Detection of serum blocking factors and antibodies to the albumin receptor on HBsAG particles in healthy persons and patients with liver diseases.
An enzyme-linked immunosorbent assay (ELISA) for the detection of serum blocking factors (BF), or antibodies to the albumin receptor on HBsAg particles, was developed, and its clinical usefulness was examined in healthy persons and patients with liver diseases. Thirteen of 80 anti-HBs-positive female (16.3%) had BF, but all 25 male anti-HBs-positive, 41 female and 32 male anti-HBs-negative subjects were negative for BF. The activity of BF in BF-positive cases was not associated with the positive reciprocal hemagglutination titer of anti-HBs. For a neutralization test of BF, the BFs from 5 cases were absorbed with IgG-immunobeads. It was determined that these IgG-BFs were antibodies to the albumin receptors on HBsAg particles. No significance between positive-BF and abnormal S-GPT levels was recognized. These results suggest that the present test for the detection of BF, or anti-albumin receptor antibody, different from anti-HBs, might be useful for diagnosis of hepatitis B and as a marker for HB virus.


Mechanistic insights into the inhibitory effect of theaflavins on virulence factors production in Streptococcus mutans.
Streptococcus mutans is the primary etiological agent associated with cariogenic process. The present study aimed to investigate the antibacterial and anti-virulence activities of theaflavins (TFs) to Streptococcus mutans UA159 as well as the underlying mechanisms. The results showed that TFs were capable of suppressing the acid production, cell adherence, water-insoluble exopolysaccharides production, and biofilm formation by S. mutans UA159 with a dosage-dependent manner while without influencing the cell growth. By a genome-wide transcriptome analysis (RNA-seq), we found that TFs attenuated the biofilm formation of S. mutans UA159 by inhibiting glucosyltransferases activity and the production of glucan-binding proteins (GbpB and GbpC) instead of directly blocking the expression of genes coding for glucosyltransferases. Further, TFs inhibited the expression of genes implicated in peptidoglycan synthesis, glycolysis, lipid synthesis, two-component system, signaling peptide transport (comA), oxidative stress response, and DNA replication and repair, suggesting that TFs suppressed the virulence factors of S. mutans UA159 by affecting the signal transduction and cell envelope stability, and weakening the ability of cells on oxidative stress resistance. In addition, an upregulated expression of the genes involved in protein biosynthesis, amino acid metabolism, and transport system upon TFs treatment indicated that cells increase the protein synthesis and nutrients uptake as one self-protective mechanism to cope with stress caused by TFs. The results of this study increase our current understanding of the anti-virulence activity of TFs on S. mutans and provide clues for the use of TFs in the prevention of dental caries.


Is patients' sexual orientation a blind spot of family physicians?
Even though certain health needs of gay, lesbian, and bisexual (GLB) patients are unique and different from those of the heterosexual patient, physicians do not usually ask patients about their sexual orientation. This study investigates family physicians' common practice regarding their patients' sexual orientation. Most of the physicians surveyed knew of less than 0.5% GLB patients in their practice; 44.4% did not know of any GLB patients. Only one physician commonly asked his patients about their sexual orientation; other physicians rarely or never asked. Asking patients about their sexual orientation significantly (P < 0.01) predicted the number of GLB patients known to the physician. Asking about patients' sexual orientation is not a common practice for family physicians, and, thus, they are usually unaware of the GLB patients in their practice.


Synchronous rhythmic flashing of fireflies. II.
Synchronized flashing by males of some firefly species involves a capacity for visually coordinated, rhythmically coincident, inter-individual behavior that is apparently unique in the animal kingdom except for a few other arthropods and for man. This paper reviews (1) diverse communicative interactions that have evolved from elementary photic signals, (2) physiological mechanisms of synchronism, and (3) theories about its biological meaning. Work of the past 20 years shows that flash synchrony is widespread geographically and taxonomically, appears in an astonishing range of spectacular display types, utilizes several neural flash-control mechanisms and is pervasively but enigmatically involved in courtship. No proposed function for synchrony has been fully established but theory and physiology concur in indicating that synchrony aids male orientation toward the female, female recognition of male flashing, or both. Increased mate choice for the female is one likely ultimate benefit.


Robust Semantic Template Matching Using A Superpixel Region Binary Descriptor.
Almost all conventional template-matching methods employ low-level image features to measure the similarity between a template image and a scene image using similarity measures such as pixel intensity and pixel gradient. Although these methods have been widely used in many applications, they cannot simultaneously address all types of robustness challenges. In this study, with the goal of simultaneously addressing the various challenges, we present a robust semantic template-matching approach (RSTM). Inspired by the local binary descriptor, we propose a novel superpixel region binary descriptor (SRBD) to construct a multilevel semantic fusion feature vector for RSTM. SRBD uses a new kernel-distance-based simple linear iterative clustering (KD-SLIC) method to extract the stable superpixels from the template image; Then, based on the average intensity difference between each superpixel region and its neighbors, the dominant gradient orientation of each superpixel can be obtained, and the semantic features of each superpixel can be described as the dominant orientation difference vector, which is coded as the rotation-invariant SRBD. In the off-line matching phase, the fusion semantic feature vector of RSTM combines the multilevel SRBD features with different numbers of superpixels. In the online matching phase, to cope with rotation invariance, a marginal probability model is proposed and applied to locate the positions of template images in the scene image. Moreover, to accelerate computation, an image pyramid is employed. We conduct a series of experiments on a large dataset randomly selected from the MS COCO dataset to fully analyze the robustness of this approach. The experimental results show that RSTM simultaneously addresses rotation changes, scale changes, noise, occlusions, blur, nonlinear illumination changes and deformation with high time efficiency while also outperforming previous stateof- the-art template-matching methods.


An option for delta-shaped gastroduodenostomy in totally laparoscopic distal gastrectomy for gastric cancer: A single-layer suturing technique for the stapler entry hole using knotless barbed sutures combined with the application of additional knotted sutures.
We report an option for delta-shaped gastroduodenostomy in totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. We detail a single-layer suturing technique for the endoscopic linear stapler entry hole using knotless barbed sutures combined with the application of additional knotted sutures. From June 2013 to February 2017, we performed TLDG with delta-shaped gastroduodenostomy in 20 patients with gastric cancer. The linear stapler was closed and fired to attach the posterior walls of the remnant stomach and the duodenum together. After creating a good view of the greater curvature side of the entry hole for the stapler by retracting the knotted suture on the lesser curvature side toward the ventral side, we performed single-layer entire-thickness continuous suturing of this hole using a 15-cm-long barbed suture running from the greater curvature side to the lesser curvature side. We placed the second and third stitches between the seromuscular layer of the remnant stomach and the entire-thickness layer of the duodenum while suturing the duodenal mucosa as minutely as possible. In addition, we routinely added one or two entire-thickness knotted sutures at the site near the greater curvature side. We placed similar additional knotted sutures at the site with a broad pitch. TLDG with this reconstruction technique was successfully performed in all patients with no occurrences of anastomotic leakage or intraabdominal abscess around the anastomosis. It is suggested that this method can be one option for delta-shaped gastroduodenostomy in TLDG due to its cost-effectiveness and feasibility.


Comparison of the prognostic value of Scarff-Bloom-Richardson and Nottingham histological grades in a series of 825 cases of breast cancer: major importance of the mitotic count as a component of both grading systems.
The most commonly used system in Europe for breast carcinoma was developed by Scarff, Bloom and Richardson (SBR). It was recently modified by Elston and Ellis and significant improvement in reproducibility has been shown by using precise grading guidelines. This study investigated whether the use of this new grade (defined as the Nottingham grade, NG) would improve the prognostic stratification of patients. The respective prognostic value of the two grading schemes was compared in a retrospective series of 825 patients uniformly treated for a small invasive breast carcinoma and followed for a median of 6 years. Univariate and multivariate analysis showed that both histological grades were strongly correlated to overall and metastasis free survival. We have separately analysed the prognostic value of each of the three components used to assess the two grading systems and found that the mitotic index was the only significant prognostic factor for 5 year survival. Univariate analysis showed the count to be more discriminant in the NG scheme (p = 0.0006) than in the SBR scheme (p = 0.04). However, in univariate and multivariate analysis, the prognostic value of the global NG was not significantly better than SBR grade. This may be related, in part, to an uneven distribution of cases reflected by a much lower number of cases with a high mitotic index in the NG system (2%) than in the SBR system (10%). Our study emphasizes the importance of the mitotic count in assessing the prognosis of breast cancers and indicates that the factors which condition this count (tissue processing, microscopic observation, threshold) must be well standardized and controlled.


Physiological and Proteomic Evidence for the Interactive Effects of Post-Anthesis Heat Stress and Elevated CO2 on Wheat.
Elevated CO2 promotes leaf photosynthesis and improves crop grain yield. However, as a major anthropogenic greenhouse gas, CO2 contributes to more frequent and severe heat stress, which threatens crop productivity. The combined effects of elevated CO2 and heat stress are complex, and the underlying mechanisms are poorly understood. In the present study, the effects of elevated CO2 and high-temperature on foliar physiological traits and the proteome of spring wheat grown under two CO2 concentrations (380 and 550 µmol mol-1 ) and two temperature conditions (ambient and post-anthesis heat stress) are examined. Elevated CO2 increases leaf photosynthetic traits, biomass, and grain yield, while heat stress depresses photosynthesis and yield. Temperature-induced impacts on chlorophyll content and grain yield are not significantly different under the two CO2 concentrations. Analysis of the leaf proteome reveals that proteins involved in photosynthesis as well as antioxidant and protein synthesis pathways are significantly downregulated due to the combination of elevated CO2 and heat stress. Correspondingly, plants treated with elevated CO2 and heat stress exhibit decreased green leaf area, photosynthetic rate, antioxidant enzyme activities, and 1000-kernel weight. The present study demonstrates that future post-anthesis heat episodes will diminish the positive effects of elevated CO2 and negatively impact wheat production.


Hydrogen-bonding motifs in 4-carboxyphenylammonium nitrate and perchlorate monohydrate, and in bis(4-carboxyphenylammonium) sulfate.
In the title compounds, C7H8NO2+.NO3-, (I), C7H8NO2+.ClO4-.H2O, (II), and 2C7H8NO2+.SO4(2-), (III), the carboxyl planes of the 4-carboxyphenylammonium cations are twisted from the aromatic plane. A homonuclear C(8) hydrogen-bonding motif of 4-carboxyphenylammonium cations is observed in both (I) and (II), leading to ;head-to-tail' layers. The cations in (III) form carboxyl group dimers, making a graph-set motif of R2(2)(8). In all the structures, anions connect the cationic layers and an infinite chain running along the c axis is observed, having the C2(2)(6) graph-set motif. Interestingly, in (II), the anions are connected through weak hydrogen bonds involving the water molecules, leading to a graph-set motif of R4(4)(12). Alternate hydrophobic and hydrophilic layers are observed in all three compounds as a result of the column-like arrangement of the aromatic rings of the cations and the anions. Furthermore, in (I), head-to-tail N-H...O interactions and interactions linking the cations and anions form an R6(4)(16) hydrogen-bonding motif, resulting in a pseudo-inversion centre at (1/2, 1/2, 0).


Long-term effect of glycyl-glutamine after elective surgery on free amino acids in muscle.
In order to evaluate the long-term effect of total parenteral nutrition supplemented with glutamine after surgery, patients (n = 17) undergoing elective abdominal surgery were randomized into two groups and studied for 30 days after surgery. During the 3 days immediately after surgery, one group (n = 8) was given total parenteral nutrition including a conventional amino acid solution (control group). The other group (n = 9) was given isocaloric and isonitrogenous total parenteral nutrition including the same amino acid solution supplemented with the dipeptide, glycyl-glutamine (GLN group). Oral food intake started on the third postoperative day and was gradually increased at will. The concentration of free amino acids in percutaneous muscle biopsy specimens was determined preoperatively and on days 3, 10, 20, and 30 after the operation. Free glutamine decreased in skeletal muscle in the control group on days 3 and 10 by 32.2 +/- 5.4% (p < .01) and 20.1 +/- 6.9% (p < .05), respectively. In the glycyl-glutamine group, the decrease in glutamine was delayed until day 10 when it was 22.1 +/- 8.1% (p < .05). The glutamine levels were restored on days 20 and 30 in both groups. Total parenteral nutrition supplemented with glutamine maintained the free glutamine levels in skeletal muscle after surgery, but when treatment was discontinued, the glutamine concentration in muscle dropped, despite a normal enteral dietary intake.


Development of a Survey to Explore Factors Influencing the Adoption of Best Practices for Diabetic Foot Ulcer Offloading.
The primary purpose of this study was to develop 2 survey tools to explore factors influencing adoption of best practices for diabetic foot ulcer offloading treatment in primary health care settings. One survey was intended for the patients receiving care for a diabetic foot ulcer in primary health care settings and the other was intended for the health professionals providing treatment. The second purpose of this study was to evaluate the psychometric properties of the 2 surveys. Development and validation of survey instruments. Two surveys were developed using a published guide. Following review of pertinent literature and identification of variables to be measured, a bank of items was developed and pretested to determine clarity of the item and responses. Psychometric testing comprised measurement of content validity index (CVI) and intraclass correlation coefficient (ICC). Only items obtaining satisfactory CVI and ICC scores were included in the final version of the surveys. The final version of the patient survey contained 41 items and the final version of the survey for health care professionals contained 21 items. The patient-intended survey's items demonstrate high content validity scores and satisfactory test-retest reliability scores. The overall CVI score was 0.98. Forty of the 49 items eligible for testing obtain satisfactory ICC scores. One item's test-retest reliability could not be tested but it was retained based on its high CVI. The health professional-intended survey, an overall CVI score of 0.91 but items had lower ICC scores (63%, 31 of the 49 items), did not achieve a satisfactory ICC score for inclusion in the final instrument. This project led to development of 2 instruments designed to identify and explore factors influencing adoption of best practices for diabetic foot ulcer offloading treatment in the primary health care setting. Future research and testing is required to translate these French surveys into English and additional languages, in order to reach a broader population.


Ollier disease: two case reports and a review of the literature.
Ollier disease is a rare tumor with unclear clinicopathological features and pathogenesis. We herein report two cases of Ollier disease in a 15-year-old boy and a 66-year-old man. We analyzed the clinicopathological, radiographical, and histochemical characteristics of Ollier disease in these two cases. Furthermore, we reviewed the literature to better understand the clinicopathological features of this disease. The boy had multiple enchondromas in the metaphysis and upper region of the left femur, and his left leg is short naturally. The 66-year-old man had multiple enchondromas in his left ribs and lower segment of the left femur. He was sent to the hospital because of pathological fracture of the ribs. In addition, he was diagnosed with gastric cancer 4 years before visiting an orthopedic clinic. Ollier disease is a rare bone disease that often renders a typical asymmetrical distribution and is confined to the appendicular skeleton. It is known as a benign bone tumor and has a high risk of malignant transformation into a chondrosarcoma (5%-50%). Correct diagnosis requires radiographic, histochemical, and morphological analyses. Better understanding of the clinical manifestations and pathological features can improve the diagnosis and prevent malignant transformation and deformity, especially in adolescent patient.


Cystic echinococcosis in children and adults: a seven-year comparative study in western Romania.
This study aims to compare the epidemiological, clinical, and laboratory aspects of cystic echinococcosis (CE) in children with those of adults from western Romania, and to determine the specifics of this disease in the younger population. The medical records of the patients diagnosed with CE and hospitalized during 2004-2010 in four western Romanian counties were retrospectively investigated. Overall, 82 children (mean age, 10.8 years) and 369 adults (mean age, 48 years) were diagnosed with CE during the study period. The yearly detection rate was 3.1/100,000 children and 3.4/100,000 adults. The incidence rate registered a peak in children aged 5-14 years (4.4/100,000) and adults aged 60-69 years (5/100,000). Female to male ratio was 1.6:1 in pediatric cases and 1.2:1 in adults. CE was almost twice more frequent in rural areas (4.4/100,000 children and 4.9/100,000 adults) as compared to urban regions (2.3/100,000 children and 2.6/100,000 adults). Hepatic cysts were found more frequently than pulmonary cysts, at a ratio of 3.6:1 in children and 12.8:1 in adults. Most of the cases had no complications (91.5% of children and 87% of adults). Children had higher eosinophil count (7%) and erythrocyte sedimentation rate (ESR) (29.7 mm/h) as compared with adults (eosinophil count, 5.3%, p<0.001; ESR, 22.4 mm/h, p=0.001). The active transmission of the parasite in western Romania is demonstrated by the high incidence of CE in children. Long-term prevention of this disease may be reached through joined legislative efforts focused on the registration of dogs, home slaughter of sheep and swine, veterinary control in abattoirs, destruction of infected materials, and restriction of dogs' access to vegetable gardens and children's parks.


Design and optimization of 3D-bioprinted scaffold framework based on a new natural polymeric bioink.
This aimed at the design and production of engineered 3D scaffold prototypes using a natural polymeric bioink made of chitosan and poly-γ-glutamic acid with a specific focus on 3D-bioprinting process and on 3D framework geometry. Prototypes were produced using a 3D bioprinter exploiting layer-by-layer deposition technology. The 3D scaffold prototypes were fully characterized concerning pore size and size distribution, stability in different experimental conditions, swelling capability, and human dermal fibroblasts viability. Hexagonal framework combined with biopaper allowed stabilizing the 3-layers structure during process manufacturing and during incubation in cell culture conditions. The stability of 3-layers structure was well preserved for 48 h. Crosslinking percentages of 2-layers and 3-layers prototype were 88.2 and 68.39, respectively. The swelling study showed a controlled swelling capability for 2-layers and 3-layers prototype, ∼5%. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results showed good biocompatibility of 3-layers prototype and their suitability for preserving 48 h cell viability in 3D cultures. Moreover, a significant increment of absorbance value was measured after 48 h, demonstrating cell growth. Bioink obtained combining chitosan and poly-γ-glutamic acid represents a good option for 3D bioprinting. A stable 3D structure was realized by layer-by-layer deposition technology; compared with other papers, the present study succeeded in using medical healthcare-grade polymers, no-toxic crosslinker, and solvents according to ICH Topic Q3C (R4).


Toxoplasmosis in immunocompromised patients in Iran: a systematic review and meta-analysis.
Although toxoplasmosis in immunocompetent individuals is generally asymptomatic, in immunocompromised patients (HIV/AIDS, cancer, and transplant patients), it can lead to serious pathological effects. This study included a systematic review and meta-analysis to comprehensively assess the seroprevalence rate of Toxoplasma infection in immunocompromised patients in Iran. Electronic English and Persian databases (PubMed, Google Scholar, ScienceDirect, Scopus, Magiran, Scientific Information Database [SID], IranMedex, and IranDoc), parasitology congresses, and projects and theses of Iranian medical universities, were systematically searched from 1997 to 2013 (published or unpublished data). In this paper, several studies that used serological methods for diagnosis of toxoplasmosis were selected. Analysis of seroprevalence estimates was pooled using a random-effects meta-analysis. Twenty-two studies, comprising 2,805 individuals, were included in the meta-analysis. Overall seroprevalence rate of Toxoplasma infection in Iranian immunocompromised patients was 50.01% (95% confidence interval, 43.85 to 56.17); however, there was significant heterogeneity among study groups. The results showed that seroprevalence rate of toxoplasmosis among transplant recipients, HIV/AIDS, and cancer patients in Iran was 55.1%, 50.05%, and 45.06%, respectively. In addition, IgM seroprevalence rate was estimated to be 4.85% (95% confidence interval, 2.22 to 8.41). This systematic review and meta-analysis identified a high seroprevalence rate of Toxoplasma infection among immunocompromised patients (50%). Consideration of management, design and provision of appropriate control measures of toxoplasmosis is highly recommended.


Image-guided, endoscopic, transcervical resection of cervical chordoma.
Chordomas are rare tumors that arise from the sacrum, spine, and skull base. Surgical management of these tumors can be difficult, given their locally destructive behavior and predilection for growing near delicate and critical structures. En bloc resection with negative margins can be difficult to perform without damaging adjacent structures and causing significant clinical morbidity. For chordomas of the upper cervical spine, surgical options traditionally involve transoral or submandibular approaches. The authors report the use of the image-guided, endoscopic, transcervical approach to the upper cervical spine as an alternative to traditional techniques for addressing upper cervical spine tumors, particularly for tumors where gross-total resection is not feasible.


Lincomycin in hospital practice.
The usefulness of the new antibiotic, lincomycin, was assessed on both bacteriological and clinical grounds. Of 3200 strains of staphylococci isolated from clinical material, only 40 were resistant to lincomycin. These 40 were all of the same phage type and in fact almost all represented different isolations of the same staphylococcus which had spread to cross-infect various patients. Sixteen of 22 patients with staphylococcal infections, nine of 14 with pneumonia, 15 of 17 with acute exacerbations of bronchitis and two patients with other bacterial infections recovered completely with lincomycin therapy. The only side effect was diarrhea in four of the 42 patients given the drug by mouth. The place of lincomycin in therapeutics seems to be principally in the treatment of chronic osteomyelitis and, in patients allergic to the penicillins, in the treatment of staphylococcal, respiratory and other infections for which penicillin is usually employed.


The Phototoxic Potential of the Flavonoids, Taxifolin and Quercetin.
Quercetin, one of the most abundant polyphenols in the plant kingdom has been shown to be photodegraded on exposure to UV light. Despite the fact, it is a component of several dermatological preparations. Its phototoxic potential has not been evaluated to date. The aim of this study was to assess whether photo-induced degradation of quercetin is linked to phototoxic effects on living cells. Its dihydro derivative, taxifolin, was included in the study. For evaluation, the 3T3 Neutral Red Uptake Phototoxicity Test according to OECD TG 432 was used. To better approximate human skin, HaCaT keratinocytes, normal human epidermal keratinocytes and dermal fibroblasts were used, apart from the Balb/c 3T3 cell line. Quercetin showed a dose-dependent photodegradation in aqueous and organic environments and a phototoxic effect on all used cells. Quercetin pretreatment and following UVA exposure resulted in increased reactive oxygen species production and intracellular glutathione level depletion in human dermal fibroblasts. Taxifolin was found completely nonphototoxic and photostable. As only in vitro methodology was used, further studies using 3D skin models and/or human volunteers are needed to confirm whether exposure to sunlight, tanning sunbeds and/or phototherapy in people using cosmetics containing quercetin is a health risk.


Measurement of the ventilatory response to hypoxia. A step hypoxia three-minute test.
A step hypoxia method for testing response of patients has been described. It involves a well-trained operator who must observe the patient while monitoring and adjusting alveolar oxygen and CO2 tensions. The advantages of the step test are that the time effects can be examined and that quantitative information in a steady-state can be obtained in a relatively short period of time. It can be done at several different levels of CO2.


The InN epitaxy via controlling In bilayer.
The method of In bilayer pre-deposition and penetrated nitridation had been proposed, which had been proven to have many advantages theoretically. To study the growth behavior of this method experimentally, various pulse times of trimethylindium supply were used to get the optimal indium bilayer controlling by metalorganic vapour phase epitaxy. The results revealed that the InN film quality became better as the thickness of the top indium atomic layers was close to bilayer. A following tuning of nitridation process enhanced the quality of InN film further, which means that a moderate, stable, and slow nitridation process by NH3 flow also plays the key role in growing better-quality InN film. Meanwhile, the biaxial strain of InN film was gradually relaxing when the flatness was increasingly improved.


Comparison of different foreground and background selection methods in marker-assisted introgression.
Three different methods for foreground selection and four different methods for background selection were compared in terms of the efficiency of marker-assisted introgression of a QTL allele from a donor line into a recipient line and also in terms of the recovery of the recipient genetic background. The results showed that for the introgression of a donor QTL allele, a direct selection on the QTL itself (when the QTL genotype can be directly identified) would ensure that the allele is successfully introgressed and rapidly fixed. However, when a direct selection on the QTL is not feasible, an indirect selection using two closely linked flanking markers can be used, which also shows similar results. For the recovery of the recipient genetic background, if the goal is to recover the whole genetic background of the recipient, genomic similarity selection or marker index selection would be the best choice: Only three generations of backcrosses were required to recover over 98% of the recipient genome. Whereas if the goal is to recover certain background traits of the recipient, MBLUP selection would give the best results, which achieved not only over 99% recovery of the recipient QTL alleles for the background traits after three generations of backcrosses, but also showed the best genetic improvement of these traits.


ANTHER SMUT DISEASE IN DIANTHUS SILVESTER (CARYOPHYLLACEAE): NATURAL SELECTION ON FLORAL TRAITS.
Mating opportunities, pollination intensity, and pollen dispersal ability may vary with variation in floral traits such as color, size, and shape. Where these traits are selected by pollinators for enhanced elaboration, they should evolve toward the equilibrium between selection for further elaboration and selection against this through reduced fecundity or vitality. Here we show that pollinator-borne fungal diseases of plants may be a factor influencing the position of this equilibrium. Populations of the rock pink, Dianthus silvester often contain individuals infected with the anther smut fungus Microbotryum violaceum (= Ustilago violacea). In a naturally infected population in the Alps of eastern Switzerland we investigated how intrapopulation variation in flower size and nectar rewards influenced spore deposition and how floral traits varied with disease status. We found that spore deposition increased with increasing petal size, suggesting that large-flowered plants were at a greater risk of disease. Spore deposition was also higher for plants growing in patches with many or a high proportion of diseased neighbors. Multiple regression analyses showed that petal size or nectar reward influenced spore deposition when the effects of neighborhood disease abundance were controlled statistically. In sequential analyses, after removing the effects of disease density or frequency and plant gender, petal length explained significant variation in spore deposition. Diseased plants had reduced female reproductive organs, but calyx size was intermediate between that of healthy perfect and female flowers of this gynodioecious-gynomonoecious species, and diseased plants bore flowers with the largest petals. This may reflect a symptom of this disease or the cause, if larger-flowered plants are more likely to become infected. We conclude that investment to pollinator attraction may bring an enhanced risk of contracting this sterilizing pollinator-borne disease, so natural selection by the fungus M. violaceum acts to lower attractiveness to pollinators.


Circadian aspects of postprandial metabolism.
Time-dependent variations in the hormonal and metabolic responses to food are of importance to human health, as postprandial metabolic responses have been implicated as risk factors in a number of major diseases, including cardiovascular disease. Early work reported decreasing glucose tolerance in the evening and at night with evidence for insulin resistance at night. Subsequently an endogenous circadian component, assessed in constant routine (CR), as well as an influence of sleep time, was described for glucose and insulin. Plasma triacylglycerol (TAG), the major lipid component of dietary fat circulating after a meal, also appears to be influenced by both the circadian clock and sleep time with higher levels during biological night (defined as the time between the onset and offset of melatonin secretion) despite identical hourly nutrient intake. These time-dependent differences in postprandial responses have implications for shiftworkers. In the case of an unadapted night shift worker, meals during work time will be taken during biological night. In simulated night shift conditions the TAG response to a standard meal, preceded by either a low-fat or a high-fat premeal, was higher after a nighttime meal than during a daytime meal, and the day/night difference was larger in men than in women. In real night shift workers in Antarctica, insulin, glucose, and TAG all showed an increased response after a nighttime meal (second day of night shift) compared to a daytime meal. Night shift workers are reported to have an approximately 1.5 times higher incidence of heart disease risk and also demonstrate higher TAG levels compared with matched dayworkers. As both insulin resistance and elevated circulating TAG are independent risk factors for heart disease, it is possible that meals at night may contribute to this risk.


UCHL1-positive extranodal lymphoma resembling multiple lymphomatous polyposis of the gastrointestinal tract.
Histopathologic and immunohistochemical studies were done on paraffin sections from a patient with alimentary tract lymphoma resembling multiple lymphomatous polyposis of the gastrointestinal tract (MLP). Diffuse, but not follicular, proliferation of medium-sized lymphoid cells was noted in the polypoid lesions of the alimentary tract, peripancreatic lymph nodes, spleen, liver, and bone marrow. These cells possessed a T-cell-related antigen (UCHL1), but were negative for the B-cell-related and myeloid cell-related antigens examined. Because neoplastic cells in MLP are usually of B-cell origin, the current case will provide important information on the relation between phenotypes and morphologic patterns of proliferation.


[Tattooing and its significance in Switzerland. A representative study of 2177 20-year-old Swiss subjects].
To investigate the incidence, significance and symbolism of tattooing in Switzerland, a representative group of 2177 young males (all liable for military service, age 19-21 years) were examined in 1988. All tattoos were sketched, the location was recorded and the individual meaning was discussed with the bearer. 135 subjects (6.2%) had 1-9 tattoos per person, showing 155 different marks. Only 13% of all tattoos were professional, moderate to large in size and most often located in the area of the upper arm and the shoulder. 87% of tattoos were self-inflicted or placed by a friend and the left side was therefore preferred (66%). In general, these were small to moderate in size, simple in design, and usually located on the forearm and the hand. The dominant significance of all tattoos was related to mental attitude (29%) and love affairs (14%). 13% were pictorial. Some were related to drug abuse, criminality of gangs, or contained magic symbolism or personal data such as zodiac signs and initials (about 4% each). Only 20% had no conventional or private meaning or involved concealed symbolism. For further understanding of the individuals' social history, it should be noted that some tattoos were characterized by minor differences of meaning, such as the "man-in-4-walls" mark (= prison), the "fuck-the-police" mark, the leaf of cannabis sativa or different cross motifs. Even greater consistency related to tattoos located in the web space between the thumb and the forefinger or on the back of the fingers. The location in itself may therefore provide additional personal information on individual circumstances at the time of tattooing.


NF-kappa B activation in airways modulates allergic inflammation but not hyperresponsiveness.
Airways display robust NF-kappaB activation and represent targets for anti-inflammatory asthma therapies, but the functional importance of NF-kappaB activation in airway epithelium remains enigmatic. Therefore, transgenic mice were created in which NF-kappaB activation is repressed specifically in airways (CC10-IkappaBalpha(SR) mice). In response to inhaled Ag, transgenic mice demonstrated significantly ameliorated inflammation, reduced levels of chemokines, T cell cytokines, mucus cell metaplasia, and circulating IgE compared with littermate controls. Despite these findings, Ag-driven airways hyperresponsiveness was not attenuated in CC10-IkappaBalpha(SR) mice. This study clearly demonstrates that airway epithelial NF-kappaB activation orchestrates Ag-induced inflammation and subsequent adaptive immune responses, but does not contribute to airways hyperresponsiveness, the cardinal feature that underlies asthma.


An interview with Alfredo Falcone and Lisa Salvatore: RECOURSE and trifluridine/tipiracil in metastatic colorectal cancer.
Professor Alfredo Falcone and Dr Lisa Salvatore speak to Roshaine Gunawardana, Managing Commissioning Editor: Professor Alfredo Falcone is the Director of the Department of Oncology and the Specialization School at the University Hospital of Pisa, Italy. He trained in Pisa and Genoa, Italy, and has held major positions in Italian oncology since 2000. He currently has more than 300 publications, including papers in peer-reviewed international and national journals, book chapters, and more than 600 abstracts of presentations to international and national conferences. The majority of his papers regard clinical and translational research, with a particular focus on metastatic colorectal cancer. Dr Lisa Salvatore is a medical oncologist in the Department of Translational Research and New Technologies in Medicine and Surgery at the University of Pisa. She has been an author on about 40 publications in major peer-reviewed publications and has made numerous presentations in national and international conferences. Her main interest is focused on clinical and translational research in metastatic colorectal cancer.


[Study on the dynamic growth rhythm of Achyranthes bidentata under different densities].
The experiment was conducted to study the dynamic growth rhythm of Achyranthes bidentata under different densities. The plant samples were collected to measure the growth rate of each organ. Under different densities, the growing dynamic rhythm of A. bidentata were similar. The growth of main root exhibited a trend of "slow-fast-slow" by stages. The increase of dry root weight was fastest during the period of 30-40 days before harvest. The dry-matter increasing rate of whole plant was fastest in the later period of branching stage. The differences of root yields among the plants growing under different densities were significant. For high yield and good quality, the density of planting of A. bidentata should be considered.


[Controversial issues and working practice in myocarditis: from scientific data to clinical grounds].
Although the cause of myocarditis often remains unknown, a large variety of infections, systemic diseases, drugs and toxins have been associated with this disease. In most cases, myocarditis is induced by cardiotropic viruses and often evolves silently without discernible prognostic impact. However, in some patients, the lack of complete viral clearance and/or the association of a heart-specific inflammation can cause persistent myocyte damage, ultimately leading to progressive myocardial dilation and dysfunction or life-threatening arrhythmias. Spontaneous improvement of left ventricular function is described for 40-50% of patients. The diagnostic work-up and prognostic assessment of myocarditis should be multiparametric and all available resources should be employed, i.e. biomarkers of myocardial damage and ventricular dysfunction (troponin I, brain natriuretic peptide), advanced echocardiography, cardiac magnetic resonance and, in selected cases, endomyocardial biopsy (with histopathologic, immunohistochemical and virological analyses). These are the necessary prerequisites for an evidence-based and personalized management of myocarditis, which may require in some cases specific immunoactive treatments. However, controversial issues regarding diagnosis (such as role and timing of cardiac magnetic resonance imaging, role of endomyocardial biopsy) and therapy of myocarditis still remain unsolved. The purpose of this review is to analyze these crucial features in order to provide useful instructions for clinical practice.


New On-Water Test for the Assessment of Blood Lactate Response to Exercise in Elite Kayakers.
Lactate thresholds are physiological parameters used to train athletes and monitor performance or training. Currently, the assessment of lactate thresholds in kayakers is performed in a laboratory setting utilizing specific ergometers; however, laboratory tests differ from on-water evaluation for several reasons. The aim of this study was to assess reliability and validity of a new on-water incremental test for the assessment of blood lactate response to exercise in flat-water kayakers. Maximal lactate steady state test (MLSS) was used as criterion measurement. Eleven junior (16.5 ± 1.9 yr) élite flat-water kayakers performed: i) an incremental cardiopulmonary test up to voluntary exhaustion on a stationary kayak ergometer to determine peak oxygen uptake; ii) an on-water 1000-m distance trial (T1000) to record best performance time and average speed (S1000); iii) two repetitions of on-water incremental kayaking test (WIK test); iv) several repetitions of on-water constant speed tests to determine MLSS. Speed, HR, and blood lactate concentrations were determined during on-water tests. The best performance time in T1000 was 262 ± 13 s, corresponding to an S1000 of 3.82 ± 0.19 m·s. Lactate threshold determined by modified Dmax method (LTDmod) during WIK test was 2.78 ± 1.02 mmol·L and the corresponding speed (SLT) was 3.34 ± 0.16 m·s. Test-retest reliability, calculated on SLT, was strong (ICC = 0.95 and r = 0.93). MLSS test corresponded to 3.06 ± 0.68 mmol·L and was reached at a speed (SMLSS) of 3.36 ± 0.14 m·s. Correlation coefficient between SLT and SMLSS was 0.90 (P = 0.0001). Interestingly, a significant correlation (r = 0.96, P < 0.0001) was observed between SLT and S1000. The WIK test showed good reliability and validity for the assessment of speed corresponding to LTDmod in flat-water kayakers and it could be a useful tool to monitor athletic performance. The speed value at LTDmod nicely predicted performance on 1000 m.


Incidence of asthma and respiratory symptoms by sex, age and smoking in a community study.
The purpose of this study was to establish incidence rates for a wide range of respiratory symptoms and asthma, and relate them to sex, age, and smoking habits. A cohort established in 1985 as a random sample from the population of Western Norway, aged 15-70 yrs, was followed-up in 1996-1997. Of the initial cohort of 3,786 subjects, a total of 2,819 replied to mailed questionnaires at both baseline and follow-up. The 11-yrs cumulative incidence of asthma was 4.0% in males and 3.5% in females. For respiratory symptoms, the cumulative incidences for both sexes varied between 2.0% (dyspnoea grade 4) and 25.8% (wheezing), being higher in females than males for most symptoms. For calculation of odds ratios (ORs) multivariate logistic regression analyses were used. The sex and smoking-adjusted incidences increased by age for all symptoms except wheezing and attacks of dyspnoea. Those starting to smoke within the follow-up had ORs of 1.9-2.2 for the cough symptoms compared to never-smokers, after adjusting for sex, age, and pack-yrs. To conclude, the 11-yrs incidence of dyspnoea increased with increasing pack-yrs, after adjusting for sex, age, and changes in smoking habits. This indicated that when analysing other risk factors, adjustment has to be made for the risks posed by smoking, sex and age.


Targeted Protein Degradation through E2 Recruitment.
Targeted protein degradation (TPD) with proteolysis targeting chimeras (PROTACs), heterobifunctional compounds consisting of protein targeting ligands linked to recruiters of E3 ubiquitin ligases, has arisen as a powerful therapeutic modality to induce the proximity of target proteins with E3 ligases to ubiquitinate and degrade specific proteins in cells. Thus far, PROTACs have primarily exploited the recruitment of E3 ubiquitin ligases or their substrate adapter proteins but have not exploited the recruitment of more core components of the ubiquitin-proteasome system (UPS). In this study, we used covalent chemoproteomic approaches to discover a covalent recruiter against the E2 ubiquitin conjugating enzyme UBE2D─EN67─that targets an allosteric cysteine, C111, without affecting the enzymatic activity of the protein. We demonstrated that this UBE2D recruiter could be used in heterobifunctional degraders to degrade neo-substrate targets in a UBE2D-dependent manner, including BRD4 and the androgen receptor. Overall, our data highlight the potential for the recruitment of core components of the UPS machinery, such as E2 ubiquitin conjugating enzymes, for TPD, and underscore the utility of covalent chemoproteomic strategies for identifying novel recruiters for additional components of the UPS.


Association of Motor Function With Cognitive Trajectories and Structural Brain Differences: A Community-Based Cohort Study.
The association of motor function with cognitive health remains controversial, and the mechanisms underlying this relationship are unclear. We aimed to examine the association between motor function and long-term cognitive trajectories and further explore the underlying mechanisms using brain MRI. In the Rush Memory and Aging Project, a prospective cohort study, a total of 2,192 volunteers were recruited from the communities in northeastern Illinois and followed up for up to 22 years (from 1997 to 2020). Individuals with dementia, disability, missing data on motor function at baseline, and missing follow-up data on cognitive function were excluded. At baseline, global motor function was evaluated using the averaged z scores of 10 motor tests covering dexterity, gait, and hand strength; the composite score was tertiled as low, moderate, or high. Global and domain-specific cognitive functions-including episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed-were measured annually through 19 cognitive tests. A subsample (n = 401) underwent brain MRI scans and regional brain volumes were measured. Data were analyzed using linear mixed-effects models and linear regression. Among the 1,618 participants (mean age 79.45 ± 7.32 years) included in this study, baseline global motor function score ranged from 0.36 to 1.82 (mean 1.03 ± 0.22). Over the follow-up (median 6.03 years, interquartile range 3.00-10.01 years), low global motor function and its subcomponents were related to significantly faster declines in global cognitive function (β = -0.005, 95% CI -0.006 to -0.005) and each of the 5 cognitive domains. Of the 344 participants with available MRI data, low motor function was also associated with smaller total brain (β = -25.848, 95% CI -44.902 to -6.795), total white matter (β = -18.252, 95% CI -33.277 to -3.226), and cortical white matter (β = -17.503, 95% CI -32.215 to -2.792) volumes, but a larger volume of white matter hyperintensities (β = 0.257, 95% CI 0.118-0.397). Low motor function is associated with an accelerated decline in global and domain-specific cognitive functions. Both neurodegenerative and cerebrovascular pathologies might contribute to this association.


Effect of ECRG2 in combination with cisplatin on the proliferation and apoptosis of EC9706 cells.
The aim of the present study was to explore the effect of esophageal cancer-related gene 2 (ECRG2) protein in combination with cisplatin (DDP) on the proliferation and apoptosis of esophageal cancer cells. A 3-(4, 5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay was used to examine the effects of ECRG2 alone and ECRG2 in combination with DDP on the proliferation of EC9706 esophageal cancer cells. Hoechst 33258 staining was performed to analyze the effects of ECRG2 alone and ECRG2 in combination with DDP on apoptosis in the EC9706 cells. The expression levels of Bcl-2-associated X protein (Bax) mRNA and protein were determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively. The results from the MTT assay revealed that ECRG2 inhibited the proliferation of EC9706 cells and that ECRG2 in combination with DDP had a greater inhibitory effect on cell proliferation. The antiproliferative effects were time- and concentration-dependent, within a certain range of concentrations. The Hoechst 33258 staining results demonstrated that the number of apoptotic cells following treatment with ECRG2 in combination with DDP for 24 h was higher than that following treatment with ECRG2 alone for the same duration. Western blot analysis and RT-PCR results revealed that the expression levels of Bax mRNA and protein were upregulated in cells treated with ECRG2 in combination with DDP compared with those in cells treated with ECRG2 alone. Thus, ECRG2 in combination with DDP had an enhanced inhibitory effect on EC9706 cell proliferation compared with that of ECRG2 alone, and an increased inductive effect on EC9706 cell apoptosis, possibly due to the upregulation of the expression of Bax.


High yield formation of o-aminobenzoic acid-7-O-beta-D-(beta-1,6-O-d-glucopyranosyl)-glucopyranosyl ester in cell suspension cultures of Solanum mammosum.
Cell suspension cultures of Solanum mammosum cultivated in modified Murashige & Skoog media could synthesize o-aminobenzoic acid-7-O-beta-D-(beta-1,6-O-D-glucopyranosyl)-glucopyranosyl ester from o-amino benzoic acid with a yield of about 20% dry weight in 7 days. The maximum production of o-aminobenzoic acid-7-O-beta-D-(beta-1,6-O-D-glucopyranosyl)-glucopyranosyl ester was 31.8% on dry weight basis.


Public (Skin) Health perspectives of gender differences in tanning habits and sun protective behaviour: a cross-sectional questionnaire survey.
Life-style-associated exposure to sunlight is a contributory factor for acute and chronic skin damage including malign melanoma. The aim of the present study was to investigate the current gender-specific attitudes and motives regarding sun tanning and sunlight protective behaviour among Austrian residents. In this cross-sectional study, a convenient sample of 563 Austrian inhabitants participated in a self-reported questionnaire-based outdoor survey. We subjected the data obtained to statistical analysis to get insight into socio-demographic and sun risk behaviour-related inter-group differences (smoking habits as well as gender). The survey revealed significant gender differences in respect to sun protective behaviour and knowledge on adverse health effects of ultraviolet light exposure. Female participants achieved a higher knowledge score, showed higher risk awareness, and performed more sun protection (all p < 0.0001). Male participants were more likely to underestimate the dangers of unprotected sun exposure, consistently resulting in a higher frequency of reported sunburns in men (p = 0.005). Although smoking habits were gender-independent, smokers compared with non-smokers sun bathed more frequently with less sun protection (all p < 0.0001), and were less sportive (p = 0.035). The study provides empirical data contributing to the development of novel approaches for target group and gender-specific Public (Skin) Health education programs and information materials. Revised strategies for improved skin health promotion and skin cancer prevention should focus on the benefits of sun light avoidance regarding long-term deterioration of physical appearance and attractiveness.


Asymmetric hybrids between hemoglobin Alberta (alpha 2 beta 2 101 Glu replaced by Gly) and hemoglobins A, A2 or F1 in different liganded states.
Isoelectric focusing in cylindrical polyacrylamide gels has been used to demonstrate the formation of asymmetric hybrids between an abnormal hemoglobin, Hb Alberta (alpha 2 beta 2 101 Glu replaced by Gly), and Hb A (alpha 2 beta 2), Hb A2 (alpha 2 delta 2) or Hb F1 (alpha 2 gamma 2 Acetyl). There was no discernible difference in the stabilities of the three hybrids (alpha 2 beta A beta Alberta, alpha 2 delta beta Alberta and alpha 2 gamma Acetyl beta Alberta) in the oxy, carboxy or cyanmet hemoglobin forms. Two mixed liganded hybrids, (alpha beta A)oxy (alpha beta Alberta)cyanmet and (alpha beta A)cyanmet (alpha beta Alberta)oxy were also demonstrated and found to have stabilities similar to that of the Hb Alberta hybrids.


Viewpoint: Role of Mind-body Therapies in the Management of Cardiovascular Disorders.
Cardiovascular disorders (CVD) are the leading cause of death across the globe. The estimated cost to the National Health Service and UK economy is £30 billion. These costs continue to escalate despite major advances in pharmacotherapy and devices, which, in part, is due to improved survival, but also greater resource utilisation per patient. Hence, there is a need to develop cost-effective adjunctive therapies beyond conventional strategies. Mind-body therapies- including mindfulness and meditation, emotional regulation, practicing 'heartfelt' emotions including gratitude and compassion- may be novel low-cost approaches to reduce morbidity and mortality in CVD.


Contemporary Management of Acute Pulmonary Embolism.
Multiple treatment options beyond anticoagulation exist for massive and submassive pulmonary embolism to reduce mortality. For some patients, systemic thrombolytics and catheter-directed thrombolysis are appropriate interventions. For others, surgical pulmonary embolectomy can be life-saving. Extracorporeal life support and right ventricular assist devices can provide hemodynamic support in challenging cases. We propose a management algorithm for the treatment of massive and submassive pulmonary embolism, in conjunction with a multidisciplinary pulmonary embolism response team, to guide clinicians in individualizing treatment for patients in a timely manner.


Phylogeny of Toll-like receptor signaling: adapting the innate response.
The Toll-like receptors represent a largely evolutionarily conserved pathogen recognition machinery responsible for recognition of bacterial, fungal, protozoan, and viral pathogen associated microbial patterns and initiation of inflammatory response. Structurally the Toll-like receptors are comprised of an extracellular leucine rich repeat domain and a cytoplasmic Toll/Interleukin 1 receptor domain. Recognition takes place in the extracellular domain where as the cytoplasmic domain triggers a complex signal network required to sustain appropriate immune response. Signal transduction is regulated by the recruitment of different intracellular adaptors. The Toll-like receptors can be grouped depending on the usage of the adaptor, MyD88, into MyD88-dependent and MyD88 independent subsets. Herein, we present a unique phylogenetic analysis of domain regions of these receptors and their cognate signaling adaptor molecules. Although previously unclear from the phylogeny of full length receptors, these analyses indicate a separate evolutionary origin for the MyD88-dependent and MyD88-independent signaling pathway and provide evidence of a common ancestor for the vertebrate and invertebrate orthologs of the adaptor molecule MyD88. Together these observations suggest a very ancient origin of the MyD88-dependent pathway Additionally we show that early duplications gave rise to several adaptor molecule families. In some cases there is also strong pattern of parallel duplication between adaptor molecules and their corresponding TLR. Our results further support the hypothesis that phylogeny of specific domains involved in signaling pathway can shed light on key processes that link innate to adaptive immune response.


Insulin-receptor tyrosine kinase activity is decreased in erythrocytes from non-obese patients with NIDDM.
We have examined insulin binding, and insulin receptor associated tyrosine kinase activity in detergent solubilized and Ricin II-agarose purified receptor preparations from erythrocytes of obese and non-obese subjects with normal glucose tolerance and non-obese patients with NIDDM. Insulin receptor activity, as assessed by [125I Tyr A14] insulin binding, was significantly lower in erythrocyte preparations from the obese group when compared with similar preparations from non-obese subjects, with either normal glucose tolerance or NIDDM. The affinity of the receptor for insulin, however, was reduced in both obese subjects and patients with NIDDM as compared to non-obese subjects with normal glucose tolerance. Insulin receptor tyrosine kinase activity, measured in the absence (basal) and presence of insulin (0.3-3000 nM), was decreased in obese and NIDDM subjects with normal glucose tolerance and in patients with NIDDM. Insulin sensitivity, measured as the dose of insulin required for half-maximal activation of kinase activity, however, was comparable among three groups. In contrast, insulin-stimulated tyrosine kinase activity, when normalized to insulin binding activity, was unchanged in both non-obese and obese subjects with normal glucose tolerance, but was reduced approximately 60% in the NIDDM group. These findings indicate that the functional behavior of insulin receptor-kinase signaling system is markedly impaired in non-obese patients with NIDDM. Furthermore, the insulin receptor-tyrosine kinase defect (i.e. decrease in activity) observed in patients with NIDDM is probably related to a reduction in coupling efficiency between insulin binding and the activation of the receptor tyrosine kinase activity.


Optimized partition of minimum spanning tree for piecewise modeling by particle swarm algorithm. QSAR studies of antagonism of angiotensin II antagonists.
In quantitative structure-activity relationship (QSAR) modeling, when compounds in a training set exhibit a significant structural distinction between each other, in particular when chemicals of biological interest interacting on the receptor involve a different mechanism, it might be difficult to construct a single linear model for the whole population of compounds of interest with desired residuals. Developing a piecewise linear local model can be effective to circumvent the aforementioned problem. In this paper, piecewise modeling by the particle swarm optimization (PMPSO) approach is applied to QSAR study. The minimum spanning tree is used for clustering all compounds in the training set to form a tree, and the modified discrete PSO is applied to divide the tree to find satisfactory piecewise linear models. A new objective function is formulated for searching the appropriate piecewise linear models. The proposed PMPSO algorithm was used to predict the antagonism of angiotensin II. The results demonstrated that PMPSO is useful for improvement of the performance of regression models.


The APOE-TOMM40 Humanized Mouse Model: Characterization of Age, Sex, and PolyT Variant Effects on Gene Expression.
The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer's disease (LOAD) and other age-related conditions. Here we developed the first humanized mouse model that contains the entire TOMM40 and APOE genes with all intronic and intergenic sequences including the upstream and downstream regions. Thus, the mouse model carries the human TOMM40 and APOE genes and their intact regulatory sequences. We generated the APOE-TOMM40 humanized mouse model in which the entire mouse region was replaced with the human (h)APOE-TOMM40 loci including their upstream and downstream flanking regulatory sequences using recombineering technologies. We then measured the expression of the human TOMM40 and APOE genes in the mice brain, liver, and spleen tissues using TaqMan based mRNA expression assays. We investigated the effects of the '523' polyT genotype (S/S or VL/VL), sex, and age on the human TOMM40- and APOE-mRNAs expression levels using our new humanized mouse model. The analysis revealed tissue specific and shared effects of the '523' polyT genotype, sex, and age on the regulation of the human TOMM40 and APOE genes. Noteworthy, the regulatory effect of the '523' polyT genotype was observed for all studied organs. The model offers new opportunities for basic science, translational, and preclinical drug discovery studies focused on the APOE genomic region in relation to LOAD and other conditions in adulthood.


Proton resonance assignments and secondary structure of bovine angiogenin.
Angiogenins are 14-kDa proteins able to induce blood vessel growth in various preparations and are thus thought to be involved in the development of solid tumors. Angiogenins have significant similarities with extracellular ribonuclease and possess a characteristic nuclease activity against large RNA molecules. These proteins are also able to induce second-messenger pathways. We have undertaken the determination of the three-dimensional structure of bovine angiogenin by using nuclear magnetic resonance (NMR) spectroscopy. Since this protein was directly purified from cow milk, it was not possible to enrich angiogenin with 13C or 15N isotopes. However, extensive use of two-dimensional and three-dimensional proton NMR experiments enabled us to identify all but four spin systems and to assign all corresponding proton resonances. Identification of most backbone-backbone nuclear Overhauser enhancements led to the characterization of the secondary structure elements of the protein. Comparison with the structure of ribonuclease A and analysis of the location of conserved residues confirmed that the two molecules have very similar structures.


Resistance to bacterial and parasitic infections in the nutritionally compromised host.
Over the past few years the relationships and interactions of diet, disease, and immunology are becoming better defined with the development and understanding of host defenses. Nutritional state, immunity, and disease all influence each other in the hospitalized patient, the elderly, and the young. Disease can alter nutritional needs and immune responses to antigens. The roles of both dietary excesses and deficiencies on cellular, secretory, and humoral immune responses are related to diseases and disease incidence in humans and experimental animals. Malnutrition alters incidence and severity of fungal, bacterial, viral, and parasitic pathogens. The mechanisms of altered disease resistance in nutritionally stressed animal models occurs via changes in the lymphoreticular endothelial system. The effects of common nutritional deficiencies, low protein, and low carbohydrate diets on antibody production, macrophage function, secretory IgA synthesis, and T-cell functions. Nutritional supplementation can increase lymphocyte function and decrease growth of some pathogens and tumors. Alternatively, obesity and high fat have roles in infectious disease and immunity.


Presentations of nausea and vomiting.
The BEACH program is a continuous national study of general practice activity in Australia. This analysis of encounters where patients presented with nausea and/or vomiting between April 2000 and March 2006 provides a backdrop against which related articles in this issue of Australian Family Physician can be further considered.


Biology in bloom: implementing Bloom's Taxonomy to enhance student learning in biology.
We developed the Blooming Biology Tool (BBT), an assessment tool based on Bloom's Taxonomy, to assist science faculty in better aligning their assessments with their teaching activities and to help students enhance their study skills and metacognition. The work presented here shows how assessment tools, such as the BBT, can be used to guide and enhance teaching and student learning in a discipline-specific manner in postsecondary education. The BBT was first designed and extensively tested for a study in which we ranked almost 600 science questions from college life science exams and standardized tests. The BBT was then implemented in three different collegiate settings. Implementation of the BBT helped us to adjust our teaching to better enhance our students' current mastery of the material, design questions at higher cognitive skills levels, and assist students in studying for college-level exams and in writing study questions at higher levels of Bloom's Taxonomy. From this work we also created a suite of complementary tools that can assist biology faculty in creating classroom materials and exams at the appropriate level of Bloom's Taxonomy and students to successfully develop and answer questions that require higher-order cognitive skills.


[Study of extracellular concentration of dopamine and its metabolites in mice striatum by a microdialysis technique at intraperitoneal administration of MPTP].
In this paper a structure of a microdialytic cannula inserted into brain areas just before a microdialysis is described. The cannula used allowed to find out a correspondence of behavioral and biochemical changes in C57BL/6 mice at various time intervals after a single dose administration (20 mg/kg) of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, without any additional pharmacological actions enhancing an extracellular striatal dopamine concentration. Immediately after 1-methyl-4-phenyl-1.2,3.6-tetrahydropyridine administration an essential disturbance of mice behavior and a significant reduction of the extracellular concentration of dopamine and homovanillic acid were observed in striatum. A week after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration neither behavior nor the extracellular dopamine and homovanillic acid striatal concentration substantially differed from those of controls. 30 days after the neurotoxin administration there was again an essential disturbance of behavior and the large reduction of dopamine and its metabolite concentration in striatum. There was suggested that a reduction of the dopamine concentration immediately after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection connected with abnormalities of dopamine synthesis and metabolism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine whereas a reduction of the extracellular striatal dopamine concentration 30 days after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration related to damage of the nigrastriatal dopaminergic system.


Early-response biological dosimetry--recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism.
The effective medical management of a suspected acute radiation overexposure incident necessitates recording dynamic medical data, measuring appropriate radiation bioassays, and estimating dose from dosimeters and radioactivity assessments in order to provide diagnostic information to the treating physician and a dose assessment for personnel radiation protection records. The accepted generic multiparameter and early-response approach includes measuring radioactivity and monitoring the exposed individual; observing and recording prodromal signs/symptoms and erythema; obtaining complete blood counts with white blood cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the "gold standard" dicentric assay (translocation assay for long times after exposure) for dose assessment; bioassay sampling, if appropriate, to determine radioactivity contamination; and using other available dosimetry approaches. In the event of a radiological mass-casualty incident, current national resources need to be enhanced to provide suitable dose assessment and medical triage and diagnoses. This capability should be broadly based and include stockpiling reagents and devices; establishing deployable (i.e., hematology and biodosimetry) laboratories and reference (i.e., cytogenetic biodosimetry, radiation bioassay) laboratories; networking qualified reference radioactivity-counting bioassay laboratories, cytogenetic biodosimetry, and deployable hematology laboratories with the medical responder community and national radiation protection program; and researching efforts to identify novel radiation biomarkers and develop applied biological dosimetry assays monitored with clinical, deployable, and hand-held analytical systems. These research and applied science efforts should ultimately contribute towards approved, regulated biodosimetry devices or diagnostic tests integrated into a national radioprotection program.


Effect of adenosine on heart rate in isolated muskrat and guinea pig hearts.
The purpose of this study was to compare the responses of isolated hearts of the diving muskrat with the nondividing guinea pig (GP) to determine the contribution of adenosine (ADO) to the profound bradycardia that was seen in isolated muskrat hearts during exposure to hypoxia. Muskrat hearts were more sensitive than GP hearts to the heart rate-lowering effects of exogenously applied ADO or a stable ADO analogue, (R)-N6-(phenylisopropyl)adenosine. The hearts of both species were unpaced, and the bradycardia appeared to be due to high degree of atrioventricular block. Radioligand binding with 8-cyclopentyl-1,3-[3H]dipropylxanthine to A1-ADO receptors was greater in cardiac membranes prepared from GP hearts than from muskrat hearts. Nucleoside transporter antagonist binding was also greater in GP hearts compared with muskrats. This was determined by membrane binding of [3H]-nitrobenzylthioinosine, an antagonist of nucleoside transport. Both muskrat and GP hearts responded to 30 min of hypoxic perfusion by releasing ADO into the coronary effluent; however, the muskrat hearts released approximately five times more than the GP hearts. When hearts were subjected to hypoxia in the presence of ADO deaminase, theophylline, or 8-(p-sulfophenyl)theophylline, the hypoxia-induced bradycardia was blocked in the GP hearts and either slightly reduced or not affected in muskrat hearts. In contrast to GP hearts, muskrat hearts release larger amounts of ADO during hypoxia and are more sensitive to the negative chronotropic effects of exogenously administered ADO; yet the hypoxia-induced bradycardia does not appear to be exclusively mediated by ADO in the muskrat as it is in the isolated GP heart.


Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation.
Calbindin, a major Ca2+ buffer in dentate granule cells (GCs), plays a critical role in shaping Ca2+ signals, yet how it regulates neuronal function remains largely unknown. Here, we found that calbindin knockout (CBKO) mice exhibited dentate GC hyperexcitability and impaired pattern separation, which co-occurred with reduced K+ current due to downregulated surface expression of Kv4.1. Relatedly, manipulation of calbindin expression in HT22 cells led to changes in CaMKII activation and the level of surface localization of Kv4.1 through phosphorylation at serine 555, confirming the mechanism underlying neuronal hyperexcitability in CBKO mice. We also discovered that Ca2+ buffering capacity was significantly reduced in the GCs of Tg2576 mice to the level of CBKO GCs, and this reduction was restored to normal levels by antioxidants, suggesting that calbindin is a target of oxidative stress. Our data suggest that the regulation of CaMKII signaling by Ca2+ buffering is crucial for neuronal excitability regulation.


Endomembrane remodeling in autophagic membrane formation.
Autophagosomal membrane sources generate autophagic membrane precursors, which later assemble into the double-membrane autophagosome. The key events happening on the membrane sources during autophagic membrane generation remain poorly characterized. Our previous work found the ER-Golgi intermediate compartment (ERGIC) as a membrane source for the phagophore, the precursor to the autophagosome. A relocation of the COPII machinery from the ER-exit sites (ERES) to the ERGIC generates vesicles for LC3 lipidation. In recent work, we made a further step by showing that a starvation-induced remodeling of ERES facilitates the relocation of COPII to the ERGIC and the generation of the autophagic membrane.


[A case of neurofibromatosis type I associated with basal meningocele and abnormal vessels].
A 21-year-old man with neurofibromatosis type 1 (NF 1) had many widespread cutaneous neurofibroma on his right face. Magnetic resonance imaging (MRI) revealed basal meningocele due to dysplasia of the skull base. Carotid and vertebral angiograms revealed occlusion of the right internal carotid artery, persistent primitive trigeminal artery. We have reviewed the clinical and radiographic features of this case of neurofibromatosis, meningocele and cerebral arterial abnormalities. NF associated with both intracranial vascular malformation and meningocele is very rare, and in our case both were thought to arise congenitally as a manifestation of mesodermal dysplasia. Careful follow up using MRI and MR angiography should be performed for such patients.


[Remittent seronegative symmetrical synovitis with pitting edema].
The symptoms and signs of remitting, seronegative symmetrical synovitis with pitting oedema (RS3PE-syndrome) are reviewed. Three patients with the disease are described, of whom one also developed multiple myeloma. All patients presented with diffuse swelling of the hands, consisting of both arthritis and oedema. Radiological examination did not disclose erosive changes, and all patients recovered. The article includes recommendations for clinical and laboratory investigations and therapy. The condition usually has a favourable outcome.


Harnessing pyrimidine as a building block for histone deacetylase inhibitors.
Histone deacetylase (HDAC) inhibitors are well-established multifaceted bioactive agents against tumors and neurodegenerative disorders. Pyrimidine and its fused and substituted derivatives were employed as a surface recognition moiety of HDAC inhibitors. De facto, the literature was loaded with different success stories of pyrimidine-based HDAC inhibitors that garnered much interest. Provoked by our continuous interest in HDAC inhibitors, we summarized and elaborated on the successful harnessing of the pyrimidine scaffold in this regard. Furthermore, we dissect our perspective that may guide medicinal chemists for an effective future design of more active chemotherapeutic agents with potential clinical applications.


HLA alleles and haplotype frequencies in Iranian population.
HLA genotyping is a prerequisite for selection of suitable donors in the process of bone marrow transplantation. In the current study, the frequencies of HLA-A, -B, -C and -DRB1 alleles and A-B-C-DRB1 haplotypes were assessed in 855 healthy Iranian persons using a low-resolution sequence specific primer (SSP) kit. Frequencies were compared between 11 subpopulations including Armani, Balouch, Bandari, Turk, Turkaman, Arab, Fars, Kurd, Gilaki, Lor and Mazani. In total, 17 HLA-A alleles were detected, one of which (HLA-A*74) was present only among Lors. HLA-A*23 and -A*26 were the most frequent HLA-A alleles among Armanis. HLA-A*23 was also common among Turkamans. HLA-A*11 and -A*26 were most frequent among the Balouch subpopulation. The former allele was also frequent among Bandaris. HLA-A*02 was identified as the most common HLA-A allele among Turk, Arab and Fars subpopulations. HLA-A*30 were strongly enriched among Gilakis. A total of 31 HLA-B alleles were detected across the target population. While all alleles were present among Fars subgroup, Armanis and Turkamans had the lowest degree of diversity among the alleles examined. Moreover, HLA-B*35 and B*49 alleles were strongly enriched among Armanis and Turkamans, respectively. A total of 13 HLA-C alleles were identified across the population, all of which were present in the Fars subpopulation. HLA-C*03 and C*04 were the only HLA-C alleles identified among the Bandari subpopulation. HLA-DRB1*08 was not detected in any subpopulation other than Fars. HLA-DRB1*16 was significantly enriched among Bandaris. These data have practical significance in anthropological studies, disease association investigations and bone marrow transplantation.


Neural circuitry underlying oscillatory motor output.
1. The stomatogastric nervous system of lobsters can be used as a model network with which to study the mechanisms involved in the generation of rhythmic behaviour. 2. The stomatogastric ganglion contains about thirty neurons and produces two rhythms, the gastric and the pyloric. 3. The gastric rhythm appears to be derived from the global properties of a twelve-cell network. 4. The pyloric rhythm is driven by a group of three endogenous bursters. 5. Both rhythms are assisted by phasic excitatory input from the two commissural ganglia. 6. Synapses found in this network appear to be located on the finest dendritic branches and are multiterminal.


Towards standardizing basophil identification by flow cytometry.
Basophils normally make up <2% of the white blood cells (WBC). There is no clear consensus for basophil identification by flow cytometry. The increased demand for basophil activation test (BAT) to identifying and monitoring allergic patients highlights the need for a standardized approach to identify basophils. Using flow cytometry we analyzed whole blood stained with antibodies against: IgE, CD123, CD193, CD203c, CD3, HLADR, FcɛRI, CRTH2 and CD45. We examined unstimulated blood as well as blood stimulated with Anti-IgE and fMLP. Finally, we compared the results to a complete blood count (CBC) from an FDA approved hematological analyzer. Basophil identification relying on just one surface marker performed worse than approaches utilizing two identification markers. The percentage of basophils from WBC determined by flow cytometry results had a good correlation with the CBC results even though the CBC results were generally higher. Stimulating whole blood with the basophil activators did not interfere with the basophil identification markers. In flow cytometry assays, two surface markers should be used for identifying basophils and if a very pure basophil fraction is desired a third marker can be considered. In our hands the approaches that included CD123 in combination with either CD193, HLADRnegative or FcɛRI performed the best.


The Genomes of the Allohexaploid Echinochloa crus-galli and Its Progenitors Provide Insights into Polyploidization-Driven Adaptation.
The hexaploid species Echinochloa crus-galli is one of the most detrimental weeds in crop fields, especially in rice paddies. Its evolutionary history is similar to that of bread wheat, arising through polyploidization after hybridization between a tetraploid and a diploid species. In this study, we generated and analyzed high-quality genome sequences of diploid (E. haploclada), tetraploid (E. oryzicola), and hexaploid (E. crus-galli) Echinochloa species. Gene family analysis showed a significant loss of disease-resistance genes such as those encoding NB-ARC domain-containing proteins during Echinochloa polyploidization, contrary to their significant expansionduring wheat polyploidization, suggesting that natural selection might favor reduced investment in resistance in this weed to maximize its growth and reproduction. In contrast to the asymmetric patterns of genome evolution observed in wheat and other crops, no significant differences in selection pressure were detected between the subgenomes in E. oryzicola and E. crus-galli. In addition, distinctive differences in subgenome transcriptome dynamics during hexaploidization were observed between E. crus-galli and bread wheat. Collectively, our study documents genomic mechanisms underlying the adaptation of a major agricultural weed during polyploidization. The genomic and transcriptomic resources of three Echinochloa species and new insights into the polyploidization-driven adaptive evolution would be useful for future breeding cereal crops.


Interaction of Salmonella phage P22 with its O-antigen receptor studied by X-ray crystallography.
The O-antigenic repeating units of the Salmonella cell surface lipopolysaccharides (serotypes A, B and D1) serve as receptors for phage P22. This initial binding step is mediated by the tailspike protein (TSP), which is present in six copies on the base plate of the phage. In addition to the binding activity, TSP also displays a low endoglycolytic activity, cleaving the alpha(1,3)-O-glycosidic bond between rhamnose and galactose of the O-antigenic repeats. The crystal structure of TSP in complex with receptor fragments allowed to identify the receptor binding site for the octasaccharide product of the enzymatic action of TSP on delipidated LPS and the active site consisting of Asp392, Asp395 and Glu359. The structure comprises a large right-handed parallel beta-helix of 13 turns. These fold independently in the trimer, whereas the N-terminus forms a cap-like structure and the C-terminal parts of the three polypeptide strands merge to a single common domain. In addition, TSP has served as model system for the folding of large, multisubunit proteins. Its folding pathway is influenced by a large number of point mutations, classified as lethal, temperature sensitive or general suppressor mutations, which influence the partitioning between aggregation and the productive folding pathway.


Octreotide-modified liposomes containing daunorubicin and dihydroartemisinin for treatment of invasive breast cancer.
Tumor invasion is considered a major promoter in the initiation of tumor metastasis, which is supposed to cause most cancer-related deaths. In the present study, octreotide (OCT)-modified daunorubicin plus dihydroartemisinin liposomes were developed and characterized. Evaluations were undertaken on breast cancer MDA-MB-435S cells and MDA-MB-435S xenografts nude mice. The liposomes were ∼100 nm in size with a narrow polydispersity index. In vitro results showed that the OCT-modified daunorubicin plus dihydroartemisinin liposomes could enhance cytotoxicity and cellular uptake by OCT-SSTRs (somatostatin receptors)-mediated active targeting, block on tumor cell wound healing and migration by incorporating dihydroartemisinin. The action mechanism might be related to regulations on E-cadherin, α5β1-integrin, TGF-β1, VEGF and MMP2/9 in breast cancer cells. In vivo, the liposomes displayed a prolonged circulating time, more accumulation in tumor location, and a robust overall antitumor efficacy with no obvious toxicity at the test dose in MDA-MB-435S xenograft mice. In conclusion, the OCT-modified daunorubicin plus dihydroartemisinin liposomes could prevent breast cancer invasion, hence providing a possible strategy for treatment of metastatic breast cancer.


Congenital Anomalies in Contaminated Sites: A Multisite Study in Italy.
The health impact on populations residing in industrially contaminated sites (CSs) is recognized as a public health concern especially in relation to more vulnerable population subgroups. The aim of this study was to estimate the risk of congenital anomalies (CAs) in Italian CSs. Thirteen CSs covered by regional CA registries were investigated in an ecological study. The observed/expected ratios (O/E) with 90% confidence intervals (CI) for the total and specific subgroups of CAs were calculated using the regional areas as references. For the CSs with waste landfills, petrochemicals, and refineries, pooled estimates were calculated. The total number of observed cases of CAs was 7085 out of 288,184 births (prevalence 245.8 per 10,000). For some CSs, excesses for several CA subgroups were observed, in particular for genital and heart defects. The excess of genital CAs observed in Gela (O/E 2.36; 90% CI 1.73-3.15) is consistent with findings from other studies. For CSs including petrochemical and landfills, the pooled risk estimates were 1.10 (90% CI 1.01-1.19) and 1.07 (90% CI 1.02-1.13), respectively. The results are useful in identifying priority areas for analytical investigations and in supporting the promotion of policies for the primary prevention of CAs. The use of short-latency effect indicators is recommended for the health surveillance of the populations residing in CSs.


Rice phytochelatin synthases OsPCS1 and OsPCS2 make different contributions to cadmium and arsenic tolerance.
Cadmium (Cd) and arsenic (As) pollution in paddy soil and their accumulation in rice (Oryza sativa) pose serious threats to human health. Rice internally detoxifies these toxic metal and metalloid to some extent, resulting in their accumulation within the edible parts. However, the mechanisms of Cd and As detoxification in rice have been poorly elucidated. Plants synthesize thiol-rich metal-chelating peptides, termed phytochelatins (PCs). We characterized rice PC synthase (PCS) and investigated its contribution to Cd and As tolerance in rice. We identified two PCS homolog genes, OsPCS1 and OsPCS2, in the rice genome. The expression of OsPCS1 was upregulated by As(III) stress in the roots but that of OsPCS2 was not significantly affected. The expression level of OsPCS2 was higher than that of OsPCS1 in the shoots and roots. Recombinant OsPCS1 and OsPCS2 proteins differed in their metal activation. OsPCS1 was more strongly activated by As(III) than by Cd; however, OsPCS2 was more strongly activated by Cd than by As(III). Genetically engineered plants having their OsPCS2 expression silenced via RNA interference (OsPCS2 RNAi) contained less PCs and more glutathione (GSH), a substrate of PC synthesis, than wild-type plants, although there was no significant difference in OsPCS1 RNAi plants. OsPCS2 RNAi plants were sensitive to As(III) stress, but Cd tolerance was little affected. On the other hand, treatment with buthionine sulfoximine, an inhibitor of GSH biosynthesis, significantly decreased Cd and As tolerance of rice seedlings. These findings indicate that OsPCS2 is a major isozyme controlling PC synthesis, and that PCs are important for As tolerance in rice. However, PC synthesis may make a smaller contribution to Cd tolerance in rice, and GSH plays crucial roles, not only as a substrate of PC synthesis.


Hemothorax After Endobronchial Ultrasound-guided Transbronchial Needle Aspiration.
Endobronchial ultrasound-guided transbronchial needle aspiration is a minimally invasive method for diagnosing paratracheal and peribronchial lesions, with a low rate of complications. However, as the procedure has gained widespread acceptance, major complications have occasionally been reported. In this report, we describe a case of hemothorax after endobronchial ultrasound-guided transbronchial needle aspiration in a patient with a right upper lobe mass.


Food dye use in enteral feedings: a review and a call for a moratorium.
Pulmonary aspiration of gastric contents is common in enterally fed patients. Tinting enteral feedings with blue dye is thought to aid the early detection of aspiration in hospitalized patients. The blue-dye method is popular despite evidence that it is not sensitive. Reports of absorption of blue dye from enteral feedings in patients with sepsis and other critical illnesses are increasing. The presence of blue and green skin and urine, and serum discoloration has been linked with death. FD&C Blue No.1 and related dyes have toxic effects on mitochondria, suggesting that dye absorption is harmful. This study reviews the literature on the dye method and dye pharmacology, reports the results of a survey of current dye use, and describes 2 recent deaths associated with blue-dye absorption. We concluded that the use of blue dye in enteral feedings should be abandoned and replaced by evidence-based methods for the prevention of aspiration.


Evaluation of Aminophylline for the Treatment of Acute Kidney Injury in Pediatric Hematology/Oncology Patients.
The purpose of this study was to compare acute kidney injury (AKI)-related outcomes of patients who received aminophylline in addition to standard of care with matched historical controls who received standard of care alone. This was a single center, retrospective, historical control cohort study that included patients treated for AKI. Patients who received aminophylline from January 2017 to June 2018 were matched for age, sex, primary diagnosis, and hematopoietic cell transplant history in a 1:2 ratio to historical controls treated for AKI from July 2015 to September 2016. The primary outcome was improvement in AKI stage at 5 and 10 days from treatment initiation. Twenty-seven patients who received aminophylline were matched to 54 historical controls. Fifty-eight patients (72%) had recently undergone hematopoietic cell transplant. At day 5, improvement in AKI stage was observed in 56% of patients in each group (p = 1.0); at day 10, improvement in AKI stage was observed in 75% of patients in the aminophylline group vs 70% of historical controls (p = 0.76). By day 10, serum creatinine levels had returned to baseline in 21% of patients in the aminophylline group and 34% of patients in the control group (p = 0.37). Findings of this study demonstrated no difference in the rate of AKI resolution or in the proportion of patients with resolved AKI when aminophylline was added to standard of care for the treatment of AKI in this pediatric hematology/oncology population.


Withdrawal reactions following cessation of central alpha-adrenergic receptor agonists.
Interruption of long-term treatment with alpha 2-adrenergic receptor agonists may be associated with reversal of their hemodynamic effects, clinical and biochemical evidence of increased peripheral sympathetic activity, and behavioral responses similar to those seen after narcotic or alcohol withdrawal. Reactions are most commonly observed after short-acting imidazoline drugs such as clonidine and tiamenidine. Reactions are less common after longer acting agents such as guanfacine. A new management approach to withdrawal has been evaluated, which uses a combination of alpha 1-blockade (prazosin) and cardioselective beta-blockade (atenolol) together with a benzodiazepine (chlordiazepoxide). Withdrawal reactions were not observed in eight patients in whom clonidine was withdrawn under cover of these agents. The mechanism of the withdrawal reaction may involve agonist-induced down regulation of alpha 2-adrenergic receptor affinity, number, or both. Experimental studies with the irreversible alpha-antagonist phenoxybenzamine on the turnover of alpha 2-receptors suggest that recovery of receptor number may be much slower in the brain than in the periphery.


Development and implementation of a molecular diagnostic platform for daily rapid detection of 15 respiratory viruses.
Acute respiratory tract infections are caused by a large number of viruses. Diagnostic methods have until recently been available only for a limited number of these viruses. With the objective to achieve sensitive assays for all respiratory viruses, a rational workflow in the laboratory, and a short turn-around time, a real-time PCR diagnostic platform for daily rapid detection of 15 respiratory viruses was developed. The system was evaluated on 585 stored nasopharyngeal aspirates from hospitalized children. Previous analysis by immunofluorescence and virus isolation identified viruses in 37% of the samples while the new PCR diagnostic panel detected 57% virus positive samples. The new platform was introduced in the laboratory in October 2007 and has then fully replaced the standard immunofluorescence assay for rapid detection of viruses and virus isolation.


Cytotoxicity of anti-beta 2-microglobulin xenoantisera to human and murine myeloid progenitor cells and lack of cross-reactivity with colony-stimulating activity.
A previous report has suggested an antigenic relationship between beta 2-microglobulin (beta 2 mu) and granulocyte colony-stimulating activity (CSA). Since human myeloid progenitor cells (CFU-C) express HLA antigens and beta 2 mu is a known molecular component of HLA antigens, we wondered whether the reported effect of anti-beta 2 mu heteroantisera on in vitro granulopoiesis might result from cytotoxicity to CFU-C rather than from cross-reactivity with CSA. To test this, we used rabbit antibody reactive with human and murine beta 2 mu (anti-beta 2 mu). Treatment of human and murine bone marrow cells with anti-beta 2 mu and complement resulted in 95+% inhibition of CFU-C colony formation compared to controls. To test for an effect on CSA, anti-beta 2 mu was incubated with human and murine sources of CSA. After addition of goat anti-rabbit Ig antiserum to precipitate immune complexes and unbound anti-beta 2 mu, the supernatant fluid retained CSA but was no longer cytotoxic to CFU-C. These results indicate that human and murine CFU-C express membrane beta 2 mu and that anti-beta 2 mu antibody does not cross-react with human or murine CSA.


Rutin via Increase in the CA3 Diameter of the Hippocampus Exerted Antidepressant-Like Effect in Mouse Model of Maternal Separation Stress: Possible Involvement of NMDA Receptors.
Mouse neonates were exposed to MS paradigm 3 hours daily from postnatal days (PND) 2 to 14. The control and MS mice were divided separately into 16 groups (n = 8) (8 groups for each set) including mice that received normal saline, mice that received rutin at doses of 10, 50, and 100 mg/kg, mice that received NMDA at a dose of 150 mg/kg, mice that received ketamine (NMDA antagonist) at a dose of 0.25 mg/kg, mice that received NMDA antagonist plus a subeffective dose of rutin, and mice that received NMDA plus an effective dose of rutin. Forced swimming test (FST) was performed. Afterwards, the hippocampus was evaluated in cases of histopathological changes as well as expression of NR2A and NR2B genes. Rutin significantly reduced immobility time in the FST. The expression of NR2A and NR2B subunits of NMDA receptor in MS mice was significantly higher than that in the control group. Rutin significantly decreased the expression of NR2B and NR2A subunits in the hippocampus. The CA3 diameter and percentage of dark neurons in the hippocampus of MS mice significantly decreased and increased, respectively, which partially reversed following rutin administration. Rutin, partially, through a neuroprotective effect on the hippocampus exerted antidepressant-like effect. We concluded that NMDA receptors, at least in part, mediated the beneficial effect of rutin.


The psychometric properties of the Illness Management and Recovery scale: client and clinician versions.
The present study examined the psychometric properties of the clinician and client versions of the Illness Management and Recovery (IMR) scale. Using a 5-point behaviorally anchored response format, these scales were designed to tap the critical illness management and recovery domains targeted by the IMR program. This program is a curriculum-based approach to helping persons with a serious mental illness (SMI) acquire the knowledge and skills they need to manage their illness effectively and to achieve personal recovery goals. Two hundred and ten persons with a diagnosis of a SMI and their 13 clinicians filled-out the client and clinician versions of the IMR questionnaire. The clients also responded to measures of coping efficacy and social support. While indicating limitations of the IMR scales and pointing to how they could be improved, this study provided some support for the construct and concurrent validity of the client and clinician versions of the IMR questionnaire. Moderate reliabilities were uncovered for these parallel versions of the questionnaire. Client responses to the client IMR scale and clinician responses to the clinician IMR scale were shown to be characterized by similar major components of the IMR intervention.


Rituximab in the treatment of peripheral neuropathy associated with monoclonal gammopathy.
Peripheral neuropathy associated with immunoglobulin (Ig)M gammopathy and anti-myelin-associated glycoprotein antibodies is frequently treatment-resistant and different treatment regimens carry substantial toxicity and side effects. More recently, the chimeric anti-CD20 monoclonal antibody rituximab has shown benefits in the treatment of peripheral neuropathy associated with IgM gammopathy with a favorable side-effect profile. There are no published reports of its use in the treatment of neuropathy associated with IgG and IgA gammopathies. Rituximab is usually given at 375 mg/m(2) intravenously with four weekly doses that may be repeated after 6-12 months. Large controlled studies are still pending but rituximab is an exciting and promising treatment offering another option in the treatment of peripheral neuropathy associated with IgM monoclonal gammopathy.


Implications of Kidney Disease on Metabolic Reduction.
Chronic kidney disease (CKD) modulates the nonrenal clearance of drugs by altering their metabolism and/or transport. While the effects of CKD on pathways of oxidative and conjugative metabolism in the liver are generally understood, the impact of CKD on hepatic reduction is not. Reduction is a critically important pathway for the metabolism of several drugs and endogenous compounds. Multiple clinical pharmacokinetic studies have reported changes in the disposition of hepatic reductase drug substrates in patients with CKD. More recently, data from experimental studies have shown that kidney disease alters the functional expression of hepatic reductases. Together, these data suggest that kidney disease may impair the nonrenal clearance of drugs mediated by reductive pathways. This review synthesizes the current evidence available regarding the effect of CKD on hepatic reduction. Areas for future investigations are also highlighted. The growing knowledge of the impact of impaired kidney function on nonrenal drug clearance may facilitate optimal drug therapy in this patient population.