heterogeneous, corresponding to a new family that we named OKP (for other K. pneumoniae beta-lactamase). Levels of susceptibility to ampicillin, cefuroxime, cefotaxime, ceftazidime, and aztreonam and inhibition by clavulanic acid were similar in the three groups. One new SHV variant, seven new LEN variants, and four OKP variants were identified. The OKP variants formed two subgroups based on nucleotide sequences, one with pIs of 7.8 and 8.1 and the other with pIs of 6.5 and 7.0. The nucleotide sequences of the housekeeping genes gyrA, coding for subunit A of gyrase, and mdh, coding for malate dehydrogenase, were also determined. Phylogenetic analysis of the three genes studied revealed parallel evolution, with the SHV, OKP, and LEN beta-lactamase families corresponding to the phylogenetic groups KpI, KpII, and KpIII, respectively. This correspondence was fully confirmed for 34 additional strains in PCR assays specific for the three beta-lactamase families. We estimated the time since divergence of the phylogenetic groups KpI and KpIII at between 6 and 28 million years, confirming the ancient presence of the beta-lactamase gene in the genome of K. pneumoniae.


Interventions for promoting reintegration and reducing harmful behaviour and lifestyles in street-connected children and young people.
Millions of street-connected children and young people worldwide live or work in street environments. They are vulnerable to many risks, whether or not they remain connected to families of origin, and despite many strengths and resiliencies, they are excluded from mainstream social structures and opportunities. Primary research objectivesTo evaluate and summarise the effectiveness of interventions for street-connected children and young people that aim to:• promote inclusion and reintegration;• increase literacy and numeracy;• facilitate access to education and employment;• promote mental health, including self esteem;• reduce harms associated with early sexual activity and substance misuse. Secondary research objectives• To explore whether effects of interventions differ within and between populations, and whether an equity gradient influences these effects, by extrapolating from all findings relevance for low- and middle-income countries (LMICs) (Peters 2004).• To describe other health, educational, psychosocial and behavioural effects, when appropriate outcomes are reported.• To explore the influence of context in design, delivery and outcomes of interventions.• To explore the relationship between numbers of components and duration and effects of interventions.• To highlight implications of these findings for further research and research methods to improve evidence in relation to the primary research objective.• To consider adverse or unintended outcomes. We searched the following bibliographic databases, searched for the original review, from inception to 2012, and various relevant non-governmental and organisational websites: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE and Pre-MEDLINE; EMBASE and EMBASE Classic; Cumulative Index to Nursing and Allied Health Literature (CINAHL); PsycINFO; Education Resource Information Center (ERIC); Sociological Abstracts; Social Services Abstracts; Social Work Abstracts; Healthstar; Latin American Caribbean Health Sciences Literature (LILACS); System for Grey literature in Europe (OpenGrey); ProQuest Dissertations and Theses; EconLit; IDEAS Economics and Finance Research; JOLIS Library Catalog of the holdings of the World Bank Group and International Monetary Fund (IMF) Libraries; British Library for Development Studies (BLDS); Google and Google Scholar. We updated the search in April 2015 for the review update, using the same methods. This review includes data from harm reduction or reintegration intervention studies that used a comparison group study design; all were randomised or quasi-randomised studies. Studies were included if they evaluated interventions provided for street-connected children and young people, from birth to 24 years, in all contexts. Two review authors independently extracted data and assessed risk of bias and other factors presented in the Discussion and Summary quality assessment (Grades of Recommendation, Assessment, Development and Evaluation (GRADE)). We extracted data on intervention delivery, context, process factors, equity and outcomes, and grouped outcomes into psychosocial outcomes, risky sexual behaviours or substance use. We conducted meta-analyses for outcomes where the outcome measures were sufficiently similar. We evaluated other outcomes narratively. We included 13 studies evaluating 19 interventions from high-income countries (HICs). We found no sufficiently robust evaluations conducted in low- and middle-income countries (LMICs). Study quality overall was low and measurements used by studies variable. Participants were classified as drop-in and shelter-based. No studies measured the primary outcome of reintegration and none reported on adverse effects.We found no consistent results on a range of relevant outcomes within domains of psychosocial health, substance misuse and sexually risky behaviours . Interventions evaluated consisted of time-limited therapeutically based programmes that proved no more effective than standard shelter or drop-in services and other control interventions used for most outcomes in most studies. Favourable changes from baseline were reported for outcomes for most participants following therapy interventions and standard services. We noted considerable heterogeneity between studies and inconsistent reporting of equity data. No studies measured the primary outcome of reintegration or reported on adverse effects. Analysis revealed no consistently significant benefit for focused therapeutic interventions compared with standard services such as drop-in centres, case management and other comparable interventions for street-connected children and young people. Commonly available services, however, were not rigorously evaluated. Robust evaluation of interventions, including comparison with no intervention, would establish a more reliable evidence base to inform service implementation. More robust research is needed in LMICs to examine interventions for street-connected children and young people with different backgrounds and service needs.


Biochemical discrimination between selenium and sulfur 2: mechanistic investigation of the selenium specificity of human selenocysteine lyase.
Selenium is an essential trace element incorporated into selenoproteins as selenocysteine. Selenocysteine (Sec) lyases (SCLs) and cysteine (Cys) desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys, respectively, and generally accept both substrates. Intriguingly, human SCL (hSCL) is specific for Sec even though the only difference between Sec and Cys is a single chalcogen atom.The crystal structure of hSCL was recently determined and gain-of-function protein variants that also could accept Cys as substrate were identified. To obtain mechanistic insight into the chemical basis for its substrate discrimination, we here report time-resolved spectroscopic studies comparing the reactions of the Sec-specific wild-type hSCL and the gain-of-function D146K/H389T variant, when given Cys as a substrate. The data are interpreted in light of other studies of SCL/CD enzymes and offer mechanistic insight into the function of the wild-type enzyme. Based on these results and previously available data we propose a reaction mechanism whereby the Sec over Cys specificity is achieved using a combination of chemical and physico-mechanical control mechanisms.


Anti-IL-8 autoantibody:IL-8 immune complexes suppress spontaneous apoptosis of neutrophils.
Our previous studies demonstrated that a significant fraction of interleukin-8 (IL-8) in lung fluids from patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 immune complexes). Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and moreover, it is well-established that apoptosis of neutrophils is delayed in patients with ALI/ARDS. The aim of this study was, therefore, to examine the role of anti-IL-8:IL-8 immune complexes in modulating spontaneous apoptosis of normal human neutrophils. Apoptosis was assessed by evaluating morphological changes, measuring enzymatic activity of caspase-3, and determining the extent of DNA degradation. We found that samples containing anti-IL-8:IL-8 immune complexes but not samples from which these complexes were removed inhibited neutrophil apoptosis. Furthermore, the former samples or effectively anti-IL-8:IL-8 complexes induced an increase in the level of antiapoptotic protein, Bcl-X(L). In contrast, levels of proapoptotic proteins Bax and Bak were decreased in the same conditions. Activity of both caspase-3 and caspase-9 was also suppressed by anti-IL-8:IL-8 complex-containing samples. Finally, we established that IgG receptor, FcgammaRIIa, mediates antiapoptotic activity of anti-IL-8:IL-8 complexes and that the key components of the FcgammaRIIa signaling pathway, Src, Syk, PI3 kinase, and ERK, may be involved in regulation of neutrophil apoptosis by the complexes. These studies demonstrate for the first time that anti-IL-8:IL-8 immune complexes have the ability to prolong neutrophil life.


miR-375 induces human decidua basalis-derived stromal cells to become insulin-producing cells.
This paper focuses on the development of renewable sources of isletreplacement tissue for the treatment of type I diabetes mellitus. Placental tissue-derived mesenchymal stem cells (MSCs) are a promising source for regenerative medicine due to their plasticity and easy availability. They have the potential to differentiate into insulin-producing cells. miR-375 is a micro RNA that is expressed in the pancreas and involved in islet development. Human placental decidua basalis MSCs (PDB-MSCs) were cultured from full-term human placenta. The immunophenotype of the isolated cells was checked for CD90, CD105, CD44, CD133 and CD34 markers. The MSCs (P3) were chemically transfected with hsa-miR-375. Total RNA was extracted 4 and 6 days after transfection. The expressions of insulin, NGN3, GLUT2, PAX4, PAX6, KIR6.2, NKX6.1, PDX1, and glucagon genes were evaluated using real-time qPCR. On day 6, we tested the potency of the clusters in response to the high glucose challenge and assessed the presence of insulin and NGN3 proteins via immunocytochemistry. Flow cytometry analysis confirmed that more than 90% of the cells were positive for CD90, CD105 and CD44 and negative for CD133 and CD34. Morphological changes were followed from day 2. Cell clusters formed during day 6. Insulin-producing clusters showed a deep red color with DTZ. The expression of pancreatic-specific transcription factors increased remarkably during the four days after transfection and significantly increased on day 7. The clusters were positive for insulin and NGN3 proteins, and C-peptide and insulin secretion increased in response to changes in the glucose concentration (2.8 mM and 16.7 mM). In conclusion, the MSCs could be programmed into functional insulin-producing cells by transfection of miR-375.


The comparative effects of remifentanil or magnesium sulfate versus placebo on attenuating the hemodynamic responses after electroconvulsive therapy.
In this prospective, randomized, double-blind, placebo-controlled, crossover study we compared the effects of remifentanil or magnesium sulfate (MgSO4) versus placebo in attenuating the sympathetic response to electroconvulsive therapy. Twenty adults underwent a total of 115 anesthetics for therapeutic electroconvulsive therapy. Patients were randomly allocated twice into each of the three test groups: placebo control, MgSO4 30 mg/kg, or remifentanil 1.0 microg/kg. Systolic and diastolic arterial blood pressures, heart rate, and oxygen saturations were recorded before IV access was established. Anesthesia was induced with thiopental 4 mg/kg. The trial drug was then administered and neuromuscular blockade was followed with succinylcholine 0.5 mg/kg before electroconvulsive therapy was performed. All measurements were repeated at 0, 1, 3 and 10 min after the seizure ended. Remifentanil and MgSO4 produced a statistically significant attenuation of the increase in systolic arterial blood pressure at 0, 1, and 3 min (P < 0.05). Remifentanil, but not MgSO4 or placebo, attenuated the increase in heart rate at 1 and 3 min but not the peak rate. Remifentanil increased the duration of apnea (mean 90 s), with no other adverse respiratory effects. Mean seizure duration time was 33 (+/- 14) s, with no difference among the groups. In conclusion, remifentanil 1.0 microg/kg and MgSO4 30 mg/kg attenuated the systolic arterial blood pressure response to electroconvulsive therapy without reducing the duration of seizure activity. Because MgSO4 has less effect on HR, it might offer advantages over remifentanil in patients at risk for post-electroconvulsive therapy bradycardia.


Unsupervised Structure Detection in Biomedical Data.
A major challenge in computational biology is to find simple representations of high-dimensional data that best reveal the underlying structure. In this work, we present an intuitive and easy-to-implement method based on ranked neighborhood comparisons that detects structure in unsupervised data. The method is based on ordering objects in terms of similarity and on the mutual overlap of nearest neighbors. This basic framework was originally introduced in the field of social network analysis to detect actor communities. We demonstrate that the same ideas can successfully be applied to biomedical data sets in order to reveal complex underlying structure. The algorithm is very efficient and works on distance data directly without requiring a vectorial embedding of data. Comprehensive experiments demonstrate the validity of this approach. Comparisons with state-of-the-art clustering methods show that the presented method outperforms hierarchical methods as well as density based clustering methods and model-based clustering. A further advantage of the method is that it simultaneously provides a visualization of the data. Especially in biomedical applications, the visualization of data can be used as a first pre-processing step when analyzing real world data sets to get an intuition of the underlying data structure. We apply this model to synthetic data as well as to various biomedical data sets which demonstrate the high quality and usefulness of the inferred structure.


Inflammatory response of mouse skin exposed to the very potent carcinogen dibenzo[a,l]pyrene: a model for tumor promotion.
The potent carcinogenicity of dibenzo[a,l]pyrene in mouse skin is associated with an inflammation unique among polycyclic aromatic hydrocarbons and expressed as erythema. The time course of erythema and the associated histological events in the skin of female SENCAR mice were determined after a single application of 6.25-200 nmol dibenzo[a,l]pyrene or selected metabolites. Dibenzo[a,l]pyrene and dibenzo[a,l]pyrene-11,12-dihydrodiol, precursor to the bay-region diol epoxide, induced an erythema first present 5-6 days after treatment. Dibenzo[a,l]pyrene-8,9-dihydrodiol and other dibenzo[a, l]pyrene metabolites, however, did not induce erythema. These findings suggest a central role for the bay-region diol epoxide in the induction of the observed inflammation. The intensity and duration of erythema were dose-dependent, whereas the delayed appearance of erythema was constant and dose-independent. These results suggest induction of an immune hypersensitivity by dibenzo[a, l]pyrene and its 11,12-dihydrodiol. Histological changes in the skin were consistent with a contact hypersensitivity reaction and included, in association with erythema, epidermal hyperplasia and the presence of mononuclear leukocytes in the dermis. Animals were tested for dibenzo[a,l]pyrene-induced contact hypersensitivity. Female SENCAR mice were treated with a single dermal application of dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene. Five days later, the animals were challenged with a single application of dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene to the ear pinna. Ear swelling exhibited features of a contact hypersensitivity reaction, including (1) delayed appearance after challenge, (2) noninducibility in animals not previously exposed to chemical sensitizer, and (3) chemical specificity. The results suggest that dibenzo[a,l]pyrene induces, via its bay-region diol epoxide, a contact hypersensitivity reaction that may promote tumor development and thereby enhance carcinogenic potency.


Electron microscope studies on the dictyosomes and acroblasts in the male germ cells of the cricket.
The dictyosome (Golgi body) in the secondary spermatocyte of the cricket appears in electron micrographs as a duplex structure composed of (a) a group of parallel double-membraned lamellae and (b) a group of associated vacuoles arranged along the compact lamellae in a chain-like fashion. This arrangement of ultramicroscopic structure for the dictyosomes is strikingly comparable to that described for the Golgi apparatus of vertebrates. Accordingly, the two are considered homologous structures. Associated with the duplex structure of the dictyosomes is a differentiated region composed of small vacuoles. This is thought to represent the pro-acrosome region described in light microscope preparations. In the spermatid the dictyosomes fuse, giving rise to the acroblast. Like the dictyosomes, the acroblasts are made up of double-membraned lamellae and associated vacuoles. In addition, a differentiated acrosome region is present which, in some preparations, may display the acrosome vacuole and granule. Both the dictyosomes and acroblasts are distinct from mitochondria.


Influence of callosal activity on units in the auditory cortex of ferret (Mustela putorius).
1. Callosal neurons in primary auditory cortex project heavily to regions of the contralateral homotopic field that are excited by stimulation of one or both ears and minimally to regions that are excited by stimulation of one ear and inhibited by stimulation of the other ear. The intent of this study is to begin assessing the function of this extensive intercortical projection in determining the response properties of single units in the recipient auditory cortex. 2. Callosal neurons in the right auditory cortex of barbiturate-anesthetized ferrets were stimulated electrically through a pair of monopolar microelectrodes that were separated by 2-3 mm and whose uninsulated tips were located 500 microns below the pial surface. Electrical stimuli consisted of a single 100-microseconds pulse delivered at a fixed intensity and temporal relationship to the onset of each of a set of monaural or binaural acoustic stimuli. Pulse amplitude was almost always < 350 microA. Acoustic stimuli consisted of 100-ms best-frequency tones delivered monaurally or binaurally at 1-s intervals. The influence exerted by electrical stimulation of the right auditory cortex on responses of single units isolated in the left auditory cortex was assessed by comparing responses evoked by the same acoustic stimuli delivered alone and when accompanied by the electrical stimulation. In addition, the latencies of discharges evoked by the electrical stimuli delivered alone were assessed. Three categories of influence were observed: suppression, excitation, and a mixed class consisting of both suppression and excitation. 3. Suppression was the most commonly observed influence of callosal input on acoustically evoked responses. Depending on the strength of the acoustic stimuli and electrical pulse and the temporal relationship between the two kinds of stimulation, responses to acoustic stimuli could be completely suppressed or reduced to a smaller version of the control responses. The duration of the inhibitory influence was often > 100 ms and the suppression was frequently effective at latencies of 2-4 ms. 4. Although unit activity was commonly excited by electrical stimulation of the right auditory cortex, facilitation of acoustically evoked responses was infrequently observed. Apparent facilitation usually was the result of the summation of acoustically and electrically evoked discharges.(ABSTRACT TRUNCATED AT 400 WORDS)


Characterization of the Immune Microenvironment in Hepatocellular Carcinoma.
Purpose: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies.Experimental Design: To characterize the immune microenvironment in HCC, IHC staining was performed for CD8-positive T lymphocytes, PD-1-positive, and LAG-3-positive lymphocytes, CD163-positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC.Results: Expression of CD8 was reduced in tumor, and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24 of 29 cases (83%), and positive expression of LAG-3 on tumor-infiltrating lymphocytes was identified in 19 of 29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted.Conclusions: LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC. Clin Cancer Res; 23(23); 7333-9. ©2017 AACR.


2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation.
Chloracne is commonly observed in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); yet, the mechanism of toxicity is not well understood. Using normal human epidermal keratinocytes, we investigated the mechanism of TCDD-mediated enhancement of epidermal differentiation by integrating functional genomic, metabolomic, and biochemical analyses. TCDD increased the expression of 40% of the genes of the epidermal differentiation complex found on chromosome 1q21 and 75% of the genes required for de novo ceramide biosynthesis. Lipid analysis demonstrated that eight of the nine classes of ceramides were increased by TCDD, altering the ratio of ceramides to free fatty acids. TCDD decreased the expression of the glucose transporter, SLC2A1, and most of the glycolytic transcripts, followed by decreases in glycolytic intermediates, including pyruvate. NADH and Krebs cycle intermediates were decreased, whereas NAD(+) was increased. Mitochondrial glutathione (GSH) reductase activity and the GSH/glutathione disulfide ratio were decreased by TCDD, ultimately leading to mitochondrial dysfunction, characterized by decreased inner mitochondrial membrane potential and ATP production, and increased production of the reactive oxygen species (ROS), hydrogen peroxide. Aryl hydrocarbon receptor (AHR) antagonists blocked the response of many transcripts to TCDD, and the endpoints of decreased ATP production and differentiation, suggesting regulation by the AHR. Cotreatment of cells with chemical antioxidants or the enzyme catalase blocked the TCDD-mediated acceleration of keratinocyte cornified envelope formation, an endpoint of terminal differentiation. Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation.


Approaches and challenges to optimising primary care teams' electronic health record usage.
Although the presence of an electronic health record (EHR) alone does not ensure high quality, efficient care, few studies have focused on the work of those charged with optimising use of existing EHR functionality. To examine the approaches used and challenges perceived by analysts supporting the optimisation of primary care teams' EHR use at a large U.S. academic health care system. A qualitative study was conducted. Optimisation analysts and their supervisor were interviewed and data were analysed for themes. Analysts needed to reconcile the tension created by organisational mandates focused on the standardisation of EHR processes with the primary care teams' demand for EHR customisation. They gained an understanding of health information technology (HIT) leadership's and primary care team's goals through attending meetings, reading meeting minutes and visiting with clinical teams. Within what was organisationally possible, EHR education could then be tailored to fit team needs. Major challenges were related to organisational attempts to standardise EHR use despite varied clinic contexts, personnel readiness and technical issues with the EHR platform. Forcing standardisation upon clinical needs that current EHR functionality could not satisfy was difficult. Dedicated optimisation analysts can add value to health systems through playing a mediating role between HIT leadership and care teams. Our findings imply that EHR optimisation should be performed with an in-depth understanding of the workflow, cognitive and interactional activities in primary care.


Socioeconomic status and smoking: a review.
Smoking prevalence is higher among disadvantaged groups, and disadvantaged smokers may face higher exposure to tobacco's harms. Uptake may also be higher among those with low socioeconomic status (SES), and quit attempts are less likely to be successful. Studies have suggested that this may be the result of reduced social support for quitting, low motivation to quit, stronger addiction to tobacco, increased likelihood of not completing courses of pharmacotherapy or behavioral support sessions, psychological differences such as lack of self-efficacy, and tobacco industry marketing. Evidence of interventions that work among lower socioeconomic groups is sparse. Raising the price of tobacco products appears to be the tobacco control intervention with the most potential to reduce health inequalities from tobacco. Targeted cessation programs and mass media interventions can also contribute to reducing inequalities. To tackle the high prevalence of smoking among disadvantaged groups, a combination of tobacco control measures is required, and these should be delivered in conjunction with wider attempts to address inequalities in health.


Leptin Function and Regulation.
We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central nervous system and we describe the properties of the neuronal networks that are mediators of leptin's effects on ingestive behavior, energy balance, and the reproductive system. The molecular targets of leptin's effects are also responsible for the attenuation and termination of the intracellular signal transduction pathway for leptin, providing a clear understanding of the mechanisms leading to leptin resistance or insensitivity. Using the tools of comparative biology, we explore the potential functions of leptin in fish and birds. Based on the highly variable expression of leptin in multiple tissues, a clear lack of expression of leptin in adipocytes in numerous species of fish and birds and an absence of changes of leptin concentrations in blood that are correlated with changes in nutritional status, it is clear that leptin is unlikely to function as a signal for triglyceride stores in nonmammalian species. This comparative survey serves to highlight the unique function of leptin in mammalian biology as a modulator of energy balance, sexual development, and fertility. © 2018 American Physiological Society. Compr Physiol 8:351-369, 2018.


Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function.
Glucocorticoids signal through the glucocorticoid receptor (GR) and are administered clinically for a variety of situations, including inflammatory disorders, specific cancers, rheumatoid arthritis, and organ/tissue transplantation. However, glucocorticoid therapy is also associated with additional complications, including steroid-induced diabetes. We hypothesized that modification of the steroid backbone is one strategy to enhance the therapeutic potential of GR activation. Toward this goal, two commercially unavailable, thiobenzothiazole-containing derivatives of hydrocortisone (termed MS4 and MS6) were examined using 832/13 rat insulinoma cells as well as rodent and human islets. We found that MS4 had transrepression properties but lacked transactivation ability, whereas MS6 retained both transactivation and transrepression activities. In addition, MS4 and MS6 both displayed anti-inflammatory activity. Furthermore, MS4 displayed reduced impact on islet β-cell function in both rodent and human islets. Similar to dexamethasone, MS6 promoted adipocyte development in vitro, whereas MS4 did not. Moreover, neither MS4 nor MS6 activated the Pck1 (Pepck) gene in primary rat hepatocytes. We conclude that modification of the functional groups attached to the D-ring of the hydrocortisone steroid molecule produces compounds with altered structure-function GR agonist activity with decreased impact on insulin secretion and reduced adipogenic potential but with preservation of anti-inflammatory activity.


Fluoride and children's intelligence: a meta-analysis.
This paper presents a systematic review of the literature concerning fluoride that was carried out to investigate whether fluoride exposure increases the risk of low intelligence quotient (IQ) in China over the past 20 years. MEDLINE, SCI, and CNKI search were organized for all documents published, in English and Chinese, between 1988 and 2008 using the following keywords: fluorosis, fluoride, intelligence, and IQ. Further search was undertaken in the website www.fluorideresearch.org because this is a professional website concerning research on fluoride. Sixteen case-control studies that assessed the development of low IQ in children who had been exposed to fluoride earlier in their life were included in this review. A qualitative review of the studies found a consistent and strong association between the exposure to fluoride and low IQ. The meta-analyses of the case-control studies estimated that the odds ratio of IQ in endemic fluoride areas compared with nonfluoride areas or slight fluoride areas. The summarized weighted mean difference is -4.97 (95%confidence interval [CI] = -5.58 to -4.36; p < 0.01) using a fixed-effect model and -5.03 (95%CI = -6.51 to 3.55; p < 0.01) using a random-effect model, which means that children who live in a fluorosis area have five times higher odds of developing low IQ than those who live in a nonfluorosis area or a slight fluorosis area.


Vitamin D Deficiency and Its Association with Iron Deficiency in African Children.
Vitamin D regulates the master iron hormone hepcidin, and iron in turn alters vitamin D metabolism. Although vitamin D and iron deficiency are highly prevalent globally, little is known about their interactions in Africa. To evaluate associations between vitamin D and iron status we measured markers of iron status, inflammation, malaria parasitemia, and 25-hydroxyvitamin D (25(OH)D) concentrations in 4509 children aged 0.3 months to 8 years living in Kenya, Uganda, Burkina Faso, The Gambia, and South Africa. Prevalence of iron deficiency was 35.1%, and prevalence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D concentrations of <30 nmol/L and <50 nmol/L, respectively. Children with 25(OH)D concentrations of <50 nmol/L had a 98% increased risk of iron deficiency (OR 1.98 [95% CI 1.52, 2.58]) compared to those with 25(OH)D concentrations >75 nmol/L. 25(OH)D concentrations variably influenced individual markers of iron status. Inflammation interacted with 25(OH)D concentrations to predict ferritin levels. The link between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African children.


Mapping indicators of sexually transmitted infection services in the South African public health sector.
Prevention and early treatment of sexually transmitted infections (STIs) is a high public health priority in South Africa. In 2002 a national survey of public health care (PHC) facilities was conducted to develop measurable indicators for monitoring and evaluation of the National STI programme. In this paper we present maps of key indicators obtained from the survey, and discuss their programmatic implications. We also address some methodological issues that arise in the context of producing appropriate maps. A national sample, stratified by subdistrict/municipality, of 962 PHC facilities was randomly selected. In each facility the senior nurse was telephonically contacted and interviewed to answer questions related to the implementation of STI prevention and management from a structured questionnaire. Responses were validated through a second phone call, and inconsistencies recorded. The following key variables were mapped: stock-outs of drugs and condoms, knowledge of correct treatment procedures, consistent record keeping, number of STI clients seen per month per 1000 adult population, number of condoms distributed per adult male, and number of trained nurses per 1000 population. Using conditional autoregressive models and Markov Chain Monte Carlo (MCMC) simulation, smoothed subdistrict level clinic responses were computed and 95% confidence limits estimated. Drug stock-outs were reported by 13% [95% CI 10-15%] and condom stock-outs were reported by 4% [95% CI 2-5%] of facilities. Underlying geographical patterns of risk were more clearly observed when maps had been smoothed and were not dominated by sampling error. Smoothed maps show that there is a finite, low risk of drug stock-outs in all areas with higher risk regions more clearly identified. The maps of indicators of STI services at PHC facilities show that there are important differences in quality of service within South Africa and underscore the usefulness of facility level routine data both for local programme monitoring and planning and for providing a national "bird's eye view" of programme performance.


Human-interpretable feature pattern classification system using learning classifier systems.
Image pattern classification is a challenging task due to the large search space of pixel data. Supervised and subsymbolic approaches have proven accurate in learning a problem's classes. However, in the complex image recognition domain, there is a need for investigation of learning techniques that allow humans to interpret the learned rules in order to gain an insight about the problem. Learning classifier systems (LCSs) are a machine learning technique that have been minimally explored for image classification. This work has developed the feature pattern classification system (FPCS) framework by adopting Haar-like features from the image recognition domain for feature extraction. The FPCS integrates Haar-like features with XCS, which is an accuracy-based LCS. A major contribution of this work is that the developed framework is capable of producing human-interpretable rules. The FPCS system achieved 91 [Formula: see text] 1% accuracy on the unseen test set of the MNIST dataset. In addition, the FPCS is capable of autonomously adjusting the rotation angle in unaligned images. This rotation adjustment raised the accuracy of FPCS to 95%. Although the performance is competitive with equivalent approaches, this was not as accurate as subsymbolic approaches on this dataset. However, the benefit of the interpretability of rules produced by FPCS enabled us to identify the distribution of the learned angles-a normal distribution around [Formula: see text]-which would have been very difficult in subsymbolic approaches. The analyzable nature of FPCS is anticipated to be beneficial in domains such as speed sign recognition, where underlying reasoning and confidence of recognition needs to be human interpretable.


Melatonin improves muscle function of the dystrophic mdx5Cv mouse, a model for Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a severe X-linked muscle-wasting disease caused by the absence of the cytoskeletal protein dystrophin. In addition to abnormal calcium handling, numerous studies point to a crucial role of oxidative stress in the pathogenesis of the disease. Considering the impressive results provided by antioxidants on dystrophic muscle structure and function, we investigated whether melatonin can protect the mdx(5Cv) mouse, an animal model for DMD. Male mdx(5Cv) mouse pups were treated with melatonin by daily intraperitoneal (i.p.) injection (30 mg/kg body weight) or by subcutaneous (s.c.) implant(s) (18 or 54 mg melatonin as Melovine® implants) from 17/18 to 28/29 days of age. Isometric force of the triceps surae was recorded at the end of the treatment. The i.p. treatment increased the phasic twitch tension of mdx(5Cv) mice. The maximal tetanic tension was ameliorated by 18 mg s.c. and 30 mg/kg i.p. treatments. Melatonin caused the dystrophic muscle to contract and relax faster. The force-frequency relationship of melatonin-treated dystrophic mice was shifted to the right. In accordance with improved muscle function, melatonin decreased plasma creatine kinase activity, a marker for muscle injury. Melatonin treatment increased total glutathione content and lowered the oxidized/reduced glutathione ratio, indicating a better redox status of the muscle. In light of the present investigation, the therapeutic potential of melatonin should be further considered for patients with DMD.


Pump-induced population changes in broadband coherent anti-Stokes Raman scattering.
Using a powerful, excimer-laser-pumped broadband coherent anti-Stokes Raman scattering (CARS) system, we have observed considerable changes in the populations of room-temperature nitrogen under atmospheric pressure. Pump-induced populations in the first, second, and third vibronic bands of N2 at room temperature resulted in an apparent vibrational temperature of 2550 K. The implications for broadband N2 CARS thermometry are discussed.


The life course in the making: gender and the development of adolescents' expected timing of adult role transitions.
Adolescents' expectations about the timing of adult role transitions have the potential to shape their actual transitions, setting the stage for their adult lives. Although expectations about timing emerge by early adolescence, little is known about how these expectations develop across adolescence. This longitudinal study examined developmental trajectories of adolescents' anticipated ages of school completion, job entry, marriage, and parenthood over the high school years, focusing on gender differences. Latent growth curve analysis of data from 411 rural youths followed from Grades 9 through 12 (age at Grade 9: M = 14.35, SD = 0.77) indicated a significant increase in adolescents' anticipated ages of entry into work and parenthood as well as gender differences in the trajectory of the expected age of marriage. Gender role attitudes, school performance, romantic relationships, and expected educational and occupational attainment were associated with the anticipated timing of role transitions, with significant variations by gender. Adolescents' expected ages of entry into adult family roles predicted their educational attainment and family role transitions in early adulthood. The findings provide insights into the process through which adolescent boys and girls construct their expectations regarding the transition to adulthood and, in turn, their future life course.


Neurological sequelae of cerebral malaria in children.
Out of 604 Gambian children admitted with falciparum malaria to one hospital between September and December, 1988, 308 had cerebral malaria and 203 were severely anaemic (haemoglobin less than 60 g/l). 14% of those with cerebral malaria died, as did 7.8% of those with severe anaemia. 32 (12%) of children surviving cerebral malaria had residual neurological deficit. 69 other children were admitted with clinical features strongly suggestive of cerebral malaria but with negative blood films; 16 of these died and 3 had residual neurological deficits. The commonest sequelae of cerebral malaria were hemiplegia (23 cases), cortical blindness (11), aphasia (9), and ataxia (6). Factors predisposing to sequelae included prolonged coma, protracted convulsions, severe anaemia, and a biphasic clinical course characterised by recovery of consciousness followed by recurrent convulsions and coma. At follow up 1-6 months later over half these children had made a full recovery, but a quarter were left with a major residual neurological deficit. Cerebral malaria in childhood may be an important cause of neurological handicap in the tropics.


Drosophila Larp associates with poly(A)-binding protein and is required for male fertility and syncytial embryo development.
As the influence of mRNA translation upon cell cycle regulation becomes clearer, we searched for genes that might specify such control in Drosophila. A maternal-effect lethal screen identified mutants in the Drosophila gene for Larp (La-related protein) which displayed maternal-effect lethality and male sterility. A role for La protein has already been implicated in mRNA translation whereas Larp has been proposed to regulate mRNA stability. Here we demonstrate that Larp exists in a physical complex with, and also interacts genetically with, the translation regulator poly(A)-binding protein (PABP). Most mutant alleles of pAbp are embryonic lethal. However hypomorphic pAbp alleles show similar meiotic defects to larp mutants. We find that larp mutant-derived syncytial embryos show a range of mitotic phenotypes, including failure of centrosomes to migrate around the nuclear envelope, detachment of centrosomes from spindle poles, the formation of multipolar spindle arrays and cytokinetic defects. We discuss why the syncytial mitotic cycles and male meiosis should have a particularly sensitive requirement for Larp proteins in regulating not only transcript stability but also potentially the translation of mRNAs.


IntelliCare: An Eclectic, Skills-Based App Suite for the Treatment of Depression and Anxiety.
Digital mental health tools have tended to use psychoeducational strategies based on treatment orientations developed and validated outside of digital health. These features do not map well to the brief but frequent ways that people use mobile phones and mobile phone apps today. To address these challenges, we developed a suite of apps for depression and anxiety called IntelliCare, each developed with a focused goal and interactional style. IntelliCare apps prioritize interactive skills training over education and are designed for frequent but short interactions. The overall objective of this study was to pilot a coach-assisted version of IntelliCare and evaluate its use and efficacy at reducing symptoms of depression and anxiety. Participants, recruited through a health care system, Web-based and community advertising, and clinical research registries, were included in this single-arm trial if they had elevated symptoms of depression or anxiety. Participants had access to the 14 IntelliCare apps from Google Play and received 8 weeks of coaching on the use of IntelliCare. Coaching included an initial phone call plus 2 or more texts per week over the 8 weeks, with some participants receiving an additional brief phone call. Primary outcomes included the Patient Health Questionnaire-9 (PHQ-9) for depression and the Generalized Anxiety Disorder-7 (GAD-7) for anxiety. Participants were compensated up to US $90 for completing all assessments; compensation was not for app use or treatment engagement. Of the 99 participants who initiated treatment, 90.1% (90/99) completed 8 weeks. Participants showed substantial reductions in the PHQ-9 and GAD-7 (P<.001). Participants used the apps an average of 195.4 (SD 141) times over the 8 weeks. The average length of use was 1.1 (SD 2.1) minutes, and 95% of participants downloaded 5 or more of the IntelliCare apps. This study supports the IntelliCare framework of providing a suite of skills-focused apps that can be used frequently and briefly to reduce symptoms of depression and anxiety. The IntelliCare system is elemental, allowing individual apps to be used or not used based on their effectiveness and utility, and it is eclectic, viewing treatment strategies as elements that can be applied as needed rather than adhering to a singular, overarching, theoretical model. Clinicaltrials.gov NCT02176226; http://clinicaltrials.gov/ct2/show/NCT02176226 (Archived by WebCite at http://www.webcitation/6mQZuBGk1).


Factors Governing Oxygen Vacancy Formation in Oxide Perovskites.
The control of oxygen vacancy (VO) formation is critical to advancing multiple metal-oxide-perovskite-based technologies. We report the construction of a compact linear model for the neutral VO formation energy in ABO3 perovskites that reproduces, with reasonable fidelity, Hubbard-U-corrected density functional theory calculations based on the state-of-the-art, strongly constrained and appropriately normed exchange-correlation functional. We obtain a mean absolute error of 0.45 eV for perovskites stable at 298 K, an accuracy that holds across a large, electronically diverse set of ABO3 perovskites. Our model considers perovskites containing alkaline-earth metals (Ca, Sr, and Ba) and lanthanides (La and Ce) on the A-site and 3d transition metals (Ti, V, Cr, Mn, Fe, Co, and Ni) on the B-site in six different crystal systems (cubic, tetragonal, orthorhombic, hexagonal, rhombohedral, and monoclinic) common to perovskites. Physically intuitive metrics easily extracted from existing experimental thermochemical data or via inexpensive quantum mechanical calculations, including crystal bond dissociation energies and (solid phase) reduction potentials, are key components of the model. Beyond validation of the model against known experimental trends in materials used in solid oxide fuel cells, the model yields new candidate perovskites not contained in our training data set, such as (Bi,Y)(Fe,Co)O3, which we predict may have favorable thermochemical water-splitting properties. The confluence of sufficient accuracy, efficiency, and interpretability afforded by our model not only facilitates high-throughput computational screening for any application that requires the precise control of VO concentrations but also provides a clear picture of the dominant physics governing VO formation in metal-oxide perovskites.


Dissociating word stem completion and cued recall as a function of divided attention at retrieval.
The aim of this study was to investigate the widely held, but largely untested, view that implicit memory (repetition priming) reflects an automatic form of retrieval. Specifically, in Experiment 1 we explored whether a secondary task (syllable monitoring), performed during retrieval, would disrupt performance on explicit (cued recall) and implicit (stem completion) memory tasks equally. Surprisingly, despite substantial memory and secondary costs to cued recall when performed with a syllable-monitoring task, the same manipulation had no effect on stem completion priming or on secondary task performance. In Experiment 2 we demonstrated that even when using a particularly demanding version of the stem completion task that incurred secondary task costs, the corresponding disruption to implicit memory performance was minimal. Collectively, the results are consistent with the view that implicit memory retrieval requires little or no processing capacity and is not seemingly susceptible to the effects of dividing attention at retrieval.


Evaluation of in vitro antioxidant capacity and reducing potential of polyherbal drug- Bhāraṅgyādi.
Present work was designed to investigate antioxidant activity of polyherbal formulation in search for new, safe and inexpensive antioxidant. Clerodendrum serratum, Hedychium spicatum and Inula racemosa, were extensively used in ayurvedic medicine and were investigated together in the form of polyherbal compound (Bhāraṅgyādi) for their antioxidant potential. Hydroalcoholic extract was prepared from the above samples and was tested for total reducing power and in vitro antioxidant activity by ABTS(+) assay, Superoxide anion scavenging activity assay and lipid per-oxidation assay. Reducing power shows dose depended increase in concentration maximum absorption of 0.677 ± 0.017 at 1000 μg/ml compared with standard Quercetin 0.856±0.020. ABTS(+) assay shows maximum inhibition of 64.2 ± 0.86 with EC50 675.31 ± 4.24. Superoxide free radical shows maximum scavenging activity of 62.45 ± 1.86 with EC50 774.70 ± 5.45. Anti-lipidperoxidation free radicals scavenge maximum absorption of 67.25± 1.89 with EC50 is 700.08 ± 6.81. Ascorbic acid was used as standard with IC50 value is 4.6 μg/ml. The result suggests polyherbal formulation to be a good potential for antioxidant activity. Oxidative stress results from imbalance between free radical-generation and radical scavenging systems. This will lead to tissue damage and oxidative stress. In conclusion, we strongly suggest that Polyherbal compounds are source of potential antioxidant for radical scavenging. The highly positive correlation of antiradical scavenging activity and total polyphenolic content in Polyherbal compounds indicates that polyphenols are important components which could be used for the free radical scavenging activity. Further study is needed for isolation and characterization of the active moiety responsible for biological activity and to treat in various stress condition.


Fate of geothermal mercury from Yellowstone National Park in the Madison and Missouri Rivers, USA.
Mercury is a worldwide contaminant derived from natural and anthropogenic sources. River systems play a key role in the transport and fate of Hg because they drain widespread areas affected by aerial Hg deposition, transport Hg away from point sources, and are sites of Hg biogeochemical cycling and bioaccumulation. The Madison and Missouri Rivers provide a natural laboratory for studying the fate and transport of Hg contributed by geothermal discharge in Yellowstone National Park and from the atmosphere for a large drainage basin in Montana and Wyoming, United States of America (USA). Assessing Hg in these rivers also is important because they support fishery-based recreation and irrigated agriculture. During 2002 to 2006, Hg concentrations were measured in water, sediment, and fish from the main stem, 7 tributaries, and 6 lakes. Using these data, the geothermal Hg load to the Madison River and overall fate of Hg along 378 km of the Missouri River system were assessed. Geothermal Hg was the primary source of elevated total Hg concentrations in unfiltered water (6.2-31.2 ng/L), sediment (148-1100 ng/g), and brown and rainbow trout (0.12-1.23 μg total Hg/g wet weight skinless filet) upstream from Hebgen Lake (the uppermost impoundment). Approximately 7.0 kg/y of geothermal Hg was discharged from the park via the Madison River, and an estimated 87% of that load was lost to sedimentation in and volatilization from Hebgen Lake. Consequently, Hg concentrations in water, sediment, and fish from main-stem sites downstream from Hebgen Lake were not elevated and were comparable to concentrations reported for other areas affected solely by atmospheric Hg deposition. Some Hg was sequestered in sediment in the downstream lakes. Bioaccumulation of Hg in fish along the river system was strongly correlated (r(2)=0.76-0.86) with unfiltered total and methyl Hg concentrations in water and total Hg in sediment.


Hydrogen Storage in the Carbon Dioxide - Formic Acid Cycle.
This year Mankind will release about 39 Gt carbon dioxide into the earth's atmosphere, where it acts as a greenhouse gas. The chemical transformation of carbon dioxide into useful products becomes increasingly important, as the CO(2) concentration in the atmosphere has reached 400 ppm. One approach to contribute to the decrease of this hazardous emission is to recycle CO(2), for example reducing it to formic acid. The hydrogenation of CO(2) can be achieved with a series of catalysts under basic and acidic conditions, in wide variety of solvents. To realize a hydrogen-based charge-discharge device ('hydrogen battery'), one also needs efficient catalysts for the reverse reaction, the dehydrogenation of formic acid. Despite of the fact that the overwhelming majority of these reactions are carried out using precious metals-based catalysts (mainly Ru), we review here developments for catalytic hydrogen evolution from formic acid with iron-based complexes.


Microtubules in cell migration.
Migration is a polarized cellular process that opposes a protrusive front edge to a retracting trailing edge. From the front to the rear, actin-mediated forces sequentially promote cell protrusion, adhesion, contraction, and retraction. Over the past decade, microtubules have revealed their pivotal role in cell migration. Through their roles in cell mechanics, intracellular trafficking, and signaling, microtubules participate in all essential events leading to cell migration. The front-rear polarization of microtubule functions relies on the asymmetric regulation of microtubule dynamics and stability; the asymmetric distribution of microtubule-associated protein complexes; and finally, the orientation of the microtubule network along the axis of migration. Microtubule network polarity controls the establishment and maintenance of the spatial and temporal coordination of migration events and is therefore the key to persistent directed migration. This review summarizes our current understanding of the functions of microtubules in persistent cell migration and of the migration-associated signals that promote microtubule network polarization.


Refining the definition of perioperative mortality following hepatectomy using death within 90 days as the standard criterion.
Defining perioperative mortality as death that occurs within 30 days of surgery may underestimate 'true' mortality among patients undergoing hepatic resection. To better define perioperative mortality, trends in the risk for death during the first 90 days after hepatectomy were assessed. Surveillance, Epidemiology and End Results (SEER) Medicare data were used to identify 2597 patients who underwent hepatic resection during 1991-2006. Data on their clinicopathological characteristics, surgical management and perioperative mortality were collected and survival was assessed at 30, 60 and 90 days post-surgery. Overall, 5.7% of patients died within the first 30 days. Postoperative mortality at 60 and 90 days were 8.3% and 10.1%. In-hospital mortality after hepatic resection was greater among patients with hepatocellular carcinoma (HCC) than among those with colorectal liver metastases (CRLM) (8.9% and 3.8%, respectively; P < 0.001). In CRLM patients, mortality increased from 4.3% at 30 days to 8.4% at 90 days, whereas mortality in HCC patients increased from 9.7% at 30 days to 15.0% at 90 days (both P < 0.05). Patients with HCC were twice as likely as CRLM patients to die within 30 days [odds ratio (OR) 2.03], 60 days (OR = 1.74) and 90 days (OR = 1.71) (all P < 0.001). Differences in 30- and 90-day mortality were greatest among HCC patients undergoing major hepatic resection (P < 0.05). Reporting deaths that occur within a maximum of 30 days of surgery underestimates the mortality associated with hepatic resection. Traditional 30-day definitions of mortality are misleading and surgeons should report all perioperative outcomes that occur within 90 days of hepatic resection.


Biomarkers of Renal Injury in Cirrhosis: Association with Acute Kidney Injury and Recovery after Liver Transplantation.
To define urine or serum biomarkers in predicting renal function recovery after liver transplantation (LT). Adults listed for LT (February 2011-July 2014) and with modified diet for renal disease-6 (MDRD-6) <60 mL/min provided urine/blood samples at baseline and serially until LT for biomarkers in serum (pg/mL) and urine (pg/mg creatinine). Of 271 LT listed patients (mean age 57 years, 63% males, median listing MELD 17.5), 1 year acute kidney injury (AKI) probability was 49%, with odds of 1.3-, 3.0-, 4.6-, and 8.5-fold times for listing MELD 16-20, 21-25, 26-30, and >30, compared to MELD <16. Thirty-seven people died over 1 year from the time of listing, with twofold increased odds with AKI. Among 67 patients with MDRD <60, only urinary epidermal growth factor was different comparing AKI (increase in serum creatinine ≥0.3 mg/dL from baseline within past 3 months) vs. no AKI (2,254 vs. 4,253, p = 0.003). Differences between acute tubular necrosis (ATN) and hepatorenal syndrome could not be ascertained for a small sample of 3 patients with ATN. Analyzing 15 of 43 receiving LT and MDRD-6 <30 prior to LT, biomarkers were not different comparing 5 patients recovering renal function (MDRD-6 >50 mL/min) at 6 months vs. 10 without recovery. AKI is common among LT listed patients, with a negative impact on transplant-free survival. Serum and urine biomarkers are not associated with the recovery of renal function after LT. Multicenter studies are suggested to (a) develop strategies to reduce the development of AKI and (b) derive novel biomarkers for use in accurately predicting renal recovery after LT.


Developing User Personas to Aid in the Design of a User-Centered Natural Product-Drug Interaction Information Resource for Researchers.
Pharmacokinetic interactions between natural products and conventional drugs can adversely impact patient outcomes. These complex interactions present unique challenges that require clear communication to researchers. We are creating a public information portal to facilitate researchers' access to credible evidence about these interactions. As part of a user-centered design process, three types of intended researchers were surveyed: drug-drug interaction scientists, clinical pharmacists, and drug compendium editors. Of the 23 invited researchers, 17 completed the survey. The researchers suggested a number of specific requirements for a natural product-drug interaction information resource, including specific information about a given interaction, the potential to cause adverse effects, and the clinical importance. Results were used to develop user personas that provided the development team with a concise and memorable way to represent information needs of the three main researcher types and a common basis for communicating the design's rationale.