Preparation of a laminated structured polyethyleneimine cryogel for carbon capture.
A cryogel solid amine adsorbent with a laminated structure has been prepared by crosslinking polyethylenimine (PEI) with ethylene glycol diglycidyl ether (EGDE) at a low temperature via liquid nitrogen treatment and freeze-drying. The effects of cryogenic treatment on the morphology of the cryogels were investigated. The liquid nitrogen treatment and freeze drying were critical to create the layered structure. The fast formation of ice crystals at 77 K served as a template which directed the ordered lamellar structure of the PEI and EGDE cross-linked polymer networks. The PEI cryogel adsorbent showed excellent CO2 adsorption performance both in dry and wet conditions. In dry conditions, the PEI-gel-5-0.25 cryogel showed a 5.60 mmol/g of CO2 adsorption capacity at 75 °C. After being swelled with water, the PEI-gel-15-0.25 cryogel showed an extremely high CO2 adsorption capacity of 11.39 mmol/g at 25 °C. The adsorption behaviors of adsorbents with varied water contents were explained using kinetic simulations and intraparticle diffusion simulations. It was found that the presence of water can significantly enhance the diffusion process. The regeneration performance was examined in both dry and wet conditions. After 20 adsorption-desorption cycles, the adsorption capacity of the regenerated PEI cryogel had barely decreased, indicating reliable regeneration stability.


Corrigendum to "Impact of new rapid transit on physical activity: A meta-analysis" Preventive Medicine Reports 10 (2018) 184-190.
[This corrects the article DOI: 10.1016/j.pmedr.2018.03.008.].


Impaired scaling of long latency postural reflexes in patients with Parkinson's disease.
Young normal subjects adapt the size of posturally stabilizing reflexes in the lower extremity to predictable and unpredictable perturbations through shifts in cognitive set. It is unknown whether limitations in this ability to shift cognitive set may contribute to impaired scaling of postural reflexes in patients with Parkinson's disease. In this study, we have addressed this issue in 12 posturally unstable Parkinson patients and 13 age- and sex-matched controls. Postural stability was disturbed by sudden toe-up rotations of a supporting platform upon which subjects were standing. Subjects' cognitive set was altered by varying the perturbation amplitude either predictably (serial 4 degrees versus serial 10 degrees) or unpredictably (random mixture of 4 degrees and 10 degrees). Posturally stabilizing long latency (LL) reflexes were recorded from the shortened tibialis anterior muscle of both legs. We found that Parkinson patients, unlike some control subjects, were unable to scale the size of their LL reflex in response to variations in perturbation amplitude during predictable conditions. In addition, we observed that Parkinson patients could not modify the amplitude of the LL reflex through alterations in cognitive set during random conditions. We conclude that Parkinson patients have a fundamental difficulty in modifying the size of posturally stabilizing LL reflexes, as reflected by both problems with amplitude scaling and difficulties with changes in cognitive set. It is possible that this inability to modify LL reflexes may be a factor contributing to postural instability in Parkinson's disease.


Dissociating restart cost and mixing cost in task switching.
Three experiments investigated the cognitive mechanisms underlying the restart cost and mixing cost in task switching. To this aim, the predictability of task order was varied (unpredictable in Experiment 1 and predictable in Experiments 2 and 3) across experiments, which employed a multiple-trial paradigm. Verbal cues for color and shape matching tasks were presented before a run of four trials. Focusing on task-repetition runs only, we measured restart cost as the difference in performance between trials 1 and 2 and mixing cost as the difference in performance on the non-cued trials under mixed-tasks conditions (Experiments 1 and 2) and single-task conditions (Experiment 3). The restart cost was observed under mixed-tasks conditions with both unpredictable and predictable task orders but not under the single-task condition. In contrast, the mixing cost was observed under the mixed-tasks condition with unpredictable task order only (Experiment 1). This finding implies that the optimal task execution on repetition trials depends on how predictable the identity of the approaching task is. Therefore, we suggest that mixing cost arises from limited preparation on repetition trials when task order is unpredictable, while restart cost arises from processes involved in cue-based task activation that is needed to resolve task interference. Together, these data suggest that restart cost and mixing cost are based on dissociable mechanisms.


Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas.
The release of pancreatic polypeptide (PP) by gut hormones, acetyl choline and adrenaline was investigated in an isolated perfused pancreas preparation. PP was potently released by 1 nmol/1 caerulein (186 +/- 12%, p is less than 0.001) and gastric inhibitory peptide (GIP) (211 +/- 31%, p is less than 0.005) as well as by 1 mumol/1 acetyl choline (1097 +/- 59%, p is less than 0.001). A significant two-fold release of PP was also evoked by 1 nmol/1 vasoactive intestinal peptide (VIP) (129 +/- 38%, p is less than 0.02 and gastrin (108 +/- 25% p is less than 0.01). Insulin release, induced by high glucose concentration was enhanced by both GIP (210 +/- 38%, p is less than (0.01) and VIP (48 +/- 5%, p is less than 0.001). In addition GIP enhanced the release of glucagon by 179 +/- 18% (p is less 0.001) at 1.4 mmol/1 glucose and by 127 +/- 24% (p is less than 0.005) at 8.3 mmol/1 glucose. Thus no simple inter-relationship appears to exist between the control of the three circulating islet hormones.


Effect of penehyclidine hydrochloride on expressions of MAPK in mice with CLP-induced acute lung injury.
Penehyclidine hydrochloride (PHC) is a new anticholinergic drug. PHC has been shown to have a good curative effect for sepsis. Mitogen-activated protein kinase (MAPK) has recently been considered to play an important role in sepsis. In this study, the role of MAPK signal pathways in protective effects of PHC preconditioning on acute lung injury in cecal ligation and puncture (CLP)-induced sepsis was investigated. Healthy female mice were randomly divided into 4 groups: sham control, CLP, and 0.3 or 0.45 mg/kg PHC. At 12 h after surgery, arterial blood was drawn for blood gas analysis, and lung tissue samples were collected to examine pulmonary microvascular permeability, IL-6 levels and myeloperoxidase (MPO) activity. MAPK protein expressions were measured using western blot technique. Compared with sham control mice, acute lung injury was induced in CLP group, which was indicated by decreased PaO(2)/FiO(2), increased pulmonary microvascular permeability, IL-6 levels and MPO activity. Furthermore, mice' exposure to CLP induced the increased protein levels of MAPK. Treatment of 0.45 mg/kg PHC markedly improved PaO(2)/FiO(2), decreased pulmonary microvascular permeability, IL-6 levels and MPO activity, and inhibited expressions of extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. Taken together, these results suggest that PHC ameliorated acute lung injury through the inhibition of extracellular signal-regulated kinase (ERK1/2) and p38 MAPK activation in septic mice.


Hepatitis B virus genotypes in the United States: results of a nationwide study.
Hepatitis B virus (HBV) genotypes may be related to severity of liver disease and treatment response. The aims of this nationwide study were to determine the prevalence of HBV genotypes in the United States and the association between HBV genotypes and patient demographics, mode of infection, and clinical status. A total of 694 consecutive chronic HBV-infected patients seen in 17 U.S. liver centers during a 1-year period were enrolled. Demographic, clinical, and laboratory data were collected. Sera were tested for HBV genotyping, precore, and core promoter variants by line-probe assays. All 7 HBV genotypes (A-G) were found, with genotypes A and C the most common. The prevalence of HBV genotypes was different in different regions of the United States. A strong correlation was found between HBV genotypes and ethnicity. HBV genotype A was prevalent among white and black patients, whereas genotypes B and C were most common among Asian patients. The predominant genotype among patients born in the United States, Europe, the Far East, and Southeast Asia were A, D, C, and B, respectively. Genotypes A and C were associated with a higher prevalence of hepatitis B e antigen. Precore variant was detected in 27% of patients and core promoter variant in 44% of patients. Our study suggests that the epidemiology of HBV infection in the United States may have changed over time as a result of immigration from countries with a high prevalence of HBV infection. HBV genotypes may account for the heterogeneity in disease manifestations among patients with chronic HBV infection.


Towards better process management in wastewater treatment plants: Process analytics based on SHAP values for tree-based machine learning methods.
Understanding the mechanisms of pollutant removal in Wastewater Treatment Plants (WWTPs) is crucial for controlling effluent quality efficiently. However, the numerous treatment units, operational factors, and the underlying interactions between these units and factors usually obfuscate the comprehensive and precise understanding of the processes. We have previously proposed a machine learning (ML) framework to uncover complex cause-and-effect relationships in WWTPs. However, only one interpretable ML model, Random forest (RF), was studied and the interpretation method was not granular enough to reveal very detailed relationships between operational factors and effluent parameters. Thus, in this paper, we present an upgraded framework involving three interpretable tree-based models (RF, XGboost and LightGBM), three metrics (R2, Root mean squared error (RMSE), and Mean absolute error (MAE)) and a more advanced interpretation system SHapley Additive exPlanations (SHAP). Details of the framework are provided along with a demonstration of its practical applicability based on a case study of the Umeå WWTP in Sweden. Results show that, for both labels TSSe (Total suspended solids in effluent) and PO4e (Phosphate in effluent), the XGBoost models are optimal whereas the RF models are the least optimal, due to overfitting and polarized fitting. This study has yielded multiple new and significant findings with respect to the control of TSSe and PO4e in the Umeå WWTP and other similarly configured WWTPs. Additionally, this study has produced two important generic findings relating to ML applications for WWTPs (or even other process industries) in terms of cause-and-effect investigations. First, the model comparison should be carried out from multiple perspectives to ensure that underlying details are fully revealed and examined. Second, using a precise, robust, and granular (feature attribution available for individual instances) explanation method can bring extra insight into both model comparison and model interpretation. SHAP is recommended as we found it to be of great value in this study.


New aspects concerning ulcerative colitis and colonic carcinoma: analysis of levels of neuropeptides, neurotrophins, and TNFalpha/TNF receptor in plasma and mucosa in parallel with histological evaluation of the intestine.
The levels of neuropeptides, neurotrophins, and TNFalpha (TNFalpha)/TNF receptor in plasma and mucosa for patients with ulcerative colitis (UC) and colonic carcinoma, and concerning plasma also for healthy controls, were examined. Moreover, the relationships between the different substances and the influence of mucosal derangement on the levels were analyzed. The levels of VIP, SP, CGRP, BDNF, NGF, and TNFalpha/TNF receptor 1 were measured using ELISA/EIA. Patients with UC demonstrated the highest levels of all analyzed substances in plasma, with the exception of BDNF. However, there were differences within the UC group, patients treated with corticosteroids, and/or nonsteroid antiinflammatory/immunosuppressive treatment having higher plasma levels than those not given these treatments. Patients with colonic carcinoma showed higher SP and TNF receptor 1 levels in plasma compared to healthy controls. Concerning mucosa, the levels of almost all analyzed substances were elevated for patients with UC compared to noncancerous mucosa of colonic carcinoma patients. There were correlations between many of the substances in both plasma and mucosa, especially concerning the 3 neuropeptides examined. There were also marked associations with mucosa derangement. Via analysis of correlations for the respective patients and via comparisons between the different patient groups, new and original information was obtained. Interestingly, the degree of mucosal affection was markedly correlated with tissue levels of the substances and the treatments were found to be of importance concerning plasma but not tissue levels of these. Combined plasma analysis of neuropeptides, neurotrophins, and TNF receptor 1 may help to distinguish UC and colonic carcinoma patients.


Spongiosis hepatis in rats treated with low doses of hepatotropic nitrosamines.
Spongiosis hepatis, a characteristic pathomorphologic entity originating from the perisinusoidal liver cells, was observed in rats after administration of relatively low doses of the hepatocarcinogens dimethylnitrosamine (DMNA) and nitrosopyrrolidine (NO-Pyr), but not after application of the urinary bladder carcinogen butyl-butanolnitrosamine (BBNA). The results support the conception that spongiosis is a persisting liver lesion due to specific changes of the perisinusoidal liver cells by hepatotropic carcinogens.


Treatment for Intracorneal Hematoma by Anterior Chamber Gas Tamponade Combined With Keratocentesis.
To report a new surgical method for intracorneal hematoma removal using combination of keratocentesis and gas tamponade in the anterior chamber. We reviewed the clinical course and outcomes of surgical intervention. An 82-year-old woman visited our department because of a sudden decline in visual acuity (20/800 on the Snellen chart) in her left eye. We observed neovascularization from the superior corneal limbus and a hematoma near the Descemet membrane, deep in the stroma of the corneal center. Filtered air was injected into the anterior chamber, keratocentesis was performed at four locations from the corneal epithelium through the stroma, and the hematoma was removed from the puncture sites. The corneal hematoma disappeared, and the best-corrected visual acuity reached 20/20 at postoperative month 4. Combination of keratocentesis and gas tamponade in the anterior chamber is a simple and effective method for removing intracorneal hematomas.


The earliest document regarding the history of cranioplasty from the Ottoman era.
Cranioplasty is one of the significant neurosurgical procedures in which the technical advances and also, by some means, drawbacks are still continuing. According to archeological findings and anthropological studies, the earliest procedures regarding cranioplasty date back to just about the same period claimed for trepanation. Ancient surgeons from different geographical sites and cultures performed both practices with remarkable survival rates. However, despite the length of the thriving past of cranioplasty, the first known written record on the topic dates back to late 16th century Europe. Further study of the Ottoman era documents revealed an intriguing text that was written about the repair of skull defects and that dates from early 16th century. This worthy discovery will add valuable contribution to the history of neurosurgery by drawing the written history of cranioplasty more than 60 years back and the use of organic grafts 160 years back. In the present study, this original text is discussed.


AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.
Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1-KO mouse model. Here we show that adeno-associated viral vector delivery of a modified and FMRP-independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS-relevant behavioral phenotypes in the Fmr1-KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.


Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.
The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.


Vaccination and malignant disease: promising therapeutic approach.
Immunotherapy of cancer is now entering its second century. Much of our understanding of the complex interaction between tumours and the host immune system has come about because of technological and immunobiological advances in very recent years. For some malignancies, such as bladder cancer and malignant melanoma, immunotherapy is becoming an accepted form of adjuvant therapy. However, for most types of cancer, immunotherapy remains experimental and the majority of surgeons will have had little experience of immunotherapy in the clinical setting. This review provides a background to the scientific basis of immunotherapy, how different forms of immunotherapy are delivered and how their effects are monitored.


CardioVerse: The cardiovascular medicine in the era of Metaverse.
The recent pandemic launched an acceleration in adopting telemedicine by cardiovascular health and triggered the flourishing of technological advancements, such as the metaverse, which is a novel interactive mix of digital worlds that leverages augmented reality with virtual reality. The CardioVerse represents a theoretical term for the embracement of the metaverse by cardiovascular medicine, encompassing the endless possibilities as well as the challenges that it holds and introduces new dimensions to disease education, prevention and diagnosis. Its applications are numerous, notably in enhancing medical visits, assisting cardiovascular interventions and reshaping the way medical education is provided. Although obstacles are expected in diverse domains such as security, technical, legislative and regulatory, the utilization of non-fungible tokens as a security asset for patient data appears as potential solution.


Multimodality imaging in the diagnosis of deep vein thrombosis and popliteal pseudoaneurysm complicating a sessile osteochondroma.
Synergistic use of ultrasonography, radiography, multidetector CT (MDCT) and MRI enabled a prompt and accurate diagnosis of a nonocclusive popliteal vein thrombus (deep venous thrombosis, DVT) and a pseudoaneurysm complicating a sessile osteochondroma in an 11-year-old boy who presented in the emergency department with sudden-onset nontraumatic pain in the posterior aspect of the knee.


Aberrant DNA repair and enhanced mutagenesis following mutagen treatment of Chinese hamster Ade-C cells in a state of purine deprivation.
Ade-C is a Chinese hamster ovary cell line auxotrophic for purines because of a mutation in the de novo synthetic pathway. We now show that, in the absence of exogenous hypoxanthine, replicative DNA synthesis is rapidly shut down. Various aspects of DNA repair have been studied in purine-starved cells. Incision, the first step of excision repair of UV damage, appears normal, as do the later steps, repair synthesis (demonstrated following chemical damage as well as UV-irradiation) and ligation. However, removal of UV-induced pyrimidine dimers is not detected, and it seems that the repair that occurs is aberrant. This behaviour is associated with an increase in cell killing by UV light, and a several-fold increase in the frequency of mutations induced by UV.


The Significance of Rectus Femoris for the Favorable Functional Outcome After Total Femur Replacement.
In treatment of tumors, we usually reconstruct after resection of the entire femur using only metallic modular endoprostheses among many procedures and defined it as a total femur replacement. We studied the interrelation between the preservation of rectus femoris and the functional outcome after total femur replacement. We rated the functional outcomes of 21 patients who underwent total femur replacement. We categorized the subjects into 2 groups: group A (rectus femoris preserved) and group B (rectus femoris unpreserved). We examined them based on the Mann-Whitney U test between the 2 groups in average through the Musculoskeletal Tumor Society functional scores. The average score of group A was 20 of 25 (11-25; 80%), whereas the average score of group B was 10 of 25 (4-13; 40%). There was significant difference between the groups (P = 0.00168877). We found that the preservation of rectus femoris is imperative for achieving the favorable functional outcome in total femur replacement.


Phytomass change in natural phytocenosis as an indicator of technogenic pollution of soils with heavy metals.
This study considered the possibility of using plant community phytomass for the assessment of soil pollution with heavy metals (HM) from industrial wastes. The three-year-long field experiment was run under the regional natural meadow vegetation; the polymetallic galvanic slime was used as an industrial waste contaminant. It is shown that soil contamination primarily causes decrease of phytomass in the growing phytocenosis. The vegetation experiments determined nonlinear dependence of cultivated and wild plant biomass on the level of soil contamination; it is described by the equations of logistic and Gaussian regression. In the absence of permanent contaminants, the soil is self-cleaned over time. It reproduces phytomass mainly due to the productivity increase of the most pollution-tolerant species in the remaining phytocenosis. This phenomenon is defined as environmental hysteresis. Soil pollution by industrial waste leads to the loss of plant biodiversity. The research shows that the study of the HM impact on ecosystems is expedient given the consideration of the "soil-phytocenosis-pollutant" complex in the "dose-response" aspect. The reaction of phytocenosis on HM showing decline in phytomass leads to serious limitations in the choice of accumulating plants, because the adsorbed HM are rejected through phytomass.


Does progressive aphantasia exist? The hypothetical role of aphantasia in the diagnosis of neurodegenerative diseases.
Aphantasia is a heterogeneous neuropsychological syndrome consisting of the inability to create mental images. We argue that its progressive form may be a harbinger of dementia. Aphantasia may manifest as the inability to create any mental images or to create complex scenes, inability to spontaneously initiate generation of mental images, and/or inability to visualize a sequence of events.


Two-stage enrichment of hydrogen-oxidizing bacteria as biofertilizers.
Biofertilizers can replace chemical fertilizers to promote the plant growth without causing any pollution. The study of hydrogen-oxidizing bacteria (HOB) enrichment as biofertilizers from mixed culture is scarce. Our recent study shows that biofertilizing HOB are successfully enriched in a short hydraulic retention time of 10 h. While, the mechanism is unknown. This study intentionally used a two-stage method to enrich biofertilizing HOB specifically with nitrate as nitrogen source in Stage 1 and then 1-aminocyclopropane-1-carboxylate (ACC) as nitrogen source in Stage 2. It was found Pseudomonas (34.46%, reported HOB) predominated in Stage 1, while Azospirillum (59.35%), Azoarcus (36%) were dominant genera and Azospirillum lipoferum strain DSM 1691 (50%), Azoarcus olearius strain DQS-4 (50%) were dominant species in Stage 2. The enriched HOB of Stage 2 showed ACC deaminase activity. Furthermore, they could also fix N2 and consume Ca3(PO4)2. Thus, the two-stage method can be used as a specific enrichment for HOB as biofertilizers, which extends the application of HOB in agriculture.


Widespread occurrence in Australian marsupials of neutralizing antibodies to a herpesvirus from a parma wallaby.
Serum neutralizing antibodies to a parma wallaby herpesvirus (PWHV) have been detected in a wide range of marsupials from different locations across Australia, including several islands. A study of 242 animals (mostly macropods) sampled in the wild showed that 23% had antibodies; a significantly higher frequency (41%) of 116 animals in captivity had antibodies, which were generally at higher levels than those of animals in the wild. Antibodies to PWHV were also detected among parma wallabies from a colony on Kawau Island, New Zealand. The highest antibody levels were found in a group of captive tammar wallabies during recurrent outbreaks of clinical infection. It is suggested that PWHV has evolved along with a marsupial host, and that the high antibody levels among captive animals reflects ease of virus transmission due to crowding, or to conditions of stress leading to expression of latent virus.


The correlation between paclitaxel chemotoxicity and the plasma albumin level in cancer patients.
The aim of this study was to evaluate the pharmacokinetics of paclitaxel in cancer patients with hypoalbuminemia following paclitaxel-containing chemotherapy and to provide a reference for the prevention of adverse events (AEs) after paclitaxel administration. Peripheral blood was collected from cancer patients treated with paclitaxel. The plasma concentration of paclitaxel was determined by ultra-high performance liquid chromatography after 24 ± 8 h of chemotherapy, and individual paclitaxel time above a threshold concentration of 0.05 μmol/L (Tc>0.05 ) was calculated using the population pharmacokinetic model. Haematological and non-haematological toxicities were monitored after chemotherapy, and the correlation between different chemotherapy toxicities and Tc>0.05 was evaluated using the Prism software. The enrolled patients were divided into the hypoalbuminemia group and normal albumin level group. The mean Tc>0.05 values in the normal albumin level and hypoalbuminemia groups were 36.89 and 24.93 h, respectively (P < 0.001). The risk of myelosuppression was positively correlated with Tc>0.05 . Due to the lower Tc>0.05 , the incidences of immediate AEs such as gastrointestinal reactions and rashes were higher in the hypoalbuminemia group than in the normal albumin level group, and the incidences of delayed AEs such as myelosuppression and neurotoxicity were lower in the hypoalbuminemia group. Plasma albumin level has a conclusive effect on Tc>0.05 , which can predict the potential clinical toxicity of paclitaxel. The study provides a theoretical basis for administration of paclitaxel.


Static and dynamic pressure prediction for prosthetic socket fitting assessment utilising an inverse problem approach.
It has been recognised in a review of the developments of lower-limb prosthetic socket fitting processes that the future demands new tools to aid in socket fitting. This paper presents the results of research to design and clinically test an artificial intelligence approach, specifically inverse problem analysis, for the determination of the pressures at the limb/prosthetic socket interface during stance and ambulation. Inverse problem analysis is based on accurately calculating the external loads or boundary conditions that can generate a known amount of strain, stresses or displacements at pre-determined locations on a structure. In this study a backpropagation artificial neural network (ANN) is designed and validated to predict the interfacial pressures at the residual limb/socket interface from strain data collected from the socket surface. The subject of this investigation was a 45-year-old male unilateral trans-tibial (below-knee) traumatic amputee who had been using a prosthesis for 22 years. When comparing the ANN predicted interfacial pressure on 16 patches within the socket with actual pressures applied to the socket there is shown to be 8.7% difference, validating the methodology. Investigation of varying axial load through the subject's prosthesis, alignment of the subject's prosthesis, and pressure at the limb/socket interface during walking demonstrates that the validated ANN is able to give an accurate full-field study of the static and dynamic interfacial pressure distribution. To conclude, a methodology has been developed that enables a prosthetist to quantitatively analyse the distribution of pressures within the prosthetic socket in a clinical environment. This will aid in facilitating the "right first time" approach to socket fitting which will benefit both the patient in terms of comfort and the prosthetist, by reducing the time and associated costs of providing a high level of socket fit.


Quorum Sensing Autoinducer(s) and Flagellum Independently Mediate EPS Signaling in Vibrio cholerae Through LuxO-Independent Mechanism.
Vibrio cholerae, the Gram-negative bacterium causing lethal diarrheal disease cholera, forms biofilm on solid surfaces to gain adaptive advantage for successful survival in aquatic reservoirs. Expression of exopolysaccharide (EPS), an extracellular matrix material, has been found critical for biofilm-based environmental persistence. In a subset of epidemic-causing V. cholerae, absence of flagellum but not motility was identified to induce elevated exopolysaccharide expression. Identification of the role played by quorum sensing autoinducer molecules, i.e., cholera autoinducer 1 (CAI-1) and autoinducer 2 (AI-2) as well as central regulator LuxO on EPS expression in the subset was explored. Deletion mutations were introduced in vital genes responsible for synthesizing CAI-1 (cqsA), AI-2 (luxS), flagellum (flaA), LuxO (luxO), flagellar motor (motX), and VpsR (vpsR) in the model strain MO10. Subsequent phenotypic alterations in terms of colony morphology, EPS expression, biofilm formation, and transcription level of relevant genes were analyzed. Autoinducer cross-feeding experiment confirmed the role of autoinducers in EPS signaling. Results reveal that autoinducers and flagellum are the two major EPS signaling units in this subset where one unit becomes predominant for EPS production in absence of the other. Moreover, either unit exerts negative influence on EPS induction by the other. Both the EPS signaling cascades are independent of LuxO contribution and essentially involve sodium-driven flagellar motor and VpsR. A cell density and flagellum-mediated, but LuxO-independent, EPS signaling mechanism is considered to be functional in these organisms that confers their survival fitness.


Host selection behavior of a thistle-feeding fly: choices and consequences.
Female Canada thistle seed flies (Orellia ruficauda) preferentially oviposit into seed heads which are a single day from opening. When flies are forced to oviposit into flower heads at other stages of development, offspring typically do slightly poorer: they attain a mature mass of about 15% less than do larvae derived from preferred hosts. Larval mass correlates strongly with reproductive success: heavy larvae develop into adults that produce eggs at a faster rate than do those developing from small larvae. After laying a clutch of eggs, flies circumscribe the rim of the flowerhead with their extended ovipositor and deposit a clear fluid. Flies reject previously-attacked hosts, bearing this apparent marking pheromone, significantly more often than they reject unattacked hosts. Costs of superparasitism in this system are relatively small, inasmuch as there is only a weak relationship between clutch size and larval success at the densities measured in this study. We speculate that flies are highly selective, when the apparent costs of making a mistake are rather low, because the information provided by phenological cues and by the putative marking pheromone is highly reliable, and low fecundity and time costs allow sufficient time to express a high level of discrimination.


Liquid chromatography tandem mass spectrometry study of urinary nucleosides as potential cancer markers.
The aim of this work was a comprehensive analysis of metabolite profiles of nucleosides from biological samples obtained from patients with urogenital cancer disease as well as an interpretation of cancer-related patterns of the analyzed profiles. In our study we proposed a targeted approach that was focused on the simultaneous determination of twelve nucleosides from over a hundred urine samples. For analytes' quantification high performance liquid chromatography technique hyphenated with tripple quadrupole mass spectrometer was applied. The developed method was validated in terms of linearity, precision, accuracy as well as in terms of limit of quantification and limit of detection. The obtained, normalized data set was analyzed using univariate statistical analysis. The achieved results revealed statistically significant (p<0.05) differences between levels of five nucleosides determined in urine samples from cancer patients and healthy volunteers, namely: 6-methyladenosine, inosine, N-2-methylguanosine, 3-methyluridine and N,N-dimethylguanosine. Basing on the putative markers we built the discrimination models using partial least squares discriminant analysis as well as K-nearest neighbor method. The sensitivity and specificity of the markers calculated from the obtained models were in the range of 61.9-88.89% and 27.78-50%, respectively. The proposed procedure can be considered as a holistic approach for metabolites' analysis and includes clinical, analytical and bioinformatics sections.


Impact of IDH1 mutation status on outcome in clinical trials for recurrent glioblastoma.
IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. However, it remains unknown whether patients (pts) with IDH1 mutated GB have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate on clinical trials for recurrence. Retrospective review of GB pts at MDACC between 2006 and 2012 identified 330 patients in recurrent GB trials. 93 patients (28 %) had either PFS6 or a complete/partial RR per RANO criteria. 49/93 (53 %) patients with PFS6 or a complete/partial RR had tumor tissue for IDH1 testing. A matched cohort of 49 patients on recurrent GB clinical trials that failed to achieve PFS6 or RR (also with tissue for IDH1 testing) was identified for comparison. IDH1 status was obtained in 92/98 (94 %) patients of which 17 (18 %) had an IDH1 mutation. PFS6 was seen in 26/49 (53 %) patients. IDH status was unknown in two of these patients. 5/24 (21 %) were IDH1 mutated compared to 5/24 (21 %) of their matched cohort without PFS6. RR was found in 47/49 (94 %) patients. IDH status was unknown in four of these patients. IDH1 mutation was present in 7/43 (16 %) patients with RR compared to 10/43 (23 %) in the matched cohort without RR (p = 0.48). Median OS for trials at first recurrence was 9.8 months for IDH1 wildtype GB vs. 19.32 months for IDH1 mutated GB (p = 0.14). IDH1 mutation status was not predictive of PFS6 or RR in recurrent GB trials for this data set. However, further examination in larger randomized prospective studies is needed.


Law, ethics and pandemic preparedness: the importance of cross-jurisdictional and cross-cultural perspectives.
To explore social equity, health planning, regulatory and ethical dilemmas in responding to a pandemic influenza (H5N1) outbreak, and the adequacy of protocols and standards such as the International Health Regulations (2005). This paper analyses the role of legal and ethical considerations for pandemic preparedness, including an exploration of the relevance of cross-jurisdictional and cross-cultural perspectives in assessing the validity of goals for harmonisation of laws and policies both within and between nations. Australian and international experience is reviewed in various areas, including distribution of vaccines during a pandemic, the distribution of authority between national and local levels of government, and global and regional equity issues for poorer countries. This paper finds that questions such as those of distributional justice (resource allocation) and regulatory frameworks raise important issues about the cultural and ethical acceptability of planning measures. Serious doubt is cast on a 'one size fits all' approach to international planning for managing a pandemic. It is concluded that a more nuanced approach than that contained in international guidelines may be required if an effective response is to be constructed internationally. The paper commends the wisdom of reliance on 'soft law', international guidance that leaves plenty of room for each nation to construct its response in conformity with its own cultural and value requirements.


Integrins uncouple Src-induced morphological and oncogenic transformation.
Expression of activated mutants of c-Src in epithelial cells can induce tumorigenicity. In addition to such oncogenic transformation, the cells undergo a dramatic morphological transformation: cell-cell contacts are disrupted, spreading on extracellular matrix proteins is suppressed, actin stress fibers and focal contacts are lost, and podosomes are formed. We have previously shown that integrin alphavbeta3 strongly supports Src-mediated oncogenic transformation through an interaction at the beta3 cytoplasmic tail. Our current findings demonstrate that this interaction does not affect Src-mediated morphological alterations, thus separating oncogenic from morphological transformation. Moreover, beta1 and beta3 integrins differently affect the various aspects of Src-induced morphological transformation. High levels of beta3, but not beta1, integrins can prevent Src-induced cell rounding although stress fiber disassembly and podosome formation still occur. Studies using chimeric integrin subunits demonstrate that this protection requires the beta3 extracellular domain. Finally, like tumor formation, podosome assembly occurs independent of beta3 phosphorylation. Instead, phosphorylation of beta1 is required to suppress Rho-mediated contractility in order to assemble podosomes. Thus, integrins regulate Src-mediated oncogenic transformation and various aspects of morphological transformation through dissociable pathways.


SOHO State of the Art Updates and Next Questions | From Biology to Therapy: Progress in Hodgkin Lymphoma.
Classic Hodgkin lymphoma (HL) is a unique lymphoid malignancy where the malignant cells comprise only 1% to 2% of the total tumor cellularity. Over the past 2 decades, the treatment of HL has evolved drastically based on the advent of novel targeted therapies. Novel agents including programmed death-1 (PD-1) inhibitors, antibody-drug conjugates such as brentuximab vedotin, bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapies have served to shape the management of HL in the frontline as well as the relapsed and refractory (R/R) setting. Some of these agents have been incorporated into treatment algorithms, while others are currently under investigation demonstrating promising results. This review focuses on highlighting the underlying tumor biology forming the basis of therapeutics in HL, and reviews some of the emerging and established novel therapies.


The role of iron metabolism in chronic diseases related to obesity.
Obesity is one of the major public health problems threatening the world, as well as a potential risk factor for chronic metabolic diseases. There is growing evidence that iron metabolism is altered in obese people, however, the highly refined regulation of iron metabolism in obesity and obesity-related complications is still being investigated. Iron accumulation can affect the body's sensitivity to insulin, Type 2 diabetes, liver disease and cardiovascular disease. This review summarized the changes and potential mechanisms of iron metabolism in several chronic diseases related to obesity, providing new clues for future research.


Neuroprotective phenylpropanoid esters of rhamnose isolated from roots of Scrophularia buergeriana.
Four phenylpropanoid esters of rhamnose, buergerisides A1, B1, B2 and C1 were isolated from roots of Scrophularia huergeriana MIQ. (Scrophulariaceae), and were characterized as 2-O-acetyl-3,4-di-O-(E)-p-methoxycinnamoyl-alpha-L-rhamnopyranosid e, 2-O-acetyl-3-O-(E)-p-methoxycinnamoyl-alpha-L-rhamnopyranoside, 2-O-acetvl-3-O-(Z)-p-methoxycinnamoyl-alpha-L-rhamnopyranosi de and 4-O-(E)-p-methoxycinnamoyl-alpha-L-rhamnopyranoside, respectively. In addition, six known phenylpropanoids were authenticated as: (E)-cinnamic acid, (E)-p-methoxycinnamic acid, (E)-p-methoxycinnamic acid methyl ester, (E)-p-coumaric acid, (E)-caffeic acid, (E)-ferulic acid and a phenylalcohol, 2-(3-hydroxy-4-methoxyphenyl)ethanol. These ten phenylpropanoids all attenuated glutamate-induced neurotoxicity when added to primary cultures of rat cortical cells in a dose-dependent manner. These results demonstrate that phenylpropanoids isolated from S. buergeriana may exert significant protective effects against glutamate-induced neurodegeneration in primary cultures of cortical neurons.


Assessing the role of intrinsic disorder in RNA-binding protein function: hnRNP K as a case study.
RNA-binding proteins (RBPs) typically bind to RNA in a sequence-specific manner, resulting in post-transcriptional gene regulation. While the various classes of RNA-binding domains are largely structured, flexible linkers are frequently observed between them. Emerging evidence suggests that these unstructured regions may help spatially position the RNA-binding domains allowing for RNA binding and/or may contribute directly to RNA association via certain sequence motifs contained within them. The importance of these unstructured regions is widely appreciated; however, understanding their contribution to RNA binding, protein stability, and function has been difficult to ascertain. Thus, it is crucial to have a set of rapid and economical assays that do not require specialized instrumentation to study their impact on RBP function. Herein, we discuss the use of plate-based and cell-based thermal shift assays to study the impact of the intrinsically disordered region on the function of a highly conserved RBP, hnRNP K.


Monitoring extent of moisture variations due to leachate recirculation in an ELR/bioreactor landfill using resistivity imaging.
Bioreactor or enhanced leachate recirculation (ELR) landfills are designed and operated for accelerated waste stabilization, accelerated decomposition, and an increased rate of gas generation. The major aspects of a bioreactor landfill are the addition of liquid and the recirculation of collected leachate back into the waste mass through the subsurface leachate recirculation system (LRS). The performance of the ELR landfill largely depends on the existing moisture content within the waste mass; therefore, it is of utmost importance to determine the moisture variations within the landfill. Traditionally, the moisture variation of the ELR landfill is determined by collecting samples through a bucket auger boring from the landfill, followed by laboratory investigation. Collecting the samples through a bucket auger boring is time consuming, labor intensive, and cost prohibitive. Moreover, it provides the information for a single point within the waste mass, but not for the moisture distribution within the landfill. Fortunately, 2D resistivity imaging (RI) can be performed to assess the moisture variations within the landfill and provide a continuous image of the subsurface, which can be utilized to evaluate the performance of the ELR landfill. During this study, the 2D resistivity imaging technique was utilized to determine the moisture distribution and moisture movement during the recirculation process of an ELR landfill in Denton, Texas, USA. A horizontal recirculation pipe was selected and monitored periodically for 2.5years, using the RI technique, to investigate the performance of the leachate recirculation. The RI profile indicated that the resistivity of the solid waste decreased as much as 80% with the addition of water/leachate through the recirculation pipe. In addition, the recirculated leachate traveled laterally between 11m and 16m. Based on the resistivity results, it was also observed that the leachate flow throughout the pipe was non-uniform. The non-uniformity of the leachate flow confirms that the flow of leachate through waste is primarily through preferential flow paths due the heterogeneous nature of the waste.


A soluble recombinant fusion protein of the transmembrane envelope protein of equine infectious anaemia virus for ELISA.
The use of the bacterial expression vector, pGex, to produce an abundant, soluble fusion protein of gp45 from equine infectious anaemia virus is described. Purification of the recombinant protein was achieved by one step affinity chromatography on immobilized glutathione using competitive elution so no harsh conditions were required. This provides a readily available antigen that is defined, plentiful and cheap. Yields of 3.5 mg of purified soluble protein/litre of bacterial culture were obtained. This antigen was found to be suitable for ELISA. Background reactivity to either the glutathione-S-transferase (GST) fusion partner by immune sera or the EIA-GST fusion protein by normal sera were negligible.


Cardiac aneurysm complicated by Salmonella abscess. A clinicopathologic correlation in two patients.
Two patients have been documented in whom a preexisting left ventricular aneurysm became complicated by myocardial abscess. Presumptive clinical diagnoses of infected pulmonary infarction and recurrent myocardial infarction were made. In each instance the abscess was revealed at necropsy. Histologic studies suggested that the abscess had occurred through direct spread from an infectious mural endocarditis. This mechanism could be related to the nature of the inner coating, which in both instances revealed evidence of organizing thrombosis with incorporation into the wall of the aneurysms. The observations reemphasize the need to consider the possibility of an infectious cardiac complication in every patient who presents with puzzling and nondiagnostic symptoms but in whom signs of an infectious process are present.


Racial disparities in treatment for pancreatic cancer and impact on survival: a population-based analysis.
Pancreatic adenocarcinoma is the fourth leading cause of cancer-related deaths in both men and women. Mortality from pancreatic cancer is higher amongst blacks compared to other races. We performed this analysis with the aim of examining racial disparity for receipt pancreatic cancer treatment and its association with survival. Using the surveillance, epidemiology, and end results (SEER) database from 1988 to 2008, cases with locoregional pancreatic cancer were analysed. Kaplan-Meier survival curves were assessed to assess the survival amongst various races. Cox proportional hazard model was built to assess the impact of receipt of treatment on the racial disparity in survival. Of 16,282 cases with locoregional pancreatic cancer, 1,806 (11%) occurred in blacks. Median survival was 8-9 months with poorest survival in blacks. Blacks and Hispanics received radiation treatment less often compared to other races. On Cox regression logistic regression analysis, blacks had 20% poorer survival compared to whites. Treatment for pancreatic cancer explained only one-fourth of this poorer survival. Blacks have worst survival from locoregional pancreatic cancer. Receiving treatment for pancreatic cancer only explains 25% of the poorer survival amongst blacks, suggesting role of other factors. Studies are suggested to (a) identify barriers in receipt of treatment for pancreatic cancer amongst blacks and (b) to assess role of genetic and other factors to examine racial differences in survival.


Properties of horizontal semicircular canal nerve-activated vestibulospinal neurons in cats.
Axonal pathways, projection levels, and locations of horizontal semicircular canal (HC) nerve-activated vestibulospinal neurons were studied. The HC nerve was selectively stimulated. Vestibulospinal neurons were activated antidromically with four stimulating electrodes, inserted bilaterally into the lateral vestibulospinal tracts (LVST) and medial vestibulospinal tracts (MVST) at the C1/C2 junction. Stimulating electrodes were also positioned in the C3, T1, and L3 segments and in the oculomotor nuclei. Most HC nerve-activated vestibulospinal neurons were located in the ventral portion of the medial, lateral, and the descending nuclei. Among the 157 HC nerve-activated vestibular neurons, 83 were antidromically activated by stimulation at the C1/C2 junction. Of these 83 neurons, axonal pathways of 56 HC nerve-activated vestibulospinal neurons were determined. Most (48/56) of these had axons that descended through the MVST, with the remainder (8 neurons) having axons that descended through the ipsilateral (i-) LVST. Laterality of the axons' trajectories through the MVST was investigated. The majority of vestibulospinal neurons (24/28) with axons descending through the contralateral MVST were also antidromically activated from the oculomotor nucleus, whereas almost all vestibulospinal neurons (19/20) with axons descending through the i-MVST were not. Most HC nerve-activated vestibulospinal neurons were activated antidromically only from the C1/C2 or C3 segments. Only one neuron that was antidromically activated from the T1 segment had an axon that descended through the i-LVST. None of the HC nerve-activated vestibulospinal neurons were antidromically activated from the L3 segment. It is likely that the majority of HC nerve-activated vestibulospinal neurons terminate in the cervical cord and have strong connections with neck motoneurons.


The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis.
A gluten-free diet (GFD) is currently the only available therapy for coeliac disease (CD). We aim to review the literature on the GFD, the gluten content in naturally gluten-free (GF) and commercially available GF food, standards and legislation concerning the gluten content of foods, and the vitamins and mineral content of a GFD. We carried out a PubMed search for the following terms: Gluten, GFD and food, education, vitamins, minerals, calcium, Codex wheat starch and oats. Relevant papers were reviewed and for each topic a consensus among the authors was obtained. Patients with CD should avoid gluten and maintain a balanced diet to ensure an adequate intake of nutrients, vitamins, fibre and calcium. A GFD improves symptoms in most patients with CD. The practicalities of this however, are difficult, as (i) many processed foods are contaminated with gluten, (ii) staple GF foods are not widely available, and (iii) the GF substitutes are often expensive. Furthermore, (iv) the restrictions of the diet may adversely affect social interactions and quality of life. The inclusion of oats and wheat starch in the diet remains controversial.


Impact of living donor liver transplantation on long-term cardiometabolic and graft outcomes in cirrhosis due to nonalcoholic steatohepatitis.
Non-alcoholic steatohepatitis (NASH) is a leading indication for liver transplantation (LT). This study aimed to determine whether living donor LT (LDLT) recipients experienced less recurrent NASH, cirrhosis, and cardiometabolic complications compared to deceased donor LT (DDLT). Patients with LDLT and DDLT for NASH between February 2002 and May 2018 at University Health Network (UHN) were compared. Cox Proportional Hazard model was used to analyze overall survival (OS), Fine and Gray's Competing Risk models were conducted to analyze cumulative incidence of post LT outcomes. One hundred and ninety-nine DDLTs and 66 LDLTs were performed for NASH cirrhosis. Time and rate of recurrence of NAFLD and NASH were comparable in both groups. Graft cirrhosis was more common in DDLT recipients (n = 14) versus LDLT (n = 0) (p < .0001). Significant fibrosis (Fibrosis ≥ F2) developed in 50 recipients (12 LDLT and 38 DDLT) post LT (DDLT vs. LDLT: HR = 1.00, 95% CI = (.52-1.93), p = .91) and there was no difference in time to significant fibrosis (p = .57). There was no difference in development of post-transplant diabetes, dyslipidemia, metabolic syndrome, cardiovascular disease, and cancers. LDLT group had better renal function at 10 years (MDRD eGFR of 57.0 mL/min vs. 48.5 mL/min, p = .047). Both groups had a comparable OS (HR = 1.83 (95% CI = .92-3.62), p = .08). Overall, LDLT recipients had significantly better renal function by virtue of having early transplantation in their disease course. LDLT was also associated with significantly less graft cirrhosis, although OS and cardiometabolic outcomes were comparable between LDLT and DDLT.


Modifiable health risk factors and medical expenditures - The case of Taiwan.
To contain escalating healthcare spending has become a great challenge for many countries around the world. Among all factors influencing medical costs, extensive studies have shown that adoption of healthy lifestyles such as not smoking, moderate drinking, eating healthy food, and exercising regularly can contribute to good health and lower the odds of having diseases that result in higher medical spending. The goal of this paper is to explore the relationship between modifiable risk factors and healthcare costs in Taiwan. A two-part model is employed to estimate the association between modifiable risk factors and medical expenditures. A logit model is used in the first stage of estimation and a generalized linear model is used in the second stage of estimation. Linking the 2001 National Health Interview Survey (NHIS) and the claims data in the National Health Insurance Research Database (NHIRD) in Taiwan, I find some significant associations between several lifestyle variables and medical expenditures. Former smokers are found to have higher probability of using medical care and incur higher medical expenses. People with exercise habits are less likely to use inpatient care services, and they incur lower inpatient expenses. Therefore, healthcare policies promoting non-smoking and physical activities should be used in Taiwan to curb rising expenditures and to achieve better care for people with chronic diseases.


Identity of maleate-stimulated glutaminase with gamma-glutamyl transpeptidase in rat kidney.
Gamma-Glutamyl transpeptidase was purified from rat kidney by a procedure involving Lubrol extraction, acetone precipitation, ammonium sulfate fractionation, treatment with bromelain, and column chromatography on DEAE-cellulose and Sephadex G-100. The final preparation (enzyme III), which exhibits a specific activity about 8-fold higher than that of the purified rat kidney transpeptidase previously obtained in this laboratory (enzyme I), was apparently homogeneous on polyacrylamide gel electrophoresis. Enzyme III is a glycoprotein containing 10% hexose, 7% aminohexose, and 1.5% sialic acid; a tentative molecular weight value of about 70,000 was obtained by gel filtration. Enzyme III has a much lower molecular weight and a different amino acid and carbohydrate content than the less active rat kidney transpeptidase preparation previously obtained, but obtained, but the catalytic properties of these preparations are virtually identical. It is suggested that bromelain treatment may liberate the transpeptidase from a brush border complex that contains other proteins. An improved method is described for the isolation of the higher molecular weight form of the enzyme (enzyme I) in which affinity chromatography on concanavalin A-Sephrose is employed. The purified transpeptidase (enzyme III) is similar to the phosphate-independent maleate-stimulated glutaminase preparation obtained from rat kidney by Katunuma and colleagues with respect to amino acid and carbohydrate content, apparent molecular weight, and relative transpeptidase and maleate-stimulated "glutaminase" activities. Both of these enzyme preparations are much more active in transpeptidation reactions with glutathione and related gamma-glutamyl compounds than with glutamine. In the absence of maleate, the enzyme catalyzes the utilization of glutamine (by conversion to gamma-glutamylglutamine, glutamate, and ammonia) at about 2% of the rate observed for catalysis of transpeptidation between glutathione and glycylglycine; the utilization of glutamine occurs about 8 times more rapidly in the presence of 0.1 M maleate. The transpeptidation and maleate-stimulated glutaminase reactions catalyzed by both enzyme preprations are inhibited by 5 mM L-serine in the presence of 5 mM sodium borate. Studies on gamma-glutamyl transpeptidase and maleate-stimulated glutaminase in the kidneys of fetal rats, newborn rats, and rats after weaning showed parallel development of these activities. The evidence reported here and earlier work in this laboratory strongly support the conclusion that maleate-stimulated glutaminase activity is a catalytic function of gamma-glutamyl transpeptidase. The studies on the ontogeny of gamma-glutamyl transpeptidase and other data are considered in relation to the proposal that this enzyme is involved in amino acid and peptide transport. Its possible role in renal formation of ammonia is also discussed.


Heterogeneity of AtT-20 cell glucocorticoid binding sites: evidence for a membrane receptor.
In previous studies we have found that intact AtT-20 cells contained two glucocorticoid binding sites with distinctly different affinities and specificity. In this paper, the nature of these sites was investigated by studying glucocorticoid binding to cytosol and to plasma membranes isolated from AtT-20 mouse pituitary tumor cells. Plasma membrane vesicles were isolated from AtT-20 cells and found to take up alpha-aminoisobutyric acid, indicating that they were properly oriented and functionally intact. Corticosterone bound to these vesicle in a time- and temperature-dependent manner. The binding exhibited a glucocorticoid preference since non-glucocorticoids such as progesterone, testosterone or estradiol were unable to inhibit binding. In addition, binding specificity differed from that of the cytoplasmic receptor since the synthetic glucocorticoids were also ineffective competitors. The major inhibitors of binding were corticosterone greater than 11-dehydrocorticosterone greater than 11-ketoprogesterone greater than cortisol. In other complementary studies, AtT-20 cell cytosol was tested to determine whether heterogenous soluble sites exhibiting a preference for the natural vs the synthetic steroid could also be identified. We found that binding sites for both steroid classes were approximately similar in number, specificity and behavior on ion-exchange chromatography. We conclude that, in addition to a classical soluble cytoplasmic glucocorticoid receptor, AtT-20 cells contain plasma membrane glucocorticoid binding sites. The affinity and specificity of these sites for the natural ligand, corticosterone, suggest that they play an important role in the subcellular mechanism of glucocorticoid action.


Simple and complex carbohydrate-rich diets and muscle glycogen content of marathon runners.
The effects of simple-carbohydrate (CHO)- and complex-CHO-rich diets on skeletal muscle glycogen content were compared. Twenty male marathon runners were divided into four equal groups with reference to dietary consumption: depletion/simple, depletion/complex, nondepletion/simple, and nondepletion/complex. Subjects consumed either a low-CHO (15% energy [E] intake), or a mixed diet (50% CHO) for 3 days, immediately followed by a high-CHO diet (70% E intake) predominant in either simple-CHO or in complex-CHO (85% of total CHO intake) for another 3 days. Skeletal muscle biopsies and venous blood samples were obtained one day prior to the start of the low-CHO diet or mixed diet (PRE), and then again one day after the completion of the high-CHO diet (POST). The samples were analysed for skeletal muscle glycogen, serum free fatty acids (FFA), insulin, and lactate and blood glucose. Skeletal muscle glycogen content increased significantly (p less than 0.05) only in the nondepletion/simple group. When groups were combined, according to the type of CHO ingested and/or utilization of a depletion diet, significant increases were observed in glycogen content. Serum FFA decreased significantly (p less than 0.05) for the nondepletion/complex group only, while serum insulin, blood glucose, and serum lactate were not altered. It is concluded that significant increases in skeletal muscle glycogen content can be achieved with a diet high in simple-CHO or complex-CHO, with or without initial consumption of a low-CHO diet.


Evaluation of Head and Neck Tumors with Functional MR Imaging.
Head and neck cancer is one of the most common cancers worldwide. MR imaging-based diffusion and perfusion techniques enable the noninvasive assessment of tumor biology and physiology, which supplement information obtained from standard structural scans. Diffusion and perfusion MR imaging techniques provide novel biomarkers that can aid monitoring in pretreatment, during treatment, and posttreatment stages to improve patient selection for therapeutic strategies; provide evidence for change of therapy regime; and evaluate treatment response. This review discusses pertinent aspects of the role of diffusion and perfusion MR imaging and computational analysis methods in studying head and neck cancer.


Glycosylated nucleoside lipid promotes the liposome internalization in stem cells.
We report new glycosyl-nucleoside-lipid based liposomes decorated with sugar moieties. The GNL-liposomes feature a suitable glycosylated surface for their internalization into ADSC stem cells.


Inferior survival and frequent hepatic dysfunction in non-Hodgkin's lymphoma patients with HBV infection: a systematic review and meta-analysis.
No clear consensus has been reached about the clinical features in hepatitis B virus (HBV)-associated non-Hodgkin's lymphoma (NHL) patients. We performed a systematic review and meta-analysis to explore the clinical characteristics and prognosis of NHL patients with chronic HBV infection (HBsAg+). Seven electronic databases were searched for relevant studies up to 31 January 2021. Hazard ratio (HR) or odds ratio (OR) corresponding to 95% confidence interval (CI) were calculated to estimate the outcomes. The primary outcome was survival outcome, including overall survival (OS) and progression-free survival (PFS). Subgroup analysis was performed in diffuse large B-cell lymphoma (DLBCL) patients. Twenty-three retrospective studies, comprising of 1202 HBsAg+ NHL patients and 4448 HBsAg- NHL patients, were included. Twenty-two studies were conducted on Chinese patients. Compared with HBsAg- NHL patients, significantly shorter OS (HR 1.68; 95% CI 1.48-1.91) and PFS (HR 1.80; 95% CI 1.20-2.71), lower rate of complete remission (OR 0.59, 95% CI 0.44-0.80) and higher frequency of hepatic dysfunction during chemotherapy (OR 3.46; 95% CI 2.61-4.57) were demonstrated in HBsAg+ NHL patients. Moreover, HBsAg+ patients were characterized by a younger age of disease onset, advanced disease stage, higher level of LDH and more frequent presence of B symptoms, and involvement of spleen and liver at diagnosis. Furthermore, subgroup analysis in DLBCL patients was also showed similar results. Our study implicated that NHL patients, especially DLBCL, with chronic HBV infection displayed inferior prognosis, higher incidence of hepatic dysfunction during chemotherapy and distinct clinical features.


Structure, dynamics, evolution, and function of a major scaffold component in the nuclear pore complex.
The nuclear pore complex, composed of proteins termed nucleoporins (Nups), is responsible for nucleocytoplasmic transport in eukaryotes. Nuclear pore complexes (NPCs) form an annular structure composed of the nuclear ring, cytoplasmic ring, a membrane ring, and two inner rings. Nup192 is a major component of the NPC's inner ring. We report the crystal structure of Saccharomyces cerevisiae Nup192 residues 2-960 [ScNup192(2-960)], which adopts an α-helical fold with three domains (i.e., D1, D2, and D3). Small angle X-ray scattering and electron microscopy (EM) studies reveal that ScNup192(2-960) could undergo long-range transition between "open" and "closed" conformations. We obtained a structural model of full-length ScNup192 based on EM, the structure of ScNup192(2-960), and homology modeling. Evolutionary analyses using the ScNup192(2-960) structure suggest that NPCs and vesicle-coating complexes are descended from a common membrane-coating ancestral complex. We show that suppression of Nup192 expression leads to compromised nuclear transport and hypothesize a role for Nup192 in modulating the permeability of the NPC central channel.


Cryopreservation by slow cooling with DMSO diminished production of Oct-4 pluripotency marker in human embryonic stem cells.
We tested a "standard" cryopreservation protocol (slow cooling with 10% DMSO) on the human embryonic stem cell (hESC) line H9 containing an Oct-4 (POU5F1) promoter-driven, enhanced green fluorescent protein (EGFP) reporter to monitor maintenance of pluripotency. Cells were cooled to -80 degrees C in cryovials and then transferred to a -80 degrees C freezer. Cells were held at -80 degrees C for 3 days ("short-term storage") or 3 months ("long-term storage"). Vials were thawed in a +36 degrees C water bath and cells were cultured for 3, 7, or 14 days. Propidium iodide (PI) was used to assess cell viability by flow cytometry. Control cells were passaged on the same day that the frozen cells were thawed. The majority of cells in control hESC cultures were Oct-4 positive and almost 99% of EGFP+ cells were alive as determined by exclusion of PI. In contrast, the frozen cells, even after 3 days of culture, contained only 50% live cells, and only 10% were EGFP-positive. After 7 days in culture, the proportion of dead cells decreased and there was an increase in the Oct-4-positive population but microscopic examination revealed large patches of EGFP-negative cells within clusters of colonies even after 14 days of culturing. After 3 months of storage at -80 degrees C the deleterious effect of freezing was even more pronounced: the samples regained a quantifiable number of EGFP-positive cells only after 7 days of culturing following thawing. It is concluded that new protocols and media are required for freezing hESC and safe storage at -80 degrees C as well as studies of the mechanisms of stress-related events associated with cell cryopreservation.


Iatrogenic mandibular fractures following removal of impacted third molars: an analysis of 130 cases.
Immediate and late mandibular fractures are a rare complication of third molar removal. We analysed 130 cases of mandibular fractures following removal of impacted third molars reported in the literature, including four managed in the maxillofacial unit and identified potential risk factors. Its occurrence is likely to be multi-factorial, with age, gender, angulation, laterality, extent and degree of impaction and associated pathologies contributing to the risk of fracture. Postoperative fractures were more common than intra-operative fractures (2.7:1) and occurred most frequently in the second and third weeks (57%). A 'cracking' noise was the most frequent presentation (77%). Intra-operative fractures were more frequent among females (M:F - 1:1.3), and differed from postoperative fractures (M:F - 3.9:1). This study analyses the results, providing suggestions to minimise the risk and to manage a mandibular fracture following removal of a third molar.


Laser capture microdissection for analysis of macrophage gene expression from atherosclerotic lesions.
Macrophage foam cells are critical mediators in atherosclerosis plaque development. A better understanding of the in vivo transcript profile of foam cells during the formation and progression of lesions may lead to novel therapeutic interventions. Toward this goal, we demonstrate for the first time that foam cell-specific RNA can be purified from atherosclerotic arteries, a tissue of mixed cellular composition. Foam cells from apolipoprotein (apo) E-/- mice were isolated by laser capture microdissection (LCM); RNA was extracted and used for molecular analysis by real-time quantitative polymerase chain reaction. Compared to whole tissue, a significant enrichment of foam cell-specific RNA transcripts was achieved. Furthermore, to test the ability to quantify differences in gene expression in response to an inflammatory stimulus, apoE-/- mice were injected with lipopolysaccharide, after which the transcriptional induction of the inflammatory mediators, VCAM, ICAM, and MCP-1, was observed in lesional macrophage foam cell RNA. These approaches will facilitate the study of macrophage gene expression under various conditions of plaque formation, regression, and response to genetic and environmental perturbations.


Nitrosative stress induced cytotoxicity in Giardia intestinalis.
To investigate the antigiardial properties of the nitrosating agents: sodium nitrite, sodium nitroprusside and Roussin's black salt. Use of confocal laser scanning microscopy and flow cytometry indicated permeabilization of the plasma membrane to the anionic fluorophore, DiBAC4(3) [bis(1,3-dibutylbarbituric acid) trimethine oxonol]. Loss of plasma membrane electrochemical potential was accompanied by loss of regulated cellular volume control. Changes in ultrastructure revealed by electron microscopy and capacity for oxygen consumption, were also consequences of nitrosative stress. Roussin's black salt (RBS), active at micromolar concentrations was the most potent of the three agents tested. These multitargeted cytotoxic agents affected plasma membrane functions, inhibited cellular functions in Giardia intestinalis and led to loss of viability. Nitrosative damage, as an antigiardial strategy, may have implications for development of chemotherapy along with suggesting natural host defence mechanisms.


Coexistence of independent myelodysplastic and Philadelphia chromosome positive clones in a patient treated with hydroxyurea.
We report a patient with Philadelphia chromosome positive (Ph +ve) chronic myelogenous leukemia (CML), treated with hydroxyurea alone, who upon disease progression developed an additional Ph - ve clone containing chromosomal abnormalities typical of myelodysplastic syndrome (MDS). Retrospective analysis of a cryopreserved stem cell specimen from diagnosis confirmed that this second clone developed during the course of treatment. The development of a clone with additional cytogenetic abnormalities in CML has only been reported after leukemogenic treatment, stem cell transplantation or interferon. We report a case of secondary Ph - ve MDS/AML during blast crisis in a patient treated with hydroxyurea for CML.


[Onychomycosis. Successful treatment with a 1064 nm Nd:YAG-Laser].
A 58-year-old man presented with a two-year history of progressive onychodystrophy of the nails of both great toes. Clinical inspection as well as KOH examination and culture confirmed the diagnosis of disto-lateral onychomycosis of both nails caused by Trichophyton rubrum). The diseased nail materially was mechanically débrided. In addition both nails were treated with a 1064 nm Nd:YAG laser (spot-diameter: 5 mm; pulse-width: 0.3 ms; fluence: 12 J/cm(2); frequency: 5 Hz; impulses: 200 per toenail). The laser therapy was repeated four times at intervals of 2 months. Seven months later the patient showed complete clearance of both nails. We here demonstrate the efficacy of the Nd:YAG laser in the treatment of onychomycosis. Non-ablative laser therapy may present a promising, effective, well-tolerated and cost-efficient option for the treatment of onychomycosis. Controlled studies with relevant patient collectives are urgently needed.


Erratum: Assessment of Government Intervention Effectiveness in Scrubbing COVID-19 Pandemic and Its Pros and Cons on Educational Activities, The Case of Dire Dawa City [Erratum].
[This corrects the article DOI: 10.2147/JMDH.S322665.].


[Late results in surgically and non-surgically treated ischemic heart disease patients with arrhythmias in relation to the extent of the myocardial lesion].
A total of 269 coronary patients with arrhythmias were followed up for 6 months to 12 years. Coronaroventriculography was performed in 264 patients. The five-year survival rate was shown to be directly proportionate to the site and spread of postinfarction cardiosclerosis in arrhythmic coronary patients. In patients with aneurysms of the heart, it was 40.6%, with a further decline over the years. Left-ventricular final diastolic pressure (FDP) and outflow fraction is an objective indicator of myocardial contractility. Five-year survival is 69.3% in cases of the normal FDP, and drops significantly (by 20 %) where it is elevated. As a rule, survival rates were much higher in postoperative patients (following aortocoronary shunts or left-ventricular aneurysm resections), irrespective of myocardial contractility values.


Cytotoxic molecule mRNA expression in chronically rejected human kidney allografts.
The pathogenesis of immunological and nonimmunological components that cause chronic kidney allograft nephropathy (CAN), is not yet completely understood. To explore the possible contribution of alloreactive cytotoxic T cells, we analyzed the transcription of cytotoxic molecules such as granzyme B and perforin using semiquantitative RT-PCR on surgically removed grafts obtained from two groups: group 1 (n = 10) were cases of CAN; group 2 (n = 3) had no CAN. Among group 1 kidneys, granzyme-B was expressed in 7 of 10, whereas perforin was detectable in 9 of 10 cases; their detection was not related to the presence of superimposed signs of acute graft lesions. Cytotoxic molecules were never found in group 2 kidneys. These results show that explanted chronically rejected grafts display cytotoxic molecule transcripts in addition to Th2 type cytokines, such as IL-10, IL-3, and IL-6, suggesting that both cellular and humoral alloreactive mechanisms may play important roles in CAN pathogenesis.


Behavioral effects following repeated exposure to hexachloronaphthalene in rats.
Polychlorinated naphthalenes (PCNs), including hexachloronaphthalene (HxCN), are widespread global environmental contaminants. Our experiments were aimed at assessing HxCN effects on motor behavior, long-term memory, pain sensitivity, magnitude of stress-induced analgesia, auditory function and sensorimotor gating, following repeated intragastric administration (28 days) of HxCN at 0.3 and 1.0 mg/kg body weight. Three weeks after the exposure termination, male Wistar rats were subjected to the neurobehavioral tests battery performed in the following order: open-field test, passive avoidance test, hot-plate test and acoustic startle response test. Repeated administration of HxCN induced disorders of motivational processes manifested by: anorectic effect caused by aphagia and adipsia; significantly reduced motor activity (hypokinesia); impaired long-term memory and acquired passive avoidance reaction; reduced pain threshold and shortened duration of anxiety reaction after pain stimulus (sensory neglect). Some of these neurobehavioral effects (impaired long-term memory, reduced pain threshold and stress-induced analgesia) were observed at 0.3 mgHxCN/kg body weight without any signs of overt toxicity. The outcome of our study shows that HxCN, like other compounds of the persistent organic pollutants (POPs) group, creates a potential risk of behavioral changes in the central nervous system in the general population as a result of environmental exposure.


Educational Quality of YouTube Videos for Patients Undergoing Elective Procedures.
YouTube has become a main resource used by patients for self-education on medicine. It is important for surgeons to understand the quality and reliability of videos that patients are likely to view about elective procedures. Videos were categorized by view count and content creators. The top 20 videos for each term, sorted by relevance, were evaluated using DISCERN criteria, a question set externally validated to assess the quality of information regarding health treatment choices. DISCERN score (DS) closer to 5 indicate higher quality information and 1 indicates the opposite. Total scores were given: 15-26 (very poor), 27-38 (poor), 39-50 (fair), 51-62 (very good), and 63-75 (excellent). Search terms included "Wound Care", "Skin Grafting", "Tracheostomy", and "percutaneous endoscopic gastrostomy tube placement". In total, 80 unique videos were evaluated with a total view of 8,848,796. The mean overall DS was 2.15 and a mean bias DS was 2.46. The median DISCERN total score for each key term was Tracheostomy: 35 (poor), Skin Grafting 26 (very poor), percutaneous endoscopic gastrostomy: 32 (poor), and Wound Care: 40 (fair). YouTube videos surrounding elective procedures should be viewed cautiously in patient education despite wide availability. The videos in this study show high levels of bias and low DS. Healthcare providers should be aware of poor-quality consumer health information often disseminated in online media such as YouTube.


The long-run cost characteristics of dental practices in the U.S.A.
The long-run cost structure of U.S. dental practices is analyzed using data collected in 1977 from a representative sample of U.S. dental practices. The practices were stratified by the number of dentists on staff before sampling. Participation rates by the sampled practices of different sizes were approx. 80% and the response rates for the data collection instruments ranged from 84 to 93%. Empirical results show that linear total and L-shaped average long-run cost curves best explain the cost structure of dental practices, indicating that dental technology exhibits constant returns to scale. Indivisibilities in production may cause firms with extremely small output to experience higher average costs than their larger counterparts. Any economies due to indivisibilities are exhausted at a rather small practice size. There is no evidence that large group practices have a substantial technical advantage over efficient one, two, and three dentist practices.


Intraspinal periosteal chondroma in upper thoracic spine causing cord compression and myelopathy: A case report.
Chondromas are slow-growing cartilage-forming benign tumors, rarely occurring in the spine. Generally, most spinal chondromas are asymptomatic; however, with slow progressive growth, these lesions may enlarge and expand and cause compressive neurological symptoms, resulting in radiculopathy or more commonly myelopathy due to direct neural compression. A 15-year-old male adolescent presented to Emergency Department with history of fall (slippage) on concrete ground while playing three months back. On neurological examination, the motor power in bilateral upper limbs was 5/5 while it was 1/5 in both lower extremities. Some muscle wasting was noted in the lower limbs. The planter reflexes were upgoing; and the sensory loss was below T6 spinal level. CT scan of dorsolumbar spine demonstrated a well-defined high-density lesion in lateral aspect of spinal canal at T2-T3 vertebral level adjacent to left T2-T3 facet joint. MRI of dorsal spine revealed a 3 × 2 × 1 cm3-sized, well-defined, non-enhancing T1 low to isointense and T2/STIR heterogeneous hyperintense lesion with osseous and cartilaginous components in the left lateral aspect of spinal canal at T1-T3 level, causing compression and contralateral displacement of spinal cord. The patient was then subjected to posterior laminectomy, complete excision, followed by laminoplasty using minicranial plates and screws. Histopathology of the mass showed bony trabeculae with hematopoietic elements and attached lobules of hyaline cartilage, chondroid matrix and lobules of mature chondrocyte and myxoid changes. Postoperatively his power was improved slightly and he was able to stand up with some assistance. On six-month follow up, patient showed significant neurological improvement. He was able to walk independently with minimal assistance. He was able to control bowel and bladder functions. Chondromas occurring in the spine are rare, accounting for only about 3% of all chondromas. Spinal chondromas are commonly encountered in the thoracic spine as in our case. Complete en bloc surgical excision is generally recommended as the treatment of choice for cases with local and/or neurological symptoms.


Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis.
To determine the effect of moderate dose dexamethasone administered before antibiotics on the outcome of African children with sepsis. The design was a randomized, double blinded, placebo-controlled trial of dexamethasone (0.2 mg/kg) vs. placebo given intravenously before antibiotic therapy. Patients were recruited from the patient populations at two missionary hospitals. Primary outcome variables were determined before analysis of data. Seventy-two children with sepsis were enrolled in the study. Treatment with dexamethasone was not associated with improved outcome for any of six outcome variables: survival to discharge (83%, dexamethasone group; 89%, placebo group); hemodynamic stability at 48 h (33%, dexamethasone group; 49%, placebo group); median length of hospital stay (11 days, dexamethasone group; 11 days, placebo group); normal at discharge (90%, dexamethasone group; 75%, placebo group); normal at follow-up (90%, dexamethasone group; 72%, placebo group); and afebrile at 48 to 72 h (61%, dexamethasone group; 44%, placebo group). These data indicate that a moderate dose of dexamethasone given before antibiotic therapy did not improve outcome in the pediatric patients with sepsis whom we studied.


Zinc chelation decreases IFN-β-induced STAT1 upregulation and iNOS expression in RAW 264.7 macrophages.
One consequence of lipopolysaccharide (LPS)-induced stimulation of macrophages is the release of Interferon (IFN)-β, and subsequently the activation of the JAK-STAT1 pathway, resulting in the expression of inducible nitric oxide synthase (iNOS). Free intracellular zinc ions (Zn2+) have a profound impact as a second messenger in LPS-dependent gene expression. Previous work had indicated a Zn2+-dependent upregulation of STAT1 mRNA in response to LPS and IFN-β, potentially affecting STAT1-dependent downstream signaling upon pre-incubation with these agents. The aim of the present study was to investigate the long-term influence of Zn2+ chelation on cellular STAT1 levels and their effect on protein levels and activity of iNOS. The LPS- and IFN-β-mediated increase of STAT1 mRNA and protein levels was abrogated by chelation of Zn2+ with the membrane permeable chelator N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) in RAW 264.7 macrophages. After 48h pre-incubation together with IFN-β, TPEN also led to reduced nitric monoxide formation in response to a second stimulation with LPS. Nonetheless, the latter was observed regardless of any pre-incubation with IFN-β, suggesting that the effect of treatment with TPEN negatively affects iNOS induction independently from cellular STAT1 levels. In conclusion, long term Zn2+ chelation does affect STAT1 protein expression, but interferes with NO production by a different, yet unknown pathway not involving STAT1. However, as there are many additional STAT1-dependent genes, there might still be effects on targets other than iNOS.


The accuracy of address coding and the effects of coding errors.
Studies that estimate the influence of characteristics of place on health often use geocoded addresses to identify location of study subjects. This study uses housing built before 1990 selected for the 1995-2001 National Health Interview Survey (N=252,421) to develop a standard against which geocodes obtained from an address-coding program are compared. The results show that geocoding is generally accurate and is more successful in urban areas. Blockgroups with missing codes are more rural and somewhat poorer than blockgroups with correct codes. The effect of incorrect codes on statistical analyses depends on the proportion rural in a study population.


Establishing and maintaining social connectivity: An understanding of the lived experiences of older adults residing in regional and rural communities.
To better understand how to plan for an ageing demographic that resides in ever-changing community typologies. Semi-structured in-depth interviews. Community settings in rural and regional towns in Queensland. Twenty-two people aged over 65 years living in regional and rural Australia. Qualitative study of social connectedness. Thematic qualitative analysis. Formal and informal social contact, through family, friends and social groups, was found to be important to the everyday lives of the participants. Social connections for older adults are important in maintaining independence and community engagement.


Pharmacokinetics and immunomodulatory effect of lipophilic Echinacea extract formulated in softgel capsules.
An attractive herbal product, softgel capsules containing 10 mg of Echinacea angustifolia lipophilic extract, was given in a single oral administration to 10 human volunteers to perform a pharmacokinetic and immunological study. The plasma concentration of the major constituent was monitored, quantifying at predetermined time points the dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides (tetraene). The plasmatic levels of IL-2, IL-6, IL-8, IL-10 and TNF-a in samples collected before and 24 h after drug administration were analyzed by cytokine assay. The total RNA was extracted from limpho-monocyte isolated from the same blood samples and the same cytokines in terms of gene expression were evaluated. With the help of proper statistical tests the differences between the values obtained at 0 and 24 h were evaluated. Results of pharmacokinetic studies attest an approximately 3.5-fold improvement of tetraene oral bioavailability compared with previously published studies. Dodeca-2E,4E-dienoic acid isobutylamide exerts immunomodulatory effects down-regulating the gene expression and reducing the protein plasmatic levels of pro-inflammatory cytokines such as IL-6, TNF-α and IL-8, and up-regulating the expression of anti-inflammatory molecules as IL-10. Student's two-sided paired t-test and non-parametric Wilcoxon-Mann-Whitney signed rank test agree in the conclusions about the differences between the ln values at 24 h and corresponding ln values at 0 h.


Facile dimethylarsenic exchange and pyramidal inversion in its cysteine and glutathione adducts.
Rapid thiolate exchange of dimethylarsonium, Me2As(+), is observed between two different thiolate species in solution. NMR is used to characterize the equilibrium constants for interthiol transfer as well the rapid intra molecular conformational dynamics which leads to the coalescence of diastereotopic methyl resonances. These rapid exchange kinetics have important consequences of arsenic's toxicity and pharmacology.


Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics.
Histone deacetylases (HDAC) are clinically validated and attractive epigenetic drug targets for human cancers. Several HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to the poor pharmacokinetics, bioavailability, selectivity of the HDAC inhibitors and most of them need to be combined with other drugs to achieve better results. Here, we describe our efforts toward the discovery of a novel series of lactam-based derivatives as selective HDAC inhibitors. Intensive structural modifications lead to the identification of compound 24g as the most active Class I HDAC Inhibitor, along with satisfactory metabolic stability in vitro (t1/2, human = 797 min) and the desirable oral bioavailability (F = 92%). More importantly, compound 24g showed good antitumor efficacy in a TMD-8 xenograft model (TGI = 77%) without obvious toxicity. These results indicated that Class I HDAC Inhibitor could be potentially used to treat certain diffuse large B-cell lymphoma therapeutics.


HapSim: a simulation tool for generating haplotype data with pre-specified allele frequencies and LD coefficients.
We have developed a simulation tool HapSim for the generation of haplotype data. The simulated haplotypes are such that their allele frequencies and linkage disequilibrium coefficients match exactly those estimated in a real sample. The program is available as an R package and can be downloaded from http://cran.r-project.org/.


The role of the right hemisphere in the production of linguistic stress.
Recent research has proposed a general prosodic disturbance associated with right hemisphere damage (RHD), one encompassing both affective and linguistic functions. The present study attempted to explore whether the ability to produce linguistic prosody was impaired in this patient population. Productions of phonemic stress tokens (e.g., Re'dcoat vs. red coa't) as well as examples of contrastive stress, or sentential emphasis (e.g., Sam hated the movie), were elicited from eight male speakers with unilateral right hemisphere CVAs and seven male control subjects. Two types of analyses were conducted on these utterances. Acoustic analysis focused on the correlates associated with word stress, namely changes in amplitude, duration, and fundamental frequency. The perceptual saliency of emerging cues to stress was also examined by presentation of test tokens to phonetically trained listeners for identification of stress placement. The patients as a group produced fewer acoustic cues to stress compared to the normal subjects, but no statistical differences were found between groups for either stress at the phrase level or at the sentence level. In the perceptual analysis, stress produced by the patient group was judged to be less salient than that for the normal group, although a high degree of variability was evident in both populations. The data suggest a spared processing mechanism for linguistic prosody in RHD speakers, thus mitigating against the view of a general dysprosody tied to RHD.


Predictors of immune recovery and the association with late mortality while on antiretroviral treatment in Cambodia.
The objectives of this study were to examine the association of the on-treatment CD4 cell count with late mortality (after >6 months of antiretroviral treatment [ART]) and to identify the determinants of the long-term CD4 cell count evolution after treatment initiation. We conducted a retrospective analysis including all antiretroviral (ARV)-naïve adults initiating ART in a tertiary hospital in Phnom Penh, Cambodia from 2003-2010. We used Cox proportional hazards modelling (mortality analysis), including time-updated CD4 counts, and mixed-effects modelling (CD4 response over time). Overall, 2840 patients were included (47% male, median age: 34 years, median baseline CD4 count: 78 cells/μL). The median time on ART was 2.5 years (IQR 1.1-4.3); 71 patients died after >6 months of ART. The baseline CD4 count was the main determinant of the on-treatment CD4 cell count. Time-updated CD4 cell counts was the strongest determinant of late mortality with a HR of 0.32 (95% CI 0.16-0.63) and 0.29 (95% CI 0.11-0.71) for CD4 values of 200-350 cells/μL and 350-500 cells/μL respectively. We conclude that baseline CD4 counts strongly determine the long-term immune recovery, which critically affects late mortality. This calls for increased efforts for early ART initiation and availability of CD4 count testing in low-income countries.


DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1.
Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests that DNAJB6b is primarily responsible for disease pathogenesis. Knockdown treatment strategies involving both isoforms carry risk, as DNAJB6 knockout is embryonic lethal. We therefore developed an isoform-specific knockdown approach using morpholinos. Selective reduction of each isoform was achieved in vitro in primary mouse myotubes and human LGMDD1 myoblasts, as well as in vivo in mouse skeletal muscle. To assess isoform specific knockdown in LGMDD1, we created primary myotube cultures from a knockin LGMDD1 mouse model. Using mass spectrometry, we identified an LGMDD1 protein signature related to protein homeostasis and myofibril structure. Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature toward wild type levels. Additional in vivo functional data is required to determine if selective reduction of DNAJB6b is a viable therapeutic target for LGMDD1.


Long-term effects of prenatal phenytoin exposure on offspring behavior in rats.
Pregnant Sprague-Dawley CD rats were administered phenytoin by gavage on days 7-18 of gestation in doses of 0 or 200 mg/kg. The offspring were tested at various ages to determine the duration of postnatal dysfunction and its replicability and generality compared to previous experiments. Phenytoin offspring had increased newborn (5.2%) and preweaning (16.7%) mortality compared to controls (0% and 3.1%, respectively), and an 8.5% reduction in average body weight at 28-70 days. No weight differences were significant at other ages. Phenytoin offspring showed increased activity on multiple tests, swam slower in a straight channel, committed more errors and took more time in the Cincinnati water maze, startled less, and had longer latencies on the Morris hidden platform test. Among phenytoin offspring 42.3% exhibited the abnormal circling defect previously described (14,17). Consequently, data were reanalyzed in terms of circlers, noncirclers, and controls to determine the contribution of this effect to the dysfunctions observed. Circlers accounted for the differences in open-field activity, figure-8 ambulation, hole-board horizontal locomotion, straight channel swimming time, water maze retention errors, tactile prepulse startle inhibition, and some trials of the Morris test. Circlers and noncirclers differed from one another and from controls on measures of figure-8 rearing, water maze errors and times, and some trials of the Morris test, with circlers more affected than noncirclers. Circlers and noncirclers did not differ from one another, but both differed from controls, on measures of early locomotion, hole-board vertical activity, and unmodified startle amplitude. Circling was hypothesized to reflect an underlying vestibular defect, however, the data also support the view that phenytoin has effects beyond those accounted for by possible vestibular effects.


Comparison of detergents for extraction and ion-exchange high-performance liquid chromatography of Sendai virus membrane proteins.
The integral membrane proteins of Sendai virus, haemagglutinin-neuraminidase (HN) and fusion protein (F) were extracted from purified virions with a non-ionic and two zwitterionic detergents, i.e., pentaethylene glycol monolauryl ether (C12E5), lauryldimethylamine oxide (LDAO) and dodecyldimethylammoniopropane-1-sulphonate (SB12), respectively. The extracts were subjected to ion-exchange high-performance liquid chromatography (HPIEC) using 0.1% of the detergent in the eluent on four different columns (MA7Q, Zorbax BioSeries SAX, Mono Q and PL-SAX) with a quaternary amine as interacting ligand and with different pore sizes: non-porous and 30, 80 nm and 400 nm, respectively. The relative recoveries of protein were similar for all the columns. The highest recovery of HN and F protein and the best separation were obtained with C12E5. Analysis of HPIEC fractions with monoclonal antibodies directed against conformational epitopes showed that C12E5 had less effect on the conformation than the other two detergents.