Elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for squamous cell carcinoma of the thoracic esophagus.
There are some reports indicating that prophylactic three-field lymph node dissection for esophageal cancer can lead to improved survival. But the benefit of ENI in CRT for thoracic esophageal cancer remains controversial. The purpose of the present study is to retrospectively evaluate the efficacy of elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for thoracic esophageal cancer. Patients with squamous cell carcinoma (SCC) of the thoracic esophagus newly diagnosed between February 1999 and April 2001 in our institution was recruited from our database. Definitive chemoradiotherapy consisted of two cycles of cisplatin/5FU repeated every 5 weeks, with concurrent radiation therapy of 60 Gy in 30 fractions. Up to 40 Gy radiation therapy was delivered to the cervical, periesophageal, mediastinal and perigastric lymph nodes as ENI. One hundred two patients were included in this analysis, and their characteristics were as follows: median age, 65 years; male/female, 85/17; T1/T2/T3/T4, 16/11/61/14; N0/N1, 48/54; M0/M1, 84/18. The median follow-up period for the surviving patients was 41 months. Sixty patients achieved complete response (CR). After achieving CR, only one (1.0%; 95% CI, 0-5.3%) patient experienced elective nodal failure without any other site of recurrence. In CRT for esophageal SCC, ENI is effective for preventing regional nodal failure. Further evaluation of whether ENI leads to an improved overall survival is needed.


Disparity in infection control practices for multidrug-resistant Enterobacteriaceae.
There is a lack of empiric evidence regarding the optimal approach to controlling the transmission of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) and carbapenem-resistant Enterobacteriaceae (CRE). In this context, we expect that infection control practices for these organisms vary widely between hospitals. A survey examining infection control practices for ESBL-E and CRE was distributed to 6 academic and 9 community hospitals in Toronto, Canada. All hospitals responded to the survey. Among 15 hospitals in 1 geographic area, 8 different approaches to the management of ESBL-E were utilized. There was wide variation in the use infection control practices including admission screening (53% and 53%), contact precautions (53% and 100%), and isolation (60% and 100%) for ESBL-E and CRE, respectively. Of hospitals performing admission screening, 75% used risk factor-based screening for ESBL-E and CRE. Even within a single geographic area, there is wide variation in infection control strategies to contain or control ESBL-E and CRE. These results are concerning given evidence that a coordinated approach may be required to prevent or limit the emergence of CRE.


Assessment of copper and zinc levels in fish from freshwater ecosystems of Moldova.
The aim of this work was to assess the levels of copper and zinc in fish from the main freshwater ecosystems of Moldova, in relation with species, habitat, age, sex, season, and development stage. Fish from Cyprinidae and Percidae families (Cyprinus carpio, Carassius auratus gibelio, Rutilus rutilus heckeli, Abramis brama, Aristichthys nobilis, Hypophtalmichthys molitrix, Sander lucioperca) were collected from Prut and Dniester rivers, Cuciurgan, Dubasari, and Costesti-Stanca reservoirs, and ponds of farms in the Dniester delta. The Cu and Zn content of fish tissues (skeletal muscles, liver, gonads, gills, skin, and scales) was determined by flame atomic absorption spectrophotometer AAS-3, of water by graphite furnace HGA 900 of AAnalist 400. The level of heavy metals accumulation in muscles of immature fish follows their dynamics in water. The highest concentration of zinc was registered in the gonads of mature fish, and of copper-in the liver. The lowest Cu and Zn contents were recorded in the muscles and are in the United Nations Food and Agriculture Organization safety-permissible levels for human consumption. Cu and Zn contents in muscles of fish depend on specimen age. Their level in fish gonads was sharply increasing during pre-spawning period. During the early developmental stages, the metal concentration in fish eggs and larvae varies within wide limits, but the accumulation pattern is similar in the investigated species. The fish represent one of the most indicative factors for the estimation of trace metals pollution in freshwater systems and this is important not only for monitoring purposes, but also for the fish culture ones.


Abrogation of CC Chemokine Receptor 9 Ameliorates Ventricular Electrical Remodeling in Mice After Myocardial Infarction.
Introduction: Myocardial infarction (MI) triggers structural and electrical remodeling. CC chemokine receptor 9 (CCR9) mediates chemotaxis of inflammatory cells in MI. In our previous study, CCR9 knockout has been found to improve structural remodeling after MI. Here, we further investigate the potential influence of CCR9 on electrical remodeling following MI in order to explore potential new measures to improve the prognosis of MI. Methods and Results: Mice was used and divided into four groups: CCR9+/+/Sham, CCR9-/-/Sham, CCR9+/+/MI, CCR9-/-/MI. Animals were used at 1 week after MI surgery. Cardiomyocytes in the infracted border zone were acutely dissociated and the whole-cell patch clamp was used to record action potential duration (APD), L-type calcium current (I Ca,L ) and transient outward potassium current (I to ). Calcium transient and sarcoplasmic reticulum (SR) calcium content under stimulation of Caffeine were measured in isolated cardiomyocytes by confocal microscopy. Multielectrode array (MEA) was used to measure the conduction of the left ventricle. The western-blot was performed for the expression level of connexin 43. We observed prolonged APD90, increased I Ca,L and decreased I to following MI, while CCR9 knockout attenuated these changes (APD90: 50.57 ± 6.51 ms in CCR9-/-/MI vs. 76.53 ± 5.98 ms in CCR9+/+/MI, p < 0.05; I Ca,L : -13.15 ± 0.86 pA/pF in CCR9-/-/MI group vs. -17.05 ± 1.11 pA/pF in CCR9+/+/MI, p < 0.05; I to : 4.01 ± 0.17 pA/pF in CCR9-/-/MI group vs. 2.71 ± 0.16 pA/pF in CCR9+/+/MI, p < 0.05). The confocal microscopy results revealed CCR9 knockout reversed the calcium transient and calcium content reduction in sarcoplasmic reticulum following MI. MEA measurements showed improved conduction velocity in CCR9-/-/MI mice (290.1 ± 34.47 cm/s in CCR9-/-/MI group vs. 113.2 ± 14.4 cm/s in CCR9+/+/MI group, p < 0.05). Western-blot results suggested connexin 43 expression was lowered after MI while CCR9 knockout improved its expression. Conclusion: This study shows CCR9 knockout prevents the electrical remodeling by normalizing ion currents, the calcium homeostasis, and the gap junction to maintain APD and the conduction function. It suggests CCR9 is a promising therapeutic target for MI-induced arrhythmia, which warrants further investigation.


Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914).
Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD + cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2-3 were observed more often with VAD + cyclosporin A than with VAD only: nausea (30% versus 8%, P = 0.015), mucositis (18% versus 5%, P = 0.13), infection (45% versus 35%, P = 0.50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (-18.5%, 26.9%)]. The median progression-free survival (PFS) was 8.6 months (VAD + cyclosporin A) versus 5.8 months (VAD): [log rank P = 0.16, hazard ratio = 0.71, 95% CI (0.44, 1.15)], and median overall survival was 13 months versus 14.6 months [log rank P = 0.89, hazard ratio = 0.96, 95% CI (0.62, 1.72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgp-positive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.


Leptin is involved in gender-related differences in insulin sensitivity.
Although the effects of insulin on leptin levels are relatively well characterized, the possible actions of leptin on insulin sensitivity are not so well studied. This study was undertaken to examine whether gender-related differences in insulin sensitivity could be explained partially by leptin levels. The study involved 22 women (13 obese) and 20 (11 obese) fat mass- and age-matched men. All participants were healthy. Several anthropometric measures of body fatness were quantified and the percentage of body fat was determined through bioelectric impedance. Oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test was performed in all subjects. Serum leptin was measured by radioimmunoassay. Nine lean women (BMI 20.4 +/- 2 kg m2 mean +/- SD) showed increased leptin levels (7.8 +/- 2.7 vs. 4.3 +/- 1.3 micrograms/l, P = 0.003), increased insulin sensitivity (5.2 +/- 1.3 vs. 2.9 +/- 0.9 min-1/mU/l, P = 0.001) and similar fat mass (11.1 +/- 3.7 vs. 13.2 +/- 7.8 kg, P = NS) in comparison with 9 age-matched lean men (33.6 +/- 6 vs. 34.5 +/- 6.3 years, P = NS). Thirteen obese women (BMI 32.5 +/- 2.7) kg m2 also showed increased leptin levels (29.6 +/- 8.4 vs. 11.7 +/- 4.8 micrograms/l, P < 0.0001), increased insulin sensitivity (1.7 +/- 0.7 vs. 0.95 +/- 0.9 min-1 mU/l, P = 0.04) and similar fat mass (34.4 +/- 8.0 vs. 30.9 +/- 9.6 kg, P = NS) in comparison with 11 age-matched obese men (34.5 +/- 7.8 vs. 38.7 +/- 8.2 years, P = NS). A strong linear association between leptin levels and insulin sensitivity (Si) was found (r = -0.67, P = 0.001, in men; r = -0.82, P < 0.0001, in women). After controlling for percentage of body fat, this association remained significant only in men (r = -0.56, P = 0.01, in men; r = -0.30, P = NS in women). In stepwise regression analysis models, both gender (P = 0.00001) and leptin (P = 0.00001) contributed to 67% of the variance in Si independently of body fat. Leptin levels and gender contribute to the variance of insulin sensitivity, independently of body fat. These results suggest that leptin could affect insulin sensitivity.


Transcription of E. coli and Euglena chloroplast tRNA gene clusters and processing of polycistronic transcripts in a HeLa cell-free system.
The transcription of cloned tRNA genes that are clustered in the Escherichia coli and Euglena gracilis chloroplast genome was studied in a HeLa cell-free extract. RNA polymerase III transcribes the tRNA gene clusters into polycistronic primary transcripts, consisting of pre-tRNAVal-tRNAAsn-tRNAArg and pre-tRNAAsp-tRNATrp transcribed from the Euglena chloroplast and E. coli tRNA locus, respectively. A UV5-lac promoter in the 5'-flanking sequence of the E. coli tRNA gene cluster can be removed without effect on transcription initiation frequency. During transcription of the tRNA gene clusters, RNA polymerase III initiates predominantly, if not solely, with the first tRNA gene. Upon removal of the first tRNA gene, RNA polymerase III initiates transcription with the following tRNA gene. The primary transcripts are subsequently processed to mature tRNAs. RNA fingerprint analysis and reincubation experiments were used to establish the steps of tRNA maturation of the pre-tRNAVal-tRNAAsn-tRNAArg. The 3' trailer is processed prior to the removal of 5' leader and before cleavage of the primary transcript in the spacer sequences. The pre-tRNAs are then processed to mature tRNA molecules.


Thermal Stability Evaluation of Resin Acids and Rosin Modified Resins.
Rosin is a sustainable resource, which is mainly composed of resin acid. Rosin-modified resin is widely used in adhesives, inks, coatings, and other fields, and its stability is very important for the production, storage, and use of products. Thermal stability and reactivity of three resin acids (levopimaric acid, neoabietic acid, and dehydroabietic acid) and four rosin-modified resins were studied using an accelerating rate calorimeter (ARC). They are stable, and exothermic reactions do not occur even when they were heated to 200 °C under a nitrogen atmosphere, but they are unstable under an oxygen atmosphere. The mechanism of the oxidation reaction process was found: first, resin acids absorb oxygen, and then an exothermic oxidation occurs. The initial exothermic temperature (T 0) of levopimaric acid, neoabietic acid, and dehydroabietic acid are 354.01, 353.83, and 398.20 K, the initial oxidation kinetics shows a second-order reaction, and the activation energies (E a) are 42.90, 58.05, and 46.60 kJ/mol, respectively. Peroxide concentration of three resin acids were determined by iodometry. The T 0 values of hydrogenated rosin, disproportionated rosin, hydrogenated rosin glyceride, and hydrogenated rosin pentaerythritol ester, the four rosin-modified resin, are 353.71, 348.32, 412.85, and 412.44 K. Levopimaric acid and neoabietic acid have higher oxidative reactivity and easily undergoes an oxidation reaction at lower temperature. Rosin-modified resins are stable and find it difficult to undergo oxidation reactions.


Alpinetin ameliorates bone loss in LPS-induced inflammation osteolysis via ROS mediated P38/PI3K signaling pathway.
Bone loss occurs in several inflammatory diseases because of chronic persistent inflammation that activates osteoclasts (OCs) to increase bone resorption. Currently available antiresorptive drugs have severe side effects or contraindications. Herein, we explored the effects and mechanism of Alpinetin (Alp) on receptor activator of nuclear factor κB ligand (RANKL)-mediated OCs differentiation, function, and in inflammatory osteolysis of mice. Primary mouse bone marrow-derived macrophages (BMMs) induced by RANKL and macrophage colony-stimulating factor (M-CSF) were utilized to test the impact of Alp on OCs differentiation, function, and intracellular reactive oxygen species (ROS) production, respectively. Expression of oxidant stress relevant factors and OCs specific genes were assessed via real-time quantitative PCR. Further, oxidative stress-related factors, NF-κB, MAPK, PI3K/AKT/GSK3-β, and NFATc1 pathways were examined via Western blot. Finally, LPS-induced mouse calvarial osteolysis was used to investigate the effect of Alp on inflammatory osteolysis in vivo. Alp suppressed OCs differentiation and resorption function, and down-regulated the ROS production. Alp inhibited IL-1β, TNF-α and osteoclast-specific gene transcription. It also blocked the gene and protein expression of Nox1 and Keap1, but enhanced Nrf2, CAT, and HO-1 protein levels. Additionally, Alp suppressed the phosphorylation of PI3K and P38, and restrained the expression of osteoclast-specific gene Nfatc1 and its auto-amplification, hence minimizing LPS-induced osteolysis in mice. Alp is a novel candidate or therapeutics for the osteoclast-associated inflammatory osteolytic ailment.


Common Wound Irrigation Solutions Produce Different Responses in Infected vs Sterile Host Tissue: Murine Air Pouch Infection Model.
Despite desirable microbicidal actions of irrigation solutions in surgical site infection treatment, several studies demonstrate potential cytotoxic effects. This study investigated tissue damage caused by irrigation solutions in the presence or absence of infection. Air pouches were created in 60 mice and evenly divided into 2 groups as infected with Staphylococcus aureus and control. Groups were then subdivided both by type of solution and by timing after irrigation. Solutions included control (0.9% saline), bacitracin (33 IU/ml), 0.2% sodium oxychlorosene, 0.05% chlorhexidine gluconate, and 0.013% benzalkonium chloride. Inflammation decreased in infected pouches compared to the sterile ones for all solutions except bacitracin on day 0 and for all on day 7. On day 0, infected pouches had increased necrosis with bacitracin (P = .006), chlorhexidine gluconate (P = .18), and benzalkonium chloride (P = .07); on day 7, there was decreased necrosis in infected pouches for all solutions (P < .05) except for sodium oxychlorosene (P = .18). Edema decreased in infected pouches on day 0 for all solutions. On day 7, infected pouches had decreased edema with 0.9% saline, bacitracin, and benzalkonium chloride (P < .05) and increased edema with chlorhexidine gluconate (P < .05) and sodium oxychlorosene (P = .069). Bacitracin allowed for more bacteria growth than sodium oxychlorosene (P = .024), chlorhexidine gluconate (P = .025), and benzalkonium chloride (P = .025). The presence of bacteria led to less immediate tissue inflammation and edema, while tissue necrosis varied over time. The current study may guide surgeons on which solution to use and whether to irrigate a possibly sterile wound or joint.


Effects of mineral buffers on the rumen flora of sheep fed grain diets.
The structure of the microbial population of rumen liquor froom sheep fed diets of roughage and of whole wheat grain with and without mineral buffer additives was studied. Addition of either 2 per cent of a mixture of 1/1/1/1 sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate and calcium hydrogen phosphate or of 1 per cent of aluminium hydroxide to grain diets acted to increase microbial concentration, allow persistance of a rumen flora of predominatly Gramnegative staining characteristic, and to increase the proportion of rods. Animals consuming these diets had an improved production performance. In the absence of dietary buffers the microbial population shifted towards a Gram-positive population with no reduction in the proportion of coccal forms.


The relationship between automation complexity and operator error.
One of the objectives of process automation is to improve the safety of plant operations. Manual operation, it is often argued, provides too many opportunities for operator error. By this argument, process automation should decrease the risk of accidents caused by operator error. However, some accident theorists have argued that while automation may eliminate some types of operator error, it may create new varieties of error. In this paper we present six case studies of explosions involving operator error in an automated process facility. Taken together, these accidents resulted in six fatalities, 30 injuries and hundreds of millions of dollars in property damage. The case studies are divided into two categories: low and high automation complexity (three case studies each). The nature of the operator error was dependent on the level of automation complexity. For each case study, we also consider the contribution of the existing engineering controls such as safety instrumented systems (SIS) or safety critical devices (SCD) and explore why they were insufficient to prevent, or mitigate, the severity of the explosion.


Contribution of influenza immunity and virosomal-formulated synthetic peptide to cellular immune responses in a phase I subunit malaria vaccine trial.
We have demonstrated recently in a phase Ia clinical trial that synthetic malaria peptides delivered by immuno-potentiating reconstituted influenza virosomes (IRIV) induced long-lived peptide-specific antibody responses in all volunteers. In the current ancillary study to this clinical trial we have investigated the cellular immune responses specific for IRIV and the surface bound synthetic malaria peptides tested. After vaccination, in 50% (8/16) of the volunteers at least one positive lymphoproliferative response specific for the 49mer peptide derived from the Plasmodium falciparum apical membrane antigen-1 (AMA-1) was observed with stimulation indices ranging from 2 to 4.5. All volunteers showed pre-existing IRIV specific cellular immunity assessed by ex vivo IFN-gamma ELISpot analysis and lymphoproliferation. The pre-existing influenza specific T cell responses did not interfere negatively with the induction of malaria peptide-specific humoral and cellular immune responses. Our results support the view that IRIV constitute a safe antigen delivery system for induction of peptide-specific immune responses in human populations.


HB F-Yamaguchi (gamma 75Thr, gamma 80Asn, gamma 136Ala) is associated with G gamma-thalassemia.
Restriction endonuclease and analyses of DNA from a known Hb F-Yamaguchi heterozygote and three of his relatives have shown a deletion of about 5 kb, which includes one of the gamma genes. This abnormality is similar to the G gamma-thalassemia described recently [4] and is probably caused by an unequal crossing over between-G gamma- and -A gamma T-genes. The abnormal-G gamma A gamma T-X-(X = Asp leads to Asn at gamma 80) hybrid gene produces the gamma-Yamaguchi chain at a level usually seen for G gamma chains only.


Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Part III: neurology.
We present a short historical review of the major figures, their administrative functions and their works that contributed to make Paris a renowned centre of physiology and neurology during the xixth and the first half of the xxth century. We purposely chose to focus on the period 1800-1950, as 1800 corresponds to the actual beginning of neurosciences, and 1950 marks their exponential rise. Our presentation is divided into four chapters, matching the main disciplines which have progressed and contributed the most to the knowledge we have of the brain sciences: anatomy, physiology, neurology, and psychiatry-psychology. The present article is the third of four parts of this review, and deals with neurology. A special credit should be given to Jean-Martin Charcot who founded the Salpêtrière School of neurology and became one of the world's most important neurologists of the xixth century. We provide below the biographical sketches of Armand Trousseau, Guillaume Benjamin Amand Duchenne, Jean-Martin Charcot, Alfred Vulpian, Désiré-Magloire Bourneville, Paul Richer, Henri Parinaud, Albert Pitres, Jules Joseph Dejerine, Mrs. Augusta Dejerine-Klumpke, Édouard Brissaud, Pierre Marie, Georges Édouard Brutus Gilles de la Tourette, Joseph Babinski, André Thomas, Georges Marinesco, Achille Alexandre Souques, Georges Guillain and Charles Foix.


Methods to stimulate national and sub-national benchmarking through international health system performance comparisons: a Canadian approach.
This paper presents, discusses and evaluates methods used by the Canadian Institute for Health Information to present health system performance international comparisons in ways that facilitate their understanding by the public and health system policy-makers and can stimulate performance benchmarking. We used statistical techniques to normalize the results and present them on a standardized scale facilitating understanding of results. We compared results to the OECD average, and to benchmarks. We also applied various data quality rules to ensure the validity of results. In order to evaluate the impact of the public release of these results, we used quantitative and qualitative methods and documented other types of impact. We were able to present results for performance indicators and dimensions at national and sub-national levels; develop performance profiles for each Canadian province; and show pan-Canadian performance patterns for specific performance indicators. The results attracted significant media attention at national level and reactions from various stakeholders. Other impacts such as requests for additional analysis and improvement in data timeliness were observed. The methods used seemed attractive to various audiences in the Canadian context and achieved the objectives originally defined. These methods could be refined and applied in different contexts.


Application of computational toxicological approaches in human health risk assessment. I. A tiered surrogate approach.
Hazard identification and dose-response assessment for chemicals of concern found in various environmental media are typically based on epidemiological and/or animal toxicity data. However, human health risk assessments are often requested for many compounds found at contaminated sites throughout the US that have limited or no available toxicity information from either humans or animals. To address this issue, recent efforts have focused on expanding the use of structure-activity relationships (SAR) approaches to identify appropriate surrogates and/or predict toxicological phenotype(s) and associated adverse effect levels. A tiered surrogate approach (i.e., decision tree) based on three main types of surrogates (structural, metabolic, and toxicity-like) has been developed. To select the final surrogate chemical and its surrogate toxicity value(s), a weight-of-evidence approach based on the proposed decision tree is applied. In addition, a case study with actual toxicity data serves as the evaluation to support our tiered surrogate approach. Future work will include case studies demonstrating the utility of the surrogate approach under different scenarios for data-poor chemicals. In conclusion, our surrogate approach provides a reasonable starting point for identifying potential toxic effects, target organs, and/or modes-of-action, and for selecting surrogate chemicals from which to derive either reference or risk values.


Colorectal cancer adjuvant treatment in elderly patients.
Colorectal adenocarcinoma ranks second as a cause of death due to cancer in the Western world. In Europe, 40% of patients with this disease is over 70 years old and only 52% of them with positive nodes usually receive an adjuvant chemotherapy. Despite early reports to the contrary, these patients tolerate cancer treatment and surgical resections as well as their younger counterparts but as a result of exclusion criteria, those receiving an adjuvant therapy are very few. This paper examines the factors pertinent to the small number of clinical trials designed for adjuvant colorectal cancer in the elderly.


Pyrethroids and enhanced inhibition in the hippocampus of the rat.
The pyrethroid insecticides have been divided into two classes on the basis of their biochemical actions and behavioral indices of toxicity. Both types of pyrethroids have effects on sodium conductance, and Type II pyrethroids have been reported to antagonize gamma-aminobutyric acid (GABA) by interacting with the t-butyl-bicyclophosphorothionate (TBPS)/picrotoxinin binding site. The dentate gyrus of the hippocampus is equipped with GABAergic recurrent inhibitory circuits. The present experiment was designed to demonstrate dissociation in the biochemistry of pyrethroids by activating the perforant path with pairs of stimulus pulses and monitoring the recurrent inhibition in this circuit. Antagonism of GABA leads to a reduction in inhibition, measured as an increase in the size of the population spike in response to the second pulse of the pair. The GABAergic properties of the pyrethroids were assessed by examining paired pulse inhibition before and after oral treatment with 20 mg/kg of cismethrin (Type I), 20 mg/kg of fenvalerate, or 10 mg/kg of deltamethrin (Type IIs). Input/output (I/O) functions revealed a reduction in excitatory postsynaptic potential (EPSP) following cismethrin and deltamethrin. Population spike height was unaffected. Fenvalerate had no effect on I/O functions. In contrast to the prediction of reduced inhibition following treatment with Type II pyrethroids, deltamethrin and fenvalerate increased inhibition up to 500 and 150 ms interpulse intervals, respectively. Cismethrin was without effect on paired pulse inhibition. These findings fail to provide evidence of GABA antagonistic properties of Type II pyrethroids and may be best explained by a differential effect of these three pyrethroids on sodium channel kinetics.


Unique N-glycosylation of a recombinant exo-inulinase from Kluyveromyces cicerisporus and its effect on enzymatic activity and thermostability.
Inulinase can hydrolyze polyfructan into high-fructose syrups and fructoligosaccharides, which are widely used in food, the medical industry and the biorefinery of Jerusalem artichoke. In the present study, a recombinant exo-inulinase (rKcINU1), derived from Kluyveromyces cicerisporus CBS4857, was proven as an N-linked glycoprotein, and the removal of N-linked glycan chains led to reduced activity. Five N-glycosylation sites with variable high mannose-type oligosaccharides (Man3-9GlcNAc2) were confirmed in the rKcINU1. The structural modeling showed that all five glycosylation sites (Asn-362, Asn-370, Asn-399, Asn-467 and Asn-526) were located at the C-terminus β-sandwich domain, which has been proven to be more conducive to the occurrence of glycosylation modification than the N-terminus domain. Single-site N-glycosylation mutants with Asn substituted by Gln were obtained, and the Mut with all five N-glycosylation sites removed was constructed, which resulted in the loss of all enzyme activity. Interestingly, the N362Q led to an 18% increase in the specific activity against inulin, while a significant decrease in thermostability (2.91 °C decrease in T m ) occurred, and other single mutations resulted in the decrease in the specific activity to various extents, among which N467Q demonstrated the lowest enzyme activity. The increased enzyme activity in N362Q, combined with thermostability testing, 3D modeling, kinetics data and secondary structure analysis, implied that the N-linked glycan chains at the Asn-362 position functioned negatively, mainly as a type of steric hindrance toward its adjacent N-glycans to bring rigidity. Meanwhile, the N-glycosylation at the other four sites positively regulated enzyme activity caused by altered substrate affinity by means of fine-tuning the β-sandwich domain configuration. This may have facilitated the capture and transfer of substrates to the enzyme active cavity, in a manner quite similar to that of carbohydrate binding modules (CBMs), i.e. the chains endowed the β-sandwich domain with the functions of CBM. This study discovered a unique C-terminal sequence which is more favorable to glycosylation, thereby casting a novel view for glycoengineering of enzymes from fungi via redesigning the amino acid sequence at the C-terminal domain, so as to optimize the enzymatic properties.


Chronic interstitial nephritis in Whipple's disease.
Report is given on a 68-year-old man who suffered primarily from progressive weight loss and repeated episodes of fever and arthralgia. Later, liver dysfunction and renal insufficiency developed. Liver and kidney biopsies disclosed granulomatous hepatitis and nephritis. Because of the morphologic and clinical findings, the diagnosis of Boeck's disease was made. Shortly before death, diarrhea developed. Autopsy revealed a massive systemic involvement in Whipple's disease proven by light and electron microscopy and immunofluorescence. Tuberculoid and epitheloid cell granulomas and isolated giant cells were found in addition to the biopsy findings in skeleton muscles, the small intestine, lymphnodes and bronchi. At autopsy, the kidney showed chronic interstitial nephritis. The literature of kidney involvement in Whipple's disease is reviewed. This is the first case with granulomatous interstitial nephritis and chronic renal insufficiency in an inadequately treated Whipple's disease.


Soluble CD27 in thyroid disorders.
We measured the soluble cytokine CD27 in a variety of thyroid disorders. Soluble CD27 was increased in untreated Graves' hyperthyroidism and in euthyroid ophthalmopathy. Levels of sCD27 were normal after the establishment of euthyroidism with propylthiouracil (PTU) or radio iodine in primary hypothyroidism, chronic thyroiditis, and the hyperthyroid and euthyroid phases of subacute thyroiditis. Soluble CD27 is a marker for cellular activation as in Graves' hyperthyroidism, but it is not predictive of the outcome of PTU therapy.


Runt-related transcription factor 3: single nucleotide polymorphism rs760805, gene expression, and methylation status in Helicobacter pylori -infected patients for determination of gastric cancer risk.
Repression of Runt-related transcription factor 3 (Runx3) gene, a tumor suppressor, has been known to be involved in Helicobacter pylori (H. pylori)-associated gastric carcinogenesis and cancer development. The present study was undertaken to study the Runx3 intronic T/A polymorphism (rs760805) in H. pylori-infected patients and uninfected controls of Tamil Nadu region, South India. Also, Runx3 gene expression, HK alpha (H,K-ATPase) gene expression and the methylation status of the Runx3 CpG island was determined. In a prospective study, tissue biopsies were collected from 40 H. pylori-infected patients and 40 infection negative controls. Single nucleotide polymorphism analysis was carried out by polymerase chain reaction (PCR)-single-strand conformational polymorphism, and DNA sequencing. Gene expression analysis of Runx3 and HK alpha was carried out using semiquantitative reverse transcriptase-PCR. Methylation analysis of Runx3 CpG island was undertaken using methylationspecific restriction digestion-PCR. The homozygous TT genotype was found to be the predominant genotype in positive samples and negative controls. No significant variation in gene expression was observed in positive samples and controls with respect to Runx3 and Hk alpha genes. Methylation analysis suggested that there was a lack of methylation except in a few subjects studied. The present study, first from this region, could neither detect significant repression of the Runx3 and HK alpha genes nor methylation in positive patients studied suggesting a lack of involvement of this tumor suppressor as a risk factor in the H. pylori-associated gastric carcinogenesis in the South Indian population studied.


Sonication effect on cellular material in sedimentation and gravitational field flow fractionation.
Sonication procedures are generally used prior to field flow fractionation (FFF) separation in order to produce suspensions without aggregates. Yeast cells manufactured in active dry wine yeast (ADWY) were placed in an ultrasound water bath in order to disrupt possible clumps and to obtain a single-cell suspension to be used in optimal conditions during fermentation processes. In order to determine whether this sample preparation procedure meets absolute needs, different yeast samples before and after sonication were analysed by two field flow fractionation techniques. It is shown that 2 min of sonication in the sample preparation process is sufficient to obtain an optimal dispersion of the yeast cells, that is, without critical percentage of aggregates. To demonstrate this effect, photographs of the yeast cell suspensions were performed with non-sonicated and sonicated yeast sample dispersion. The resulting data are compared with the elution profiles obtained from the two different FFF techniques. It is demonstrated that fractogram profiles prove the effectiveness of sonication methodologies.


Neural basis underlying the association between expressive suppression and procrastination: The mediation role of the dorsolateral prefrontal cortex.
Procrastination can lead to a variety of negative consequences, including poorer health conditions and more financial issues. Previous researches highlight that procrastination is a result of the failure of emotion-regulation. Although substantial studies have shown that emotion regulation plays an essential role in procrastination, little is known about the neural basis of the relationship between expressive suppression and procrastination. To address this question, we employed the voxel-based morphometry (VBM) method to investigate the neural basis underlying how expressive suppression links to procrastination across two independent samples (sample1, N = 98). Expressive suppression was significantly negatively associated with procrastination. Furthermore, VBM results indicated that expressive suppression was positively correlated with gray matter (GM) volumes of the right dorsolateral prefrontal cortex (dlPFC). More importantly, the GM volumes in dlPFC mediated the relationship between expressive suppression and procrastination, which was further replicated in an independent sample (sample 2, N = 110). These findings suggest that dlPFC, which plays a crucial role in inhibitory control, may be the key brain region mediating the relation between expressive suppression and procrastination. The current work provides a new perspective to understand how emotion regulation in terms of expressive suppression plays a role in procrastination.


Hemodynamic influences upon the variance of disposition residence time distribution of drugs.
A recirculation model of drug disposition is used to interpret the physiological meaning of the variance of residence time distribution (VDRT). The pharmacokinetic parameter VDRT is determined by the means and variances of the transfer times across the organs, as well as by the respective blood flow and extraction ratios. The model is illustrated for a specified distribution of organ transit times assuming flow limited mass transport. Based on data from the literature, the influence of changes in cardiac output and its regional distribution on the variance of recirculation and residence times, respectively, is predicted for lidocaine. Thereby the study is focused on the effect of certain cardiovascular states (shock, hypoxia, exercise, sympathomimetic drugs). Unlike pharmacokinetic parameters derived from the zeroth and first curve moments, the relative residence time dispersion is found to be affected by a redistribution of the blood flow among the noneliminating organs. The equations presented allow a simple and rapid calculation of clinically relevant pharmacokinetic parameters from physiological and physicochemical data.


Analysis of matches and partial-matches in a Danish STR data set.
Over the recent years, the national databases of STR profiles have grown in size due to the success of forensic DNA analysis in solving crimes. The accumulation of DNA profiles implies that the probability of a random match or near match of two randomly selected DNA profiles in the database increases. We analysed 53,295 STR profiles from individuals investigated in relation to crime case investigations at the Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark. Incomplete STR profiles (437 circa 0.8% of the total), 48 redundant STR profiles from monozygotic twins (0.09%), 6 redundant STR profiles of unknown cause and 1283 STR profiles from repeated testing of individuals were removed leaving 51,517 complete 10 locus STR profiles for analysis. The number corresponds to approximately 1% of the Danish population. We compared all STR profiles to each other, i.e. 1.3×10(9) comparisons. With these large number of comparisons, it is likely to observe DNA profiles that coincide on many loci, which has concerned some commentators and raised questions about "overstating" the power of DNA evidence. We used the method of Weir [11,12] and Curran et al. [3] to compare the observed and expected number of matches and near matches in the data set. We extended the methods by computing the covariance matrix of the summary statistic and used it for the estimation of the identical-by-descent parameter, θ. The analysis demonstrated a number of close relatives in the Danish data set and substructure. The main contribution to the substructure comes from close relatives. An overall θ-value of 1% compensated for the observed substructure, when close familial relationships were accounted for.


Centrifugal microfluidics for sorting immune cells from whole blood.
Sorting and enumeration of immune cells from blood are critical operations involved in many clinical applications. Conventional methods for sorting and counting immune cells from blood, such as flow cytometry and hemocytometers, are tedious, inaccurate, and difficult for implementation for point-of-care (POC) testing. Herein we developed a microscale centrifugal technology termed Centrifugal Microfluidic Chip (CMC) capable of sorting immune cells from blood and in situ cellular analysis in a laboratory setting. Operation of the CMC entailed a blood specimen layered on a density gradient medium and centrifuged in microfluidic channels where immune cell subpopulations could rapidly be sorted into distinct layers according to their density differentials. We systematically studied effects of different blocking molecules for surface passivation of the CMC. We further demonstrated the applicability of CMCs for rapid separation of minimally processed human whole blood without affecting immune cell viability. Multi-color imaging and analysis of immune cell distributions and enrichment such as recovery and purity rates of peripheral blood mononuclear cells (PBMCs) were demonstrated using CMCs. Given its design and operation simplicity, portability, blood cell sorting efficiency, and in situ cellular analysis capability, the CMC holds promise for blood-based diagnosis and disease monitoring in POC applications.


Novel applications of magnetic resonance imaging to image tissue inflammation after stroke.
Experimental studies suggest that stroke-induced brain damage progresses during subacute stages. Cerebral ischemic injury is associated with the induction of a series of inflammatory events, including the infiltration of circulating immune cells and activation of resident cells. Local brain inflammation is spatiotemporally related to the occurrence of delayed apoptotic cell death. Therefore, ischemia-associated inflammation may not only play a major role in the pathogenesis of neurodegeneration associated with stroke, but may also mediate beneficial effects such as lesion demarcation, wound healing, and tissue regeneration especially via secretion of nerve growth factors. In this context, noninvasive imaging of inflammation associated with ischemic stroke lesions could have a predictive value and may be helpful for the development of cytoprotective drugs.


Determinants of broiler chicken meat quality and factors affecting them: a review.
Broiler production at mass level has already been achieved and now emphasis is being laid on increasing meat quality by altering various characteristics of broiler meat. Appearance, texture, juiciness, wateriness, firmness, tenderness, odor and flavor are the most important and perceptible meat features that influence the initial and final quality judgment by consumers before and after purchasing a meat product. The quantifiable properties of meat such as water holding capacity, shear force, drip loss, cook loss, pH, shelf life, collagen content, protein solubility, cohesiveness, and fat binding capacity are indispensable for processors involved in the manufacture of value added meat products. Nutrition of birds has a significant impact on poultry meat quality and safety. It is well known that dietary fatty acid profiles are reflected in tissue fatty acid. Management of poultry meat production is reflected mostly on consumption features (juiciness, tenderness, flavour) of meat. After slaughter, biochemical changes, causing the conversion of muscle to meat, determine final meat quality. Postmortem carcass temperature has profound effect on rigor mortis and the physicochemical changes observed in PSE muscles are attributed to postmortem glycolysis, temperature, and pH. Primary processing and further processing have become a matter of concern with respect to nutritional quality of broiler meat. Genetic variation among birds could contribute to large differences in the rate of rigor mortis completion and meat quality. Heritability estimates for meat quality traits in broilers are amazingly high (0.35-0.81), making genetic selection a best tool for improvement of broiler meat quality.


Bis-(di-methylamine-κN)bis[4-(1,2,4-triazol-1-yl)benzoato-κO]copper(II).
In the title compound, [Cu(C9H6N3O2)2(C2H7N)2], the Cu2+ cation is situated on an inversion center and is coordinated by the N atoms of two di-methyl-amine ligands and the carboxyl-ate O atoms of two 4-(1,2,4-triazol-1-yl)benzoate anions, leading to a slightly distorted square-planar N2O2 coordination environment. In the crystal, inter-molecular N-H⋯N hydrogen bonds between the amine function and the central N atom of the triazole ring lead to the formation of ribbons parallel to [11]. Weak inter-molecular C-H⋯O hydrogen-bonding inter-actions are also observed that consolidate the crystal packing.


Papillary renal cell carcinoma: a single institutional study of 199 cases addressing classification, clinicopathologic and molecular features, and treatment outcome.
The morphologic spectrum of type 1 papillary renal cell carcinoma (PRCC) is not well-defined, since a significant proportion of cases have mixed type 1 and 2 histology. We analyzed 199 cases of PRCC with any (even if focal) type 1 features, with a median follow-up of 12 years, to identify clinicopathological features associated with outcome. Ninety-five tumors (48%) of the cohort contained some type 2 component (median amount: 25%; IQR: 10%, 70%). As a group they showed high rates of progression-free (PFS) and cancer-specific survival (CSS). Tumor size, mitotic rate, lymphovascular invasion, sarcomatoid differentiation, sheet-like architecture, and lack of tumor circumscription were significantly associated with CSS (p ≤ 0.015) on univariate analysis. While predominant WHO/ISUP nucleolar grade was associated with PFS (p = 0.013) and CSS (p = 0.030), the presence of non-predominant (<50%) nucleolar grade did not show association with outcome (p = 0.7). PFS and CSS showed no significant association with the presence or the amount of type 2 morphology. We compared the molecular alterations in paired type 1 and type 2 areas in a subset of 22 cases with mixed type 1 and 2 features and identified 12 recurrently mutated genes including TERT, ARID1A, KDM6A, KMT2D, NFE2L2, MET, APC, and TP53. Among 78 detected somatic mutations, 61 (78%) were shared between the paired type 1 and type 2 areas. Copy number alterations, including chromosome 7 and 17 gains, were similar between type 1 and 2 areas. These findings support that type 2 features in a PRCC with mixed histology represent either morphologic variance or clonal evolution. Our study underscores the notion that PRCC with any classic type 1 regions is best considered as type 1 PRCC and assigned the appropriate WHO/ISUP nucleolar grade. It provides additional evidence that type 2 PRCC as a separate category should be re-assessed and likely needs to be abandoned.


Rosin-based chiral wormlike Micelles: Rheological behavior and its application in preparing ultrasmall gold nanoparticles.
Innovations in surfactant structures are a feasible way to prepare unique molecular aggregates with interesting properties. Herein, taking dehydroabietic acid as the starting material, a new amine oxide surfactant, abbreviated as R-8-AO, was synthesized. Cryogenic transmission electron microscopy (cryo-TEM) images and circular dichroism (CD) spectra reveal that at suitable concentrations, R-8-AO molecules form rarely discovered right-handed chiral wormlike micelles, which have a cross-sectional diameter of 5-6 nm. The overlap concentration of R-8-AO is approximately 8 mM, above which the wormlike micelles began to entangle in solutions. Due to the strong van der Waals forces between R-8-AO molecules, the scaling law gives an exponent of 7.88, which is higher than the theory predicted value. Gold nanoparticles were synthesized in-situ by irradiating mixed solutions of HAuCl4 and wormlike micelles formed by R-8-AO with UV light. These ultrasmall spherical gold nanoparticles, which are located at the surface of wormlike micelles, have a uniform particle size of 3 ± 1 nm, as observed by TEM. In addition, the gold nanoparticles form a worm-like morphology induced by the wormlike micelles, showing soft-aggregate-directed nanoparticle assembly. This work is first to reveal the effectiveness of preparing ultrasmall gold nanoparticles with new morphological wormlike micelles as soft templates. The resulting organic-inorganic hybrid aggregates are also expected to find applications in catalysis and electronic fields.


A new approach to child mental healthcare within general practice.
Child and adolescent mental health problems are frequently not identified and properly treated within general practice. Politicians in the Netherlands are promoting more primary healthcare treatment for mental health problems. The current study aims to evaluate an integrated primary mental healthcare approach for child and adolescent emotional and behavioural problems. This integrated approach allows general practitioners (GPs) to comprehensively explore the request for help, followed by an informed decision to refer, offer short-term treatment within general practice or postpone a decision by asking for additional consultations with youth mental health specialists. The study is a naturalistic evaluation of Dutch general practices with pre-test and post-test comparison with controls based on data from Electronic Medical Records (EMR). The intervention started in September 2010. EMR data of all GP contacts with children aged 4 to 18 (including diagnosis, prescriptions, referrals) from practices involved in the intervention was used from 1 January 2009 to 31 December 2012. Extra codes were added to the EMR to record aspects of the intervention. Comparable EMR data was used in control practices in 2011. GPs in the intervention group were able to identify more emotional and behavioural problems after the integrated service had started. They also identified more problems than GPs in the control practices. They were already reluctant to prescribe psychopharmacological medication to children before the intervention, and levels of prescription at intervention GP practices remained low for psychotropic drugs compared to control practices. Referral rates to mental healthcare remained relatively steady after the introduction of the integrated service, but referrals switched from specialized to primary mental healthcare. An integrated mental healthcare approach within general practice may lead to an increase in detected psychosocial problems among children, and these problems can mainly be treated within the primary care setting.


Warfarin monitoring in ambulatory older individuals receiving antimicrobial therapy.
To determine the frequency of monitoring of international normalized ratio (INR) within 14 days of coprescription of warfarin and antimicrobial therapy and to evaluate differences in INR monitoring among antimicrobials. Retrospective cohort study. Group model health maintenance organization. Patients aged 65 years or older who were taking warfarin and an antimicrobial agent. Patients who received dispensings of both warfarin and an antimicrobial agent were identified. We found 2959 coprescribing instances in 1816 patients. The INR values were obtained for 2267 (77%) coprescribing situations within 14 days. Monitoring occurred more frequently (p<0.001) when warfarin was coprescribed with fluoroquinolones (641 [85%] of 755 situations), metronidazole (59 [81%] of 73), tetracyclines (274 [80%] of 341), or macrolides (201 [83%] of 243) than when warfarin was coprescribed with sulfonamides (35 [66%] of 53), penicillins (604 [71%] of 856), or cephalosporins (419 [71%] of 591). Among monitored patients, a higher proportion of monitoring (p<0.001) occurred within 7 days for patients prescribed antifungals (87%), fluoroquinolones (88%), tetracyclines (82%), metronidazole (86%), sulfonamides (86%), or macrolides (85%) than for patients prescribed cephalosporins (68%) or penicillins (75%). Most older patients coprescribed warfarin and an antimicrobial in our organization had INR monitoring within 7 days. This is consistent with appropriate practice to manage a risk of clinically important drug-drug interaction between an antimicrobial agent and warfarin. Prospective identification of patients requiring INR monitoring after coprescription of interacting drugs by using merged administrative pharmacy and laboratory data should be further evaluated as a tool to improve clinical outcomes.


Axonal projections to the ventrolateral nucleus of the solitary tract revealed by double labelling of retrograde fluorescent markers in the cat.
The retrofacial nucleus project bilaterally to the ventrolateral nucleus of the tractus solitarius (vlNTS) as revealed by means of retrograde transport of the fluorescent markers, Fast blue (FB) and Diamidino yellow (DY), in the cat. Some of the neurons of the retrofacial nucleus send axonal ramifications to both vlNTS. Extensive projections from other brainstem respiratory related nuclei to the vlNTS were also observed: bilaterally from the nucleus ambiguus, nucleus retroambiguus and nucleus parabrachialis medialis, and ipsilaterally from the Kölliker-Fuse nucleus. Axonal projections from the contralateral vlNTS were also observed.


Judgments of learning: evidence for a two-stage process.
Three experiments tested the hypothesis that people make judgments of learning (JOLs) by attempting to retrieve the target first. If this were the whole story, then the reaction time (RT) functions for making JOLs with no special instructions would parallel those found when people are told to first attempt retrieval and then make a JOL. In the present data, monotonic functions, showing an increase in RT with decreasing JOL, were found when people were instructed to retrieve covertly or overtly and then make a JOL, as would be expected if retrieval fluency entirely determined JOLs. However, the functions for making uninstructed JOLs were different: Low JOLs were made quickly, not slowly, and the curves were inverted U shapes, rather than linear. Furthermore, people's memory performance was somewhat better, especially on low-JOL items, when they were instructed to first retrieve as opposed to when they were told only to make JOLs. To account for these data, we propose a two-stage model of JOLs, with the first stage occurring prior to attempted retrieval.


[Development of Auditory Processing and Perception Skills with and without APD in Primary School Age].
We examined two student age groups (1st and 4th class) in a control-group comparison whether the maturation processes of the central hearing system in typically developing children are also present in children with Central Auditory Processing Disorders (CAPD) at primary-school age. The analyses included results of a behavioral test battery from 82 first graders (40 with CAPD; 42 healthy controls) and 65 fourth graders (35 with CAPD; 30 healthy controls). An ANOVA with the total value of the following 7 standardized examinations, and subsequently a MANOVA with the detailed test results were carried out: Speech (words) in Noise Recognition (Göttinger Sprachaudiometrie II); Dichotic Word Pair Understanding (Uttenweiler-Test); Heidelberger Phoneme Discrimination Subtests: Phoneme Discrimination, Phoneme Identification, Phoneme Analysis; the Subtest Auditory Sequential Memory for Digits of the Illinois Test of Psycholinguistic Abilities (German version); Mottier's Nonword Repetition Test. The ANOVA showed significant main effects of "class" (1st versus 4th; p < 0.001, η² = 0.418) and "group" (CAPD versus healthy controls; p < 0.001; η² = 0.690), but no interaction effects between both. The result of the MANOVA was similar. Main effects, but only for two tests (phoneme identification; phoneme analysis) as well as the interaction of "class" and "group" were statistically significant, with statistically small effect sizes of 3 and 6 %. Based on this cross-sectional study, the difference between the two study groups appears to be independent of the school class level. At primary-school age, there is evidence of maturation of the central hearing system for both children with CAPD and healthy children.


Evidence of the chemical uniaxial strain effect on electrical conductivity in the spin-crossover conducting molecular system: [Fe(III)(qnal)2][Pd(dmit)2]5.acetone.
A novel spin-crossover molecular conductor, [Fe(qnal)2][Pd(dmit)2]5.acetone, was prepared and characterized. The crystal structural analyses of both the low- and high-temperature phases revealed that the supramolecular pi-pi interactions between the spin-crossover Fe(qnal)2 cations as well as the cation contraction play an important role in the uniaxial lattice deformation which will modulate the electrical conductivity of the conducting Pd(dmit)2 layer.


Helium charged particle radiotherapy for meningioma: experience at UCLBL. University of California Lawrence Berkeley Laboratory.
Evaluate the use of helium charged particle radiotherapy in the treatment of residual or unresectable meningioma adjacent to critical structures. Twenty-nine patients with meningioma of the skull base or spine were irradiated with helium charged particle radiotherapy at the University of California Lawrence Berkeley Laboratory (UCLBL) during the period 1981-1992. Twenty-six patients were treated for intracranial and three for spinal tumors. Total doses of 53.0-80.4 Gray equivalent (GyE) with a mean of 63 GyE were delivered using the helium ion beam. Ten-year local control and survival rates calculated by the Kaplan-Meier product limit method were 84% and 80% respectively. Doses of 60.0 GyE were delivered with a low rate of complications. The only failures were in massive, recurrent tumors. High doses using helium charged particle radiotherapy can be safely and effectively delivered to large residual or unresectable meningioma near radiosensitive structures.


Nursing work: challenges for health management in the northeast of Brazil.
Social exchange theory is used as the framework to examine the interaction between supervisor-subordinate relationships, training and affective commitment for Northeast Brazilian public sector nursing professionals. There are continuing challenges to nursing management worldwide in terms of the supply of nursing professionals, their work relationships, nurse training and commitment to their employing organisations. The interplay between these factors for nurses in the Northeast of Brazil has not been well understood. Quantitative data were collected from 550 nursing professionals using a cross-sectional, survey-base design. Qualitative data were collected from 25 participants using in-depth interviews and focus group discussions. Using path analysis, and the ordinary least squares approach, the findings demonstrated a significant, but weak, linkage between supervisor-subordinate relationships, training and organisational commitment. The qualitative data suggest that contracting out may be a causative factor. Healthcare managers in Brazil need to create more positive environments to strengthen supervisor-nurse relationships, improve the provision of training and to strengthen organisational commitment. Healthcare policy-makers in hospital can make significant contributions to improving organisational commitment by reducing multiple job holding, improving the ratio of registered nurses to nursing technicians/assistants and beginning nurse supervision training in effective people management.


[A contribution to the pharmacodynamics of guanidine hydrochloride (author's transl)].
The concentration of guanidine was determined in blood serum and urine of healthy humans following oral administration of guanidine hydrochloride. The biological half life is 12 h, the renal clearance is 40--50 ml. An improved method for the determination of guanidine in body fluids is described.


[Rare case of haemangioma of the pharynx].
The hemangioma is a benign tumour located mostly in the region of head and neck. It can appear at any age but especially it is diagnosed among children. The disease can be successfully treated with surgery, criotherapy, propranolol or endovascular procedures. The rare case of the 59-year-old, male patient with huge heamangioma of the pharynx was shown in this paper. The patient was mildly symptomatic - he neglected difficulty with swallowing or breathing and there was no pain. The only one complaint was experiencing a worsened hearing in the left ear. The patient was referred to the laryngologist with acute pharyngitis and with the suspicion of peritonsillar abscess. In the ENT examination apart from acute tonsillitis, the tumour of pharynx was diagnosed. Diagnostic puncture of the tumour showed blood. Ambulatory treatment with antibiotics was administered. The inflammation of pharynx was cured but the tumour remained. In the ENT department the patient underwent diagnostic process including CT of the head, angioCT of carotid arteries and consultation of vascular surgeon. The diagnosis was established and patient was referred for endovascular treatment. The outcome of the embolization of hemangioma resulted in reducing the tumour size and decreasing patient's symptoms. The epidemiology, diagnostic problems and therapy were described.


Eradication rates of Helicobacter pylori in treatment-naive patients following 14-day vonoprazan-amoxicillin dual therapy: A multicenter randomized controlled trial in China.
Potassium-competitive acid blockers (P-CAB) are recommended for the treatment of Helicobacter pylori infections, but dual therapy of P-CAB with amoxicillin has been poorly studied. The current study compared the efficacy, adverse reactions, compliance, and effects on gut microbiota of 14-day vonoprazan-amoxicillin (VA) dual therapy with esomeprazole, bismuth potassium citrate, amoxicillin, and metronidazole (EBAM) quadruple therapy in treatment-naive patients with H. pylori. This was a multicenter, open-label, randomized, and controlled, non-inferiority study. Patients (n = 194) enrolled from six centers were randomly divided into either the VA or EBAM group. H. pylori eradication was determined using 13 C urea breath tests (UBT) 4-6 weeks post-treatment. Fecal samples were collected, and gut microbial populations were analyzed by 16S rDNA and metagenomic sequencing technology. Eradication rates of H. pylori in the VA and EBAM groups were 88.7% and 91.8%, respectively, according to intention-to-treat (ITT) analysis; 95.6% and 96.7% with per-protocol (PP) analysis; and 94.5% and 96.7% with modified ITT (mITT) analysis (all p > 0.05). The incidence of adverse reactions in the VA group was significantly lower compared to the EBAM group, and compliance within both groups was good. There was no difference in α-diversity or microbial composition in the VA and EBAM groups at one-month post-treatment compared to baseline, except for a markedly reduced abundance of Bacteroides in the EBAM group. VA therapy achieved excellent eradication rates with low adverse reactions, good compliance, and little impact on gut microbiota. VA therapy should be recommended as a first-line treatment against H. pylori.


Anatomic pathology of hepatocellular carcinoma: histopathology using classic and new diagnostic tools.
Hepatocellular carcinoma can be diagnosed on a needle biopsy of the liver; however, uncertainty may arise because of the inherent complexity of liver histology. This article aims to provide practicing pathologists with tools for the approach to mass-directed liver biopsies clinically concerning for hepatocellular carcinoma. The examination of routine hematoxylin-eosin stains and the use of ancillary histochemical and immunohistochemical stains are discussed. Sections reviewing liver carcinoma with biphenotypic differentiation and the challenge of dysplastic nodules are included.


Gender equality, education, economic growth and religious tensions nexus in developing countries: A spatial analysis approach.
Gender inequality is a more pronounced phenomenon in developing countries, which may be rooted in poor governance, and inadequate social and religious institutions. Therefore, this research tests the effects of religious tensions, governance, economic growth, and education on gender equality in a panel of 59 developing countries from 1995-2015. Moreover, religious tensions may have spillovers in neighboring countries in this modern age of media and globalization. Therefore, we apply Spatial Durbin and Autoregressive models to consider spatial autocorrelation in the religious tensions model. We find that both gender equality and religious tensions have spillovers in neighboring countries. Moreover, reducing religious tensions and increasing economic growth promote gender equality and have positive spillovers in neighboring countries as well. Bureaucratic quality has a positive effect on gender equality in home countries and has insignificant spillovers on gender equality in the neighboring countries. However, education could not affect gender equality in developing countries.


Total nitrogen vs. amino-acid profile as indicator of protein content of beef.
In most cited food composition studies and tables, the proximate system measures protein as total nitrogen (N) (determined by Kjeldahl or Dumas method) multiplied by a specific factor. A factor of 6.25 is used for determining total protein from total N (Jones, Munsey, & Walker, 1942). Although more expensive, it is considered more accurate to base protein content of foods on amino acid data (Greenfield & Southgate, 2003). A study on the nutrient composition of beef analysed the full amino-acid profile of fifteen retail cuts from three age groups and six fat codes, as well as determined total nitrogen content to determine proximate protein composition. For all cuts, the correlation coefficient of total amino acids to protein (N×6.25) was 0.635. This indicates a poor correlation for predicting actual protein content (as determined by total amino acid count), based on the nitrogen factor of 6.25. On average, the sum of amino acids per cut amounted to 91% of total determined protein (N×6.25) for the same cut.


Clinical significance of small colorectal polyps.
Since the concept of "advanced" or "dangerous" adenomas was introduced in 1992, less concern has been directed to diminutive colorectal adenomas. They apparently confer no increased risk of metachronous colorectal cancer and some investigators have suggested that they need neither follow-up nor treatment. This study is intended to discover how often small colorectal adenomas have unfavorable histologic features. Since 1995 the details of all colorectal polyps have been entered into a database, along with data concerning patients, symptoms, treatment, and outcome. Using this database all adenomas were categorized into three groups: Group I, <6 mm diameter, Group II, 6 to 10 mm diameter, and Group III, >10 mm diameter. "High risk" adenomas were defined as those containing >25 percent villous architecture, those with severe dysplasia, and those over 10 mm in size. Thus all Group III adenomas are high-risk by definition. The effects of family history, patient age, and polyp location on the proportions of Group I and Group II adenomas that were histologically high risk were examined. There were 5,722 polyps of which 4,381 (76.6 percent) were Group I, 666 (11.6 percent) were Group II, and 675 (11.8 percent) were Group III. These included 24 invasive cancers (2 in Group I, 1 in Group II, and 21 in Group III. Of the Group I adenomas, 91/2,064 (4.4 percent) were high risk compared to 65/417 (15.6 percent) in Group II. Of the 564 Group III adenomas, 326 (57.8 percent) had unfavorable histology. There was no effect of age, family history, or site of the polyp on the proportion of polyps that were high risk. Four percent of adenomas less than 6 mm diameter and 16 percent of those between 6 and 10 mm have unfavorable histology. Small adenomas can still be clinically significant and should not be ignored. Since the concept of "advanced" or "dangerous" adenomas was introduced in 1992, less concern has been directed to diminutive colorectal adenomas. They apparently confer no increased risk of metachronous colorectal cancer and some investigators have suggested that they need neither follow-up nor treatment. This study is intended to discover how often small colorectal adenomas have unfavorable histologic features.


The influence of normal guinea-pig serum and tissue culture assay system on foot-and-mouth disease virus neutralisation.
The inclusion of normal guinea-pig serum in neutralisation reactions involving foot-and-mouth disease virus (FMDV) increased the neutralisation titre and rate of neutralisation by guinea-pig antiserum derived from animals convalescent from FMDV. Such inclusion had little or no effect on neutralisation involving guinea-pig antiserum collected early in infection or early or convalescent bovine antisera. Higher neutralisation titres and more rapid neutralisation were found from assay in bovine thyroid cells than in IB-RS-2 cells. Not all the increase in neutralising activity was removed by heating at 56 degrees C, indicating that other factors in addition to complement were responsible. In some tests a virus fraction resisting neutralisation was found and, when rabbit anti-guinea-pig gamma-globulin was added, an increase in neutralisation resulted, suggesting that most of the persistent virus fraction was due to the presence of infective virus-antibody complexes.


Over diagnosis of bradykinin angioedema in patients treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.
Bradykinin angioedemas are a potentially serious side effect of angiotensin-converting enzyme inhibitors (ACEI) and more controversially of angiotensin II receptor blockers (ARB). Their challenging diagnosis is based on the absence of any recurrence after more than 6 months of drug discontinuation; otherwise mast-cell driven angioedemas as a differential diagnosis must be considered. The aim of this study was to determine the prevalence of recurrent angioedema in patients referred for ACEI/ARB-induced bradykinin angioedema, after more than 6 months of drug discontinuation. We included ACEI/ARB-treated patients referred for angioedema(s) without hives and unresponsive to antihistamines, after they discontinued ACEI/ARB for at least 6 months. Any C1-inhibitor deficiency was excluded. The primary endpoint was the prevalence of patients with recurrent angioedema after more than 6 months of drug discontinuation and/or developing hives during follow-up. The secondary endpoint was the identification of epidemiological factors associated with any final diagnosis. Thirty-eight of 93 patients (41%) with a suspicion of ACEI/ARB-induced bradykinin angioedema still had recurrent angioedema (n = 27) or developed hives (n = 2) or both (n = 9) after 6 months of drug discontinuation. Good response to icatibant and facial but not oral localization were predictive for the final diagnosis of ACEI/ARB-induced bradykinin angioedema and mast-cell driven angioedema, respectively. In patients referred for acquired angioedema without wheals occurring during ACEI/ARB therapy, 59% finally had a diagnosis of ACEI/ARB-induced bradykinin angioedema whereas 41% were rather diagnosed with mast-cell driven angioedema. The overdiagnosis of ACEI/ARB-induced bradykinin angioedema may deteriorate the management of severe cardiovascular conditions.


Machine learning for predicting opioid use disorder from healthcare data: A systematic review.
The US opioid epidemic has been one of the leading causes of injury-related deaths according to the CDC Injury Center. The increasing availability of data and tools for machine learning (ML) resulted in more researchers creating datasets and models to help analyze and mitigate the crisis. This review investigates peer-reviewed journal papers that applied ML models to predict opioid use disorder (OUD). The review is split into two parts. The first part summarizes the current research in OUD prediction with ML. The second part evaluates how ML techniques and processes were used to achieve these results and suggests improvements to refine further attempts to use ML for OUD prediction. The review includes peer-reviewed journal papers published on or after 2012 that use healthcare data to predict OUD. We searched Google Scholar, Semantic Scholar, PubMed, IEEE Xplore, and Science.gov in September of 2022. Data extracted includes the study's goal, dataset used, cohort selected, types of ML models created, model evaluation metrics, and the details of the ML tools and techniques used to create the models. The review analyzed 16 papers. Three papers created their dataset, five used a publicly available dataset, and the remaining eight used a private dataset. Cohort size ranged from the low hundreds to over half a million. Six papers used one type of ML model, and the remaining ten used up to five different ML models. The reported ROC AUC was higher than 0.8 for all but one of the papers. Five papers used only non-interpretable models, and the other 11 used interpretable models exclusively or in combination with non-interpretable ones. The interpretable models were the highest or second-highest ROC AUC values. Most papers did not sufficiently describe the ML techniques and tools used to produce their results. Only three papers published their source code. We found that while there are indications that ML methods applied to OUD prediction may be valuable, the lack of details and transparency in creating the ML models limits their usefulness. We end the review with recommendations to improve studies on this critical healthcare subject.


Effects of acquisition time and reconstruction algorithm on image quality, quantitative parameters, and clinical interpretation of myocardial perfusion imaging.
Recently introduced iterative reconstruction algorithms with resolution recovery (RR) and noise-reduction technology seem promising for reducing scan time or radiation dose without loss of image quality. However, the relative effects of reduced acquisition time and reconstruction software have not previously been reported. The aim of the present study was to investigate the influence of reduced acquisition time and reconstruction software on quantitative and qualitative myocardial perfusion single photon emission computed tomography (SPECT) parameters using full time (FT) and half time (HT) protocols and Evolution for Cardiac Software. We studied 45 consecutive, non-selected patients referred for a clinically indicated routine 2-day stress/rest (99m)Tc-Sestamibi myocardial perfusion SPECT. All patients underwent an FT and an HT scan. Both FT and HT scans were processed according to our standard procedure with both ordered-subset expectation maximization (OSEM) + filtered back projection (FBP) reconstructions and a second reconstruction of HT scans was performed with the RR software producing three datasets for each patient for visual analysis (FT-OSEM, HT-OSEM, and HT-RR) and for quantitative analysis (FT-FBP, HT-FBP, and HT-RR). The datasets were analyzed using commercially available QGS/QPS software and read by two observers evaluating image quality and clinical interpretation. Image quality was assessed on a 10-cm visual analog scale score. HT imaging was associated with loss of image quality that was compensated for by RR reconstruction. HT imaging was also associated with increasing perfusion defect extents, an effect more pronounced using RR than FBP reconstruction. Compared to standard FT-FBP, HT-RR significantly reduced left ventricular volumes whereas HT-FBP increased end-systolic volume. HT imaging had no effect on measured left ventricular ejections fraction or measures of reversibility. Image interpretation found a higher level of concordance between FT-OSEM and HT-RR than between FT-OSEM and HT-OSEM without any observable systematic effects. Use of RR reconstruction algorithms compensates for loss of image quality associated with reduced scan time. Both HT acquisition and RR reconstruction algorithm had significant effects on motion and perfusion parameters obtained with standard software, but these effects were relatively small and probably of limited clinical importance. Although no systematic effects on image interpretation were observed, the influence on diagnostic accuracy remains to be determined.


Development of free-living stages of equine strongyles in faeces on pasture in a tropical environment.
The development of the free-living stages and yields of infective third stage strongyle larvae in faeces from a horse with a mixed natural infection deposited on pasture plots were studied over a 2-year period in a coastal area in tropical north Queensland. Two sets of faecal masses (one exposed to, and the other protected from the action of a natural population of dung beetles) were deposited monthly and after 7 days faecal samples were taken for larval recovery and counts. Hatching and development of the free-living stages occurred in faeces on pasture throughout the year. Development was rapid as infective stages were reached within a week of faecal deposition in all months. Yields of infective larvae were affected by the season and the action of dung beetles on the faecal masses. Highest yields were obtained from both beetle-exposed and protected faeces during winter (June to August) and lowest yields were in spring (September to November). High temperatures in spring and summer resulted in low yields of larvae, however, the dry conditions in spring made this season the most unfavourable period. In autumn and winter the temperatures were never low enough to stop or markedly slow down the rate of development, and allowed the development of large numbers of infective larvae. Dung beetle activity was observed throughout the year, and exposed faeces were usually completely dispersed within 24 h of deposition. This resulted in lower yields of infective larvae from these than from protected faeces. Though larval yields were lower, the actual numbers were still substantial so as to cast doubt on the usefulness of these beetles as biological control agents for equine strongylosis in the dry tropics.


Shortening of the patellar tendon length does not influence the patellofemoral alignment in a cadaveric model.
Anterior cruciate ligament (ACL) reconstruction with the use of autograft tissue represents the standard treatment. The use of a bone-patellar tendon-bone transplant for symptomatic ACL deficiency achieves good long-term results. The purpose of the study was to investigate in a cadaveric model whether reproducible patellar tendon shortening changes the patellofemoral alignment. Using five cadaveric knees, an MRI investigation was performed with the patellar tendon left unchanged, shortened 5 mm and shortened 10 mm, respectively, in both 20 and 45 degrees of knee flexion. The lateral patellofemoral and the congruence angles were measured and compared using a one-way analysis of variance for repeated measurements. Shortening the patella tendon by approximately 20% did not significantly influence the patellofemoral alignment. Although anterior cruciate ligament-reconstruction using the patellar tendon has become a standard procedure, postoperative problems such as anterior knee pain, and patellofemoral osteoarthritis occur quite often. In this cadaver study we did not find a significant difference for the patellofemoral alignment, irrespective of the patellar tendon length.


Geofencing in location-based behavioral research: Methodology, challenges, and implementation.
This manuscript presents a novel geofencing method in behavioral research. Geofencing, built upon geolocation technology, constitutes virtual fences around specific locations. Every time a participant crosses the virtual border around the geofenced area, an event can be triggered on a smartphone, e.g., the participant may be asked to complete a survey. The geofencing method can alleviate the problems of constant location tracking, such as recording sensitive geolocation information and battery drain. In scenarios where locations for geofencing are determined by participants (e.g., home, workplace), no location data need to be transferred to the researcher, so this method can ensure privacy and anonymity. Given the widespread use of smartphones and mobile Internet, geofencing has become a feasible tool in studying human behavior and cognition outside of the laboratory. The method can help advance theoretical and applied psychological science at a new frontier of context-aware research. At the same time, there is a lack of guidance on how and when geofencing can be applied in research. This manuscript aims to fill the gap and ease the adoption of the geofencing method. We describe the current challenges and implementations in geofencing and present three empirical studies in which we evaluated the geofencing method using the Samply application, a tool for mobile experience sampling research. The studies show that sensitivity and precision of geofencing were affected by the type of event, location radius, environment, operating system, and user behavior. Potential implications and recommendations for behavioral research are discussed.


Acute injury to the central nervous system.
Central nervous system (CNS) trauma is divided into brain and spinal cord injury. A basic understanding of the pathophysiology of CNS trauma helps the practitioner more accurately evaluate, treat, and prognose cases of CNS trauma. The progressive nature of CNS injuries and the contribution of microvascular ischemic are explored.


Two-dimensional self-assembled Au-Ag core-shell nanorods nanoarray for sensitive detection of thiram in apple using surface-enhanced Raman spectroscopy.
The development of substrate with high sensitivity and good reproducibility for surface-enhanced Raman scattering (SERS) detection of contaminants in foods has attracted more and more attention. Herein, a stable two-dimensional (2D) Au-Ag core-shell nanorods (Au@Ag NRs) nanoarray substrate with high-performance SERS activity was developed based on interface self-assembly strategy and successfully applied to the detection of thiram in apple sample. A broad linearity range of 0.01-10 mg/L and a low limit of detection of 0.018 mg/L were achieved for thiram solution. The substrate was stable and exhibited satisfactory sensitivity after preserving at ambient temperature for 4 weeks. Furthermore, this method presented the comparable result to that acquired from high-performance liquid chromatography (HPLC) with satisfactory recoveries of 93-116%. The study indicated that the prepared Au@Ag NRs nanoarray substrate was promising for SERS detection of contaminants such as pesticides in foods.


Determination of morphine and codeine in urine by gas chromatography-mass spectrometry.
GC-MS is one of the recommended analytical techniques for the identification and confirmation of opiates in urine. A method for the qualitative detection and quantitation of codeine and morphine in urine samples by this technique has been developed. This method is also suitable for the detection of their main metabolites in urine: norcodeine and normorphine. It also allows the identification of 6-monoacetylmorphine in urine, which can be used as a confirmatory marker of heroine abuse. The derivatized compounds are separated by capillary gas chromatography (GC) and identified by mass spectrometry (MS) in the selective ion monitoring acquisition mode (SIM). The recoveries from urine at concentrations of 1000 ng ml-1 are 72% for codeine and 80% for morphine. The method is linear in the range studied (0-1000 ng ml-1) for codeine and morphine.


Free style facial artery perforator flap for one stage reconstruction of the nasal ala.
The nasolabial skin is the ideal donor site for nasal ala reconstruction. The classic techniques involve a two-stage procedure to reconstruct an aesthetically pleasing nasal ala. A one-stage technique for reconstruction of the nasal ala with a free style nasolabial perforator flap is presented in this article. The technique has been used in eight patients between November 2004 and June 2007. In most of the cases (seven out of eight) the whole alar subunit was reconstructed. Besides a small distal 2mm necrosis in one flap--which healed without further treatment--all the flaps healed uneventfully with aesthetically pleasing results using the one-stage technique. The free style perforator nasolabial island flap has become the method of choice in the authors' institution for nasal ala reconstruction, especially when the defect involves the whole subunit. It allows one-stage reconstruction with very similar tissue and a concealed scar in the natural groove.


When should the hypoplastic right ventricle be used in a Fontan operation? An experimental and clinical correlation.
Eight anesthetized dogs underwent closure of the tricuspid valve and a Fontan procedure, and the right ventricular cavity was reduced in stepwise fashion. There was an increase in right atrial pressure from 9.3 +/- 2.2 to 14.1 +/- 2.4 mm Hg (p less than 0.001), a decrease in pulmonary artery pulse pressure from 10.8 +/- 2.2 to 6.8 +/- 2.2 mm Hg (p less than 0.01), and a decrease in cardiac index from 2.7 +/- 0.3 to 2.2 +/- 0.2 L/min/m2 (p less than 0.001) when the ventricular size was dropped from 50% to 25% of normal. The difference between mean pulmonary artery pressure and mean right atrial pressure, which reflects the positive stroke work index of the ventricle, disappeared once the right ventricular cavity was reduced to 25% of normal (15.0 +/- 6.1 versus 14.1 +/- 2.4 mm Hg; p = not significant). Experimental results were correlated with postoperative catheterization data from 19 patients with tricuspid atresia who had the Fontan operation. Mean right atrial pressure was 18 +/- 4.6 mm Hg and cardiac index was 2.35 +/- 0.65 L/min/m2 in patients with a direct atrium-pulmonary artery anastomosis or an atrioventricular anastomosis with a right ventricular cavity less than 30% of normal versus 13 +/- 3.2 mm Hg and 3.42 +/- 0.46 L/min/m2 for those with an atrioventricular connection and a right ventricular cavity greater than 30% of normal (p less than 0.05 and p less than 0.02, respectively). The right ventricle enlarged from 27% +/- 6% of normal preoperatively to 35% +/- 10% of normal on follow-up (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Restriction in IgM expression--V. Fine structure analysis in the anti-lactose system.
A methodology for the analysis of the fine specificity of monoclonal anti-lactose IgM and IgG antibodies is described using structural variants of the homologous lactoside epitope. These variants are used as inhibitors of the binding of a reference ligand N-(5-dimethylaminonaphthalene-1-sulfonyl)-p-aminophenyl-beta-lactoside. Excitation of the antibody with bound ligand at 295 nm leads to resonance energy transfer to and fluorescence emission by the ligand. Titration of the antibody-ligand mixture with the inhibitor and measurement of the emission at 550 nm provide the data for the calculation of the binding constants of the inhibitors. A comparison of two IgM and two IgG antibodies showed that the higher affinity of the IgG antibodies arises from their specific interaction with both hexosides of the lactoside in contrast to IgM antibodies which do not engage the non-terminal hexoside as effectively. The quantitative significance of this difference is a differential free energy contribution of about -3 kcal/mole to the binding of lactoside by IgG. A finer discrimination between homologous and several cross-reactive molecules is evident with IgG antibody compared to IgM. The former exhibits about 100-fold greater difference in their binding constants than does IgM. These differences applied to biologically relevant multivalent interactions, where functional affinity governs complex formation, suggest a possible explanation for the IgM to IgG conversion characteristic of the humoral immune response.


Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors.
The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT1B receptor binding in human brain has been examined with PET using radioligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radioligand may affect imaging performance, two high-affinity full 5-HT1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates. [11C]4 was obtained through Pd(0)-mediated insertion of [11C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [11C]5 was obtained through N-11C-methylation of N-desmethyl precursor 6 with [11C]methyl triflate. [11C]4 and [11C]5 were studied with PET in rhesus or cynomolgus monkey. [11C]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for [11C]4 (pKa, logD and conformational energetics) were evaluated. Both [11C]4 and [11C]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [11C]4, brain radioactivity peaked at a low level (0.2 SUV). Pretreatment with tariquidar, an inhibitor of the brain P-gp efflux transporter, increased brain exposure four-fold whereas pretreatment with a high pharmacological dose of the 5-HT1B antagonist, AR-A000002, had no effect on the binding. Ex-vivo experiments in rats showed no radiometabolites entering brain. [11C]5 also failed to enter monkey brain under baseline conditions. [11C]4 and [11C]5 show too low brain uptake and specific binding to be useful PET radioligands. Low brain uptake is partly ascribed to efflux transporter action as well as unfavorable conformations.


Immunoglobulin G4-Related Disease, Lymphadenopathy, and Lymphoma: Histopathologic Features and Diagnostic Approach.
Lymphadenopathy occurring in patients with immunoglobulin G4 (IgG4)-related disease, termed IgG4-related lymphadenopathy, shows morphologic heterogeneity and overlap with other nonspecific causes of lymphadenopathy including infections, immune-related disorders, and neoplasms. This review describes the characteristic histopathologic features and diagnostic approach to IgG4-related disease and IgG4-related lymphadenopathy, with comparison to nonspecific causes of increased IgG4-positive plasma cells in lymph nodes, and with emphasis on distinction from IgG4-expressing lymphoproliferative disorders.


Age-dependent appearance of A-specific ovarian glycolipids and syngeneic "natural" anti-A hemolysin in mice.
C57BL/10 inbred mice produce a "natural" antibody which in the presence of complement selectively lyses human blood group A erythrocytes, and the sera of females display significantly higher levels than the sera of males. This pronounced anti-A hemolysin production in females follows the appearance of specific endogenous A-determinants which are associated with water-soluble ovarian glycolipids specifically blocking the syngeneic anti-A hemolysin activity. Moreover, this hemolysin activity develops poorly in mice ovariectomized at the age of 20 days. The coincidental production of (auto)antigenic structures in morphologically and functionally normal ovarian tissue and of antibodies against them is thought to be tolerated through the modulation of a thymusdirected control mechanism.


RNA virome diversity and Wolbachia infection in individual Drosophila simulans flies.
The endosymbiont bacteria of the genus Wolbachia are associated with multiple mutualistic effects on insect biology, including nutritional and antiviral properties. Members of the genus Wolbachia naturally occur in fly species of the genus Drosophila, providing an operational model host for studying how virome composition may be affected by its presence. Drosophila simulans populations can carry a variety of strains of members of the genus Wolbachia, with the wAu strain associated with strong antiviral protection under experimental conditions. We used D. simulans sampled from the Perth Hills, Western Australia, to investigate the potential virus protective effect of the wAu strain of Wolbachia on individual wild-caught flies. Our data revealed no appreciable variation in virus composition and abundance between individuals infected or uninfected with Wolbachia associated with the presence or absence of wAu. However, it remains unclear whether wAu might affect viral infection and host survival by increasing tolerance rather than inducing complete resistance. These data also provide new insights into the natural virome diversity of D. simulans. Despite the small number of individuals sampled, we identified a repertoire of RNA viruses, including nora virus, galbut virus, thika virus and La Jolla virus, that have been identified in other species of the genus Drosophila. Chaq virus-like sequences associated with galbut virus were also detected. In addition, we identified five novel viruses from the families Reoviridae, Tombusviridae, Mitoviridae and Bunyaviridae. Overall, this study highlights the complex interaction between Wolbachia and RNA virus infections and provides a baseline description of the natural virome of D. simulans.


A sparse Bayesian factor model for the construction of gene co-expression networks from single-cell RNA sequencing count data.
Gene co-expression networks (GCNs) are powerful tools that enable biologists to examine associations between genes during different biological processes. With the advancement of new technologies, such as single-cell RNA sequencing (scRNA-seq), there is a need for developing novel network methods appropriate for new types of data. We present a novel sparse Bayesian factor model to explore the network structure associated with genes in scRNA-seq data. Latent factors impact the gene expression values for each cell and provide flexibility to account for common features of scRNA-seq: high proportions of zero values, increased cell-to-cell variability, and overdispersion due to abnormally large expression counts. From our model, we construct a GCN by analyzing the positive and negative associations of the factors that are shared between each pair of genes. Simulation studies demonstrate that our methodology has high power in identifying gene-gene associations while maintaining a nominal false discovery rate. In real data analyses, our model identifies more known and predicted protein-protein interactions than other competing network models.


Exploring the microbial mechanisms of organic matter transformation during pig manure composting amended with bean dregs and biochar.
This study researched the impacts of biochar (B) and bean dregs (BD) on organic matter degradation and humification, as well as the bacterial community and functional characteristics during pig manure (PM) composting. The temperature, pH, and dissolved organic carbon (DOC) were reached the maturity of compost. Results indicated that BD + B treatment promoted organic matter degradation and increased humic acid content by 19.5-25.1% from the control (CK). Additionally, the bacterial communities were determined by high-throughput sequencing, and their metabolic functions were evaluated through the phylogenetic investigation of communities by reconstructing unobserved states (PICRUSt). BD + B influenced the microbial community structure of compost, and the PICRUSt results indicated that BD + B strengthened the metabolism of carbohydrates and amino acids. Redundancy analysis (RDA) was conducted, and a positive correlation was observed between organic matter transformation and temperature, pH, DOC, and community structure. Therefore, regulating these compost properties can effectively promote organic matter transformation during composting.


Effects of heat stress on cyto(chemo)kine and inflammasome gene expression and mechanical properties in isolated red and white blood cells from 4 commercial broiler lines and their ancestor jungle fowl.
Commercial broilers have been selected for high growth rate and productivity; however, this has negatively impacted their susceptibility to heat stress (HS). Insight into the molecular mechanisms underlying this vulnerability can help design targeted strategies for improvement of HS tolerance. Red blood cells (RBC) and white blood cells (WBC) were isolated from red jungle fowl and 4 lines of commercial modern broilers. Lines A and B are considered standard-yielding lines, whereas Lines C and D are high-yielding. Cells were cultured at either 37°C or 45°C for 2 h to induce heat stress (HS). Gene expression of cytokines, chemokines, and inflammasome components were measured. Heat shock proteins 27 and 70 (HSPs) in RBC were significantly affected by line (P < 0.05), whereas HSP27 and 60 were affected by temperature (P < 0.05). In WBC, there was a significant line effect on HSP gene expression (P < 0.05), and a significant increase (P < 0.05) in HSP90 in Line D in HS compared to TN conditions. In RBC, there was a main effect of HS on TNFα, CCL4, and CCLL4 (P < 0.05). HS significantly increased IL-8L1 (>30-fold, P < 0.0001) in Line C. Inflammasome genes (NLRP3, NLRC5 and NLRC3) were significantly affected by the line studied (P < 0.05). In WBC, the effect of line was significant for all cytokines, chemokines, and inflammasome components studied (P < 0.05). To examine the mechanical properties of isolated RBC from the 4 commercial lines and jungle fowl, RBC were placed into nematic liquid crystals, where Lines B and D were the most strained, and Line A and the jungle fowl were the least strained. Together, these findings indicate not only the dynamic nature of circulating cells, but the differences in the stress and inflammatory response among commercially available lines and their common ancestor. These profiles have the potential to serve as a future marker for stress responses in broilers, though further study is warranted.