Hepatitis B Core-Related Antigen: From Virology to Clinical Application.
Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a marker of intrahepatic viral activity, which may influence the risk of hepatocellular carcinoma. In this article, we review the virology and role of HBcrAg in defining phases of chronic hepatitis B. Furthermore, the function of HBcrAg in predicting treatment outcomes and its role in monitoring response to novel antiviral agents will be discussed.


Globe Axial Length Growth at Age 10.5 Years in the Infant Aphakia Treatment Study.
To report the change in globe axial length (AL) from the time of unilateral cataract surgery at age 1-7 months to age 10.5 years for infants enrolled in the Infant Aphakia Treatment Study, and to compare AL growth of operated eyes with that of fellow unoperated eyes. Comparative case series. AL growth was analyzed relative to treated vs fellow eye, contact lens (CL) vs intraocular lens (IOL), visual acuity (VA) outcome, and the need for surgery for visual axis opacification. Eyes with glaucoma or glaucoma suspect were excluded from the primary analysis but reported separately. Fifty-seven patients have reliable AL data available at both visits. AL was shorter in treated eyes preoperatively (P < .0001) and at 10.5 years of age (P = .021) but AL growth was not different (4.7 mm, P = .99). The growth (70.2% up to age 5 and 29.8% from age 5 to 10.5) was similar in the CL and the IOL group (P = .79). Eyes grew 4.4 mm when visual acuity (VA) was better than 20/200, and 5.2 mm when VA was 20/200 or worse (P = .076). Eyes receiving additional surgery grew more than eyes not receiving additional surgery (P = .052). Patients with glaucoma showed significantly more eye growth (7.3 mm) than those without glaucoma (4.7 mm) and glaucoma suspects (5.1 mm) (P < .05). Eyes with glaucoma or poor VA often grew longer than the fellow eye. Overall, treated eyes grew similarly in the IOL and CL groups and also kept pace with the growth of the fellow eyes.


Intake of Bifidobacterium lactis Probio-M8 fermented milk protects against alcoholic liver disease.
Alcoholic liver disease (ALD) is a liver disease caused by long-term heavy drinking, which is characterized by increased inflammation and oxidative stress in the liver and gut dysbiosis. The purpose of this study was to investigate the protective effect of administering ordinary and probiotic- (containing the Bifidobacterium animalis ssp. lactis Probio-M8 strain; M8) fermented milk to rats. Several biochemical parameters and the fecal metagenomes were monitored before (d 0) and after (d 42) the intervention. Our results confirmed that alcohol could cause significant changes in the liver levels of the proinflammatory cytokine IL-1β, antioxidation indicators, and liver function-related indicators; meanwhile, the gut bacterial and viral microbiota were disrupted with significant reduction in microbial diversity and richness. Feeding the rats with Probio-M8-fermented milk effectively maintained the gut microbiota stability, reduced liver inflammation and oxidative stress, and mitigated liver damages in ALD. Moreover, the Probio-M8-fermented milk reversed alcohol-induced dysbiosis by restoring the gut microbiota diversity, richness, and composition. Four predicted fecal metabolites (inositol, tryptophan, cortisol, and vitamin K2) increased after the intervention, which might help regulate liver metabolism and alleviate ALD-related symptoms. In short, our data supported that consuming Probio-M8-fermented milk effectively mitigated ALD. The protective effect against ALD could be related to changes in the gut microbiome after probiotic-fermented milk consumption. However, such observation and the causal relationship among probiotic milk consumption, changes in gut microbiome, and disease alleviation would still need to be further confirmed. Nevertheless, this study has shown in a rat model that consuming probiotic-fermented milk could protect against ALD.


Experimental characterization of a direct conversion amorphous selenium detector with thicker conversion layer for dual-energy contrast-enhanced breast imaging.
Dual-energy contrast-enhanced imaging is being investigated as a tool to identify and localize angiogenesis in the breast, a possible indicator of malignant tumors. This imaging technique requires that x-ray images are acquired at energies above the k-shell binding energy of an appropriate radiocontrast agent. Iodinated contrast agents are commonly used for vascular imaging, and require x-ray energies greater than 33 keV. Conventional direct conversion amorphous selenium (a-Se) flat-panel imagers for digital mammography show suboptimal absorption efficiencies at these higher energies. We use spatial-frequency domain image quality metrics to evaluate the performance of a prototype direct conversion flat-panel imager with a thicker a-Se layer, specifically fabricated for dual-energy contrast-enhanced breast imaging. Imaging performance was evaluated in a prototype digital breast tomosynthesis (DBT) system. The spatial resolution, noise characteristics, detective quantum efficiency, and temporal performance of the detector were evaluated for dual-energy imaging for both conventional full-field digital mammography (FFDM) and DBT. The zero-frequency detective quantum efficiency of the prototype detector is improved by approximately 20% over the conventional detector for higher energy beams required for imaging with iodinated contrast agents. The effect of oblique entry of x-rays on spatial resolution does increase with increasing photoconductor thickness, specifically for the most oblique views of a DBT scan. Degradation of spatial resolution due to focal spot motion was also observed. Temporal performance was found to be comparable to conventional mammographic detectors. Increasing the a-Se thickness in direct conversion flat-panel imagers results in better performance for dual-energy contrast-enhanced breast imaging. The reduction in spatial resolution due to oblique entry of x-rays is appreciable in the most extreme clinically relevant cases, but may not profoundly affect reconstructed images due to the algorithms and filters employed. Degradation to projection domain spatial resolution is thus outweighed by the improvement in detective quantum efficiency for high-energy x-rays.


Exploring Potential Binding Modes of Small Drug-like Molecules to the Polo-Box Domain of Human Polo-like Kinase 1.
Purpurogallin (PPG) and Poloxin have been reported as inhibitors of the polo-box domain (PBD) of human polo-like kinase 1 (Plk1). However, our experimental results demonstrated that PPG, but not Poloxin, binds to the phospho-binding pocket of the PBD, suggesting that their modes of PBD inhibition are distinct. Induced fit docking (IFD) analyses led us to propose that PPG fills the SpT pocket via pi-pi stacking and hydrogen bonding interactions, thus providing a rationale for designing novel PBD inhibitors. In contrast, Poloxin may fill a different site present near the SpT pocket by forming a covalent bond with a nucleophilic Cys residue.


Distinct roles of retinoic acid and BMP4 pathways in the formation of chicken primordial germ cells and spermatogonial stem cells.
This study demonstrated different effects of bone morphogenetic protein 4 (BMP4) and retinoic acid (RA) signaling on the induction of germ cell formation in chickens. In vitro, BMP4 significantly promoted primordial germ cell (PGC) formation, while RA promoted spermatogonial stem cell (SSC) formation. Hematoxylin-Eosin (HE) staining of reproductive ridge and testicular slices showed that BMP4 signaling was activated during PGC formation but was inhibited during PGC differentiation into SSC. In contrast, RA signaling was significantly activated during PGC differentiation to SSC. Mechanistically, elevated expression of phosphorylated mothers against decapentaplegic homolog 5 (p-Smad5) activated BMP4 signaling, while inhibition of p-Smad5 significantly reduced the PGC formation. Additionally, BMP4 regulated the PGC formation through histone acetylation and DNA methylation in deleted in azoospermia-like (DAZL) gene. Luciferase report showed RA binding to RARα regulated stimulated by RA 8 (Stra8) promoter activity during SSC formation, while mutations in RAR binding sites inhibited the Stra8 expression and SSC formation. Further, both HAT and HDAC regulated the RARα isoform, and HAT binding to RARα activated the Stra8 transcription. RNA-seq of embryonic stem cells (ESC), PGC, and SSC showed inverse expression of genes related to the BMP4 and RA pathways during PGC and SSC formation. Additionally, Smad5 and Smurf were critical for the interactions between the two pathways. Specifically, through Smurf promotion of Smad5 ubiquitination, RA could inhibit the BMP4 signal transduction. In conclusion, the BMP4 and RA signaling pathways play opposing roles in germ cell formation, driven by epigenetic processes such as phosphorylation, ubiquitination, and histone acetylation.


The role of thymidine phosphorylase and thrombospondin-1 in angiogenesis and progression of intrahepatic cholangiocarcinoma.
Thymidine phosphorylase (TP), an important regulator of angiogenesis, is correlated with progression, metastasis, and prognosis in various types of tumor. In contrast, both positive and negative effects of thrombospondin-1 (TSP-1) on angiogenesis have been reported. In the present study, we examined the expression of TP and TSP-1 in carcinoma cells in 67 primary intrahepatic cholangiocarcinomas (ICCs) immunohistochemically and its correlation with angiogenesis, clinicopathological features, and prognosis. Twenty-six (38.8%) cases were classified as exhibiting positive TP expression. TP expression showed a significant correlation with vascular invasion, lymphatic permeation, perineural invasion, and lymph node metastasis. Thirty-four (50.7%) cases were classified as exhibiting positive TSP-1 expression. TSP-1 expression was significantly correlated with only lymphatic permeation. The microvessel count in positive TP expression cases was significantly higher than that in negative cases. In contrast, the microvessel count in negative TSP-1 expression cases was significantly higher than that in positive cases. Survival in patients who were positive for both TP and TSP-1 expression was significantly poor. Our results suggest that the increased TP expression and decreased TSP-1 expression contribute to angiogenesis, but that the role of angiogenesis in ICC is not closely related to tumor aggressiveness. The TP and TSP-1 expression in ICC may enhance tumor aggressiveness.


Examination of human meibum collection and extraction techniques.
To compare various meibum collection methods and extraction techniques. Sixty subjects, all successful contact lens wearers, were seen on two visits. Meibum was collected from the lower lid of the right eye with a glass microcapillary tube, and with a Dacron swab, cytology microbrush, or spatula from the left eye. Extraction with 2:1 chloroform:methanol was done either immediately or after data collection was complete. Individual samples were divided into four equal aliquots for analysis of total lipids, cholesterol, and inorganic phosphates by assay-based techniques. Effects of collection method, extraction, and dry eye status were examined using repeated measures analysis of variance and logistic regression. Total lipids showed significance for collection device (p < 0.0001) but not for extraction technique (p = 0.13) or dry eye status (p = 0.97). Dacron swab collection was associated with more total lipid on average than each other collection device (p < 0.0001). The cholesterol assay showed significance of collection device (p < 0.0001) and extraction technique (p = 0.0002) but not dry eye status (p = 0.55). Spatula collection was associated with more cholesterol on average than each other collection device (p < 0.0001). For inorganic phosphates, immediate extraction (p < 0.0001), cytology microbrush collection (p < 0.0001), and non-dry eye status (p = 0.03) were associated with the greater likelihood of detection. Dacron swab collection was associated with the highest average amount of total lipid detected, whereas spatula collection and immediate extraction was associated with the highest average amount of cholesterol detected. Cytology microbrush collection with immediate extraction on non-dry eye subjects was associated with the highest probability of detection of inorganic phosphates.


Risk of rupture from incidental cerebral aneurysms.
Controversy still exists about the risk estimation for rupture of untreated saccular aneurysms presenting for causes other than subarachnoid hemorrhage (SAH). The object of this study was to address this issue. Between January 1976 and December 1997 in the Aizu Chuou Hospital, 62 patients underwent observation for more than 6 months for saccular, nonthrombotic, noncalcified unruptured aneurysms at locations not related to the cavernous sinus, which were detected in cerebral angiography studies performed for causes other than SAH. Clinical follow-up data in those 62 patients were reviewed to identify the risk of SAH. All patients were followed until July 1998, with the observation period ranging from 6 months to 17 years (mean 4.3 years). Seven patients (11.3%) developed SAH confirmed on computerized tomography (CT) scanning at a mean interval of 4.8 years, six of whom died and one of whom recovered with a major deficit. In addition, one patient died of the mass effect of the aneurysm, and another after sudden onset of headache and vomiting. The 5- and 10-year cumulative risks of CT-confirmed SAH calculated by the Kaplan-Meier method were 7.5% and 22.1%, respectively, for total cases, 33.5% and 55.9%, respectively, for large (> 10 mm) aneurysms, and 4.5% and 13.9%, respectively, for small (< 10 mm) aneurysms. Although based on a relatively small, single-institution series, our data indicated that the risk of rupture from incidental, intradural, saccular aneurysms was higher than previously reported, and may support preventive surgical treatment of incidental aneurysms, considering the fatality rate of SAH.


Aortic and peripheral prosthetic graft infection: differential management and causes of mortality.
This report of 25 patients with prosthetic graft infection has compared the diagnosis, management, and outcome in 14 patients with infected aortic grafts with 11 patients with infected peripheral grafts (two axillofemorofemoral, five femorofemoral, five femoropopliteal, and one femoral interposition). Peripheral graft infection had a significantly shorter interval to diagnosis compared with aortic graft infection. Total graft removal combined with either autogenous revascularization or extraanatomic bypass using prosthetic graft was performed in all 14 patients with infected aortic grafts. Management of peripheral graft infection consisted of total graft removal in eight patients (four with autogenous revascularization and two with amputation) and partial graft removal in three patients (two with amputation). Mortality and amputation rates for infected aortic grafts were 43 percent and 25 percent, respectively compared with 36 percent and 27 percent for infected peripheral grafts. Recommendations for management of the infected aortic prosthetic graft include total graft removal, but methods and timing of revascularization are dependent on the specific features of the individual case. However, preferred management for the infected peripheral prosthetic graft includes total graft removal and, if indicated, revascularization using autogenous tissue.


Partitioning of body fluids and cardiovascular responses to circulatory hypovolaemia in the turtle, Pseudemys scripta elegans.
Investigations were conducted (1) to measure the steady state compartmentation of body fluids and (2) to assess the efficacy of blood volume and pressure maintenance during haemorrhage-induced hypovolaemia in the pond turtle, Pseudemys scripta elegans. The pre-haemorrhage blood volume, as determined by tracer dilution of 51Cr-labelled erythrocytes, averaged 6.89 +/- 0.33% of the body mass, and was part of comparatively large extracellular (40.2 +/- 0.70%) and total body fluid volumes (75.25 +/- 1.48%). Turtles exhibited progressive reductions in systemic arterial pressure throughout a cumulative haemorrhage of -48% of their original blood volume, despite dramatic increases in heart rate and comparatively large magnitudes of transcapillary fluid transfer from interstitial to intravascular spaces. Arterial blood pressure returned to pre-haemorrhage values 2h after experimental haemorrhage ceased, concomitant with the restoration of the original blood volume. Our results support arguments made in previous studies that the resistance to fluid movement between vascular and extravascular locations in reptiles is comparatively low. Furthermore, the haemodynamic responses of turtles to experimental hypovolaemia suggest that barostasis through adjustments in vascular tone is less effective than that observed in other reptiles.


Impact of KMN network genes on progression and prognosis of non-small cell lung cancer.
The Knl1-Mis12-Ndc80 (KMN) network genes (including KNL, MIS12 and NDC80 complexes) encode a highly conserved network of protein complexes that act in cell mitosis. In recent years, multiple studies revealed that KMN network genes also play a vital role in tumor appearance and growth. However, the role of the KMN gene network in non-small cell lung cancer (NSCLC) remains unknown. In this study, we analyzed the effects of KMN genes expression and clinical phenotype in patients with lung adenocarcinoma (LUAD). The expression of KMN network genes and related clinical information was extracted from The Cancer Genome Atlas. The samples were classified into cluster I and II by consistent clustering. We analyzed the gene distribution by principal component analysis, and the potential risk characteristics were analyzed using the least absolute shrinkage and selection operator Cox regression algorithm. Univariate and multivariate Cox regression analyses were used to analyze the clinical information. The Database for Annotation, Visualization, and Integrated Discovery, Gene MANIA and gene set enrichment analysis were used to analyze function and correlation among genes of the KMN network. The expression levels of nine out of ten KMN genes were significantly up-regulated in LUAD and were associated with poor overall survival (OS). Higher expression of NDC80 and KNL1 was related to low OS in both univariate and multivariate analyses. According to two independent prognostic KMN network genes (KNL1 and NDC80), a risk signature was established to predict the prognosis of patients with LUAD. Additionally, the genes NDC80 and KNL1 were considerably enriched in pathways associated with signaling pathways, biological processes, and the cell cycle. The results indicate that KMN network genes are intimately related to lung adenocarcinoma. KMN network genes are involved in the malignant process of LUAD. Assessment of NDC80 and KNL1 might be helpful for prognostic stratification and treatment strategy development.


Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review.
Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5-10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient's immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL.


Identification and molecular characterization of BP75, a novel bromodomain-containing protein.
We here describe the identification and characterization of a novel bromodomain-containing protein, the bromodomain protein of 75 kDa (BP75). Initially, we identified BP75 in a two-hybrid screening for proteins that interact with the first PDZ (acronym for post-synaptic density protein PSD-95, Drosophila discs large tumor suppressor DlgA and the tight junction protein ZO-1) domain in protein tyrosine phosphatase-BAS-like (PTP-BL). We found that BP75 is expressed ubiquitously and show that both BP75 and a PTP-BL deletion mutant consisting of the first PDZ domain are located mainly in the nucleus, although cytoplasmic localization is also evident. Full-length PTP-BL, on the contrary, is predominantly localized in the cytoplasm, although some basal nuclear staining is observed. The described molecular interaction may reflect a mechanism of coupling submembraneous signalling events and nuclear events.


[Improved survival after in-hospital cardiac arrest].
Internationally, survival among patients suffering in-hospital cardiac arrest is relatively low and unchanged at about 15%. Our experience at Sahlgrenska Hospital in Göteborg indicates a higher rate. We found survival to be related to the type of arrhythmia initially encountered, the highest rate having been observed among patients in ventricular fibrillation. We also found survival among patients suffering cardiac arrest to be higher in monitored as opposed to non-monitored wards. Whether the improved survival rate observed at Sahlgrenska as compared with international observations among patients suffering cardiac arrest is due to improvements in the organization or to patient selection is not clear. In order to achieve a higher survival rate after in-hospital cardiac arrest an efficient organization in which health care providers are given regular training and feed back is most likely of the utmost importance.


Quantitative coronary arterial stenosis assessment by multidetector CT and invasive coronary angiography for identifying patients with myocardial perfusion abnormalities.
Semi-quantitative stenosis assessment by coronary CT angiography only modestly predicts stress-induced myocardial perfusion abnormalities. The performance of quantitative CT angiography (QCTA) for identifying patients with myocardial perfusion defects remains unclear. CorE-64 is a multicenter, international study to assess the accuracy of 64-slice QCTA for detecting ≥50% coronary arterial stenoses by quantitative coronary angiography (QCA). Patients referred for cardiac catheterization with suspected or known coronary artery disease were enrolled. Area under the receiver-operating-characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the most severe coronary artery stenosis in a subset of 63 patients assessed by QCTA and QCA for detecting myocardial perfusion abnormalities on exercise or pharmacologic stress SPECT. Diagnostic accuracy of QCTA for identifying patients with myocardial perfusion abnormalities by SPECT revealed an AUC of 0.71, compared to 0.72 by QCA (P = .75). AUC did not improve after excluding studies with fixed myocardial perfusion abnormalities and total coronary arterial occlusions. Optimal stenosis threshold for QCTA was 43% yielding a sensitivity of 0.81 and specificity of 0.50, respectively, compared to 0.75 and 0.69 by QCA at a threshold of 59%. Sensitivity and specificity of QCTA to identify patients with both obstructive lesions and myocardial perfusion defects were 0.94 and 0.77, respectively. Coronary artery stenosis assessment by QCTA or QCA only modestly predicts the presence and the absence of myocardial perfusion abnormalities by SPECT. Confounding variables affecting the relationship between coronary anatomy and myocardial perfusion likely account for some of the observed discrepancies between coronary angiography and SPECT results.


Mixed lead-tin perovskite films with >7 μs charge carrier lifetimes realized by maltol post-treatment.
Mixed lead-tin (Pb-Sn) halide perovskites with optimum band gaps near 1.3 eV are promising candidates for next-generation solar cells. However, the performance of solar cells fabricated with Pb-Sn perovskites is restricted by the facile oxidation of Sn(ii) to Sn(iv), which induces self-doping. Maltol, a naturally occurring flavor enhancer and strong metal binding agent, was found to effectively suppress Sn(iv) formation and passivate defects in mixed Pb-Sn perovskite films. When used in combination with Sn(iv) scavenging, the maltol surface treatment led to high-quality perovskite films which showed enhanced photoluminescence intensities and charge carrier lifetimes in excess of 7 μs. The scavenging and surface treatments resulted in highly reproducible solar cell devices, with photoconversion efficiencies of up to 21.4% under AM1.5G illumination.


Castor bean allergy among workers in the felt industry.
We describe occupational allergy to castor bean in workers in a felt manufacturing plant. Twenty-six (37%) of the workers complained they were affected by the felt and were examined by us. Of these, 12 were considered to have occupational allergy. These 12 subjects had raised specific IgE levels to both felt and castor bean extracts. In addition, three subjects without occupational allergy had raised specific IgE. The presence of castor bean allergens in the felt was suggested by the correlation between the RAST scores to the felt and castor bean and confirmed by RAST inhibition experiments. The RAST results correlated well with the results of skin prick tests to felt and castor bean extracts. In addition it was found that atopy did not predispose the workers to castor bean allergy.


Effect of virgin olive oil phenolic compounds on in vitro oxidation of human low density lipoproteins.
Substantial evidence suggests that oxidative modifications of low density lipoproteins (LDL) critically contribute to the pathogenesis and progression of human atherosclerosis. Oxidized LDL (oxLDL) are present in atherosclerotic plaques and contain oxysterols that exhibit a variety of adverse biological activities. Antioxidants have also been shown to prevent LDL modification. We have therefore assessed the efficacy of virgin olive oil phenolic compounds in preventing oxidative modifications of human LDL oxidized by UV light. Cholesterol oxides formed during LDL photo-oxidation were determined by UV-HPLC in the presence of different concentrations of phenolic compounds and their pure components (tyrosol and oleuropein), and probucol, a widely used synthetic antioxidant. Electrophoretic mobility was also assayed. The results demonstrate that phenolic compounds are much more potent in preventing cholesterol oxide formation and apoproteic moiety modification than their pure components and probucol. The beneficial effects of a Mediterranean diet may be ascribable not only to the high unsaturated/saturated fatty acid ratio characteristic of olive oil, but also to the unique antioxidant properties of its phenolic compounds.


Effect of zinc supplementation on the distribution of various elements in the serum of diabetic rats subjected to an acute swimming exercise.
The present study aims to examine the effect of supplementation of zinc on the distribution of various elements in the sera of diabetic rats subjected to an acute swimming exercise. A total of 80 Sprague-Dawley-type adult male rats were equally allocated to one of eight groups: Group 1, general; Group 2, zinc-supplemented; Group 3, zinc-supplemented diabetic; Group 4, swimming control; Group 5, zinc-supplemented swimming; Group 6, zinc-supplemented diabetic swimming; Group 7, diabetic swimming; and Group 8, diabetes. The rats were injected with 40 mg/kg/day subcutaneous streptozotocin (STZ) twice, with a 24-h interval between two injections. Zinc was supplemented at a dose of 6 mg/kg/day (ip) for 4 weeks. Blood samples were collected at the end of the 4-week study, and serum levels of lead, cobalt, molybdenum, chrome, sulfur, magnesium, manganese, sodium, potassium, phosphorus, copper, iron, calcium, zinc, and selenium (mg/L) were determined with atomic emission. The lowest molybdenum, chrome, copper, iron, potassium, magnesium, sodium, phosphorus, lead, selenium, and zinc values were obtained in Group 7 and 8. These same parameters were higher in the swimming exercise group (Group 4), relative to all other groups. The values in zinc-supplemented groups were found lower than the values in Group 4, but higher than those in Group 6 and 7. The results obtained from the study demonstrate that acute swimming exercise and diabetes affect the distribution of various elements in the serum, while zinc supplementation can prevent the negative conditions associated with both exercise and diabetes.


Physicians' experience with follow-up care of childhood cancer survivors - challenges and needs.
Regular follow-up care is essential for childhood cancer survivors, but we know little about physicians' experience with it. We aimed to describe: (1) involvement of Swiss physicians in follow-up care; (2) content of follow-up care provided; (3) problems encountered; and (4) additional resources needed. Within this cross-sectional survey we sent adapted questionnaires via professional associations to a sample of medical oncologists (MOs), paediatric oncologists (POs), general practitioners (GPs) and paediatricians (P) in Switzerland. Only oncologists involved in follow-up care were asked to report problems. GPs and Ps not involved in follow-up could indicate why. All physicians were asked about the content of follow-up care provided and additional resources needed. A total of 183 physicians responded (27 MO, 13 PO, 122 GP, 21 P). Involved in follow-up were 81% of MOs, 85% of POs, 39% of GPs and 81% of Ps. Follow-up content differed between oncologists (MO and PO) and generalists (GP and P), with generalists examining or informing less in regard to the former cancer. POs reported more problems than MOs: many POs reported problems with transition of survivors to adult care (91%), and because of financial resources (73%) and time restraints (73%). MOs reported most problems during transition (23%). Not being aware of a survivor was the most common reason for GPs and Ps not participating in follow-up (74%). All groups reported a need for standardised protocols (85-91%) and specialised training (55-73%). GPs (94%) and Ps (100%) additionally desired more support from oncologists. To improve quality and efficiency of follow-up care a national follow-up care model including standardised protocols and guidelines needs to be developed.


[Methodical influences on the determination of prececal digestibility].
With ileum-cannulated sows (flexible, large-luminal T-shape cannulas after method of Kesting et al., 1986) the influence of level of intake, individuality of animal and relation of additional feed in the diet on the determination of precaecal digestibility were tested. The results showed that precaecal values of digestibility were affected by method. The authors recommend the isogravimetrical determination (exchange trial) of additional feeds.


Modulation of wireless (2.45 GHz)-induced oxidative toxicity in laryngotracheal mucosa of rat by melatonin.
It is well known that oxidative stress induces larynx cancer, although antioxidants induce modulator role on etiology of the cancer. It is well known that electromagnetic radiation (EMR) induces oxidative stress in different cell systems. The aim of this study was to investigate the possible protective role of melatonin on oxidative stress induced by Wi-Fi (2.45 GHz) EMR in laryngotracheal mucosa of rat. For this purpose, 32 male rats were equally categorized into four groups, namely controls, sham controls, EMR-exposed rats, EMR-exposed rats treated with melatonin at a dose of 10 mg/kg/day. Except for the controls and sham controls, the animals were exposed to 2.45 GHz radiation during 60 min/day for 28 days. The lipid peroxidation levels were significantly (p < 0.05) higher in the radiation-exposed groups than in the control and sham control groups. The lipid peroxidation level in the irradiated animals treated with melatonin was significantly (p < 0.01) lower than in those that were only exposed to Wi-Fi radiation. The activity of glutathione peroxidase was lower in the irradiated-only group relative to control and sham control groups but its activity was significantly (p < 0.05) increased in the groups treated with melatonin. The reduced glutathione levels in the mucosa of rat did not change in the four groups. There is an apparent protective effect of melatonin on the Wi-Fi-induced oxidative stress in the laryngotracheal mucosa of rats by inhibition of free radical formation and support of the glutathione peroxidase antioxidant system.


Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.
IL-17 and IL-23 are known to be absolutely central to psoriasis pathogenesis because drugs targeting either cytokine are highly effective treatments for this disease. The efficacy of these drugs has been attributed to blocking the function of IL-17-producing T cells and their IL-23-induced expansion. However, we demonstrate that mast cells and neutrophils, not T cells, are the predominant cell types that contain IL-17 in human skin. IL-17(+) mast cells and neutrophils are found at higher densities than IL-17(+) T cells in psoriasis lesions and frequently release IL-17 in the process of forming specialized structures called extracellular traps. Furthermore, we find that IL-23 and IL-1β can induce mast cell extracellular trap formation and degranulation of human mast cells. Release of IL-17 from innate immune cells may be central to the pathogenesis of psoriasis, representing a fundamental mechanism by which the IL-23-IL-17 axis mediates host defense and autoimmunity.


An acute intake of plant stanol esters alters immune-related pathways in the jejunum of healthy volunteers.
Plant sterols and stanols inhibit intestinal cholesterol absorption and consequently lower serum LDL-cholesterol (LDL-C) concentrations. The underlying mechanisms are not yet known. In vitro and animal studies have suggested that changes in intestinal sterol metabolism are attributed to the LDL-C-lowering effects of plant stanol esters. However, similar studies in human subjects are lacking. Therefore, we examined the effects of an acute intake of plant stanol esters on gene expression profiles of the upper small intestine in healthy volunteers. In a double-blind cross-over design, fourteen healthy subjects (eight female and six male; age 21-55 years), with a BMI ranging from 21 to 29 kg/m², received in random order a shake with or without plant stanol esters (4 g). At 5 h after consumption of the shake, biopsies were taken from the duodenum (around the papilla of Vater) and from the jejunum (20 cm distal from the papilla of Vater). Microarray analysis showed that the expression profiles of genes involved in sterol metabolism were not altered. Surprisingly, the pathways involved in T-cell functions were down-regulated in the jejunum. Furthermore, immunohistochemical analysis showed that the number of CD3 (cluster of differentiation number 3), CD4 (cluster of differentiation number 4) and Foxp3⁺ (forkhead box P3-positive) cells was reduced in the plant stanol ester condition compared with the control condition, which is in line with the microarray data. The physiological and functional consequences of the plant stanol ester-induced reduction of intestinal T-cell-based immune activity in healthy subjects deserve further investigation.


Effects of an intervention promoting proactive coping competencies in middle and late adulthood.
We tested the effectiveness of a brief educational program that is based on proactive coping theory. The program entails a four-session group intervention for people aged between 50 and 75 years and was intended to improve proactive coping competencies. Furthermore, we investigated the positive as well as negative side effects and differential effectiveness of the program. A total of 158 middle aged and older men and women participated in the study. In a prospective randomized control trial with an experimental group and a waiting control group, we collected questionnaire data at three points (baseline, after completion of the program, and 3 months postintervention). The program improved proactive coping competencies significantly. Three months after completion of the intervention, these results remained stable. Nearly all effect sizes in the experimental group were medium or higher. The program did not have negative side effects in terms of worrying or negative mood, and it did not change levels of self-efficacy. Demographic characteristics of participants did not predict changes in proactive competencies. Differential effectiveness could only be shown for a few psychological characteristics: Lower levels of well-being, higher levels of proactive orientation, and lower levels in the consideration of future consequences of one's own behavior predicted an increase in proactive coping competencies. Participants who formulated personal goals in concrete terms also profited more from the intervention. Conceptualizing proactive coping as a set of competencies allows the translation of this approach into interventions. Competencies that facilitate future-oriented self-regulation can be improved by a brief educational program in middle and late adulthood.


[Depressive disorders in children and adolescents].
Depressive disorders in children and adolescents are marked by core symptoms similar to those seen in adults, although symptom expression varies greatly with developmental stage. These disorders are common, chronic, and recurrent, and they are often associated with comorbid psychiatric conditions and poor prognosis that can be alleviated by early identification and treatment. The psychiatric assessment of depressed children and adolescents can be difficult and must be performed by an expert clinician. Recent research into the treatment of depression in children and adolescents has been focused on the effectiveness of cognitive-behavioural therapy and selective serotonin reuptake inhibitors.


Metabolic network structure and function in bacteria goes beyond conserved enzyme components.
For decades, experimental work has laid the foundation for our understanding of the linear and branched pathways that are integrated to form the metabolic networks on which life is built. Genetic and biochemical approaches applied in model organisms generate empirical data that correlate genes, gene products and their biological activities. In the post-genomic era, these results have served as the basis for the genome annotation that is routinely used to infer the metabolic capabilities of an organism and mathematically model the presumed metabolic network structure. At large, genome annotation and metabolic network reconstructions have demystified genomic content of non-culturable microorganisms and allowed researchers to explore the breadth of metabolisms in silico. Mis-annotation aside, it is unclear whether in silico reconstructions of metabolic structure from component parts accurately captures the higher levels of network organization and flux distribution. For this approach to provide accurate predictions, one must assume that the conservation of metabolic components leads to conservation of metabolic network architecture and function. This assumption has not been rigorously tested. Here we describe the implications of a recent study (MBio 5;7(1): e01840-15), which demonstrated that conservation of metabolic components was not sufficient to predict network structure and function.


A machine learning-based prognostic predictor for stage III colon cancer.
Limited biomarkers have been identified as prognostic predictors for stage III colon cancer. To combat this shortfall, we developed a computer-aided approach which combing convolutional neural network with machine classifier to predict the prognosis of stage III colon cancer from routinely haematoxylin and eosin (H&E) stained tissue slides. We trained the model by using 101 cancers from West China Hospital (WCH). The predictive effectivity of the model was validated by using 67 cancers from WCH and 47 cancers from The Cancer Genome Atlas Colon Adenocarcinoma database. The selected model (Gradient Boosting-Colon) provided a hazard ratio (HR) for high- vs. low-risk recurrence of 8.976 (95% confidence interval (CI), 2.824-28.528; P, 0.000), and 10.273 (95% CI, 2.177-48.472; P, 0.003) in the two test groups, from the multivariate Cox proportional hazards analysis. It gave a HR value of 10.687(95% CI, 2.908-39.272; P, 0.001) and 5.033 (95% CI,1.792-14.132; P, 0.002) for the poor vs. good prognosis groups. Gradient Boosting-Colon is an independent machine prognostic predictor which allows stratification of stage III colon cancer into high- and low-risk recurrence groups, and poor and good prognosis groups directly from the H&E tissue slides. Our findings could provide crucial information to aid treatment planning during stage III colon cancer.


Chronic triclosan exposure induce impaired glucose tolerance by altering the gut microbiota.
Triclosan (TCS) is an antimicrobial compound incorporated into more than 2000 consumer products. This compound is frequently detected in the human body and causes ubiquitous contamination in the environment, thereby raising concerns about its impact on human health and environmental pollution. Here, we demonstrated that 20 weeks' exposure of TCS drove the development of glucose intolerance by inducing compositional and functional alterations in intestinal microbiota in rats. Fecal-transplantation experiments corroborated the involvement of gut microbiota in TCS-induced glucose-tolerance impairment. 16S rRNA gene-sequencing analysis of cecal contents showed that TCS disrupted the gut microbiota composition in rats and increased the ratio of Firmicutes to Bacteroidetes. Cecal metabolomic analyses detected that TCS altered host metabolic pathways that are linked to host glucose and amino acid metabolism, particularly branched-chain amino acid (BCAA) biosynthesis. BCAA measurement confirmed the increase in serum BCAAs in rats exposed to TCS. Western blot and immunostaining results further confirmed that elevated BCAAs stimulated mTOR, a nutrient-sensing complex, and following IRS-1 serine phosphorylation, resulted in insulin resistance and glucose intolerance. These results suggested that TCS may induce glucose metabolism imbalance by regulating BCAA concentration by remodeling the gut microbiota.


Knowledge, attitudes, and practices regarding diabetic retinopathy among primary health care physicians in Al-Hasa, Saudi Arabia.
Diabetic retinopathy (DR) has been shown to be the third most observed cause of visual loss in Saudi Arabia. In the Al-Hasa region in particular, the prevalence of DR has been shown to be 30%. Primary health centre (PHC) physicians play a central role in the early detection and prevention of DR. The aim of this study was to evaluate the knowledge, attitudes, and practices regarding DR of PHC physicians in Al-Hasa, Saudi Arabia. A cross-sectional descriptive study was conducted at PHCs in Al-Hasa, Saudi Arabia. A self-administered questionnaire was provided to every participant along with a consent form. Out of 71 centres in the region, 63 were included in this study. The questionnaire consisted of three sections and a total of 18 questions. Statistical analysis was carried out using the Statistical Package for the Social Sciences version 21 software program (IBM Corp., Armonk, NY, USA). One hundred forty-one of 209 physicians completed the questionnaire for a response rate of 67%. The mean of overall knowledge score for all participants was 2.6 ± 1.16 points out of four points. Only 34 (24.1%) of the participants correctly referred their diabetic patients according to the guidelines of the American Academy of Ophthalmology. Additionally, only 52 (36.9%) physicians educated their patients regarding the early detection of diabetic complications. The present study concluded that there exist gaps in applying the correct guidelines. Physicians' attitudes toward patient education were overall satisfactory. Further medical symposiums and workshops are warranted to teach physicians about diabetic complications and screening schedules, including DR.


Partner Fidelity and Asymmetric Specialization in Ecological Networks.
AbstractSpecies are embedded in complex networks of interdependencies that may change across geographic locations. Yet most approaches to investigate the architecture of this entangled web of life have considered exclusively local communities. To quantify to what extent species interactions change at a biogeographic scale, we need to shed light on how among-community variation affects the occurrence of species interactions. Here we quantify the probability for two partners to interact wherever they co-occur (i.e., partner fidelity) by analyzing the most extensive database on species interaction networks worldwide. We found that mutualistic species show more fidelity in their interactions than antagonistic ones when there is asymmetric specialization (i.e., when specialist species interact with generalist partners). Moreover, resources (e.g., plants in plant-pollinator mutualisms or hosts in host-parasite interactions) show a higher partner fidelity in mutualistic interactions than in antagonistic interactions, which can be explained neither by sampling effort nor by phylogenetic constraints developed during their evolutionary histories. In spite of the general belief that mutualistic interactions among free-living species are labile, asymmetric specialization is very much conserved across large geographic areas.


A green approach for the analysis of emtricitabine bictegravir and tenofovir in a pharmaceutical preparation using novel HPLC and spectrophotometric methods.
Two spectrophotometric techniques and a novel HPLC method were consecutively applied for the simultaneous quantification of the active ingredients of emtricitabine (EMC), tenofovir (TNF), and bictegravir (BIC). The first spectrophotometric method is the dual amplitude difference method coupled with the ratio difference method. TNF was determined using the dual amplitude difference method, while BIC and EMC were determined using the ratio difference method. The second spectrophotometric method was the constant multiplication with absorbance extraction method, and was applied for the determination of active substances used in the treatment of human immunodeficiency virus (HIV) infection. BIC was determined by the constant multiplication method, whereas EMC and TNF were determined using the absorbance extraction method. For the HPLC method, the XBridge C18 column was used. The solvent system comprised acetonitrile:phosphate buffer (pH 6.8; 30:70 v/v). All active ingredients were detected at 260.0 nm, and the flow rate was 0.5 mL/min. The experiment was completed within 5.5 min. The experiments carried out enabled the simultaneous analysis of the three active substances and they were economical, fast, environmentally friendly, and simple. The methods have been successfully applied to prepare mixtures and tablets without matrix interference. The methods were evaluated in terms of green chemistry. The methods have been validated according to International Council for Harmonisation (ICH) guidelines.


Ex vivo quantification of lanthanum and gadolinium in post-mortem human tibiae with estimated barium and iodine concentrations using K x-ray fluorescence.
Lanthanum (La) and gadolinium (Gd) are known to deposit in bone of exposed populations, namely those who are orally administered lanthanum carbonate (LaC, La2(CO3)3) or are injected with Gd-based contrast agents, respectively. In this work, bone La and Gd concentrations from the environment and diet were measured using x-ray fluorescence in ten post-mortem human tibiae. As a secondary objective, bone barium (Ba) and iodine concentrations were estimated. Two calibration lines were produced for La and Gd and the minimum detection limits (MDLs) of the system were determined using a 180° irradiation-detection geometry. The MDLs of the system were 0.4 µg La g-1 bone mineral and 0.5 µg Gd g-1 bone mineral. The mean concentrations were -0.02 ± 0.1 µg La g-1 bone mineral and 0.1 ± 0.2 µg Gd g-1 bone mineral in tibiae. The average Ba and iodine concentrations estimated from the experimental La calibration line and Monte-Carlo derived sensitivity factors were determined to be 3.4 ± 0.8 µg Ba g-1 bone mineral and -0.5 ± 0.3 µg iodine g-1 bone mineral. Since it was discovered that four donors previously received an iodine-based contrast agent, the mean concentrations in these donors was 27.8 ± 28.4 µg iodine g-1 bone mineral. The XRF system has determined baseline concentrations of these four heavy metals in trace quantities from natural exposure pathways (with the exception of iodine in four donors). This indicates that the system can measure low levels in ex vivo tibiae samples and can potentially be further developed for in vivo studies involving live subjects who are directly exposed to these metals.


Source modeling of ElectroCorticoGraphy (ECoG) data: Stability analysis and spatial filtering.
Electrocorticography (ECoG) measures the distribution of the electrical potentials on the cortex produced by the neural currents. A full interpretation of ECoG data requires solving the ill-posed inverse problem of reconstructing the spatio-temporal distribution of the neural currents. This study addresses the ECoG source modeling developing a beamformer method. We computed the lead-field matrix by using a novel routine provided by the OpenMEEG software. We performed an analysis of the numerical stability of the ECoG inverse problem by computing the condition number of the lead-field matrix for different configurations of the electrodes grid. We applied a Linear Constraint Minimum Variance (LCMV) beamformer to both synthetic data and a set of real measurements recorded during a rapid visual categorization task. For all considered grids the condition number indicates that the ECoG inverse problem is mildly ill-conditioned. For realistic SNR we found a good performance of the LCMV algorithm for both localization and waveforms reconstruction. The flow of information reconstructed by analyzing real data seems consistent with both invasive monkey electrophysiology studies and non-invasive (MEG and fMRI) human studies. Despite a growing interest from the neuroscientific community, solving the ECoG inverse problem has not quite yet reached the level of systematicity found for EEG and MEG. Starting from an analysis of the numerical stability of the problem we considered the most widely utilized method for modeling neurophysiological data based on the beamformer method in the hope to establish benchmarks for future studies.


The importance of arterial blood gas analysis as a systemic diagnosis approach in assessing and preventing chronic diseases, from emergency medicine to the daily practice.
Blood gas analysis is a diagnostic tool to evaluate the partial pressures of gas in blood and acid-base content. The use of blood gas analysis enables a clear understanding of respiratory, circulatory, and metabolic disorders. The arterial blood gas (ABG) explicitly analyzes blood taken from an artery, assessing the patient's partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2) pH (acid/base). PaO2 indicates the oxygenation status, and PaCO2 indicates the ventilation status (chronic or acute respiratory failure). PaO2 is affected by hyperventilation, characterized by rapid or deep breathing, and hypoventilation, characterized by slow or shallow breathing. The acid-base balance tested by the ABG procedure measures the pH and PaCO2 directly, while the use of the Hasselbach equation gives the serum bicarbonate (HCO3) and base deficit or excess. The measured HCO3 is based on a strong alkali that frees all CO2 in serum, including dissolved CO2, carbamino compounds, and carbonic acid. The calculation uses a standard chemistry analysis, giving the amount of "total CO2"; the difference will amount to around 1.2 mmol/L. Though ABG is frequently ordered in emergency medicine contests for acute conditions, it may also be needed in other clinical settings. The ABG analysis shows to be an exceptional diagnostic tool, including the group of diseases known as acid-base diseases (ABDs), which include a great variety of conditions such as severe sepsis, septic shock, hypovolemic shock, diabetic ketoacidosis, renal tubular acidosis, chronic respiratory failure, chronic heart failure, and diverse metabolic diseases.


Small efficient cell-penetrating peptides derived from scorpion toxin maurocalcine.
Maurocalcine is the first demonstrated example of an animal toxin peptide with efficient cell penetration properties. Although it is a highly competitive cell-penetrating peptide (CPP), its relatively large size of 33 amino acids and the presence of three internal disulfide bridges may hamper its development for in vitro and in vivo applications. Here, we demonstrate that several efficient CPPs can be derived from maurocalcine by replacing Cys residues by isosteric 2-aminobutyric acid residues and sequence truncation down to peptides of up to 9 residues in length. A surprising finding is that all of the truncated maurocalcine analogues possessed cell penetration properties, indicating that the maurocalcine is a highly specialized CPP. Careful examination of the cell penetration properties of the truncated analogues indicates that several maurocalcine-derived peptides should be of great interest for cell delivery applications where peptide size matters.


[Features of photochemical properties of hemoglobin under native conditions].
The photochemistry of human hemoglobin (Hb) in the blood and blood serum (lambda = 254-578 nm) was studied, using spectrophotometric methods. The Hb photochemistry is a complex set of photoreactions leading to successive photoconversions of Hb forms: from oxy- to met- to deoxy- and, finally, to carboxy-form. The photodestruction of Hb and the photoreactions involving other serum proteins were found to occur simultaneously. In the blood Hb photomodifications are localized directly in erythrocytes. The conditions necessary for the photo--induced rupture of erythrocyte membranes and the subsequent release of Hb into the blood plasma, were determined. Although the general characteristics of Hb photochemistry are the same for model systems and for native conditions, there are some distinctions in the effectiveness of the photoconversion. It seems likely that the observed effects are due to the antioxidant properties of the serum. These properties may be the cause of the inhibition of blood photohemolysis upon irradiation (lambda greater than or equal to 300 nm).


Polymorphism and Geographic Variation in the Feeding Behavior of the Garter Snake Thamnophis elegans.
Geographic variation in behaviors that influence resource utilization is a key component in current ecological theory, but the phenomenon has been poorly documented. Propensity to attack slugs varies geographically in a western garter snake, Thamnophis elegans. Many naive, newborn snakes from inland localities in California refuse to eat slugs. In contrast, virtually all naive young from coastal localities eat slugs. There is, however, no demonstrable polymorphism or geographic variation for propensity to eat anurans. Both coastal and inland snakes consistently eat anurans.


Music evoked autobiographical memory after severe acquired brain injury: preliminary findings from a case series.
Music evoked autobiographical memories (MEAMs) have been characterised in the healthy population, but not, to date, in patients with acquired brain injury (ABI). Our aim was to investigate music compared with verbal evoked autobiographical memories. Five patients with severe ABI and matched controls completed the experimental music (MEAM) task (a written questionnaire) while listening to 50 "Number 1 Songs of the Year" (from 1960 to 2010). Patients also completed the Autobiographical Memory Interview (AMI) and a standard neuropsychological assessment. With the exception of Case 5, who reported no MEAMs and no autobiographical incidents on the AMI and who also had impaired pitch perception, the range of frequency and type of MEAMs in patients was broadly in keeping with their matched controls. The relative preservation of MEAMs in four cases was particularly noteworthy given their impaired verbal and/or visual anterograde memory, and in three cases, autobiographical memory impairment. The majority of MEAMs in both cases and matched controls were of a person/people or a period of life. In three patients music was more efficient at evoking autobiographical memories than the AMI verbal prompts. This is the first study of MEAMs after ABI. The findings suggest that music is an effective stimulus for eliciting autobiographical memories, and may be beneficial in the rehabilitation of autobiographical amnesia, but only in patients without a fundamental deficit in autobiographical recall memory and intact pitch perception.


Medical oncologists' attitudes and practice in cancer pain management: a national survey.
To evaluate the attitudes, knowledge, and practices of US medical oncologists that are related to management of cancer pain. An anonymous survey was mailed to a geographically representative sample of medical oncologists randomly selected from the American Medical Association's Physician Master File. From a total of 2,000 oncologists, 354 responded to the original questionnaire and 256 responded to one of two subsequent shortened versions (overall response rate, 32%). Responders were demographically similar to all US medical oncologists. Using numeric rating scales of 0 to 10, oncologists rated their specialty highly for the ability to manage cancer pain (median, 7; interquartile range [IQR], 6 to 8) but rated their peers as more conservative prescribers than themselves (median, 3; IQR, 2 to 5). The quality of pain management training during medical school and residency was rated as 3 (IQR, 1 to 5) and 5 (IQR, 3 to 7), respectively. The most important barriers to pain management were poor assessment (median, 6; IQR, 4 to 7) and patient reluctance to take opioids (median, 6; IQR, 5 to 7) or report pain (median, 6; IQR, 4 to 7). Other barriers included physician reluctance to prescribe opioids (median, 5; IQR, 3 to 7) and perceived excessive regulation (median, 4; IQR, 2 to 7). In response to two vignettes describing challenging clinical scenarios, 60% and 87%, respectively, endorsed treatment decisions that would be considered unacceptable by pain specialists. Frequent referrals to pain or palliative care specialists were reported by only 14% and 16%, respectively. These data suggest that, for more than 20 years, a focus on cancer pain has not adequately addressed the perception of treatment barriers or limitations in pain-related knowledge and practice within the oncology community. Additional efforts are needed to achieve meaningful progress.


Variability of Doppler ankle pressures with arterial occlusive disease: an evaluation of ankle index and brachial-ankle pressure gradient.
The variability of Doppler ankle pressures was studied in 35 men with clinically stable claudication. An average of 6.8 measurements was obtained from each man. The mean range of ankle index was 0.18 with a mean standard deviation of 0.07. The brachial-ankle pressure gradient had a wider spread, with a mean range of 38 mm Hg and a standard deviation of 13.9. The amount of variation in a given patient was unrelated to mean blood pressure or mean ankle index. The results of this study show that the ankle index must change at least 0.15 before it can be considered significant. Based on the variability found, we recommend that multiple baseline determinations be obtained on patients who are to be followed longitudinally.


Did the acute impact of the COVID-19 pandemic on drinking or nicotine use persist? Evidence from a cohort of emerging adults followed for up to nine years.
This study examined the impact of the COVID-19 pandemic on drinking and nicotine use through June of 2021 in a community-based sample of young adults. Data were from 348 individuals (49% female) enrolled in a long-term longitudinal study with an accelerated longitudinal design: the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) Study. Individuals completed pre-pandemic assessments biannually from 2016 to early 2020, then completed up to three web-based, during-pandemic surveys in June 2020, December 2020, and June 2021. Assessments when individuals were 18.8-22.4 years old (N = 1,458) were used to compare drinking and nicotine use pre-pandemic vs. at each of the three during-pandemic timepoints, adjusting for the age-related increases expected over time. Compared to pre-pandemic, participants were less likely to report past-month drinking in June or December 2020, but there was an increase in drinking days among drinkers in June 2020. By June 2021, both the prevalence of past-month drinking and number of drinking days among drinks were similar to pre-pandemic levels. On average, there were no statistically significant differences between pre-pandemic and during-pandemic time points for binge drinking, typical drinking quantity, or nicotine use. Young adults who reported an adverse financial impact of the pandemic showed increased nicotine use while their peers showed stable or decreased nicotine use. Initial effects of the pandemic on alcohol use faded by June 2021, and on average there was little effect of the pandemic on nicotine use.


Initial Correction Rate Can be Predictive of the Outcome of Brace Treatment in Patients With Adolescent Idiopathic Scoliosis.
A retrospective study. To determine the definite cut-off value of initial correction rate (ICR) that could be predictive of bracing outcome in patients with adolescent idiopathic scoliosis. Earlier studies showed that braced patients with a better ICR could finally have a higher probability of successful outcome. However, it remains controversial what definitive cut-off value of ICR is required to accurately predict the outcome. A cohort of 488 adolescent idiopathic scoliosis patients who have completed the brace treatment with a minimum of 2-year follow-up were included in the current study. Curve progression of ≤5 degrees was used to define the success of brace treatment. The success group and the failure group were compared in terms of initial Risser sign, initial age, sex, curve pattern, initial curve magnitude, and ICR. The receiver operating characteristics curve was used to define the definite cut-off point of initial curve correction rate. A logistic regression model was created to determine the independent predictors of the bracing outcome. At the beginning of brace treatment, the mean age of the cohort was 13.2±1.5 years, and the mean curve magnitude was 29.5 ± 6.6 degrees. At the final follow-up, 368 patients were successfully treated by bracing. Compared with the success group, the failure group was found to have significantly younger age, lower Risser sign, and lower ICR. According to the receiver operating characteristic curve, the best cut-off value of ICR was 10%. The logistic regression model showed that ICR was significantly associated with the outcome of brace treatment with an odds ratio of 9.61. Patients with low ICR, low Risser sign, and young age could have a remarkably high risk of bracing failure. A rate of 10% was the optimal cut-off point for ICR, which can be used to effectively stratify braced patients.


Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction.
We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than "bulk" cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.


[The antagonism of phosphorus-containing heterocyclics with the anticholinesterase agent Phosphacol (paraoxon)].
Effects of 15 derivatives of 2-R-oxo-(tioxo-3,5,5-trimethyl-1,2-oxaphospholan-3-ol (OPh) on lethality and protective action on cholinesterase (ChE) of mice brain and blood serum as a result of phosphacolum (paraoxonum) poisoning were investigated. Oxo and tioxo derivatives of OPh with O-methyl and O-ethyl, but not O-propyl and O-butyl radicals at phosphoric atom prevented the lethality of mice poisoned with phosphacolum and preserved brain and blood ChE of inhibition. Ethylic and phenylic OPh derivatives also prevented the lethality of poisoned animals, although without the protection of brain and blood plasma ChE. Combined application of OPh O-ethylic derivative with atropinum and dipiroxinum significantly potentiated antidotal effect m mice poisoned by phosphacolum.


Determination of atmospheric heavy metal pollution in Canakkale and Balikesir provinces using lichen (Cladonia rangiformis) as a bioindicator.
A regional study was conducted to assess the current level of atmospheric heavy metal pollution (Pb, Zn, Cr, Cu, Cd) in the Canakkale and Balikesir provinces of Turkey, and also to establish a baseline for future studies of atmospheric heavy metal pollution. The lichen Cladonia rangiformis was used for determining the distribution of heavy metals in the atmosphere. The highest concentration of all these elements was observed in the vicinity of Balikesir province where there is an abandoned lead-zinc main. On the other hand, apart from the mining area, the concentration of heavy metals was similar to the data reported for unpolluted areas. Maximum values of Pb, Zn, Cr, Cu, and Cd were 33.8, 47.6, 13.0, 5.29, and 0.69 mg/kg in dry weight, respectively. Spatial distribution of these elements, apart from Cr, was similar. Correlation coefficients between Zn-Pb, Cr-Zn, Cu-Pb, Cu-Zn, Cd-Zn, and Cd-Cr were high and positive, and indicated that they come from the same sources.


Tissue specificity of Caenorhabditis elegans enhanced RNA interference mutants.
Gene knockdown by RNA interference (RNAi) in Caenorhabditis elegans is readily achieved by feeding bacteria expressing double-stranded RNA (dsRNA). Enhanced RNAi (Eri) mutants facilitate RNAi due to their hypersensitivity to dsRNA. Here, we compare eight Eri mutants for sensitivity to ingested dsRNA, targeting a variety of tissue-specific genes.


Gestational carriers: A viable alternative for women with medical contraindications to pregnancy.
Compare the efficacy of surrogate or gestational carrier (GC) cycles to that of autologous in vitro fertilization (IVF)/intracytoplasmic sperm injections (ICSI) in patients with gynecologic or medical co-morbidities contraindicative to pregnancy. Retrospective cohort study. Infertility patients from a single university hospital-based program from 1998-2009. 128 GC cycles from 80 intended parents were identified and compared with 15,311 IVF or ICSI cycles. The peak estradiol (E2), number of oocytes retrieved, cycle cancellation, ongoing pregnancy, and live-birth were compared between GCs and autologous IVF carriers. Indications for GC use were also identified. Multiple cycles contributed by the same patient were accounted for using multivariable generalized estimating equations and two-sided Wald p-values. Uterine factors (67%) was the most common indication for using a GC, followed by non-gynecologic medical conditions including coagulopathies (13%), end stage renal disease (10%), cardiovascular disease (5%) and cancer (5%). Adjusting for age, ovulation induction in GC cycles had similar peak E2 levels and number of oocytes retrieved relative to IVF cycles (p = 0.23 and 0.43, respectively). Clinical pregnancy (49% vs. 42%, p = 0.28) and live-birth rates (31% vs. 32%, p = 0.74) were also comparable. A sub-analysis of GC cycles in those women with uterine factor indications, demonstrated significantly higher clinical pregnancy rates (OR = 2.0; CI = 1.2 - 3.5) with 60% greater odds of live-birth relative to IVF/ICSI cycles, however this odds was not statistically significant for differences in live-birth (CI = 0.9 - 2.9). Conclusions: GCs are a viable alternative to start families for patients with medical co-morbidities precluding pregnancy.


Age- and Sex-associated Differences in Phenotypic and Functional Characteristics of Peripheral Blood Lymphocytes in Chimpanzees (Pan troglodytes).
Chimpanzees are the closest phylogenetic relatives to humans, sharing more than 98% genetic sequence identity. Thesegenetic similarities prompted the belief that chimpanzees can serve as an ideal model for human disease conditions andvaccine development. However, in light of the recent NIH decision to phase out biomedical research in chimpanzees and retire NIH-supported chimpanzees, data from the present study will continue to provide value for the care of aged and sick chimpanzees located in zoos, sanctuaries, and primate centers. Surprisingly little information has been published regarding the normal chimpanzee immune system, and most extant studies have been based on small numbers of animals. In the current study, we provide a better understanding of the chimpanzee immune system with regard to age and sex. We examined immune parameters of chimpanzees (n = 94; 51 female, 43 male; age, 6 to 47 y) by using flow cytometry, immune function analysis, and cytokine analysis. Because lymphocytes are key mediators of cellular immune responses, particularly to intracellular pathogens such as viruses, we surveyed the phenotypic and functional attributes of T and B lymphocytes in this healthy and age-stratified population of chimpanzees. We noted a significantly higher percentage of CD16+T cells in male compared with female chimpanzees but no significant changes in percentages of CD3+, CD4+, CD8+, or CD4+CD8+ T cells with age or sex. In addition, aging was associated with decreased proliferative responses to mitogens in both sexes. Sex-specific differences also were present in the percentage of NK cells but not in their cytotoxic activity and in circulating cytokine levels in plasma. Going forward, the data presented here regarding immune cell changes associated with aging in healthy chimpanzees will serve to enhance the care of geriatric and ill animals.


A semantic rule based digital fraud detection.
Digital fraud has immensely affected ordinary consumers and the finance industry. Our dependence on internet banking has made digital fraud a substantial problem. Financial institutions across the globe are trying to improve their digital fraud detection and deterrence capabilities. Fraud detection is a reactive process, and it usually incurs a cost to save the system from an ongoing malicious activity. Fraud deterrence is the capability of a system to withstand any fraudulent attempts. Fraud deterrence is a challenging task and researchers across the globe are proposing new solutions to improve deterrence capabilities. In this work, we focus on the very important problem of fraud deterrence. Our proposed work uses an Intimation Rule Based (IRB) alert generation algorithm. These IRB alerts are classified based on severity levels. Our proposed solution uses a richer domain knowledge base and rule-based reasoning. In this work, we propose an ontology-based financial fraud detection and deterrence model.


Accelerated lymphocyte reconstitution and long-term recovery after transplantation of lentiviral-transduced rhesus CD34+ cells mobilized by G-CSF and plerixafor.
Granulocyte colony-stimulating factor (G-CSF) in combination with plerixafor produces significant mobilization of CD34(+) cells in rhesus macaques. We sought to evaluate whether these CD34(+) cells can stably reconstitute blood cells with lentiviral gene marking. We performed hematopoietic stem cell transplantation using G-CSF and plerixafor-mobilized rhesus CD34(+) cells transduced with a lentiviral vector, and these data were compared with those of G-CSF and stem cell factor mobilization. G-CSF and plerixafor mobilization resulted in CD34(+) cell yields that were twofold higher than yields with G-CSF and stem cell factor. CD123 (interleukin-3 receptor) expression was greater in G-CSF and plerixafor-mobilized CD34(+) cells when compared to G-CSF alone. Animals transplanted with G-CSF and plerixafor-mobilized cells showed engraftment of all lineages, similar to animals who received G-CSF and stem cell factor-mobilized grafts. Lymphocyte engraftment was accelerated in animals receiving the G-CSF and plerixafor-mobilized CD34(+) cells. One animal in the G-CSF and plerixafor group developed cold agglutinin-associated skin rash during the first 3 months of rapid lymphocyte recovery. One year after transplantation, all animals had 2% to 10% transgene expression in all blood cell lineages. G-CSF and plerixafor-mobilized CD34(+) cells accelerate lymphocyte engraftment and contain hematopoietic stem cell capable of reconstituting multilineage blood cells. These findings indicate important differences to consider in plerixafor-based hematopoietic stem cell mobilization protocols in rhesus macaques.


Porphyrin metabolism in lymphocytes of miners exposed to diesel exhaust at oil shale mine.
The present study was carried out on the evaluation and application of new biomarkers for populations exposed to occupational diesel exhaust at oil shale mines. Since not only genotoxic effects may play an important role in the generation of tumors, the level of porphyrin metabolism was proposed as a biomarker of diesel exhaust exposure effects. The data on determination of 5-aminolevulinic acid (ALA) synthesis and heme formation in lymphocytes from groups of 50 miners exposed to diesel exhaust and 50 unexposed surface workers of oil shale mine are presented. All workers were examined and interviewed using structured questionnaires. The levels of benzene, carbon monoxide and nitric oxides in air as well as concentrations of 1-nitropyrene and elemental carbon in particulate matter were used for evaluation of exposure to diesel exhaust in mine. The levels of ALA and protoporphyrin (PP), activities of ALA synthetase (ALA-S) and ferrochelatase (FC), as well as levels of PP associated with DNA (PP/DNA) were investigated in lymphocytes spectrophotometrically. Significant differences in activity of ALA synthesis and heme formation between exposed miners and surface workers were found (207+/-23 vs. 166+/-14 pmol/10(6) lymp./30' for ALA-S and 46.1+/-3.8 vs. 54.8+/-4.1 pmol/10(6) lymp./60' for FC activities, respectively, P<0.001). ALA-S activity was higher and ALA accumulated in lymphocytes of exposed miners. Inhibition of FC activity caused PP cellular accumulation and an increase in the PP/DNA level (P<0.05). Tobacco smoking led to the increase of ALA biosynthesis in lymphocytes of both surface and underground smokers. The comparison of data obtained for non-smokers and smokers of both groups of workers has shown a significant difference (P<0.05). The work duration of underground or surface workers did not significantly influence the investigated biochemical parameters. The determination of ALA synthesis in lymphocytes could be a useful biomonitoring index of organism sensitivity to underground working. The alterations of PP levels, FC activity and PP/DNA association in peripheral lymphocytes of miners illustrate the harmful effects of exposure to diesel exhaust.


Evaluation of valvular heart disease with cine gradient echo magnetic resonance imaging.
Electrocardiographic referenced repetitive gradient echo magnetic resonance imaging (cine GRE) has been used to detect and quantify valvular regurgitation. Regurgitation is recognized as a signal void in the high intensity blood pool on these images. Mitral regurgitation causes a signal void in the left atrium in systole, and aortic regurgitation produces one in the left ventricle in diastole. The specificity, sensitivity, and diagnostic accuracy of cine GRE for the detection of mitral and aortic regurgitation was greater than 0.93, 0.89, and 0.92, respectively. The severity of regurgitation has been quantified as the difference in the stroke volume between the two ventricles by measuring the volume of the blood pool, as shown in the stack of magnetic resonance tomograms. Severity has also been assessed by measuring the volume of the signal void. Finally, measurements of the volume of aortic regurgitation have recently been achieved by using velocity-encoded cine GRE. This technique provides a direct measurement of retrograde flow in the aorta during diastole. New cine GRE imaging techniques provide a noninvasive means for quantification of valvular as well as ventricular function.


The pink-eyed dilution locus controls the biogenesis of melanosomes and levels of melanosomal proteins in the eye.
The pink-eyed dilution (p) locus is known to control the quantity of melanin pigment made within melanocytes and retinal pigment epithelium (RPE) in the eye. We have examined the effects of several mutant allele combinations at the murine p locus on the number and morphology of melanosomes in choroidal melanocytes and RPE cells as well as on the levels of four proteins known to be present within melanosomes: tyrosinase, tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2) and lysosome-associated membrane protein-1 (LAMP-1). By electron microscopy, we observed a modest diminution in the size and number of choroidal melanosomes in pbs/pJ mice but a more dramatic decrease in the RPE in comparison with wild-type P/P mice. By contrast, a drastic reduction in melanosome size and number was present in the choroid and RPE of pun/pun and p6H/pcp mice, and in the RPE of p6H/pcp mice, melanosomes were essentially undetectable. In wild-type mice, levels of tyrosinase, TRP-1 and TRP-2 were high at birth and showed a second peak of expression at 10-14 days of age, declining to undetectable levels by 42 days. All three mutant allele combinations reduced the levels of these melanosomal proteins with the relative severity of effects being p6H/pcp>pun/pun>pbs/pJ. In the null p6H/pcp mice, levels of these proteins were extremely low at birth, no postnatal peak was observed, and levels declined to undetectable by 14 days. Levels of LAMP-1 in wild-type mice rose initially and then declined whereas in the mutant mice, levels decreased gradually from birth. Higher levels of LAMP-1 were observed in each of the mutants than in the wild-type mice at 21 days of age. Our results demonstrate that mutations at the p locus affect the size, number, shape and contents of melanosomes, implicating the p gene product in the normal biogenesis of this organelle.


Investigating the impact of an online hydration intervention in care homes using the COM-B model: a mixed methods study.
Antimicrobial resistance is a serious threat to public health. To reduce antimicrobial resistance, interventions to reduce gram-negative infections, specifically urinary tract infections, are vital. Early evidence suggests increased fluid intake is linked with a reduction in UTIs and subsequently has potential to reduce antibiotic usage. Care homes have a high prevalence of UTIs and provide an opportunity in a closed setting to deliver an intervention focused on increasing fluid intake, where it is supported and monitored by health care workers. The study aimed to evaluate the impact and feasibility of an online staff focused intervention over a 30 day period to increase the hydration of care home residents with a view to reducing the burden of AMR in this setting. The study was a pre and post intervention with a sequential explanatory mixed methods design. The intervention was delivered online in 3 care homes, containing 3 main components underpinned by the COM-B model including hydration training, 7 structured drinks rounds and a hydration champion to change behaviour of care home staff. A pre and post questionnaire assessed the impact of the intervention on staff and data was collected on fluid intake, drinks rounds delivered to residents, UTIs, antibiotic used to treat UTIs, falls and hospitalisation. Descriptive statistics summarised and assessed the impact of the study. Focus groups with care home staff provided qualitative data which was thematically analysed. Staff increased in self-perceived knowledge across the six components of hydration care. 59% of residents had an increase in median fluid intake post intervention. During the time of the intervention, a 13% decrease in UTIs and antibiotic usage to treat UTIs across the 3 care homes was recorded, however falls and hospitalisations increased. Themes arising from focus groups included the role of information for action, accessibility of online training, online training content. This study demonstrates that a brief, low cost, online multi-component intervention focused on care home staff can increase the fluid intake of residents. A reduction in UTIs and antibiotic consumption was observed overall. Empowering care home staff could be a way of reducing the burden of infection in this setting.


Renin-angiotensin-aldosterone system in diabetes mellitus.
The renin-angiotensin-aldosterone system appears to function normally in uncomplicated diabetes mellitus. Alterations in this system, however, have been observed in several of the microvascular and electrolyte complications associated with this disease. Plasma renin activity (PRA) and aldosterone are decreased in diabetic with nephropathy and hypertension, in those with neuropathy including orthostatic hypotension, and in those with hypoaldosteronism. PRA is low in rats with uncontrolled, nonketotic diabetes, and pressor responsiveness to angiotension II is increased in patients with diabetic retinopathy. Potential mechanisms responsible for the decreased PRA include plasma volume expansion, hyalin destruction of the juxtaglomerular cells, defective synthesis of renin, and inadequate catecholamine stimulation of renin, and inadequant cathecholamine stimulation of renin release. In diabetic ketoacidosis, PRA and aldosterone are stimulated secondary to the associated dehydration with hypovolemia. This report reviews the current status of the function of the renin-angiotensin-aldosterone system in diabetes mellitus and proposes a possible role for the altered function of this system in the pathophysiology of several diabetic complications.


Randomized Double-blind Placebo-controlled Proof-of-concept Trial of Resveratrol for Outpatient Treatment of Mild Coronavirus Disease (COVID-19).
Resveratrol is a polyphenol that has been well studied and has demonstrated anti-viral and anti-inflammatory properties that might mitigate the effects of COVID-19. Outpatients (N=105) were recruited from central Ohio in late 2020. Participants were randomly assigned to receive placebo or resveratrol. Both groups received a single dose of Vitamin D3 which was used as an adjunct. The primary outcome measure was hospitalization within 21 days of symptom onset; secondary measures were ER visits, incidence of pneumonia and pulmonary embolism. Five patients chose not to participate after randomization. Twenty-one day outcome was determined of all one hundred participants (mean [SD] age 55.6 [8.8] years; 61% female) (or their surrogates). There were no clinically significant adverse events attributed to resveratrol. Outpatients in this phase 2 study treated with resveratrol had a lower incidence compared to placebo of: hospitalization (2% vs. 6%, RR 0.33, 95% CI 0.04-3.10), COVID-related ER visits (8% vs. 14%, RR 0.57, 95% CI 0.18-1.83), and pneumonia (8% vs. 16%, RR 0.5, 95% CI 0.16-1.55). One patient (2%) in each group developed pulmonary embolism (RR 1.00, 95% CI: 0.06-15.55). This underpowered study was limited by small sample size and low incidence of primary adverse events. A larger trial could determine efficacy. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT04400890 26/05/2020; FDA IND #150033 05/05/2020.


Recovery of second trimester pre-eclampsia after fetal reduction of a triplet.
Women with a multiple pregnancy are at increased risk of developing hypertensive disorders of pregnancy. We describe a case of a dichorionic triamniotic triplet pregnancy complicated by severe hypertension, proteinuria and maternal symptoms, fitting with the diagnosis of pre-eclampsia, apart from the early gestational age of only 16 weeks. After reduction of the monochorionic pair, the disease resolved and pre-eclampsia was diagnosed again at 30 weeks of gestation, resulting in a delivery on maternal indication at 33 weeks of gestation. In a review of the literature, we found six papers including eight cases on multifetal pregnancy reduction on maternal indication. Multifetal pregnancy reduction resulted in a prolongation of pregnancy of two to 21 weeks and may be considered in extreme early onset pre-eclampsia in dichorionic multiple pregnancies.


Compositional analysis of glyphosate-tolerant soybeans treated with glyphosate.
The compositional analyses and safety assessment of glyphosate-tolerant soybeans (GTS) were previously described. These analyses were extensive and included addressing the potential effects on seed composition from the genetic modification. Detailed compositional analyses established that GTS, which had not been treated with glyphosate, were comparable to the parental soybean line and to other conventional soybeans. In this study, two GTS lines, 40-3-2 and 61-67-1, were treated with commercial levels of glyphosate, the active ingredient in Roundup herbicide. The composition of the seed from soybeans sprayed with glyphosate was compared to that of a nonsprayed parental control cultivar, A5403. The nutrients measured in the seed included protein, oil, ash, fiber, carbohydrates, and amino acids. The concentration of isoflavones (also referred to as phytoestrogens) was also measured as these compounds are derived from the same biochemical pathway that was engineered for glyphosate tolerance. The analytical results from these studies demonstrate that the GTS soybeans treated with glyphosate were comparable to the parental soybean cultivar, A5403, and other conventional soybean varieties.


Logographic reading by TMR adults.
Ten moderately retarded adults learned a set of 16 logographic signs. Subjects were asked to demonstrate sentences formed from the signs using dolls and other toys. They were also asked to pick out signs and form a sentence after watching the experimenter demonstrate an event. All subjects were able to demonstrate sentences with only minor errors. Only about half were completely successful in constructing four- and five-word sentences. The method of construction of most subjects revealed a semantic--syntactic disengagement; the signs were chosen in nonsentence order, apparently in order of salience of the referents. After collecting the signs, most subjects were able to put them in correct sentence order. The results support the feasibility of a logographic system for nonreading retarded adults.


Expression and activation of the vacuolar processing enzyme in Saccharomyces cerevisiae.
Vacuolar processing enzymes (VPEs) are cysteine proteinases responsible for maturation of various vacuolar proteins in plants. A larger precursor to VPE synthesized on rough endoplasmic reticulum is converted to an active enzyme in the vacuoles. In this study, a precursor to castor bean VPE was expressed in a pep4 strain of the yeast Saccharomyces cerevisiae to examine the mechanism of activation of VPE. Two VPE proteins of 59 and 46 kDa were detected in the vacuoles of the transformant. They were glycosylated in the yeast cells, although VPE is not glycosylated in plant cells in spite of the presence of two N-linked glycosylation sites. During the growth of the transformant, the level of the 59 kDa VPE increased slightly until a rapid decrease occurred after 9 h. By contrast, the 46 kDa VPE appeared simultaneously with the disappearance of the 59 kDa VPE. Vacuolar processing activity increased with the accumulation of the 46 kDa VPE, but not of the 59 kDa VPE. The specific activity of the 46 kDa VPE was at a similar level to that of VPE in plant cells. The 46 kDa VPE instead of proteinase A mediated the conversion of procarboxypeptidase Y to the mature form. This indicates that proteinase A responsible for maturation of yeast vacuolar proteins can be replaced functionally by plant VPE. These findings suggest that an inactive VPE precursor synthesized on the endoplasmic reticulum is transported to the vacuoles in the yeast cells and then processed to make an active VPE by self-catalytic proteolysis within the vacuoles.


Canine pluripotent hematopoietic stem cells and CFU-GM express Ia-like antigens as recognized by two different class II-specific monoclonal antibodies.
A previous study showed failure of autologous engraftment in lethally irradiated dogs when marrow was treated before infusion with anti-class II antibody 7.2 and complement. The current study extended this observation to a second monoclonal antibody (HB10a) that identifies a different determinant on Ia-like molecules. These results suggest the presence of Ia-like antigens on pluripotent hematopoietic stem cells or on "accessory cells" needed for sustained engraftment to occur. To distinguish between these two possibilities, stem cell-depleted Ia-positive peripheral blood leukocytes obtained by discontinuous albumin density gradient were added as probable source of accessory cells to the marrow inoculum that was depleted of Ia-positive cells by treatment with antibody 7.2 and complement. Eight of ten dogs failed to show engraftment, providing further support for the hypothesis that pluripotent stem cells and not accessory cells were affected by cytolytic treatment. To provide direct evidence for the presence of Ia-like antigens on canine pluripotent hematopoietic stem cells, autologous transplants were performed using 0.7 to 13 X 10(6) Ia (7.2)-positive marrow cells per kg obtained with the help of fluorescence-activated cell sorter. Of three evaluable dogs, two showed sustained and complete engraftment, indicating that Ia-like antigens, as recognized by anti-class II antibody 7.2, are expressed at least on part of canine pluripotent hematopoietic stem cells. Concurrent in vitro studies revealed that canine CFU-GM also expressed Ia-like antigens as recognized by the class II-specific monoclonal antibodies 7.2 and HB10a.


Burden of illness review of obesity: are the true costs realised?
Obesity can no longer be viewed as merely a cosmetic or social problem, but must be acknowledged as a serious disease, responsible for the premature death and morbidity of millions and for significant expenditure of limited healthcare resources. In addition, there are significant costs to the individual with regard to social status and quality of life. It has been argued that obesity is one of the most important preventable causes of ill health in the UK today. This is especially important when one considers that the incidence of obesity is actually rising, with 13% of men and 16% of women in the UK in 1997 being obese. To begin treating such a disease it is essential to raise awareness of this problem, not only from the associated morbidity and mortality risks that have been well documented, but the socio-economic and psychological costs. This paper reviews the literature available globally, giving some measure of the magnitude of the associated burden of illness.


Cattle with the BoLA class II DRB3*0902 allele have significantly lower bovine leukemia proviral loads.
The bovine MHC (BoLA) class II DRB3 alleles are associated with polyclonal expansion of lymphocytes caused by bovine leukemia virus (BLV) infection in cattle. To examine whether the DRB3*0902 allele, one of the resistance-associated alleles, is associated with the proviral load, we measured BLV proviral load of BLV-infected cattle and clarified their DRB3 alleles. Fifty-seven animals with DRB3*0902 were identified out of 835 BLV-infected cattle and had significantly lower proviral load (P<0.000001) compared with the rest of the infected animals, in both Japanese Black and Holstein cattle. This result strongly indicates that the BoLA class II DRA/DRB3*0902 molecule plays an important immunological role in suppressing viral replication, resulting in resistance to the disease progression.


Perceived bitterness character of beer in relation to hop variety and the impact of hop aroma.
The impact of hop variety and hop aroma on perceived beer bitterness intensity and character was investigated using analytical and sensory methods. Beers made from malt extract were hopped with 3 distinctive hop varieties (Hersbrucker, East Kent Goldings, Zeus) to achieve equi-bitter levels. A trained sensory panel determined the bitterness character profile of each singly-hopped beer using a novel lexicon. Results showed different bitterness character profiles for each beer, with hop aroma also found to change the hop variety-derived bitterness character profiles of the beer. Rank-rating evaluations further showed the significant effect of hop aroma on selected key bitterness character attributes, by increasing perceived harsh and lingering bitterness, astringency, and bitterness intensity via cross-modal flavour interactions. This study advances understanding of the complexity of beer bitterness perception by demonstrating that hop variety selection and hop aroma both impact significantly on the perceived intensity and character of this key sensory attribute.


The cancer/testis antigen prostate-associated gene 4 (PAGE4) is a highly intrinsically disordered protein.
The cancer/testis antigens (CTAs) are an important group of heterogeneous proteins that are predominantly expressed in the testis in the normal human adult but are aberrantly expressed in several types of cancers. Prostate-associated gene 4 (PAGE4) is a member of the CT-X family of CTAs that in addition to testis, is highly expressed in the fetal prostate, and may also play an important role both in benign and malignant prostate diseases. However, the function of this gene remains poorly understood. Here, we show that PAGE4 is a highly (100%) intrinsically disordered protein (IDP). The primary protein sequence conforms to the features of a typical IDP sequence and the secondary structure prediction algorithm metaPrDOS strongly supported this prediction. Furthermore, SDS-gel electrophoresis and analytical size exclusion chromatography of the recombinant protein revealed an anomalous behavior characteristic of IDPs. UV circular dichroism (CD) and NMR spectroscopy confirmed that PAGE4 is indeed a highly disordered protein. In further bioinformatic analysis, the PredictNLS algorithm uncovered a potential nuclear localization signal, whereas the algorithm DBS-Pred returned a 99.1% probability that PAGE4 is a DNA-binding protein. Consistent with this prediction, biochemical experiments showed that PAGE4 preferentially binds a GC-rich sequence. Silencing PAGE4 expression induced cell death via apoptosis and in mice carrying PCa xenografts, siRNA-mediated knockdown of the PAGE4 mRNA attenuated tumor growth in vivo. Furthermore, overexpressing PAGE4 protected cells from stress-induced death. To our knowledge, PAGE4 is the first example of a CTA that is an IDP with an anti-apoptotic function.