Comprehensive screening of a light-inducible split Cre recombinase with domain insertion profiling.
Splitting proteins with light- or chemically-inducible dimers provides a mechanism for post-translational control of protein function. However, current methods for engineering stimulus-responsive split proteins often require significant protein engineering expertise and laborious screening of individual constructs. To address this challenge, we use a pooled library approach that enables rapid generation and screening of nearly all possible split protein constructs in parallel, where results can be read out using sequencing. We perform our method on Cre recombinase with optogenetic dimers as a proof of concept, resulting in comprehensive data on split sites throughout the protein. To improve accuracy in predicting split protein behavior, we develop a Bayesian computational approach to contextualize errors inherent to experimental procedures. Overall, our method provides a streamlined approach for achieving inducible post-translational control of a protein of interest.


Sacroiliac joint pain after lumbar fusion. A study with anesthetic blocks.
Low back pain persisting or appearing after a technically successful lumbar fusion challenges clinicians. In this context, the sacroiliac joint could be a possible source of pain, but the frequency of its responsibility is not really known. We used sacroiliac anesthetic blocks, the gold standard for diagnosis, to determine this frequency. Our second goal was to search predictive factors for a positive block. Our prospective series consisted of 40 patients with persistent low back pain after a technically successful fusion who received a sacroiliac anesthetic block under fluoroscopic control. The diagnostic criterion was a relief of more than 75% of the pain on a visual analog scale. We found a 35% rate of positive blocks. The only criterion that characterized these patients was a postoperative pain different from the preoperative pain in its distribution ( p =0.017). A free interval of more than 3 months between surgery and appearance of the pain had an indicative value ( p =0.17). An increased uptake in the sacroiliac on bone scintigraphy or a past history of posterior iliac bone-graft harvesting had no significant value ( p =0.74 and p =1.0, respectively). The sacroiliac joint is a possible source of pain after lumbar fusion. The anesthetic block under fluoroscopic control remains the gold standard.


Differential protection of normal and malignant human myeloid progenitors (CFU-GM) from Ara-C toxicity using cycloheximide.
Cycloheximide, a reversible protein synthesis inhibitor, is thought to block DNA replication in normal cells by preventing synthesis of a labile protein. In animal systems, cycloheximide protects normal cells from cytotoxic S-phase specific agents, such as cytosine arabinoside (Ara-C). Malignant cells appear not to be susceptible to cycloheximide-induced cycle arrest and, subsequently, may not be protected from Ara-C cytotoxicity. The effect of cycloheximide on granulocyte/macrophage progenitors (CFU-GM) after in vitro Ara-C exposure was examined using normal human bone marrow, malignant progenitors from patients with chronic myelogenous leukemia (CML), and clonogenic cells from the human acute nonlymphocytic leukemia cell lines HL-60 and KG-1. Mononuclear or clonogenic cells were incubated for one hour with cycloheximide, followed by the addition, for three or 17 hours, of Ara-C before being plated in a methylcellulose culture system. CFU-GM survival was significantly increase if normal cells were treated with cycloheximide before Ara-C exposure. Similar cycloheximide pretreatment of CML progenitors and clonogenic HL-60 and KG-1 cells failed to protect CFU-GM from Ara-C-induced cytotoxicity.


Transforming practice into clinical scholarship.
The aims of this paper were to explicate clinical scholarship as synonymous with the scholarship of application and to explore the evolution of scholarly practice to clinical scholarship. Boyer contributed an expanded view of scholarship that recognized various approaches to knowledge production beyond pure research (discovery) to include the scholarship of integration, application and teaching. There is growing interest in using Boyer's framework to advance knowledge production in nursing but the discussion of clinical scholarship in relation to Boyer's framework is sparse. Discussion paper. Literature from 1983-2015 and Boyer's framework. When clinical scholarship is viewed as a synonym for Boyer's scholarship of application, it can be aligned to this well established framework to support knowledge generated in clinical practice. For instance, applying the three criteria for scholarship (documentation, peer review and dissemination) can ensure that the knowledge produced is rigorous, available for critique and used by others to advance nursing practice and patient care. Understanding the differences between scholarly practice and clinical scholarship can promote the development of clinical scholarship. Supporting clinical leaders to identify issues confronting nursing practice can enable scholarly practice to be transformed into clinical scholarship. Expanding the understanding of clinical scholarship and linking it to Boyer's scholarship of application can assist nurses to generate knowledge that addresses clinical concerns. Further dialogue about how clinical scholarship can address the theory-practice gap and how publication of clinical scholarship could be expanded given the goals of clinical scholarship is warranted.


Different insulin-secretory responses to calcium-channel blockers in islets of lean and obese (ob/ob) mice.
The purpose of these experiments was to determine whether the activity of the voltage-dependent Ca2+ channel was modulated in the same manner in islets of the ob/ob mouse as in islets of homozygous lean mice of the same strain. The effect of agents that are known to alter the concentrations and movements of intracellular Ca2+ were investigated in relation to glucose-stimulated insulin secretion and in relation to the effect of forskolin. In islets of obese mice, verapamil and nifedipine both inhibited glucose-induced insulin release, nifedipine being the more potent inhibitor. Forskolin-stimulated secretion was inhibited either not at all (verapamil) or much less (nifedipine) in islets of the ob/ob mouse compared with those of lean mice. At basal glucose concentrations, verapamil initiated insulin secretion in islets of the ob/ob mouse and acted synergistically with forskolin to evoke a secretory activity that was 3-fold greater than that evoked by 20 mM-glucose. Nifedipine also initiated secretion at basal glucose concentrations and acted synergistically with forskolin, but its effect was considerably smaller than that of verapamil. A comparison of the effect of forskolin in the presence of Ca2+-channel blockers and in the absence of Ca2+ suggests that, in the obese mouse, the operation of the voltage-dependent Ca2+ channel is impaired.


Water- versus land-based treatment for postural control in postmenopausal osteoporotic women: a randomized, controlled trial.
To compare the effects of water-based and land-based physical therapy on postural control of older women with osteoporosis. Thirty-six postmenopausal women with osteoporosis were allocated into two groups: land-based or water-based. Volunteers received 12 weeks of a supervised land-based or water-based physical therapy treatment. The outcome measure was postural control of the body during quiet standing on upright stance (eyes opened and closed), tandem and one-limb stance on a force plate. A two-way ANOVA with a Tukey HSD post-hoc test were used to highlight differences between pre- and post-intervention evaluations. Effect sizes were measured with Cohen d coefficient. For all variables, a level of 5% of significance was adopted. Significant improvements at tandem (p < 0.05, effect sizes from -0.67 to -1.35) and one-limb stance (p < 0.05, effect sizes from -0.76 to -1.03) for women carrying out water-based treatment were observed. Land-based treatment did not present significant improvement. Group-based water-based physical therapy treatment may be more effective than land-based therapy to improve postural control at one-limb stance in women with osteoporosis.


Recent advances in the diagnosis and treatment of polymyalgia rheumatica.
Polymyalgia rheumatica is one of the most common rheumatic inflammatory disorders in people older than 50 years characterized by aching and prolonged morning stiffness in the shoulder and pelvic girdle and neck.. In this review, we will focus on recent advances on the diagnosis and management of PMR. Expert commentary: Controversy exist whether PMR represent a single entity disease or is an umbrella term that comprises a clinical presentation common to a range of related conditions (polymyalgic syndrome). To date there are no specific diagnostic tests, and the diagnosis remains clinical, although ultrasonography, positron emission tomography scan and the recent ACR/EULAR classification criteria may help to confirm the clinical diagnosis. A step-wise process for the diagnosis of PMR has been proposed. Low-dose steroids are highly effective in the majority of patients and remain the mainstay of treatment, but relapses occur in about 50% of patients and glucocorticoid related adverse event are common. The steroid sparing effects of the immunosuppressive treatment evaluated to date are unclear.


Antiretroviral drug resistance--implications for HIV/AIDS reduction in sub-Saharan Africa and other developing countries.
The introduction of the highly active antiretroviral therapy in the mid-1990s has significantly reduced morbidities and prolonged the lifespan of people living with HIV. However, the emergence of resistance to the antiretroviral drugs is becoming a major cause of treatment failure. While the problem of drug resistance is being tackled in developed countries, not much seem to be done in this regard in developing countries of Africa, Asia and Latin America. This review looked at the regional distribution of HIV groups and subtypes and how this has affected the pattern of antiretroviral resistance. The review was sourced from papers presented at international conferences on HIV/AIDS and rational drug use, relevant journals and Medline search using the keywords--Antiretroviral drugs, drug resistance, HIV subtypes and resistance testing. The types, groups, subtypes, sub-subtypes and recombinant forms of HIV-1 have been identified according to their geographical distributions. The evolution of HIV viral mutations, process (es) involved in development of primary and secondary antiretroviral drug resistance, including the role of HIV genetic polymorphisms, and transmitted resistance have been discussed. The pitfalls in the current resistance testing based on HIV-1 subtype B have been highlighted. The design of resistance testing algorithm based on HIV-1 subtype non-B has been suggested for the developing world.


Proteins rapidly transported to the synapses of a single identified neuron of Aplysia californica.
The cell body of R2, a giant cholinergic neuron of Aplysia californica, resides in the abdominal ganglion, whereas its synapses are on thousands of unicellular mucus glands located in the skin. Due to the great spatial separation between the site of macromolecular synthesis and the presynaptic terminals, rapid axonal transport can be used to segregate synaptic proteins from those to be used elsewhere in the cell. The proteins of R2 were labeled by incubating the abdominal ganglion in [35S]methionine for 5 hr in a chamber separated from the rest of the isolated central nervous system. After 50 hr, 28 radiolabeled proteins were reproducibly found by one- and two-dimensional polyacrylamide gel electrophoresis to be transported to the distal regions of peripheral nerves P6, P7, and P8 that innervate the parapodia and middle body wall. We are sure that R2 is the source of these proteins since radioautography of sections taken throughout the nervous system, complemented by cobalt tracings, showed that R2 is the only neuron in the abdominal ganglion with axons in these nerves. Nine of the 28 transported proteins are glycoproteins since they were also labeled after injecting R2's cell body with [3H]-L-fucose. There is evidence that the proteins and glycoproteins are destined for R2's presynaptic terminals. For example, in experiments in which the body wall and parapodium remained attached to the nerves, the proteins were transported to the skin region that contains the glands. Moreover, analyses of the distribution of the rapidly transported proteins by qualitative radioautography and by extrusion of axoplasm indicated that none are constituents of the axolemma.(ABSTRACT TRUNCATED AT 250 WORDS)


Evolutionary interactions between haemagglutinin and neuraminidase in avian influenza.
Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. It has been suggested that productive viral infection requires a balance in the level of functional activity of HA and NA, arising from their closely interacting roles in the viral life cycle, and that this functional balance could be mediated by genetic changes in the HA and NA. Here, we investigate how the selective pressure varies for H7 avian influenza HA on different NA subtype backgrounds. By extending Bayesian stochastic mutational mapping methods to calculate the ratio of the rate of non-synonymous change to the rate of synonymous change (d(N)/d(S)), we found the average d(N)/d(S) across the avian influenza H7 HA1 region to be significantly greater on an N2 NA subtype background than on an N1, N3 or N7 background. Observed differences in evolutionary rates of H7 HA on different NA subtype backgrounds could not be attributed to underlying differences between avian host species or virus pathogenicity. Examination of d(N)/d(S) values for each subtype on a site-by-site basis indicated that the elevated d(N)/d(S) on the N2 NA background was a result of increased selection, rather than a relaxation of selective constraint. Our results are consistent with the hypothesis that reassortment exposes influenza HA to significant changes in selective pressure through genetic interactions with NA. Such epistatic effects might be explicitly accounted for in future models of influenza evolution.


Exploring predictors of instructional resilience during emergency remote teaching in higher education.
In 2020, Higher Education institutions were pressed to swiftly implement online-based teaching. Among many challenges associated with this, lecturers in Higher Education needed to promptly and flexibly adapt their teaching to these circumstances. This investigation adopts a resilience framing in order to shed light on which specific challenges were associated with this sudden switch and what helped an international sample of Higher Education lecturers (N = 102) in coping with these challenges. Results suggest that Emergency Remote Teaching was indeed challenging and quality of teaching was impeded but these effects are more nuanced than expected. Lecturers displayed instructional resilience by maintaining teaching quality despite difficulties of Emergency Remote Teaching and our exploration of predictors shows that personality factors as well as prior experience may have supported them in this. Our findings may contribute to the emerging literature surrounding Emergency Remote Teaching and contributes a unique resilience perspective to the experiences of Higher Education lecturers.


[Studies on erythromycin stearate capsules (OE-7) (author's transl)].
The blood concentration and urinary excretion of OE-7 (erythromycin stearate capsules) and control drug were investigated in 6 volunteers having gastroptosis. OE-7, newly arranged capsules containing erythromycin stearate, was investigated and obtained the results of high blood concentration by oral administration. To confirm the above, we measured blood concentration and urinary excretion of OE-7 comparing with ordinary erythromycin stearate capsules in 6 volunteers having gastroptosis. The peaks of blood concentration were noted at 3 hours after administration in 6 volunteers uniformly. The mean maximum blood concentration of OE-7 was 1.17 mcg/ml which was significantly higher than ordinary erythromycin stearate capsules. In time course of mean blood concentration, the blood concentration levels of OE-7 were higher than those of control erythromycin stearate capsules at any measurement. Effective blood levels were continuously high in OE-7. Urinary excretion of OE-7 reached to the maximum from 4 to 6 hours after administration which was also higher than control erythromycin stearate. Clinical efficacy of OE-7 was investigated in 28 cases in acute respiratory infection. The results noted were excellent in 5 cases (17.9%), good in 16 cases (57.1%), no change in 6 cases (21.4%), and undetermined in 1 case (3.6%). There were 5 cases of slight gastro-intestinal discomfort as the side effects. As the conclusion, OE-7 revealed good bioavailability and seemed to be useful antibiotic for acute respiratory infections.


Increased Clinical Specificity with Ultrasensitive Detection of Clostridioides difficile Toxins: Reduction of Overdiagnosis Compared to Nucleic Acid Amplification Tests.
Clostridioides difficile infection (CDI) is one of the most common health care-associated infections, resulting in significant morbidity, mortality, and economic burden. Diagnosis of CDI relies on the assessment of clinical presentation and laboratory tests. We evaluated the clinical performance of ultrasensitive single-molecule counting technology for detection of C. difficile toxins A and B. Stool specimens from 298 patients with suspected CDI were tested with the nucleic acid amplification test (NAAT; BD MAX Cdiff assay or Xpert C. difficile assay) and Singulex Clarity C. diff toxins A/B assay. Specimens with discordant results were tested with the cell cytotoxicity neutralization assay (CCNA), and the results were correlated with disease severity and outcome. There were 64 NAAT-positive and 234 NAAT-negative samples. Of the 32 NAAT+/Clarity- and 4 NAAT-/Clarity+ samples, there were 26 CCNA- and 4 CCNA- samples, respectively. CDI relapse was more common in NAAT+/toxin+ patients than in NAAT+/toxin- and NAAT-/toxin- patients. The clinical specificity of Clarity and NAAT was 97.4% and 89.0%, respectively, and overdiagnosis was more than three times more common in NAAT+/toxin- than in NAAT+/toxin+ patients. The Clarity assay was superior to NAATs for the diagnosis of CDI, by reducing overdiagnosis and thereby increasing clinical specificity, and the presence of toxins was associated with negative patient outcomes.


Enteric viral infections of turkey poults: incidence of infection.
Four flocks from one commercial market-turkey operation in Ohio were monitored for the presence of enteric viruses. Each flock was sampled at intervals from placement until at least 7 weeks of age; sampling was more frequent in the first 4 weeks of life. The earliest infections detected were astrovirus infections or combination infections of astrovirus and rotavirus-like virus (RVLV) or astrovirus and rotavirus. During the first 4 weeks of life, astrovirus was the most frequently detected virus, followed by RVLV, then rotavirus. These viruses were seldom detected beyond 4 weeks of age. In three of the four flocks, no viruses were detected in samples collected before 6 days of age; in one flock, however, rotavirus and astrovirus were identified from samples collected at 3 days of age. Experimental infection of specific-pathogen-free poults with astrovirus and RVLV produced enteric diseases in poults and demonstrated that astrovirus was shed into the intestinal tract before RVLV. Poults experimentally infected with astrovirus and RVLV displayed clinical signs of diarrhea and upon necropsy exhibited dilated ceca, frothy gaseous intestinal contents, and loss of intestinal tone.


A comparison of 60 Hz uniform magnetic and electric induction in the human body.
High-resolution computations of induced fields are used to assess equivalent source levels for human exposure to uniform low-frequency electric and magnetic fields. These results pertain to 60 Hz foot-to-head electric excitation of the body in three positions with respect to a ground plane, and to magnetic excitation by three orthogonal source orientations. All computations are based on an anatomically derived human body model composed of 1736873 cubic voxels with 3.6 mm edges. The data for magnetic excitation are computed using a scalar potential finite difference (SPFD) method, while those for electric excitation are computed using a hybrid method based on the SPFD method coupled with a quasistatic finite difference time domain code. The data are analysed in two ways, using an induced current density threshold of 1 mA m-2. Firstly, the various field strengths required to produce a whole-body average current density magnitude equal to the threshold are derived for each configuration, and the associated current density levels in various organs and tissues are presented. It is found that the average current density magnitude values in at least one tissue group can be up to 3 (5) times greater than the whole-body average under electric (magnetic) excitation, and that the associated maximum values can be up to 46 (28) times greater than the whole-body average under electric (magnetic) excitation, for at least one source/body configuration. Secondly, the data are analysed from the opposite point of view, in which the source levels required to induce average or maximum induced current density magnitudes at the threshold level in specific tissue groups are determined. Evaluations such as the present one should prove useful in the development of protection standards, and are also expected to aid in the understanding of results from various animal and tissue culture studies.


The moderation effect of social capital in the relationship between own income, social comparisons and subjective well-being: Evidence from four international datasets.
In this paper we check whether social capital changes the association of subjective well-being with own income and social comparisons. We use panel data from Germany and publicly available data from three international surveys, for a total of nearly 500,000 respondents from industrial countries. Results show that the association of own income and social comparisons to subjective well-being weakens for individuals with high social capital. This finding holds in a variety of settings, and is robust to various measures of subjective well-being, of social capital, and of social comparisons. We also find evidence indicating that the role of social capital is, at least in part, causal. Finally, our findings support the macro-level implication that income differences are less related to subjective well-being differences in countries with high social capital.


A new widespread subclass of carbonic anhydrase in marine phytoplankton.
Most aquatic photoautotrophs depend on CO2-concentrating mechanisms (CCMs) to maintain productivity at ambient concentrations of CO2, and carbonic anhydrase (CA) plays a key role in these processes. Here we present different lines of evidence showing that the protein LCIP63, identified in the marine diatom Thalassiosira pseudonana, is a CA. However, sequence analysis showed that it has a low identity with any known CA and therefore belongs to a new subclass that we designate as iota-CA. Moreover, LCIP63 unusually prefers Mn2+ to Zn2+ as a cofactor, which is potentially of ecological relevance since Mn2+ is more abundant than Zn2+ in the ocean. LCIP63 is located in the chloroplast and only expressed at low concentrations of CO2. When overexpressed using biolistic transformation, the rate of photosynthesis at limiting concentrations of dissolved inorganic carbon increased, confirming its role in the CCM. LCIP63 homologs are present in the five other sequenced diatoms and in other algae, bacteria, and archaea. Thus LCIP63 is phylogenetically widespread but overlooked. Analysis of the Tara Oceans database confirmed this and showed that LCIP63 is widely distributed in marine environments and is therefore likely to play an important role in global biogeochemical carbon cycling.


Change in Dietary Patterns and Change in Waist Circumference and DXA Trunk Fat Among Postmenopausal Women.
To examine whether changes in diet quality predict changes in central adiposity among postmenopausal women. At baseline and 3-year follow-up, Women's Health Initiative Observational Study participants completed food frequency questionnaires, and waist circumference was measured (WC, n = 67,175). In a subset, trunk fat was measured via dual-energy X-ray absorptiometry (DXA, n = 4,254). Using multivariable linear regression, 3-year changes in dietary patterns (Healthy Eating Index-2010, Alternate Healthy Eating Index-2010, Alternate Mediterranean Diet, and Dietary Approaches to Stop Hypertension) were examined as predictors of concurrent changes in WC and, secondarily, DXA. Mean (SD) age and 3-year changes in weight and WC were 63 (7) years, 0.52 (4.26) kg, and 0.94 (6.65) cm. A 10% increase in any dietary pattern score, representing improved diet quality, was associated with 0.07 to 0.43 cm smaller increase in WC over 3 years (all P < 0.05). After adjusting for weight change, associations attenuated to 0.02 to 0.10 cm but remained statistically significant for all patterns except Alternate Mediterranean Diet. Results were similar for DXA trunk fat. Three-year improvements in diet quality are modestly protective against gain in WC and partially explained by lesser weight gain. Achieving and maintaining a healthful diet after menopause may protect against gains in central adiposity.


Leptin produces anorexia and weight loss without inducing an acute phase response or protein wasting.
The ob gene product leptin is known to produce anorexia and loss of body fat when chronically administered to both lean and genetically obese mice. The current study was undertaken to examine whether administration of recombinant leptin in quantities sufficient to produce decreases in food intake and body weight and alterations in body composition would elicit either an hepatic acute phase protein response or preferential loss of carcass lean tissue. Mice were administered increasing quantities of recombinant human leptin or human tumor necrosis factor-alpha as a positive control. Although leptin (at 10 mg/kg body wt) produced significant anorexia and weight loss (both P < 0.05), human leptin administration did not appear to induce an hepatic acute phase protein response in either lean or genetically obese mice, as determined by protein synthetic rates in the liver or changes in the plasma concentration of the murine acute phase protein reactants, amyloid A, amyloid P, or seromucoid (alpha1-acid glycoprotein). In addition, human leptin administration did not induce a loss of fat-free dry mass (protein) in lean or obese animals. The findings suggest that at doses adequate to alter food intake and body weight leptin is not a significant inducer of the hepatic acute phase response nor does leptin promote the preferential loss of somatic protein characteristic of a chronic inflammatory process.


Post-vasectomy pain syndrome: diagnosis, management and treatment options.
Vasectomy is the most effective form of sterilization for men. With approximately 500,000 vasectomies performed each year in the United States, 1-2% of these patients will experience chronic testicular pain for greater than three months after the procedure. Post-vasectomy pain syndrome (PVPS) is diagnosis of exclusion, and may be caused by direct damage to spermatic cord structures, compression of nerves in the spermatic cord via inflammation, back pressure from epididymal congestion, and perineural fibrosis. Treatment should begin with the most noninvasive options and progress towards surgical management if symptoms persist. Noninvasive therapies include acupuncture, pelvic floor therapy and pharmacologic options. Ultimately, management of PVPS requires a multimodal approach. Thorough understanding of the potential etiologies of PVPS along with the therapeutic options currently available is important to improve quality of life.


The prevalence estimates of macular telangiectasia type 2: the Melbourne Collaborative Cohort Study.
The purpose of this study was to determine the prevalence estimates of macular telangiectasia type 2 in an Australian population based on nonmydriatic digital fundus photography. Participants of the Melbourne Collaborative Cohort Study, initiated to investigate risk factors for common aging diseases, had nonmydriatic digital macular images taken from both eyes and graded for any macular abnormalities. Prevalence of the features suggestive of macular telangiectasia type 2 was assessed. Macular images from the 22,062 subjects with a mean age of 64.96 years (range, 47-85 years) were assessed. Of these images, 43,234 images were gradable (21,708 images of the right eye and 21,526 images of the left eye). Using only the grading features of the macular images taken by the nonmydriatic digital fundus photography, 5 subjects with signs consistent with bilateral macular telangiectasia type 2 in this population were found by the authors. Based on the Gass-Blodi staging of this disease, all (5) were determined to be in stages 2 and 3. In an Australian population, the prevalence estimates of macular telangiectasia type 2 were found to be 1 of 22,062 to 5 of 22,062 or 5 to 23 cases per 100,000 people in which disease was at least at stages 2 and 3.


Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol-paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study.
We aimed to evaluate the safety and efficacy of a fixed-dose combination (FDC) of tramadol and diclofenac versus a standard approved FDC of tramadol and paracetamol, in patients with acute moderate to severe pain. A total of 204 patients with moderate to severe pain due to acute musculoskeletal conditions (n=52), acute flare of osteoarthritis (n=52), acute flare of rheumatoid arthritis (n=50), or postoperative pain (n=50) were enrolled in the study at baseline. Each disease category was then randomized to receive either of two treatments for 5 days: group A received an FDC of immediate-release tramadol hydrochloride (50 mg) and sustained-release diclofenac sodium (75 mg) (one tablet, twice daily), and group B received an FDC of tramadol hydrochloride (37.5 mg) and paracetamol (325 mg) (two tablets every 4-6 hours, up to a maximum of eight tablets daily). The primary efficacy end points were reductions in pain intensity from baseline at day 3 and day 5 as assessed by a Visual Analog Scale (VAS) score. Group A showed a significant reduction in the VAS score for overall pain from baseline on day 3 (P=0.001) and day 5 (P<0.0001) as compared with group B. The combination of tramadol-diclofenac resulted in few mild to moderate adverse events (nausea, vomiting, epigastric pain, and gastritis), which required minimal management, without any treatment discontinuation. The number of adverse events in group A was nine (8.82%) compared with 22 (21.78%) in group B, after 5 days of treatment. An FDC of tramadol-diclofenac showed a significantly greater reduction in pain intensity and was well tolerated compared with tramadol-paracetamol, resulting in better analgesia in patients suffering from moderate to severe pain due to acute musculoskeletal conditions, postoperative pain following orthopedic surgery, or acute flare of osteoarthritis and rheumatoid arthritis.


Protein accumulation and rumen stability of wheat γ-gliadin fusion proteins in tobacco and alfalfa.
The nutritional value of various crops can be improved by engineering plants to produce high levels of proteins. For example, because methionine deficiency limits the protein quality of Medicago Sativa (alfalfa) forage, producing alfalfa plants that accumulate high levels of a methionine-rich protein could increase the nutritional value of that crop. We used three strategies in designing methionine-rich recombinant proteins that could accumulate to high levels in plants and thereby serve as candidates for improving the protein quality of alfalfa forage. In tobacco, two fusion proteins, γ-gliadin-δ-zein and γ-δ-zein, as well as δ-zein co-expressed with β-zein, all formed protein bodies. However, the γ-gliadin-δ-zein fusion protein accumulated to the highest level, representing up to 1.5% of total soluble protein (TSP) in one transformant. In alfalfa, γ-gliadin-δ-zein accumulated to 0.2% of TSP, and in an in vitro rumen digestion assay, γ-gliadin-δ-zein was more resistant to microbial degradation than Rubisco. Additionally, although it did not form protein bodies, a γ-gliadin-GFP fusion protein accumulated to much higher levels, 7% of TSP, than a recombinant protein comprised of an ER localization signal fused to GFP in tobacco. Based on our results, we conclude that γ-gliadin-δ-zein is a potential candidate protein to use for enhancing methionine levels in plants and for improving rumen stability of forage protein. γ-gliadin fusion proteins may provide a general platform for increasing the accumulation of recombinant proteins in transgenic plants.


Virtual Surgery for the Nasal Airway: A Preliminary Report on Decision Support and Technology Acceptance.
Nasal airway obstruction (NAO) is a common problem that affects patient quality of life. Surgical success for NAO correction is variable. Virtual surgery planning via computational fluid dynamics (CFD) has the potential to improve the success rates of NAO surgery. To elicit surgeon feedback of a virtual surgery planning tool for NAO and to determine if this tool affects surgeon decision making. For this cross-sectional study, 60-minute face-to-face interviews with board-certified otolaryngologists were conducted at a single academic otolaryngology department from September 16, 2016, through October 7, 2016. Virtual surgery methods were introduced, and surgeons were able to interact with the virtual surgery planning tool interface. Surgeons were provided with a patient case of NAO, and open feedback of the platform was obtained, with emphasis on surgical decision making. Likert scale responses and qualitative feedback were collected for the virtual surgery planning tool and its influence on surgeon decision making. Our 9 study participants were all male, board-certified otolaryngologists with a mean (range) 15 (4-28) number of years in practice and a mean (range) number of nasal surgeries per month at 2.2 (0.0-6.0). When examined on a scale of 1 (not at all) to 5 (completely), surgeon mean (SD) score was 3.4 (0.5) for how realistic the virtual models were compared with actual surgery. On the same scale, when asked how much the virtual surgery planning tool changed surgeon decision making, mean (SD) score was 2.6 (1.6). On a scale of 1 (strongly disagree) to 7 (strongly agree), surgeon scores for perceived usefulness of the technology and attitude toward using it were 5.1 (1.1) and 5.7 (0.9), respectively. Our study shows positive surgeon experience with a virtual surgery planning tool for NAO based on CFD simulations. Surgeons felt that future applications and areas of study of the virtual surgery planning tool include its potential role for patient counseling, selecting appropriate surgical candidates, and identifying which anatomical structures should be targeted for surgical correction. NA.


Transcranial magnetic stimulation and PAS-induced cortical neuroplasticity in the awake rhesus monkey.
Externally induced neuroplasticity may be of therapeutic value in several neuro-psychiatric disorders. To facilitate research on mechanisms and to make possible the design of prospective, advanced stimulation protocols without exposing human subjects to risk, we have developed a primate model which allows us to assess changes of motor cortical excitability using transcranial magnetic stimulation (TMS). TMS hand muscle representation and cortical excitability were determined in two awake trained rhesus monkeys. Neuroplastic changes of cortical excitability were established by 13min of paired associative stimulation (PAS) with interstimulus intervals of either 15 or 5ms. The representational areas of FDI and APB muscles (3.02-4.96cm(2)) were located between the spur of the arcuate and the superior precentral sulcus, indicating the potential to carry out spatially selective cortical stimulation. PAS with an interstimulus interval of 15ms strongly increased cortical excitability for up to two hours, while 5ms interval had no effect. This first systematic TMS and PAS primate study demonstrates that the trained rhesus monkeys represent an exceptional animal model that allows cortical TMS mapping as well as non-invasive assessment and induction of cortical neuroplasticity. This animal model offers additional advantageous options not possible with humans, namely an alternative to invasive, morphological or molecular analyses, making it highly suitable for preclinical development of advanced neuroplasticity paradigms without exposing human subjects to risk.


RAD51 plays a crucial role in halting cell death program induced by ionizing radiation in bovine oocytes.
Reproductive health of humans and animals exposed to daily irradiants from solar/cosmic particles remains largely understudied. We evaluated the sensitivities of bovine and mouse oocytes to bombardment by krypton-78 (1 Gy) or ultraviolet B (UV-B; 100 microjoules). Mouse oocytes responded to irradiation by undergoing massive activation of caspases, rapid loss of energy without cytochrome-c release, and subsequent necrotic death. In contrast, bovine oocytes became positive for annexin-V, exhibited cytochrome-c release, and displayed mild activation of caspases and downstream DNAses but with the absence of a complete cell death program; therefore, cytoplasmic fragmentation was never observed. However, massive cytoplasmic fragmentation and increased DNA damage were induced experimentally by both inhibiting RAD51 and increasing caspase 3 activity before irradiation. Microinjection of recombinant human RAD51 prior to irradiation markedly decreased both cytoplasmic fragmentation and DNA damage in both bovine and mouse oocytes. RAD51 response to damaged DNA occurred faster in bovine oocytes than in mouse oocytes. Therefore, we conclude that upon exposure to irradiation, bovine oocytes create a physiologically indeterminate state of partial cell death, attributed to rapid induction of DNA repair and low activation of caspases. The persistence of these damaged cells may represent an adaptive mechanism with potential implications for livestock productivity and long-term health risks associated with human activity in space.


Measures of treatment burden in dialysis: A scoping review.
Dialysis is a life-sustaining treatment for patients with advanced kidney failure, but it is extremely burdensome. Despite this, there are very few tools available to assess treatment burden within the dialysis population. To conduct a scoping review of generic and disease-specific measures of treatment burden in chronic kidney disease, and assess their suitability for use within the dialysis population. We searched CINAHL, MEDLINE and the Cochrane Library for kidney disease-specific measures of treatment burden. Studies were initially included if they described the development, validation or use of a treatment burden measure or associated concept (e.g., measures of treatment satisfaction, quality of life, illness intrusiveness, disease burden etc.) in adult patients with chronic kidney disease. We also updated a previous scoping review exploring measures of treatment burden in chronic disease to identify generic treatment burden measures. One-hundred and two measures of treatment burden or associated concepts were identified. Four direct measures and two indirect measures of treatment burden were assessed, using adapted established criteria, for suitability for use within the dialysis population. The researchers outlined eight key dimensions of treatment burden: medication, financial, administrative, lifestyle, health care, time/travel, dialysis-specific factors, and health inequality. None of the measures adequately assessed all dimensions of treatment burden. Current measures of treatment burden in dialysis are inadequate to capture the spectrum of issues that matter to patients. There is a need for dialysis-specific burdens and health inequality to be assessed when exploring treatment burden to advance patient care.


Stance dependence of automatic postural adjustments in humans.
This study investigated the effect of initial stance configuration on automatic postural responses in humans. Subjects were tested in both bipedal and quadrupedal stance postures. The postural responses to horizontal translations of the supporting surface were measured in terms of the forces at the ground, movement of the body segments, and electromyographic (EMG) activity. Postural responses to the same perturbations changed with initial stance posture; these responses were biomechanically appropriate for restoring centre of mass. A change in stance configuration prior to platform movement led to a change in both the spatial and temporal organization of evoked muscle activation. Specifically, for the same direction of platform movement, during bipedal stance muscles on one side of the lower limb were activated in a distal to proximal sequence; during quadrupedal stance, muscles on the opposite side of the lower limb were activated and in a proximal to distal sequence. The most significant finding was an asymmetry in the use of the upper limbs and the lower limbs during postural corrections in quadrupedal stance. Whereas antagonists of the upper limb were either co-activated or co-inhibited, depending on the direction of translation, lower limb antagonists were reciprocally activated and inhibited. Human subjects in a quadrupedal stance posture used the lower limbs as levers, protracting or retracting the hips in order to propel the trunk back to its original position with respect to the hands and feet. Postural responses of the subjects during quadrupedal stance were remarkably similar to those of cats subjected to similar perturbations of the supporting surface. Furthermore, the same predominance of lower limb correction is characteristic of both species, suggesting that the standing cat is a good model for studying postural control in humans.


Cutaneous Lupus Erythematosus: Review and Considerations for Older Populations.
Though more common earlier in life, increasing attention is being focused on the development of cutaneous lupus erythematosus (CLE) in patients with advancing age. Studies show that CLE is more common in older populations than previously thought, and all CLE subtypes are possible in this group. Just like patients in the third or fourth decade of life, CLE may appear alongside or independent of systemic lupus erythematosus. Older populations manifesting CLE for the first time seem to have a lower risk of progression to systemic disease than younger peers, and are more commonly White. CLE must be carefully distinguished from other skin conditions that have a predilection for presentation in older populations, including rosacea, lichen planus, and other autoimmune conditions such as dermatomyositis or pemphigus/pemphigoid. It is thought that most CLE in older populations is drug-induced, with drug-induced subacute cutaneous lupus erythematosus being the most common subtype. Management of CLE in older patients focuses on eliminating unnecessary medications known to induce CLE, and otherwise treatment proceeds similarly to that in younger patients, with a few special considerations.


A Comprehensive Algorithm for Management of Neuropathic Pain.
The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy. Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations. The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain. The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.


Prognostic importance of anaemia in HIV type-1-infected patients starting antiretroviral therapy: collaborative analysis of prospective cohort studies.
In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined. We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1,120 (9%) had moderate (male 8.0-<11.0 g/dl and female 8.0- < 10.0 g/dl) and 2,971 (25%) had mild (male 11.0- < 13.0 g/ dl and female 10.0- < 12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+ T-cell count, age, sex and other variables. During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17-1.73), for moderate anaemia 2.56 (2.07-3.18) and for severe anaemia 5.26 (3.55-7.81). Corresponding figures for progression to AIDS were 1.60 (1.37-1.86), 2.00 (1.66-2.40) and 2.24 (1.46-3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months. Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART.


[Carotinoid retinopathy. II. Electrophysiologic findings in 23 carotenoid-treated patients].
Twenty-three patients on long-term therapy (up to 14 years) with carotenoids (up to 336 g) were tested electrophysiologically. The EOG revealed a small but not significant delay of the light peak. Arden's ratio, however, was normal. The ERG was depressed as far as photopic activity was concerned. At low dosages of carotenoids the scotopic ERG amplitudes were found to be hypernormal, whereas at higher dosages the increase in amplitude during dark-adaptation was markedly delayed. There was a dose-dependent prolongation of b-wave implicit time and a dose-dependent reduction in oscillatory potentials. The marked effect on the b-wave and on the oscillatory potentials and the site of the retinal crystals permit the assumption that a mechanism of carotenoid action is located in the middle layers of the retina.


Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study.
To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study. Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later. Each SD increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular (p = 0.013), 110 mm3 smaller hippocampal (p = 0.013), 519 mm3 smaller occipital (p = 0.009), and 532 mm3 smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently. Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.


Self-care and yoga-academic-practice collaboration for occupational health.
High rates of stress and burnout among nurses and other health care providers justify the exploration of innovative interventions designed to reduce stress and promote self-care among this population. A growing body of evidence supports the physical and psychosocial benefits of yoga and suggests the potential for yoga to support self-care and reduce stress among health care providers. This article describes the formation of an academic-practice collaboration to use yoga as a model for occupational health and wellness among nurses employed at a tax-supported urban health system. In addition, recommendations for program sustainability over time are discussed.


Augmentation grafting of the maxillary sinus and simultaneous implant placement in patients with 3 to 5 mm of residual alveolar bone height.
This study assessed the efficacy of augmentation grafting of the maxillary sinus with simultaneous placement of dental implants in patients with less than 5 mm of alveolar crestal bone height in the posterior maxilla prior to grafting, although the procedure has traditionally been contraindicated based on empirical data. A total of 160 hydroxyapatite-coated implants was placed into 63 grafted maxillary sinuses in 63 patients whose crestal bone height in this region ranged from 3 to 5 mm. Patients were followed for 2 to 4 years after the placement of definitive prostheses. There were no postoperative sinus complications. Following uncovering of the implants at 9 months after surgery, there was no clinical or radiographic evidence of crestal bone loss around the implants. Histologic examination of bone cores from the grafted sites revealed successful integration and a high degree of cellularity. All patients maintained stable implant prostheses during follow-up. These findings indicate that the single-step procedure is a feasible option for patients with as little as 3 mm of alveolar bone height prior to augmentation grafting, utilizing hydroxyapatite-coated implants and autogenous bone.


Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion.
Gap-junctional communication coordinates the behavior of individual cells in arterioles. Gap junctions are formed by connexins 40 (Cx40), Cx43, Cx37, and Cx45 in the vasculature. Previously, we have shown that lack of Cx40 impairs conduction of dilatory signals along arterioles. Herein, we examined whether hypertension is present in conscious animals and whether this is a direct effect or due to secondary mechanisms. Mean arterial pressure was elevated by 20-25 mmHg in conscious Cx40-deficient mice (Cx40(-/-)) compared with wild-type controls in both sexes. Differences in heart rate were not observed. Blockade of NO synthase increased pressure equally in both genotypes. Conversely, the angiotensin AT(1)-receptor antagonist, candesartan, decreased pressure to similar extents in Cx40(-/-) and wild-type mice. Acetylcholine and sodium nitroprusside (0.05-15 nmol) were equally potent and effective in decreasing pressure and inducing dilatory responses in the microcirculation. However, in contrast to wild type, Cx40(-/-) arterioles exhibited spontaneous, irregular vasomotion leading temporarily to complete vessel closure. We conclude that loss of Cx40 is associated with hypertension independent of the action of angiotensin II. It is also not related to an altered efficacy of NO or other endothelial dilators. However, the observed irregular vasomotion suggests that peripheral vascular resistance is affected.


Vpx proteins of SIVmac239 and HIV-2ROD interact with the cytoskeletal protein alpha-actinin 1.
vpx genes of human immunodeficiency virus type 2 (HIV-2) and immunodeficiency viruses from macaques (SIVmac), sooty mangabeys (SIVsm) and red-capped mangabeys (SIVrcm) encode a 112 aa protein that is packed into virion particles via interaction with the p6 domain of p55(gag). Vpx localizes to the nucleus when expressed in the absence of other viral proteins. Moreover, Vpx is necessary for efficient nuclear import of the pre-integration complex (PIC) and critical for virus replication in quiescent cells, such as terminally differentiated macrophages and memory T cells. Vpx does not contain sequence elements that are homologous to previously characterized nuclear localization signals (NLSs). Therefore, it is likely that Vpx-dependent import of the PIC is mediated by interaction of Vpx with cellular proteins that do not belong to the classical import pathways. By using a yeast two-hybrid screen, alpha-actinin 1, a cytoskeletal protein, was identified to interact with SIVmac239 Vpx. Interestingly, deletion of the proline-rich C-terminal domain (aa 101-112) of Vpx, which is important for nuclear localization, resulted in loss of interaction with alpha-actinin 1. These findings suggest that the interaction with alpha-actinin 1 may play an important role in the transport of Vpx to the nucleus and in Vpx-mediated nuclear import of the PIC.


Sociology's misfortune: disciplines, interdisciplinarity and the impact of audit culture.
This paper is about tendencies to the subversion of sociology as a discipline. It connects external factors of the wider socio-political environment of higher education in the UK, especially those associated with the audit culture and new systems of governance, with the internal organization of the discipline. While the environment is similar for all social science subjects, the paper argues that there are specific consequences for sociology because of characteristics peculiar to the discipline. The paper discusses these consequences in terms of the changing relationship between sociology and the growing interdisciplinary area of applied social studies as a form of 'mode 2 knowledge'. It argues that while sociology 'exports' concepts, methodologies and personnel it lacks the internal disciplinary integrity of other 'exporter' disciplines, such as economics, political science and anthropology. The consequence is an increasingly blurred distinction between sociology as a discipline and the interdisciplinary area of applied social studies with a potential loss of disciplinary identity. The paper concludes with a discussion of how this loss of identity is associated with a reduced ability to reproduce a critical sensibility within sociology and absorption to the constraints of audit culture with its preferred form of mode 2 knowledge.


LncRNA HMlincRNA717 is down-regulated in non-small cell lung cancer and associated with poor prognosis.
Long non coding RNAs (lncRNAs) have emerged recently as major players in tumor biology and may be used for cancer diagnosis, prognosis, and potential therapeutic targets. The lncRNA HMlincRNA717, a newly identified lncRNA, was demonstrated to be down-regulated in gastric cancer. However, little is known about its role in non small cell lung cancer (NSCLC). Expression of lncRNA HMlincRNA717 in tumor and their matched non-tumor tissues was determined by quantitative real-time PCR (qRT-PCR) in NSCLC patients. Then, we analyzed the potential relationship between lncRNA HMlincRNA717 expression levels in tumor tissues and clinicopathological features of NSCLC, and clinical outcome. lncRNA HMlincRNA717 expression level was significantly decreased in NSCLC tissues in comparison to adjacent non-tumor tissues. It was also proved that HMlincRNA717 expression was to be associated with NSCLC histological grade, and lymph node metastasis. In addition, survival analysis proved that down-regulated HMlincRNA717 expression was associated with poor overall survival of NSCLC patients. Multivariate survival analysis also proved that HMlincRNA717 was an independent prognostic factor for NSCLC patients. The present study showed the down-regulation of HMlincRNA717 and its association with tumor progression in human NSCLC. It also provided that HMlincRNA717 expression was an independent prognostic factor for patients with NSCLC, which might be a potential prognostic biomarker and therapeutic target for NSCLC.


Causes, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China.
Drug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited. All 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied. A total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs. 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs. 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs. 18/39, p=0.031). Most cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable.


G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35.
It is widely appreciated that G protein-coupled receptors have been the most successfully exploited class of targets for the development of small molecule medicines. Despite this, to date, less than 15% of the non-olfactory G protein-coupled receptors in the human genome are the targets of a clinically used medicine. In many cases, this is likely to reflect a lack of understanding of the basic underpinning biology of many G protein-coupled receptors that are not currently in the spotlight, as well as a paucity of pharmacological tool compounds and appropriate animal models to test in vivo function of such G protein-coupled receptors in both normal physiology and in the context of disease. 'Open Innovation' arrangements, in which pharmaceutical companies and public-private partnerships provide wider access to tool compounds identified from ligand screening programmes, alongside enhanced medicinal chemistry support to convert such screening 'hits' into useful 'tool' compounds will provide important routes to improved understanding. However, in parallel, novel approaches to define and fully appreciate the selectivity and mode of action of such tool compounds, as well as better understanding of potential species orthologue variability in the pharmacology and/or signalling profile of a wide range of currently poorly understood and understudied G protein-coupled receptors, will be vital to fully exploit the therapeutic potential of this large target class. I consider these themes using as exemplars two G protein-coupled receptors, free fatty acid receptor 2 and GPR35.


Defocus Map Estimation From a Single Image Based on Two-Parameter Defocus Model.
Defocus map estimation (DME) is highly important in many computer vision applications. Nearly, all existing approaches for DME from a single image are based on a one-parameter defocus model, which does not allow for the variation of depth over edges. In this paper, a novel two-parameter model of defocused edges is proposed for DME from a single image. We can estimate the defocus amounts for each side of the edges through this proposed model, and the confidence that the edge is a pattern edge, where the depth remains the same over the edge, can be generated. Then, we modify the TV-L1 algorithm for structure-texture decomposition by taking advantage of this confidence to eliminate pattern edges while preserving structural ones. Finally, the defocus amounts estimated at the edge positions are used as initial values, and the structure component is employed as a guidance in the following Laplacian matting procedure to avoid the influence of pattern edges on the final defocus map. Experiment results show that the proposed method can effectively eliminate the influence of pattern edges compared with the state-of-art method. Furthermore, the estimated defocus map is feasible in applications of depth estimation and foreground/background segmentation.


Serological surveillance for Tahyna virus (California encephalitis orthobunyavirus, Peribunyaviridae) neutralizing antibodies in wild ungulates in Austria, Hungary and Romania.
A serosurvey for Tahyna virus (TAHV), a mosquito-borne California encephalitis orthobunyavirus (Peribunyaviridae) endemic to Europe, was performed to estimate the activity of TAHV on a broad geographic scale. Sera from wild boar (Sus scrofa), roe deer (Capreolus capreolus) and red deer (Cervus elaphus) were collected from Austria, Hungary and Romania. Samples were tested for neutralizing antibodies against TAHV using a virus microneutralization assay. The results demonstrate that TAHV transmission to mammals is widespread in Europe, particularly in the wild boar population where the mean rate of seroconversion is 15.2%.


Biocatalytic carbon capture via reversible reaction cycle catalyzed by isocitrate dehydrogenase.
The practice of carbon capture and storage (CCS) requires efficient capture and separation of carbon dioxide from its gaseous mixtures such as flue gas, followed by releasing it as a pure gas which can be subsequently compressed and injected into underground storage sites. This has been mostly achieved via reversible thermochemical reactions which are generally energy-intensive. The current work examines a biocatalytic approach for carbon capture using an NADP(H)-dependent isocitrate dehydrogenase (ICDH) which catalyzes reversibly carboxylation and decarboxylation reactions. Different from chemical carbon capture processes that rely on thermal energy to realize purification of carbon dioxide, the biocatalytic strategy utilizes pH to leverage the reaction equilibrium, thereby realizing energy-efficient carbon capture under ambient conditions. Results showed that over 25 mol of carbon dioxide could be captured and purified from its gas mixture for each gram of ICDH applied for each carboxylation/decarboxylation reaction cycle by varying pH between 6 and 9. This work demonstrates the promising potentials of pH-sensitive biocatalysis as a green-chemistry route for carbon capture.


68 Ga-PSMA Uptake in Solar Elastosis.
68 Ga-prostate specific membrane antigen (PSMA) PET/CT scan for staging revealed increased 68 Ga-PSMA uptake in solar elastosis in a patient with prostate cancer. Solar elastosis is a degenerative condition of elastic tissue in the dermis caused by prolonged sun exposure. A few studies have demonstrated 68 Ga-PSMA uptake in cutaneous lesions. This case illustrates another instance of a benign cutaneous lesion accompanied by increased 68 Ga-PSMA uptake.


CD40 ligation of human keratinocytes inhibits their proliferation and induces their differentiation.
While CD40-CD40 ligand interactions are known to regulate B cell proliferation and differentiation, much less is known about the role this receptor plays on other cell types, especially those of nonhemopoietic origin. We report here that CD40 is expressed in normal human epidermis in situ, especially on the basal cell layer, and that it is maintained on cultured epidermal basal cells. Immunoprecipitation and SDS-PAGE analysis confirms that CD40 expressed by epidermal basal cells is immunologically related to the B cell CD40. IFN-gamma up-regulates CD40 expression on cultured keratinocytes, whereas other proinflammatory cytokines, such as IL-1 or TNF-alpha, have little effects. Using CD40-ligand-transfected L cells (CD40Lc), we demonstrated that CD40 triggering results in an enhanced secretion of both IL-8 and TNF-alpha by cultured epidermal basal cells, suggesting that CD40-CD40L interactions may play a role in amplifying the cutaneous inflammatory reactions. More importantly, we found that keratinocyte proliferation was significantly inhibited when the cells were grown on CD40Lc, as compared with CD32-transfected, or nontransfected, L cells. This inhibitory effect can be reversed substantially by pretreatment of keratinocytes with anti-CD40 mAb. In addition, inhibition of proliferation could be obtained by adding a soluble form of CD40 ligand to the keratinocyte cultures. Interestingly, inhibition of keratinocyte proliferation on CD40Lc correlates with differentiation of the cells, as assessed by morphologic analysis and increased profilaggrin content. Collectively, these results demonstrate that CD40 is expressed and functional on human epidermal basal cells and that, on these cells, CD40 ligation may be a signal for limitation of cell growth and induction of differentiation.


Evaluation of the effect of berry extracts on carboxymethyllysine and lysine in ultra-high temperature treated milk.
Both the Maillard reaction (MR) and thermal treatment influence the nutritional value of milk. In this paper, the capability of polyphenolic berry extract (PBE) to inhibit MR in an ultra-high temperature (UHT) treated milk was investigated. Total polyphenol content and antioxidant capacity of blueberry (BE) and raspberry extracts (RE) were also tested. A gas chromatography-mass spectrometry (GC-MS) method was developed to monitor the MR product N ε-(carboxymethyl)-L-lysine (CML) and L-lysine (LYS). PBE was added to milk at 0.05 and 0.1% w/v prior to UHT processing. Data revealed that formation of CML was significantly reduced (23.4 ± 5.1%) by addition of 0.1% w/v BE. The final concentrations of LYS measured following the addition of PBE prior to thermal treatment were statistically similar to the control milk which was not subjected to thermal processing. Additionally, the metabolic profile of milk samples was investigated by GC-MS and visualised using 'FancyTiles'.


GenoType MTBDRplus assay for molecular detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis strains and clinical samples.
The purpose of this study was to evaluate the GenoType MTBDRplus assay (Hain Lifescience GmbH, Nehren, Germany) for its ability to detect resistance to rifampin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis clinical strains and directly in clinical samples. A total of 62 clinical strains characterized with the Bactec 460TB system were included. For the INH-resistant strains, the MIC was measured and sequencing was performed. Sixty-five clinical samples from 28 patients (39 smear-positive samples and 26 smear-negative samples) were also tested directly. The corresponding isolates of the clinical specimens were studied with the Bactec 460TB system. The overall rates of concordance of the MTBDRplus assay and the Bactec 460TB system for the detection of RIF and INH susceptibility in clinical strains were 98.3% (61/62) and 79% (49/62), respectively. The rate of concordance between the Bactec 460TB system and the MTBDRplus test for the detection of INH resistance in the group of 27 strains with low-level resistance was 62.9% (17/27), and that for the detection of INH resistance in the group of 21 strains with high-level resistance was 85.71% (18/21). Valid test results were obtained for 78.45% (51/65) of the clinical samples tested. The rates of concordance between both assays for the detection of drug resistance in these samples were 98% (50/51) for RIF and 96.2% (49/51) for INH. Taking into account only one sample per patient, the overall rate of concordance between both tests was 92.85% (26/28). The GenoType MTBDRplus assay is easy to perform and is a useful tool for the management of tuberculosis, as it allows the detection of resistance to RIF and INH in M. tuberculosis strains and also in clinical samples.


A comparison of patient position displacements from body surface laser scanning and cone beam CT bone registrations for radiotherapy of pelvic targets.
Optical surface detection has attractive features as a mean in radiotherapy for patient positioning tasks such as set-up, monitoring and gating. To aid in hitting radiotherapy targets the correlation between detected surface displacements and internal structure displacements is crucial. In this study, we compare set-up displacements derived from a body surface laser scanning (BSLS) system to displacements derived from bone registrations with a cone beam computed tomography (CBCT) system in order to quantify the accuracy and applicability of BSLS for fractionated treatments in the pelvic region. Displacements from concurrent BSLS and CBCT registrations were compared for 40 patients treated in the pelvic region for a total of 170 set-ups. Surface data captured by BSLS at the first treatment fraction (BSLSref) was used as main reference for the BSLS system, while bony structures from the planning CT were used as a reference for the CBCT method. As comparison, the patient outline extracted from the planning CT was used as BSLS reference (CTref). The displacements detected by the CBCT system (skin-marks-only) was also used for comparison. The mean differences (± 1 SD) between the BSLS and CBCT displacements were -0.01 (± 0.17) cm, 0.00 (± 0.21) cm and 0.01 (± 0.17) cm in the lateral, longitudinal and vertical directions, respectively. The median length of the difference was 0.26 cm (0.24-0.29 cm, 95% CI). The median of the difference between CBCT and BSLS displacements based on CTref was 0.37 cm (0.30-0.39 cm) and the median for skin-marks-only was 0.38 cm (0.34-0.42 cm). The BSLS system is a good supplement to the CBCT system for accurate set-up for fractions when no CBCT is deemed necessary for pelvic targets. Inter-fractional skin movement in relation to bone was estimated to be 0.2 cm in the lateral (X), longitudinal (Y) and vertical direction (Z), respectively.


Analysis of signs and pathology of H5N1-infected ducks from the 2010-2011 Korean highly pathogenic avian influenza outbreak suggests the influence of age and management practices on severity of disease.
We compared the clinical signs, histopathological lesions and distribution of viral antigens among infected young (meat-type) and older (breeder) ducks that were naturally infected with the highly pathogenic avian influenza (HPAI) virus during the 2010-2011 Korean outbreak. The meat-type ducks had a high mortality rate (30%) and showed severe neurological signs such as head tremors and paresis. In contrast, HPAI-infected breeder ducks had minimal clinical signs but a decreased egg production rate. The histopathological characteristics of infected meat-type ducks included necrotic lesions of heart and brain, which may have primarily contributed to the high mortality rate. In contrast, the breeder ducks only presented necrotic splenitis, and viral antigens were only detected in the trachea, lungs and spleen. Younger ducks had a high viral titre in the organs, high levels of viral shedding and a high mortality rate after experimental HPAI virus infection. Compared to the breeder ducks, the meat-type ducks were raised in smaller farms that had poor quarantine and breeding facilities. It is therefore possible that better biosecurity in the breeder farms could have reduced the infection dose and subsequently the severity of the disease. Thus, age and management may be the influencing factors for HPAI susceptibility in ducks.


Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.
To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A(1c) (HbA(1c)) > or = 6.5 and < or = 10%] on metformin monotherapy. After a metformin dose titration/stabilization period (> or = 1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA(1c) changes from baseline at Week 52 using a per-protocol approach. From a mean baseline of 7.5%, HbA(1c) changes from baseline were -0.67% at Week 52 in both groups, confirming non-inferiority. The proportions achieving an HbA(1c) < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were -0.56 mmol/l (-10.0 mg/dl) and -0.42 mmol/l (-7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated patients compared with 50 events in sitagliptin-treated patients. Sitagliptin led to weight loss (change from baseline =-1.5 kg) compared with weight gain (+1.1 kg) with glipizide [between-treatment difference (95% confidence interval) =-2.5 kg (-3.1, -2.0); p < 0.001]. In this study, the addition of sitagliptin compared with glipizide provided similar HbA(1c)-lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.


Imaging features of uterine and ovarian fibromatosis in Nevoid Basal Cell Carcinoma Syndrome.
Gorlin-Goltz Syndrome also known as Nevoid Basal Cell Carcinoma Syndrome is an autosomal dominant multisystem disorder. It is characterized by basal cell carcinomas, odontogenic keratocysts, skeletal abnormalities and in a minority of female patients bilateral calcified ovarian fibromas. It is challenging to radiologically assess ovarian fibromas as they have similar imaging patterns to some malignant ovarian lesions. However, it is vitally important to differentiate between benign and malignant lesions to determine patients' suitability for fertility-sparing surgery. This report describes a case of a 25 year-old patient with Gorlin-Goltz Syndrome and bilateral ovarian fibromas.


The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.
PRDM (PRDI-BF1 and RIZ domain containing) proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines. PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.


The torments of the cohesin ring.
Cohesin is a ring-shaped protein complex which comprises the Smc1, Smc3 and Scc1 subunits. It topologically embraces chromosomal DNA to connect sister chromatids and stabilize chromatin loops. It is required for proper chromosomal segregation, DNA repair and transcriptional regulation. We have recently reported that cohesin rings can adopt a "collapsed" rod-like conformation which is driven by the interaction between the Smc1 and Smc3 coiled coil arms and is regulated by post-translational modifications. The "collapsed" conformation plays a role in cohesin ring assembly and its loading on the DNA. Here we speculate about the mechanism of cohesin's conformational transitions in relation to its loading on the DNA and draw parallels with other Smc-like complexes.


Percutaneous vertebroplasty for osteoporotic compression fracture: multivariate study of predictors of new vertebral body fracture.
To investigate the risk factors and relative risk of new compression fractures following vertebroplasty. Initially, we enrolled 104 consecutive patients with vertebral compression fractures caused by osteoporosis. A total of 83 of the 104 patients visited our hospital for follow-up examinations for more than 4 weeks after vertebroplasty. Logistic regression analysis of the data obtained from these 83 patients was used to determine relative risks of recurrent compression fractures, using 13 different factors. We identified 59 new fractures in 30 of the 83 patients: 41 new fractures in vertebrae adjacent to treated vertebrae; and 18 new fractures in vertebrae not adjacent to treated vertebrae. New fractures occurred in vertebrae adjacent to treated vertebrae significantly more frequently than in vertebrae not adjacent to treated vertebrae. Only cement leakage into the disk was a significant predictor of new vertebral body fracture after vertebroplasty (odds ratio = 4.633). None of the following covariates were associated with increased risk of new fracture: age, gender, bone mineral density, the number of vertebroplasty procedures, the number of vertebrae treated per procedure, the cumulative number of vertebrae treated, the presence of a single untreated vertebra between treated vertebrae, the presence of multiple untreated vertebrae between treated vertebrae, the amount of bone cement injected per procedure, the cumulative amount of bone cement injected, cement leakage into the soft tissue around the vertebra, and cement leakage into the vein.


[Results of combined myocardial scintigraphy and radionuclide ventriculography before and after transluminal coronary angioplasty of critical coronary artery stenoses].
This study compares exercise radionuclide ventriculography (RNVG) and exercise myocardial scintigraphy with 201Tl (MSC) both computed trisectorially. 137 patients before and after transluminal angioplasty (TCA) were investigated. While specificity equivalent was set at 90% for both methods (10% percentile of the controls [n = 29]) overall sensitivity for RNVG was 79% (n = 86) and for MSC 78% (n = 98). Sensitivity of RNVG for lesions of the posterior wall was lower than for the anterior wall: LAD stenoses 83% (n = 46), RCA stenoses 71% (n = 17), and LCX stenoses 63% (n = 8). Sensitivity of MSC presents only a slight difference between anterior and posterior wall lesions: LAD stenoses 78% (n = 51), RCA stenoses 73% (n = 22), RCX stenoses 100% (n = 8). Reproducibility of pathological findings before and after non-successful TCA and the determination of the stenosed vessel was slightly better with MSC than with RNVG. Functional improvement after a successful TCA is predictable by MSC, whereas RNVG documents the functional improvement.


Perspective: transforming chronic care for older persons.
The size and impending morbidity of the aging baby boom generation could soon overwhelm the U.S. health care system. Transforming chronic care for older persons to avert this calamity will require rapid increases in the number of physicians who are skilled in providing chronic care and prompt adoption of new models for providing high-quality, cost-effective chronic care. The authors propose a new approach for attaining these objectives, recommending that today's leaders of academic medicine help transform geriatrics into a collaborative discipline of clinicians with advanced skills in leading educational, organizational, and research-related initiatives; that they support the collaboration of geriatrics with primary care and specialty disciplines in preparing physicians to practice effectively in new models of chronic care for older persons; and that they energetically promote rigorous training in chronic care at all levels of medical education. Implementing this strategy would require firm commitment by the Association of American Medical Colleges, specialty boards, accrediting organizations, academic institutions, the Centers for Medicare and Medicaid Services, legislators, and business leaders. Although garnering such support would be challenging and controversial, this approach could leverage the expertise of geriatric educator-leaders to help transform chronic care in the United States and to make high-quality, cost-effective chronic care accessible to most chronically ill Americans within 20 years.


In vivo analysis of tumor vascularization in the rat.
By using transparent chambers in rats, we have directly observed tumor-induced neovascularization in the early stage and the formation of intricate networks in Yoshida rat ascites hepatoma AH109A and Sato lung carcinoma at high magnification. We counted branching point numbers per unit area in the microvascular network with and without tumors in order to clarify the sites from which new vascular sprouts originate. Branching point number per unit area in normal tissue was 13.6 +/- 7.4/0.1 mm2 in the field near a terminal arteriole, and 12.9 +/- 7.3/0.1 mm2 in the field distant from a terminal arteriole. There was no significant difference between these two fields in the normal vascular network. On the other hand, in the tumor vascular network, the branching point number in the field near a terminal arteriole was 50.4 +/- 12.6/0.1 mm2, and 30.1 +/- 11.5/0.1 mm2 in the field distant from a terminal arteriole. The difference is highly significant (P less than 0.001). The frequency with which new capillaries originated from veins and venules was very low. We concluded from these results that the position from which tumor vessels originated was usually the terminal portion of a terminal arteriole.


Betel-Nut Chewing Increases Difficulty in Tracheal Intubation.
Betel-nut chewing (BC) causes oral submucous fibrosis (OSF), and this leads to difficult tracheal intubation (DI). Unanticipated DI was reported in chewers with apparently normal preoperative airway evaluations (PAEs). This analysis aims to investigate whether BC is an independent risk on DI besides the common DI risk prediction factors. After the approval of Institutional Review Board and the written informed consent were obtained, 2,682 patients were enrolled in a cohort. PAEs, intubation difficulty scale (IDS), intubation time, and perceived DI were recorded prospectively. All 805 male patients received classical intubation, 307 with BC and 498 without BC were analyzed. Data were analyzed by Student's t-test and chi-square test. Stepwise logistic regression was performed to identify BC effects on IDS adjusting for related factors with WEKA (Waikato Environment for Knowledge Analysis; Machine Learning Group at the University of Waikato, Hamilton, New Zealand). Fewer BC patients were Cormack-Lehane (CL) grade I (38.9% vs. 47.6%) or IDS degree 〞Easy〞 (24.8% vs. 33.5%). Compared with IDS degree 〞Easy〞, patients in the BC group had a significantly higher odds ratio (OR) for 〞Slight + Moderate-Major〞 degree than in the non-BC group (adjusted OR, 1.75; 95% CI, 1.15-2.68). Compared with CL grade I, patients with BC was an independent risk for II (adjusted OR, 1.53; 95% CI, 1.02-2.32) and IV (adjusted OR, 3.25; 95% CI 1.01-10.49). Otherwise, patient's age ≥ 46 and the presence of teeth were also significant risk factors for IDS degree 〞Slight + Moderate-Major〞. BC increased not only the tracheal intubation difficulty in patients with apparent OSF but also in patients with PAEs. BC is an independent risk factor besides the commonly used DI prediction factors. We suggest physicians operating on BC patients to be better prepared for DI.


An index for estimation of oxygen consumption in rat heart by hemodynamic parameters.
To find a suitable index for the estimation of O2 consumption of rat hearts by use of hemodynamic parameters, isolated hearts were perfused under different working conditions. Coronary flow, arteriovenous O2 difference, cardiac output, and ventricular pressure curve were recorded and continuously fed into a computer. O2 consumption and different hemodynamic parameters such as dP/dtmax, maximum ventricular pressure, pressure-time integral, and heart rate were computed on-line. With the use of these data of 64 different steady states, numerous formulas containing hemodynamic parameters were tested with respect to their ability to predict O2 consumption. The best fit of the data was obtained by a linear combination of the products of rate times dP/dtmax and rate times pressure-time integral of one beat (r = 0.993). Indexes containing approximations of wall stress were not found to improve the predictive ability.


[Data on the establishment of group MPEL for natural and modified colophony in the workplace air].
The results of the toxico-hygienic study of 12 types of rosins are presented. It is established that these compounds are moderately hazardous products with slightly pronounced local irritating and skin resorptive effect accompanied by moderate sensitizing activity. Rosins' cumulative characteristics are not manifested at the lethal level. Lim(ac) are within 110-193 mg/m3 and Lim(ch) within 38.0-42.0 mg/m3. The analyzed types of rosins possess polytropic general toxicity with primary impact on the functional state of liver, kidneys and the nervous system. The above studies have enabled one to recommend group MAC for rosins in the workplace air at the level of 4 mg/m3 and their marking as allergens.


Activation of Transient Receptor Potential Vanilloid 1 Channels in the Nucleus of the Solitary Tract and Activation of Dynorphin Input to the Median Preoptic Nucleus Contribute to Impaired BAT Thermogenesis in Diet-Induced Obesity.
The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neurons that project to the MnPO. Many of the neurons in the LPBd that expressed c-fos during cold challenge were dynorphinergic. In HFD rats, nanoinjections of the κ opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), in the MnPO rescued the impaired BAT SNA and thermogenic responses to cold. These data suggest that HFD increases the content of endogenous ligands of TRPV1 in the NTS, which increases the drive to LPBd neurons that in turn release dynorphin in the MnPO to impair activation of BAT.


Nuclear magnetic resonance of heme protein crystals. General aspects.
A new technique capable of determining the static and dynamic structures of heme protein crystals is reported. It is shown that microcrystals of a variety of paramagnetic heme proteins, suspended in approximately 90% saturated (NH4)2SO4, may be perfectly aligned by an intense static external magnetic field, H0, due to the large anisotropy in the magnetic susceptibility of the protein caused by the paramagnetic center. Myoglobin from sperm whale (Physeter catodon) was isotopically enriched at the C epsilon methyl groups of methionine residues 55 and 131 with either 13C or 2H and studied in the crystalline solid state by 2H-quadrupole echo and 13C-Fourier transform nuclear magnetic resonance spectroscopy. It was found that suspensions of both high (S = 5/2) and low (S = 1/2) spin ferric forms of the labeled protein were ordered, the axis of ordering being approximately perpendicular to the low temperature minimum g tensor valve, even though upper Kramers levels are populated at room temperature. The paramagnetic CoII derivative "coboglobin" showed similar ordering behavior, but the diamagnetic carboxymyoglobin was unaffected. The magnetic ordering method permits the recording of "single crystal" NMR spectra from microcrystalline arrays of proteins which cannot be prepared in large enough form (approximately 1 cm3) for single crystal NMR spectroscopy and thereby allows the resolution and assignment of numerous single atom sites in the crystalline solid state. The information from a "single crystal" NMR spectrum combined with that obtained on the crystal powder allows for the direct determination of (i) the spatial orientation of the particular labeled residue within the protein crystal and (ii) the rates and types of side chain motion. Resonances were assigned by spin label broadening experiments and by use of existing x-ray data to predict 2H-NMR spectra. This new technique opens up the possibility of determining directly the dynamic structure of protein crystals and of comparing the structures of proteins in the crystalline solid state with that in solution and is applicable to other heme proteins, e.g. catalase.


Maternal attitudes and behaviours differentially shape infant early life experience: A cross cultural study.
Early life environments afford infants a variety of learning opportunities, and caregivers play a fundamental role in shaping infant early life experience. Variation in maternal attitudes and parenting practices is likely to be greater between than within cultures. However, there is limited cross-cultural work characterising how early life environment differs across populations. We examined the early life environment of infants from two cultural contexts where attitudes towards parenting and infant development were expected to differ: in a group of 53 mother-infant dyads in the UK and 44 mother-infant dyads in Uganda. Participants were studied longitudinally from when infants were 3- to 15-months-old. Questionnaire data revealed the Ugandan mothers had more relational attitudes towards parenting than the mothers from the UK, who had more autonomous parenting attitudes. Using questionnaires and observational methods, we examined whether infant development and experience aligned with maternal attitudes. We found the Ugandan infants experienced a more relational upbringing than the UK infants, with Ugandan infants receiving more distributed caregiving, more body contact with their mothers, and more proximity to mothers at night. Ugandan infants also showed earlier physical development compared to UK infants. Contrary to our expectations, however, Ugandan infants were not in closer proximity to their mothers during the day, did not have more people in proximity or more partners for social interaction compared to UK infants. In addition, when we examined attitudes towards specific behaviours, mothers' attitudes rarely predicted infant experience in related contexts. Taken together our findings highlight the importance of measuring behaviour, rather than extrapolating expected behaviour based on attitudes alone. We found infants' early life environment varies cross-culturally in many important ways and future research should investigate the consequences of these differences for later development.


Type-A CpG oligonucleotides activate exclusively porcine natural interferon-producing cells to secrete interferon-alpha, tumour necrosis factor-alpha and interleukin-12.
Natural interferon-producing cells (NIPC), also referred to as immature plasmacytoid dendritic cells (PDC), constitute a small population of leucocytes secreting high levels of type I interferons in response to certain danger signals. Amongst these signals are those from DNA containing unmethylated CpG motifs. The present work demonstrated that the CpG oligonucleotides (CpG-ODN) 2216, D32 and D19 induce high amounts of interferon-alpha (IFN-alpha), tumour-necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12 in porcine peripheral blood mononuclear cells (PBMCs). Swine workshop cluster 3 (SWC3)1ow CD4high cells, with high IL-3-binding activity, representing NIPC, were the exclusive cytokine-producing cells responding to the CpG-ODN. These cells did not express CD6, CD8 or CD45RA. Importantly, monocyte-derived DC did not respond to CpG-ODN by secretion of IFN-alpha or TNF-alpha or by the up-regulation of costimulatory molecule expression. CpG-ODN up-regulated MHC class II and CD80\86 expression on the NIPC, but were unable to promote NIPC survival. Interestingly, certain CpG-ODN, incapable of inducing NIPC to secrete IFN-alpha or up-regulate MHC class II and CD80\86, did promote NIPC viability. Taken together, the influence of CpG-ODN on porcine NIPC, monocytes and myeloid DCs relates to that observed with their human equivalents. These results represent an important basis for the application of CpG-ODN as adjuvants for the formulation of novel vaccines and demonstrate the importance of the pig as an alternative animal model for this approach.


Neuro-Inspired Reinforcement Learning to Improve Trajectory Prediction in Reward-Guided Behavior.
Hippocampal pyramidal cells and interneurons play a key role in spatial navigation. In goal-directed behavior associated with rewards, the spatial firing pattern of pyramidal cells is modulated by the animal's moving direction toward a reward, with a dependence on auditory, olfactory, and somatosensory stimuli for head orientation. Additionally, interneurons in the CA1 region of the hippocampus monosynaptically connected to CA1 pyramidal cells are modulated by a complex set of interacting brain regions related to reward and recall. The computational method of reinforcement learning (RL) has been widely used to investigate spatial navigation, which in turn has been increasingly used to study rodent learning associated with the reward. The rewards in RL are used for discovering a desired behavior through the integration of two streams of neural activity: trial-and-error interactions with the external environment to achieve a goal, and the intrinsic motivation primarily driven by brain reward system to accelerate learning. Recognizing the potential benefit of the neural representation of this reward design for novel RL architectures, we propose a RL algorithm based on [Formula: see text]-learning with a perspective on biomimetics (neuro-inspired RL) to decode rodent movement trajectories. The reward function, inspired by the neuronal information processing uncovered in the hippocampus, combines the preferred direction of pyramidal cell firing as the extrinsic reward signal with the coupling between pyramidal cell-interneuron pairs as the intrinsic reward signal. Our experimental results demonstrate that the neuro-inspired RL, with a combined use of extrinsic and intrinsic rewards, outperforms other spatial decoding algorithms, including RL methods that use a single reward function. The new RL algorithm could help accelerate learning convergence rates and improve the prediction accuracy for moving trajectories.