Atrial fibrillation and peripheral arterial disease define MPN patients with very high risk of thrombosis.
Myeloproliferative neoplasms (MPNs) are associated with a high risk of thrombotic and hemorrhagic complications, especially in elderly patients. Atrial fibrillation (AF) and peripheral arterial disease (PAD), also frequently discovered in aging patients, are associated with similar complications. We analysed the incidence and complication rates of AF and PAD in a large cohort of MPN patients. In total, 289/1113 patients (26 %) suffered at least one of these diseases as follows: 179 (16.1 %) with AF alone, 81 with PAD alone (7.3 %) and 29 (2.6 %) with both conditions. Postdiagnosis thrombotic events were observed in 31.3 % of AF patients (p = 0.002, OR = 1.80 [1.23;2.61]), 35.8 % of PAD patients (p = 0.002, OR = 2.21[1.31;3.67]) and 62.1 % of AF/PAD patients (p < 0.0001, OR = 6.47 [2.83;15.46]) compared to 20.1 % of no-AF/no-PAD patients. Postdiagnosis hemorrhagic events were also identified in 17.9 %, 16 %, 24.1 % and 10.1 % of AF, PAD, AF/PAD, and no-AF/no-PAD patients, respectively (p = 0.003). This significantly higher risk of thrombosis/bleeding was also observed in patients <60 years old. AF and PAD were significant risk factors for both thrombotic and hemorrhagic risks in multivariate analysis. We identified AF and PAD as criteria for high risk of thrombosis, hemorrhage, and death, emphasizing the interest in early detection and efficient treatment of these conditions.


Isolated Pure Malignant Rhabdoid Tumor (MRT) of the Bladder: Case Report and Lessons Learned.
Pediatric extrarenal malignant rhabdoid tumors (MRTs) are rare, aggressive tumors with a poor prognosis (20% 5-year survival). There are currently fewer than 10 published case reports of primary MRT of the bladder. We report the case of an 18-month-old female with an isolated MRT of the bladder which was initially misdiagnosed as an inflammatory myofibroblastic tumor on biopsy. We review the history, tumor biology, histology, and current management of extrarenal MRT, along with lessons learned from the difficulty with the patient's initial diagnosis.


Hepatocellular adenoma in glycogen storage disorder type I: a clinicopathological and molecular study.
Glycogen storage disease type I is a metabolic disorder resulting from deficiency of the glucose-6-phosphate complex. Long-term complications include the development of hepatocellular adenoma (HCA). In this retrospective study, our aim was to reclassify according to geno-phenotypic characteristics nodular lesions identified in hepatectomy specimens of such patients transplanted between 1998 and 2008 at our institution. Clinicopathological data of seven consecutive transplanted patients with glycogen storage disease type I were reviewed. Liver nodules were re-examined histologically and by immunohistochemistry. Molecular analysis was performed additionally in a case with specific features. Four patients had multiple tumours. We concluded that 26 of 38 nodules available for study had features of inflammatory hepatocellular adenomas, seven comprised adenomas not otherwise specified and five were found to be focal nodular hyperplasia. Further studies are needed to clarify the pathogenesis of hepatocellular adenomas in glycogen storage disease; in particular to determine whether they share abnormal metabolic pathways with inflammatory adenomas in the general population. Testing for acute phase proteins may be a helpful tool in the early detection of HCA in such patients. Finally, there is a need to further define their risk of malignant transformation, in relation to age and possible cofactors.


Perioperative Management of Diabetes Mellitus: Novel Approaches.
Several studies have demonstrated the benefits of glycemic control in the perioperative period and there is ongoing interest in development of systematic approaches to achieving glycemic control. This review discusses currently available data and proposes a new approach to the management of hyperglycemia in the perioperative period. In a recent study, we demonstrated that early preoperative identification of patients with poorly controlled diabetes and proactive treatment through various phases of surgery improves glycemic control, lowers the risk of surgical complications, and decreases the length of hospital stay. Implementation of a perioperative diabetes program that systematically identifies and treats patients with poor glycemic control early in the preoperative period is feasible and improves clinical care of patients undergoing elective surgery.


Production of volatile organic compounds (VOCs) by yeasts isolated from the ascocarps of black (Tuber melanosporum Vitt.) and white (Tuber magnatum Pico) truffles.
Twenty-nine yeast strains were isolated from the ascocarps of black and white truffles (Tuber melanosporum Vitt. and Tuber magnatum Pico, respectively), and identified using a polyphasic approach. According to the conventional taxonomic methods, MSP-PCR fingerprinting and sequencing of the D1/D2 domain of 26S rDNA, the strains were identified as Candida saitoana, Debaryomyces hansenii, Cryptococcus sp., Rhodotorula mucilaginosa, and Trichosporon moniliiforme. All isolates assimilated L: -methionine as a sole nitrogen source and produced the volatile organic compounds (VOCs), 2-methyl butanol, 3-methyl butanol, methanethiol, S-methyl thioacetate, dimethyl sulfide, dimethyl disulfide, dimethyl trisulfide, dihydro-2-methyl-3(2H)-thiophenone and 3-(methylthio)-1-propanol (MTP). ANOVA analysis of data showed significant (P<0.01) differences in VOCs produced by different yeasts, with MTP as the major component (produced at concentrations ranging from 19.8 to 225.6 mg/l). In addition, since some molecules produced by the isolates of this study are also characteristic of truffle complex aroma, it is possible to hypothesize a complementary role of yeasts associated with this ecosystem in contributing to final Tuber spp. aroma through the independent synthesis of yeast-specific volatile constituents.


Behavioral and neurochemical modifications induced by apomorphine treatment.
By means of quantitative receptor autoradiography, the modifications of dopamine (DA) receptors in selected target regions of A9 and A10 DA neurons were studied after chronic apomorphine treatment, at a dosage able to induce behavioral changes that are claimed to be due to the activation of the target areas of A9 neurons. An increase in [3H]spiperone binding sites (cold (+)-butaclamol) was observed in the dorsal and ventrolateral striatum, receiving fibers from A9 neurons, while there were no changes in the ventromedial and ventrocentral striatum, in the nucleus accumbens and in the cerebral cortex receiving fibers from A10 neurons. Our results suggest that the anatomical division of the DA target regions corresponds with a functional one.


The NLstart2run study: Training-related factors associated with running-related injuries in novice runners.
The incidence of running-related injuries is high. Some risk factors for injury were identified in novice runners, however, not much is known about the effect of training factors on injury risk. Therefore, the purpose of this study was to examine the associations between training factors and running-related injuries in novice runners, taking the time varying nature of these training-related factors into account. Prospective cohort study. 1696 participants completed weekly diaries on running exposure and injuries during a 6-week running program for novice runners. Total running volume (min), frequency and mean intensity (Rate of Perceived Exertion) were calculated for the seven days prior to each training session. The association of these time-varying variables with injury was determined in an extended Cox regression analysis. The results of the multivariable analysis showed that running with a higher intensity in the previous week was associated with a higher injury risk. Running frequency was not significantly associated with injury, however a trend towards running three times per week being more hazardous than two times could be observed. Finally, lower running volume was associated with a higher risk of sustaining an injury. These results suggest that running more than 60min at a lower intensity is least injurious. This finding is contrary to our expectations and is presumably the result of other factors. Therefore, the findings should not be used plainly as a guideline for novices. More research is needed to establish the person-specific training patterns that are associated with injury.


Correlation of heterogeneity index score (HIS) of DNA content in bladder cancer recurrence.
Automated flow cytometry (FCM) has been used to monitor the effects of therapy and progression of human bladder carcinoma. We have previously reported a computer-based model which has shown a correlation to relative mean DNA content in cell populations analyzed by FCM. Two patients with superficial transitional cell carcinoma of the bladder were followed for several months. Using FCM the patients' tissue samples were examined and heterogeneity index scores (HIS) were determined. Both cases had recurrence. The first patient has increased in grade with a respective increase in HIS within four months (grade I----II, HIS 27.2----80.8). The second patient also has recurrence in three months both times with a grade I tumor and a score of 106.2. High scores reflect large aneuploid populations which have shown to recur. Since such a correlation exists HIS may not only offer a more objective technique with quantitative results to monitor patients but possibly can distinguish the degree of tumor malignancy.


Effect of glutamine on acute lung injury in rats with endotoxemia.
We administered endotoxin to rats to produce an acute lung injury model, and assessed the effect on respiratory function when glutamine was added to the solution for total parenteral nutrition. Rats given total parenteral nutrition with glutamine as 33% of the amino acid content were compared with rats given no glutamine. Endotoxin (500 microg/kg) was administered intravenously after 72 h of total parenteral nutrition. The survival rate and the nitrogen balance were significantly improved (P < 0.05) at 48 h after endotoxin administration as a result of glutamine treatment. In addition, the arterial oxygen partial pressure was significantly increased (P < 0.01) and the wet: dry lung weight ratio was decreased (P < 0.05) by glutamine. These results suggested that glutamine improved endotoxin-induced acute lung injury in rats.


Systems-level decoding reveals the cognitive and behavioral profile of the human intraparietal sulcus.
The human intraparietal sulcus (IPS) covers large portions of the posterior cortical surface and has been implicated in a variety of cognitive functions. It is, however, unclear how cognitive functions dissociate between the IPS's heterogeneous subdivisions, particularly in perspective to their connectivity profile. We applied a neuroinformatics driven system-level decoding on three cytoarchitectural distinct subdivisions (hIP1, hIP2, hIP3) per hemisphere, with the aim to disentangle the cognitive profile of the IPS in conjunction with functionally connected cortical regions. The system-level decoding revealed nine functional systems based on meta-analytical associations of IPS subdivisions and their cortical coactivations: Two systems-working memory and numeric cognition-which are centered on all IPS subdivisions, and seven systems-attention, language, grasping, recognition memory, rotation, detection of motions/shapes and navigation-with varying degrees of dissociation across subdivisions and hemispheres. By probing the spatial overlap between systems-level co-activations of the IPS and seven canonical intrinsic resting state networks, we observed a trend toward more co-activation between hIP1 and the front parietal network, between hIP2 and hIP3 and the dorsal attention network, and between hIP3 and the visual and somatomotor network. Our results confirm previous findings on the IPS's role in cognition but also point to previously unknown differentiation along the IPS, which present viable starting points for future work. We also present the systems-level decoding as promising approach toward functional decoding of the human connectome.


Biocatalytic degradation of reactive blue 221 and direct blue 297 dyes by horseradish peroxidase immobilized on iron oxide nanoparticles with improved kinetic and thermodynamic characteristics.
In present study, we describe the biodegradation of direct blue (DB) 297 and reactive blue (RB) 221 by immobilizing horseradish peroxidase (HRP) isolated from fresh leaves of Moringa Oliefera on iron oxide nanoparticles. Iron oxide nanoparticles were synthesized by co-precipitation method and showed a maximum immobilization efficiency of 87%. The surface topography of iron oxide nanoparticles was envisaged by scanning electron microscopy (SEM), results showed that magnetic nanoparticles (MNPs) were in the form of aggregates having size of 1 μm. Furthermore, immobilization was confirmed via functional group identification performed by Fourier transformed infrared spectroscopy (FTIR). Immobilization phenomena displaced the optimum temperature from 35 °C to 50 °C moreover, pH optima were altered from 5.0 to 7.0. Vmax and Km for free and immobilized HRP, were 303 U/mg and 1.66 mM and 312 U/mg and 1.94 mM, respectively. Enzymatic thermodynamic measurements (ΔH*, ΔS*, Ea, ΔG*) were also evaluated for immobilized HRP and its free counterpart. Optimum degradation of reactive blue (RB) and direct blue (DB) 297 with free and immobilized HRP was observed at pH 5 and at temperature 40 °C respectively. The removal efficiency of DB 297 and RB 221 with free HRP was 75% and 86% while with immobilized HRP was 81% and 92% respectively. Furthermore, biodegradation of reactive blue (RB) 221 and direct blue (DB) 297 with immobilized and free biocatalyst was also investigated by Fourier transform infrared spectroscopy (FTIR) by identification of groups involved in dye degradation. FTIR results confirmed the 100% degradation of dyes. Immobilized HRP retained significant catalytic activity after five consecutive cycles of dye degradation. In conclusion, Fe3O4 nanoparticles are promising and environmentally friendly media for enzyme immobilization. Moreover, immobilized HRP showed more thermal stability, pH stability and higher dye degradation efficiency as compared to free HRP. Furthermore, the immobilized HRP, economically more convenient and easily removable from reaction media. Owing to its thermal stability, ease of separation from reaction media and reusability, the magnetically separatable immobilized HRP can be exploited successfully for treatment of dye contaminated textile effluents.


Viability of lyophilized anaerobes in two media.
Viability of 15 species of anaerobes was followed after freeze-drying and storage for 1 year. Organisms maintained in a 12% sucrose concentration in chopped meat carbohydrate broth survived longer and maintained higher viability counts than those organisms in double-strength skim milk.


[Clinical course, diagnosis and surgical treatment of Raynaud's disease].
The work is based on the experience with treatment of 86 patients with Raynaud's disease. 41 patients were treated conservatively, in 45 patients thoracic sympathectomy was performed. All 45 patients subjected to thoracic sympathectomy showed excellent and good immediate results. Late results were favourable in 20 out of 23 operated patients, examined within the terms from 5 to 15 years postoperatively. Thus, thoracic sympathectomy is an effective method of treatment for Raynaud's disease.


Diagnosis: Michael Moore--media paint filmmaker to be health care system's main problem.
The media reporting on Sicko, Michael Moore's documentary about the failures of the U.S. health care system, provides an example of how corporate media continue to twist and restrict the much-needed debate on health care reform. Aside from an occasional concession that having 46 million uninsured Americans is indeed problematic, the media's hype-filled conversation on health care avoids the issues and echoes old myths about the dangers of "government-run" and "socialized" health care. But in the face of the media demonization, universal health care is remarkably popular among the public.


PET study using [11C]FTIMD with ultra-high specific activity to evaluate I2-imidazoline receptors binding in rat brains.
We recently developed a selective (11)C-labeled I(2)-imidazoline receptor (I(2)R) ligand, 2-(3-fluoro-4-[(11)C]tolyl)-4,5-dihydro-1H-imidazole ([(11)C]FTIMD). [(11)C]FTIMD showed specific binding to I(2)Rs in rat brains having a high density of I(2)R, as well as to I(2)Rs those in monkey brains, as illustrated by positron emission tomography (PET) and autoradiography. However, [(11)C]FTIMD also showed moderate non-specific binding in rat brains. In order to increase the specificity for I(2)R in rat brains, we synthesized [(11)C]FTIMD with ultra-high specific activity and evaluated its binding. [(11)C]FTIMD with ultra-high specific activity was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [(11)C]methyl iodide, which was produced by iodination of [(11)C]methane using the single-pass method. Dynamic PET scans were conducted in rats, and the kinetic parameters were estimated. [(11)C]FTIMD with ultra-high specific activity was successfully synthesized with an appropriate level of radioactivity and ultra-high specific activity (4470 ± 1660 GBq/μmol at end of synthesis, n = 11) for injection. In the PET study, distribution volume (V(T)) values in all the brain regions investigated whether I(2)R expression was greatly reduced in BU224-pretreatead rats compared with control rats (29-45% decrease). Differences in V(T) values between control and BU224-pretreated rats using [(11)C]FTIMD with ultra-high specific activity were greater than those using [(11)C]FTIMD with normal specific activity (17-34% decrease) in all brain regions investigated. Quantitative PET using [(11)C]FTIMD with ultra-high specific activity can contribute to the detection of small changes in I(2)R expression in the brain.


Impact of graft cell dose on transplant outcomes following unrelated donor allogeneic peripheral blood stem cell transplantation: higher CD34+ cell doses are associated with decreased relapse rates.
Peripheral blood stem cells (PBSC) have been increasingly used in the matched unrelated donor (MUD) transplant setting, but the impact of CD34(+) cell dose on outcomes in this setting have not been well characterized. We analyzed 181 consecutive patients who underwent MUD-PBSC transplantation at the City of Hope between August 2000 to December 2004. Patients were conditioned with either full-intensity regimen or reduced-intensity regimen. There was a significant inverse relationship between higher CD34(+) cell dose and faster neutrophil engraftment (r = -0.16, P = .035). By univariate analysis, a CD34(+) cell dose > or =4.2 x 10(6)/kg (above the lowest quartile) was associated with significantly lower relapse risk (hazard ratio [HR] = 0.67, P = .0126), with a trend for corresponding improvement for disease-free survival (HR = 0.84, P = .12) but not overall survival (HR = 0.91, P = .46). The impact of the CD34(+) cell dose remained significant in multivariate analysis. The higher CD34(+) cell dose was significantly associated with faster recovery of absolute lymphocyte counts on day +30 posttransplant. Subset analysis demonstrated that the higher CD34(+) cell dose was associated with (1) greater reduction in relapse in myeloid malignancies than that in lymphoid malignancies, (2) greater reduction in reduced-intensity conditioning than in full-intensity conditioning, (3) greater reduction in relapse when there is a inhibitory killer-cell immunoglobulin-like receptor ligand (iKIRL)-mismatch in the gravft-versus-host (GVH) direction, and (4) greater reduction in relapse when there is a lack of iKIRL, suggesting that the protective effect of CD34(+) cell dose against relapse may be immune-mediated, possibly through NK cell recovery.


Eimeria vermiformis and E. mitis: inhibition of development in vivo by cyclosporin A.
Treatment of the host (Mus musculus, Gallus domesticus) with cyclosporin A during infection with Eimeria vermiformis or E. mitis resulted in a reduction in the numbers of oocysts passed in the feces and/or a delay in patency. The general immunosuppressive effects of the treatment were confirmed in chickens by monitoring their antibody responses to human erythrocytes and lymphoproliferative responses to phytohemagglutinin. Nevertheless, mice and chickens treated with cyclosporin A during a primary infection with E. vermiformis or E. mitis, respectively, were immune to subsequent challenge with these organisms. Thus, cyclosporin A did not interfere with priming. The antiparasite effect of the drug did not allow an evaluation of its effect on established immunity to the coccidia when it was administered at the time of challenge. In an exceptional treated chicken, however, delayed patency of the challenge infection was followed by the production of a number of oocysts similar to that found in unprimed animals. This suggests that the mechanisms of immunity to challenge may be susceptible to disruption by cyclosporin A.


The comparison of the migration and transformation behavior of heavy metals during pyrolysis and liquefaction of municipal sewage sludge, paper mill sludge, and slaughterhouse sludge.
Municipal sewage sludge, paper mill sludge, and slaughterhouse sludge were pyrolyzed and liquefied for the production of bio-char. The migration and transformation behavior of Cu, Cr, and Zn during pyrolysis and liquefaction of these sludges were studied. Pyrolysis and liquefaction promoted mobile fraction (F1 and F2) to stable fraction (F3 and F4). The results showed that pyrolysis and liquefaction largely affected the redistribution of Cu and Zn in raw materials. The environmental risk assessment results indicated that the environmental risk levels of Cu and Zn were significantly reduced in bio-char, and risk level of Cr was slightly decreased after pyrolysis or liquefaction. Both pyrolysis and liquefaction were promising detoxification technologies for the three sludges in terms of the mitigation of heavy metals toxicity. It was suggested that dewatered sludge could be reduced toxicity/risk before utilization by pyrolysis or liquefaction technology, especially for Cu and Zn in slaughterhouse sludge.


Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level.
Mechanisms of N-methyl-D-aspartate receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of N-methyl-D-aspartate receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the N-methyl-D-aspartate receptor glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of N-methyl-D-aspartate receptors at synapses in the amygdala under low activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced N-methyl-D-aspartate receptor-mediated synaptic events, serving an essential function in the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation in fear conditioning pathways.


Barriers to and enablers of type 2 diabetes screening among women with prior gestational diabetes: A systematic review update and qualitative synthesis applying the Theoretical Domains Framework.
Women with prior gestational diabetes have nearly 10 times the risk of developing type 2 diabetes. Postpartum screening for type 2 diabetes is recommended for early diagnosis and management, yet uptake is low. This work updates a previous systematic review and advances it through the application of the Theoretical Domains Framework (TDF) to synthesise personal-level factors impacting type 2 diabetes screening and the Capability, Opportunity, Motivation-Behaviour model (COM-B), to develop messaging recommendations for use in clinical practice and screening promotion interventions. We searched seven academic databases from September 2017 (prior review) to April 2021, reference lists and grey literature. Two reviewers independently screened articles against inclusion criteria (qualitative studies exploring factors impacting postpartum diabetes screening, any language) and extracted data. Using an inductive-deductive model, we coded determinants to the TDF and mapped onto the COM-B model. We identified 38 eligible papers from 34 studies (N = 1291 participants). Most (71%) reported sample sizes of N ≥ 16. The ratio of barriers to enablers was three to one. Eight key TDF domains were identified. Evidence-based recommendations include addressing knowledge, risk perception, fear of diabetes diagnosis, low prioritisation of personal health and fatalism. The risk of bias was low and confidence in findings was moderate to high. A limitation was conceptual overlap between TDF domains, which we addressed via the study procedure. The theoretical categorisation of determinants enables the development of messaging and interventions at the personal level, to promote women's uptake of postpartum type 2 diabetes screening.


Genetic, spatial, and social relationships among adults in a group of howler monkeys (Alouatta palliata) from Barro Colorado Island, Panama.
Kinship plays an important role in the social behavior of many primate species, including patterns of intra-group affiliation and cooperation. Within social groups, kinship is strongly affected by dispersal patterns, with the degree of relatedness among group-mates expected to decrease as the tendency to disperse increases. In primate species characterized by bisexual dispersal, relatedness among adult group-mates is predicted to be low, with social interactions shaped largely by factors other than kinship. To date, however, few studies have examined the role of kinship in social interactions in bisexually dispersing species. Accordingly, we collected genetic, spatial and behavioral data on all adult members (three males, six females) in a group of free-ranging mantled howler monkeys (Alouatta palliata)--a bisexually dispersing species of atelid primate--from Barro Colorado Island (BCI), Panama. Analyses of microsatellite variation revealed that relatedness was greater among adult males in this group (mean pairwise relatedness = 0.32 for males versus 0.09 for females). Relatedness among individuals, however, was not associated with either spatial proximity or frequency of social interactions. Instead, sex was a better predictor of both of these aspects of social behavior. While relatedness among adults had no discernible effect on the intra-group social interactions documented in this study, we postulate that kinship may facilitate affiliative and cooperative behaviors among male group-mates when interacting competitively with neighboring howler groups over access to food or potential mates.


Extensive evaluation of sample preparation workflow for gas chromatography-mass spectrometry-based plasma metabolomics and its application in rheumatoid arthritis.
GC-MS platform has been proved to be an important analytical technique for plasma metabolomics, but lack of efficient sample preparation strategies prior to sample injection has limited its wide application. In the present work, twenty two extraction protocols including protein precipitation (PPT), liquid-liquid extraction (LLE), solid-phase extraction (SPE) and ultrafiltration were simultaneously evaluated using non-spiked and metabolite standards spiked human plasma. Sample-to-extraction solvent ratio and metabolites derivatization conditions were also investigated and optimised. The results demonstrated that stepwise LLE protocol (MeOH-H2O/CHCl3/CHCl3-MeOH) was the most efficient extraction strategy for the combination of untargeted and targeted metabolomics. Sample-to-extraction solvent ratio of 1:3 (v:v) was found to perform better than higher solvent ratios. Also, the maximum derivatization performance was obtained when using 30 μL N-methyl-N-tri-methylsilyltrifluoroacetamide (MSTFA) and 1% trimethyl-chlorosilane (TMCS) incubated at 60 °C for 120 min. In the end, the optimised sample preparation method was applied successfully to plasma untargeted metabolomics of rheumatoid arthritis (RA) and four metabolites (gamma-butyrolactone, MG (0:0/18:0/0:0), tocopherol and oxalic acid) were found to be potential biomarkers for the diagnosis of RA.


Collection efficiencies of MNC subpopulations during autologous CD34+ peripheral blood progenitor cell (PBPC) harvests in small children and adolescents.
There is increasing demand for mononuclear cell (MNC) harvests not only for PBPC but also for immune therapies using dendritic cells and donor lymphocytes. We determined the collection efficiencies (CE) of various MNC subpopulations during CD34+ cell harvests using a Fenwal CS 3000 Plus Omnix system in small children and adolescents. The cell content of 140 leukapheresis products (LP) was prospectively evaluated in 45 pretreated patients with solid tumors and hematological malignancies. The median age was 12 years (range 0.8-22), and the median body weight (BW) 43 kg (range 9-92). Depending upon the BW of the patients, the media used for priming were saline (SP) in 86, human albumin (HA, HAP) in 10, and packed red blood cells (BP) in 44 apheresis procedures. The major nucleated cell (NC) fractions collected were monocytes (52% of NC) and CD3+ T cells (26%). The median cell yield for monocytes was 174 * 10(6)/kg (range 24-613) representing a CE of 55%. The median number of CD3(+) T cells was 84 * 10(6)/kg (range 5.6-380; CE = 74%). CD34+ cells represented a very small cell fraction of the LP (1.3% of NC), with a median yield of 4.2 * 10(6)/kg (range 0.2-87) and a CE of 63%. The cell yield of various MNCs was significantly correlated with the cell count in the peripheral blood (PB) and with the blood volume processed (ANOVA, P < 0.0001). No influence on the CE was observed for the priming procedure, the patients' age or sex, or the other adaptations used in the harvesting protocol. In conclusion, the Fenwal CS 3000 Plus OMNIX system with the CD34+ cell program and the described adaptations, is also predictably useful for harvest of monocytes or lymphocytes in pediatric patients. We present regression equations that predict the cell yield of various MNC subpopulations in apheresis products.


Plasmid segregation: is a total understanding within reach?
Recent in vitro and in vivo studies of the proteins responsible for the active partitioning of bacterial plasmids suggest that it will be possible to develop a quantitative, molecular understanding of this form of DNA segregation.


A review of healthcare service and education provision of Autism Spectrum Condition in mainland China.
Little is known about the current situation regarding Autism Spectrum Conditions in mainland China. Electronic databases and bibliographies were searched to identify literature on service provision for ASC in both English and Chinese databases. 14 studies and 6 reports were reviewed. The findings of identified papers on service provision were summarized according to four settings for ASC including healthcare, mainstream education, private special education, and state-run special education. The literature on the situation of the healthcare system and educational services for children with ASC in China was profoundly limited. There were great financial problems faced by the parents of autistic children which were partly due to the under-developed healthcare and educational system for ASC.


Abundance, complexation, and trafficking of Wnt/beta-catenin signaling elements in response to Wnt3a.
Wnt3a regulates a canonical signaling pathway in early development that controls the nuclear accumulation of beta-catenin and its activation of Lef/Tcf-sensitive transcription of developmentally important genes. Using totipotent mouse F9 teratocarcinoma cells expressing Frizzled-1 and biochemical analyses, we detail the influence of Wnt3a stimulation on the expression, complexation, and subcellular trafficking of key signaling elements of the canonical pathway, i.e., Dishevelled-2, Axin, glycogen synthase kinase-3beta, and beta-catenin. Cellular content of beta-catenin and Axin, and phospho-glycogen synthase kinase-3beta, but not Dishevelled-2, increases in response to Wnt3a. Subcellular localization of Axin in the absence of Wnt3a is symmetric, found evenly distributed among plasma membrane-, cytosol-, and nuclear-enriched fractions. Dishevelled-2, in contrast, is found predominately in the cytosol, whereas beta-catenin is localized to the plasma membrane-enriched fraction. Wnt3a stimulates trafficking of Dishevelled-2, Axin, and glycogen synthase kinase-3beta initially to the plasma membrane, later to the nucleus. Bioluminescence resonance energy transfer measurements reveal that complexes of Axin with Dishevelled-2, with glycogen synthase kinase-3beta, and with beta-catenin are demonstrable and they remain relatively stable in response to Wnt3a stimulation, although trafficking has occurred. Mammalian Dishevelled-1 and Dishevelled-2 display similar patterns of trafficking in response to Wnt3a, whereas that of Dishevelled-3 differs from the other two. This study provides a detailed biochemical analysis of signaling elements key to Wnt3a regulation of the canonical pathway. We quantify, for the first time, the Wnt-dependent regulation of cellular abundance and intracellular trafficking of these signaling molecules. In contrast, we observe little effect of Wnt3a stimulation on the level of protein-protein interactions among these constituents of Axin-based complexes themselves.


Hemodialysis and extracorporeal removal after pediatric and adolescent poisoning reported to a state poison center.
There is currently limited literature regarding the use of hemodialysis after acute pediatric and adolescent poisoning. We sought to characterize the use of hemodialysis (HD) and other extracorporeal removal techniques (ECR) in the treatment of acutely poisoned children and adolescents reported to a state poison control system over a 10-year period. After institutional review board approval, a state poison control system database was queried for all cases coded for hemodialysis and other ECR after pediatric and adolescent (0-19 years old) poisoning. We also analyzed National Poison System Data to determine national trends. Ninety patients were reviewed after exclusions for errors in coding or incomplete documentation. HD was the principle method of ECR employed. One case of hemoperfusion and hemofiltration was reported. HD was used, on average, nine times per year. ECR was used predominantly in adolescent patients (age ≥ to 12 years) (84 patients, 93%) for intentional ingestions (82 patients, 91%). Fifteen different toxins were encountered, with salicylates (29 patients) and ethylene glycol (23 patients) most commonly encountered. Ethylene glycol and methanol blood levels were not available before initiation of hemodialysis in all but one case. All salicylate-poisoned patients who underwent HD demonstrated clinical findings indicative of toxicity even in the absence of elevated levels advocated by some as indication for HD. HD and other ECR are rarely used in the management of pediatric and adolescent poisoning.


The chemical biology of ubiquitin.
This mini-review will cover the various chemical biology approaches employed to prepare and modulate ubiquitin chains and the ubiquitin-proteasome system. Emphasis will be given to the biochemistry and chemical biology of poly-ubiquitin chain preparation as a tool to elucidate its roles in biological systems as well as the hijacking of the ubiquitin proteasome system using heterobifunctional compounds to induce intracellular ubiquitination.


Gene transfer of eNOS to the thick ascending limb of eNOS-KO mice restores the effects of L-arginine on NaCl absorption.
The thick ascending limb of the loop of Henle (THAL) plays an essential role in the regulation of sodium and water homeostasis by the kidney. l-Arginine, the substrate for nitric oxide synthase (NOS), decreases NaCl absorption by THALs. We hypothesized that eNOS produces the NO that regulates THAL NaCl transport and that selective expression of eNOS in the THAL of eNOS knockout(-/-) mice would restore the effects of l-arginine on NaCl absorption. eNOS-/- mice were anesthetized, the left kidney was exposed, and the renal interstitium was injected with recombinant adenoviral vectors that expressed green fluorescent protein (GFP) or eNOS driven by the promoter of the Na/K/2Cl cotransporter Ad-NKCC2GFP and Ad-NKCC2eNOS, respectively. In Ad-NKCC2eNOS-transduced kidneys, eNOS expression was detected 7 days after injection but was absent in Ad-NKCC2GFP-transduced kidneys. In THALs from eNOS-/- mice transduced with Ad-NKCC2eNOS, adding L-arginine increased DAF-2DA fluorescence, a measure of NO production, by 9.1+/-1.1% (P<0.05; n=5), but not in THALs transduced with Ad-NKCC2GFP. In THALs from eNOS-/- mice transduced with Ad-NKCC2eNOS, Cl absorption averaged 85.9+/-11.8 pmol/min per millimeter. Adding l-arginine (1 mmol/L) to the bath decreased Cl absorption to 59.7+/-11.0 pmol/min per millimeter (P<0.05; n=6). In THALs transduced with Ad-NKCC2GFP, Cl absorption averaged 96.0+/-21.0 pmol/min per millimeter. Adding L-arginine to the bath did not significantly affect Cl absorption (100.6+/-20.6 pmol/min per millimeter; n=4). We concluded that gene transfer of eNOS to the THAL of eNOS-/- mice restores L-arginine-induced inhibition of NaCl transport and NO production. These data indicate that eNOS is essential for the regulation of THAL NaCl transport by NO.


Incident Heart Failure Risk Reclassification With Race-Independent Estimated Glomerular Filtration Rate: A National Heart, Lung, and Blood Institute Pooled Cohorts Analysis.
This study compared the predictive value of the race-independent creatinine- and cystatin C-based estimated glomerular filtration rate (eGFRcr-cys) and the race-dependent creatinine-based eGFR (eGFRcr) for incident heart failure (HF). This study combined the participant-level data from ARIC (Atherosclerosis Risk in Communities) (visit 4) and MESA (Multi-Ethnic Study of Atherosclerosis) (visit 1) to calculate eGFRcr-cys and eGFRcr. The primary outcome of the study was adjudicated incident HF over a follow-up period of 10 years. Multivariable Cox models were used to assess the risk of incident HF with the quartiles of eGFRcr-cys and eGFRcr. Among 15,615 individuals (median age: 62 [57-68] years; 55.0% females; 23.9% Black), the median eGFRcr-cys and eGFRcr were 91.4 (79.4, 102.0) mL/min/1.73m2 and 84.7 (72.0, 94.7) mL/min/1.73m2, respectively. Compared with the fourth quartile of eGFRcr-cys, the hazard ratio for incident HF was 1.02 (95% CI:0.80-1.30) in the third quartile, 1.02 (95% CI:0.80-1.30) in the second quartile, and 1.47 (95% CI:1.16-1.86) in the first quartile. Compared with the 4th quartile of the eGFRcr, the risk of incident HF was similar in the 3rd (HRadj:0.90 [95% CI:0.73-1.12]), 2nd (HRadj: 0.96 [95% CI:0.77-1.20]), and 1st (HRadj:1.15 [95% CI:0.93-1.44]) quartiles. C-statistics were similar for the multivariable-adjusted Cox models for incident HF using eGFRcr (0.80 [0.79-0.81]) and eGFRcr-cys (0.80 [0.79-0.82]). The eGFRcr and eGFRcr-cys had comparable predictive values for incident HF.


Denosumab, a Potential Alternative to the Surgical Treatment of Distal Radius Giant Cell Tumor of Bone: Case Report.
Juxta-articular giant cell tumors can pose major surgical challenges. Aggressive distal radius giant cell tumors often require complex reconstructive procedures that are associated with numerous complications. We present a case of a 25-year old man with a Campanacci grade 3 giant cell tumor of the distal radius that was successfully treated with denosumab without complex reconstructive procedures. At 3.5-year follow-up and 1-year drug free period, the patient remained asymptomatic without histologic evidence of recurrent tumor. With denosumab therapy, patients can potentially avoid surgery and achieve a successful outcome.


Knowledge retention after an online tutorial: a randomized educational experiment among resident physicians.
The time course of physicians' knowledge retention after learning activities has not been well characterized. Understanding the time course of retention is critical to optimizing the reinforcement of knowledge. Educational follow-up experiment with knowledge retention measured at 1 of 6 randomly assigned time intervals (0-55 days) after an online tutorial covering 2 American Diabetes Association guidelines. Internal and family medicine residents. Multiple-choice knowledge tests, subject characteristics including critical appraisal skills, and learner satisfaction. Of 197 residents invited, 91 (46%) completed the tutorial and were randomized; of these, 87 (96%) provided complete follow-up data. Ninety-two percent of the subjects rated the tutorial as "very good" or "excellent." Mean knowledge scores increased from 50% before the tutorial to 76% among those tested immediately afterward. Score gains were only half as great at 3-8 days and no significant retention was measurable at 55 days. The shape of the retention curve corresponded with a 1/4-power transformation of the delay interval. In multivariate analyses, critical appraisal skills and participant age were associated with greater initial learning, but no participant characteristic significantly modified the rate of decline in retention. Education that appears successful from immediate posttests and learner evaluations can result in knowledge that is mostly lost to recall over the ensuing days and weeks. To achieve longer-term retention, physicians should review or otherwise reinforce new learning after as little as 1 week.


Calorimetric evidence of interaction of brominated flame retardants with membrane model.
The presence of polybrominated flame retardants in the environment seems to be increasing in the past decade. Considering the toxic effects of these pollutants, it is important evaluating the potential interaction with biological membranes for a risk assessment. In this study low and high brominated biphenyls and biphenyl ethers were used to investigate their interaction with biological membrane models constituted by liposomes, using differential scanning calorimetry (DSC) technique. The medium influence on membrane absorption was also assessed. The findings indicate that membrane interaction is controlled by compound structural characteristics. The membrane absorption is allowed by lipophilic medium; instead hydrophilic medium prevents membrane permeation.


A novel MRI-based data fusion methodology for efficient, personalised, compliant simulations of aortic haemodynamics.
We present a novel, cost-efficient methodology to simulate aortic haemodynamics in a patient-specific, compliant aorta using an MRI data fusion process. Based on a previously-developed Moving Boundary Method, this technique circumvents the high computational cost and numerous structural modelling assumptions required by traditional Fluid-Structure Interaction techniques. Without the need for Computed Tomography (CT) data, the MRI images required to construct the simulation can be obtained during a single imaging session. Black Blood MR Angiography and 2D Cine-MRI data were used to reconstruct the luminal geometry and calibrate wall movement specifically to each region of the aorta. 4D-Flow MRI and non-invasive pressure measurements informed patient-specific inlet and outlet boundary conditions. Luminal area closely matched 2D Cine-MRI measurements with a mean error of less than 4.6% across the cardiac cycle, while physiological pressure and flow distributions were simulated to within 3.3% of patient-specific targets. Moderate agreement with 4D-Flow MRI velocity data was observed. Despite lower peak velocity, an equivalent rigid-wall simulation predicted a mean Time-Averaged Wall Shear Stress (TAWSS) 13% higher than the compliant simulation. The agreement observed between compliant simulation results and MRI data is testament to the accuracy and efficiency of this MRI-based simulation technique.


Highly efficient activation of peroxymonosulfate by biomass juncus derived carbon decorated with cobalt nanoparticles for the degradation of ofloxacin.
The cobalt nanoparticles decorated biomass Juncus derived carbon (Co@JDC) was prepared by facile calcination strategy and applied to activate peroxymonosulfate (PMS) for eliminating ofloxacin (OFX) in the water environment. The results of catalytic experiments show that 97% of OFX degradation efficiency and 70.4% of chemical oxygen demand removal rate are obtained within 24 min at 0.1 g L-1 Co@JDC, 0.2 g L-1 PMS, 20 mg L-1 OFX (100 mL), and pH = 7, which indicates that Co@JDC/PMS system exhibits excellent performance. Meanwhile, the experimental results of affect factor show that Co@JDC/PMS system can operate in a wider pH range (3-9) and Cl-1, NO3-1, and SO42- have an ignorable effect on OFX degradation. The radical identification experiments confirm that SO4˙-, ·OH, O2˙-, and 1O2 are involved in the process of PMS activation, especially SO4˙- and 1O2 are the main contributors. Furthermore, a possible PMS activation mechanism by Co@JDC was proposed and the degradation pathways of OFX were deduced. Finally, the stable catalytic activity, negligible leaching of Co2+, and the outstanding degradation efficiency for other antibiotics prove that Co@JDC possesses good stability and universality.


A basal ganglia-like cortical-amygdalar-hypothalamic network mediates feeding behavior.
The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop "no-eat" signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.


Neuropsychological deficits in children associated with increased familial risk for schizophrenia.
By studying neuropsychological performance in children genetically at-risk for schizophrenia, greater understanding may be obtained regarding the developmental processes of schizophrenia and associated cognitive weaknesses. A variety of cognitive deficits in genetically at-risk children have been reported. The present study was designed to examine cognitive tasks that have traditionally differentiated children genetically at-risk for schizophrenia (e.g. working memory) from normal children, while also assessing abilities that have received scant attention in this population. Aspects of emotional perception, verbal abilities, inhibition, visuo-spatial skills, and working memory were assessed in children of schizophrenic parents and normal children. Significant differences in performances were identified in at-risk children on measures of verbal skills, working memory and inhibition. Findings suggest that children genetically at-risk for developing schizophrenia exhibit neurocognitive weaknesses generally consistent with those noted in the literature. However, inhibition also appeared to be a cognitive process that significantly differentiated the groups. The possibility of a developmental expression of neurocognitive deficits is discussed.


Oligomeric beta-amyloid(1-42) induces the expression of Alzheimer disease-relevant proteins in cholinergic SN56.B5.G4 cells as revealed by proteomic analysis.
Alzheimer's disease (AD) is characterized by cholinergic dysfunction and progressive basal forebrain cell loss which has been hypothesized to be associated with extensive accumulation of beta-amyloid (Abeta). To reveal whether oligomeric Abeta displays a particular toxicity for cholinergic neurons, the cholinergic cell line SN56.B5.G4 (SN56) was used as a model. Recently performed microarray analyses demonstrated that genes affected by exposure of SN56 cells with 50 microM oligomeric Abeta(1-42) for 24 h were involved in protein modification and degradation [Heinitz, K., Beck, M., Schliebs, R., Perez-Polo, J.R., 2006. Toxicity mediated by soluble oligomers of beta-amyloid(1-42) on cholinergic SN56.B5.G4 cells. J. Neurochem. 98, 1930-1945]. Using a proteomic approach, we compared the levels of proteins and specially of phosphorylated proteins in cytosolic fractions of cell lysates from cholinergic SN56 cells exposed to 50 microM Abeta(1-42) for 24h to those in control incubations. We show here that the levels of calreticulin, and mitogen-activated protein kinase (MAPK) kinase 6c were up-regulated in cholinergic SN56 cells exposed to Abeta(1-42), while gamma-actin appeared down-regulated. Abeta(1-42) exposure of cholinergic SN56 cells led to decreased phosphorylation of phosphoproteins, such as the Rho GDP dissociation inhibitor, the ubiquitin carboxyl terminal hydrolase-1, and the tubulin alpha-chain isotype Malpha6, as compared to untreated control lysates. The proteins identified have also been reported to be affected in brains of AD patients, suggesting a potential role of Abeta in influencing the integrity and functioning of the proteome in AD.


Shaping the immune response to parasites: role of dendritic cells.
Parasites represent a diverse group of pathogens that often trigger highly polarized immune responses that become tightly regulated during chronic infection. Recent studies have implicated the parasite-dendritic-cell interaction as a key determinant of the host response to these eukaryotic invaders. Dendritic cells appear to be pivotal in the initiation of cellular immunity against parasites as well as in directing Th1/Th2 effector choice. Moreover, there is increasing evidence that parasites regulate dendritic-cell function for the purposes of evading host immunity. This regulation also benefits parasites by protecting their host niche from the potentially lethal consequences of an uncontrolled inflammatory response.


Disparities in access to translational research.
Translational research describes the process of applying observations and scientific discoveries made in the laboratory to clinical applications that can improve the health of individual patients, most often through clinical trials. To apply the findings of translational research studies to the broader population, the study population must accurately reflect the group of patients afflicted by a particular disease. Yet, it is well known that significant disparities exist for underrepresented groups and lower socioeconomic populations in clinical trials. In fact, only 20% of randomized controlled studies published in high-impact oncology journals include subgroup analyses to assess differences in outcomes based on race or ethnicity.1 If effective interventions to decrease health disparities in research are to be implemented, it is critical to understand the multifactorial influences that create such differences. These are complex and include individual patient factors, family and social support, provider and organizational factors, as well as policy and community factors. Patient access to tertiary or quaternary care academic centers or designated cancer centers with the funding and resources to carry out translational research and knowledge of ongoing available research endeavors is often critical. Active community engagement and outreach and deep understanding of a particular health system's catchment area are necessary to increase both awareness and participation in clinical trials. Without significant progress in biomedical research patient recruitment, existing racial and ethnic health disparities will be challenging to overcome.


Etiology impacts survival in patients with severe aortic regurgitation: results from a cohort of 756 patients.
Severe aortic regurgitation (AR) is caused by a variety of mechanisms, which include the degenerative process, bicuspid aortic valve (BAV), aortic root dilation, endocarditis or a combination of these. Their frequency in a contemporary clinical series, and their impact on survival, are currently unknown. The authors' echocardiographic database between 1993 and 2007 was screened for patients with severe AR, and yielded 756 patients. Detailed chart reviews were performed to acquire clinical and demographic data. Mortality data were obtained from the social security death index and analyzed as a function of the condition's etiology. The probable etiologies for AR were: degenerative in 29% of patients, BAV in 10%, aortic root pathology in 11%, endocarditis in 10%, and mixed or unclear mechanism in 40%. Survival was a function of the etiology (p < 0.0001), with degenerative mechanism having the worst prognosis and BAV the best. This differential impact on mortality remained significant after adjusting for age, gender, coronary artery disease, diabetes mellitus, renal insufficiency, left ventricular ejection fraction and aortic valve replacement, using the Cox regression model (p < 0.0001). Etiology has a significant independent impact on mortality in patients with severe AR, with the worst survival being seen in degenerative AR.


Chronic fatigue syndrome and health control in adolescents and parents.
To explore the locus of health control in adolescents with chronic fatigue syndrome (CFS) and their parents in comparison with healthy adolescents and their parents. In this cross-sectional study 32 adolescents with CFS were compared with 167 healthy controls and their respective parents. The Multidimensional Health Locus of Control (MHLC) questionnaire was applied to all participants. There was significantly less internal health control in adolescents with CFS than in healthy controls. An increase of internal health control of one standard deviation was associated with a 61% reduced risk for CFS (OR = 0.39, 95% CI 0.25 to 0.61). Internal health control of the parents was also protective (OR fathers: 0.57 (95% CI 0.38 to 0.87); OR mothers: 0.74 (95% CI 0.50 to 1.09)). The external loci of health control were higher in adolescents with CFS and in their parents. Increased levels of fatigue (56%) were found in the mothers of the adolescents with CFS, in contrast with the fathers who reported a normal percentage of 13. In comparison with healthy adolescents, adolescents with CFS and their parents show less internal health control. They attribute their health more to external factors, such as chance and physicians. This outcome is of relevance for treatment strategies such as cognitive behaviour therapy, for which health behaviour is the main focus.


Role of apoptosis in autoimmunity.
Autoimmune diseases are characterized by the activity of autoreactive lymphocytes that produce antibodies targeting self tissue or organ for destruction. Although the pathogenesis of these diseases is poorly understood, during the past two decades basic research has indicated apoptosis as the pivotal molecular mechanism leading to autoimmunity. Recently cytokines have been invoked in the regulation of the apoptosis-related factors and death receptors in autoimmune target destruction. These research advances have contributed to the identification of mechanisms controlling autoimmunity for defining novel therapeutic strategies.


Lower bone turnover and relative bone deficits in men with metabolic syndrome: a matter of insulin sensitivity? The European Male Ageing Study.
We examined cross-sectional associations of metabolic syndrome and its components with male bone turnover, density and structure. Greater bone mass in men with metabolic syndrome was related to their greater body mass, whereas hyperglycaemia, hypertriglyceridaemia or impaired insulin sensitivity were associated with lower bone turnover and relative bone mass deficits. Metabolic syndrome (MetS) has been associated with lower bone turnover and relative bone mass or strength deficits (i.e. not proportionate to body mass index, BMI), but the relative contributions of MetS components related to insulin sensitivity or obesity to male bone health remain unclear. We determined cross-sectional associations of MetS, its components and insulin sensitivity (by homeostatic model assessment-insulin sensitivity (HOMA-S)) using linear regression models adjusted for age, centre, smoking, alcohol, and BMI. Bone turnover markers and heel broadband ultrasound attenuation (BUA) were measured in 3129 men aged 40-79. Two centres measured total hip, femoral neck, and lumbar spine areal bone mineral density (aBMD, n = 527) and performed radius peripheral quantitative computed tomography (pQCT, n = 595). MetS was present in 975 men (31.2 %). Men with MetS had lower β C-terminal cross-linked telopeptide (β-CTX), N-terminal propeptide of type I procollagen (PINP) and osteocalcin (P < 0.0001) and higher total hip, femoral neck, and lumbar spine aBMD (P ≤ 0.03). Among MetS components, only hypertriglyceridaemia and hyperglycaemia were independently associated with PINP and β-CTX. Hyperglycaemia was negatively associated with BUA, hypertriglyceridaemia with hip aBMD and radius cross-sectional area (CSA) and stress-strain index. HOMA-S was similarly associated with PINP and β-CTX, BUA, and radius CSA in BMI-adjusted models. Men with MetS have higher aBMD in association with their greater body mass, while their lower bone turnover and relative deficits in heel BUA and radius CSA are mainly related to correlates of insulin sensitivity. Our findings support the hypothesis that underlying metabolic complications may be involved in the bone's failure to adapt to increasing bodily loads in men with MetS.


Is Sleeve Gastrectomy Always an Absolute Contraindication in Patients with Barrett's?
The incidence of esophageal adenocarcinoma is not rising at the same rate as severe obesity, and incidence-based mortality is marginally going down since 2000. Laparoscopic sleeve gastrectomy (LSG) is now the preferred operation for weight loss in several countries including the USA. Recent objective studies of reflux before and 2 years after LSG show improvement by GERD Symptom Assessment Scale score, DeMeester score, total acid exposure, as well as unchanged lower esophageal sphincter pressure measurements. Therefore, sleeve gastrectomy improves symptoms and reduces reflux in most morbidly obese patients with preoperative reflux. At the last LSG consensus conference, 94.5% of experts mentioned Barrett's esophagus to be a major contraindication for the performance of LSG, a change from 2011 (81%). But the actual incidence of Barrett's is only 1% in the severely obese. Therefore, 99% of patients should be able to get a LSG. Further, after 25 years of duodenal switch operations (which includes a sleeve gastrectomy, there are still no reports of esophageal adenocarcinoma. Hence, LSG is not a contraindication in GERD patients without Barrett's.


Modulation of physiological and biochemical traits of two genotypes of Rosa damascena Mill. by SiO2-NPs under In vitro drought stress.
Drought is a major abiotic stress that restricts plant growth and efficiency although some nutrients such as silicon improve drought tolerance by regulating the biosynthesis and accumulating some osmolytes. In this regard, a completely randomized factorial design was performed with three factors including two genotypes ('Maragheh' and 'Kashan'), three concentrations of silicon dioxide nanoparticles (SiO2-NPs) (0, 50, and 100 mg L- 1), and five concentrations of PEG (0, 25, 50, 75, and 100 g L- 1) with three replications. The findings showed that drought stress decreased protein content and it was improved by SiO2-NPs, so the genotype of 'Maragheh' treated with 100 mg L- 1 SiO2-NPs had the highest protein content. Under severe drought stress, had a higher membrane stability index (MSI) than 'Kashan', and the 'Maragheh' explants subjected to 100 mg L- 1 SiO2-NPs exhibited the uppermost MSI. The explants supplemented with 100 mg L- 1 SiO2-NPs sustained their photosynthetic parameters more in comparison with other treatments under drought stress conditions and as well as 100 mg L- 1 SiO2-NPs showed higher content of protein and proline of 'Maragheh' than 'Kashan'. Drought stress reduced Fm, Fv/Fm, and Fv, while SiO2-NPs treatment enhanced these parameters. SiO2-NPs also improved water deficit tolerance by enhancing the activity of antioxidant enzymes such as catalase (CAT), peroxidase (POD), guaiacol peroxidase (GPX), and superoxide dismutase (SOD) and reducing lipid peroxidation and H2O2 concentration. According to the findings, the genotype 'Maragheh' was more tolerance to drought stress than 'Kashan' by improving water balance, antioxidant enzyme activities, and membrane stability as it was obtained from the unpublished previous evaluation in in vivo conditions and we concluded based on these results, in vitro culture can be used for drought screening in Damask rose plants. The results of the current study revealed that the induced drought stress by polyethylene glycol (PEG) in two Damask rose genotypes was ameliorated with SiO2-NPs and the tolerance genotypes were better than the sensitive ones in response to SiO2-NPs treatment.


Epoxy pipe relining - an emerging contact allergy risk for workers.
Epoxy pipe relining is a method of repairing old and worn water pipes supplying households. The method, using epoxy resin systems (ERSs), involves creating a new pipe inside an existing pipe. Large amounts of epoxy are normally handled at small, temporary worksites. To describe working conditions and contact allergies to ERSs in 8 patients with occupational contact dermatitis related to their work in the relining trade. Eight patients with suspected work-related eczema in the relining trade were referred to our Occupational and Environmental Dermatology outpatient unit. They were examined and patch-tested between August 2010 and May 2011. Seven patients were patch test-positive to ERSs, and 6 of 8 reacted to the epoxy resin (MW 340) in the baseline series. Five of the patients were patch test-positive to their own work products. Seven of the cases had to leave the relining trade because of skin problems. Relining is a widely used alternative to replacing old pipes, and entails a risk of massive skin exposure to ERSs and consequently a high risk of developing allergic contact dermatitis. Further mapping of working methods and use of personal protective equipment (PPE) is crucial to reduce hazardous skin exposure.


Predictors for delayed antibiotic administration among bacteraemic patients in the Emergency Department: Differences between medical and surgical interns.
Bloodstream infections (BSIs) have been associated with high mortality. The aim of the study was to identify predictors of early (within 3 hours from triage) administration of first antibiotic dose among patients evaluated in the Emergency Department (ED) with BSI and their role in mortality. All adult patients with BSI at the ED of the Hospital of Jura, Switzerland during a 3 year period (July 2014 to June 2017) were included. Among 364 BSI, the most common sites of infection were urinary tract (39.6% of BSIs), lower respiratory tract (15.4%), intra-abdominal (15.4%) and primary BSI (9.1%). One-hundred-seventy-eight patients (48.9%) received the first antibiotic dose within 3 hours from triage. Multivariate analysis identified evaluation by internal medicine intern, triage scales 1 and 2, as predictors of early antibiotic administration, while, primary BSI was associated with delayed antibiotic administration. Thirty-day mortality was 12.9% (47 patients). Charlson comorbidity index, septic shock, low respiratory tract infection were independently associated with mortality, while antibiotic administration within 3 hours from triage and source control within 48 hours from triage were associated with survival. The majority of patients received the first antibiotic dose after 3 hours Patients evaluated by surgical interns had a significant delay in administration of antibiotics as compared to those treated by medical interns.


Schizophrenia: measurements of psychopathology.
A key problem in schizophrenia research is how to assess the effects of treatment interventions given the spectrum of schizophrenia symptoms and patients' functioning. Measuring symptoms is complex, because these symptoms cover a wide variety of psychopathologic domains. The commonly recognized domains are the positive, negative, cognitive, excitement, and depression domains. This article critically reviews some of the available assessment tools of these domains together with other associated syndromes. The instruments discussed cover the broad range of psychopathology found in patients who have schizophrenia.


The risk of second malignancy after adjuvant chemotherapy for stomach cancer.
BACKGROUND: Although many trials have been conducted to evaluate the feasibility and effectiveness of adjuvant chemotherapy (ACT) for patients with stomach cancer, the benefits of ACT remain unclear. Moreover, some authors have reported that ACT increased the incidence of second malignancy. The risk of second malignancy was evaluated in patients who underwent treatment for stomach cancer in the past 20 years at Osaka Medical Center for Cancer and Cardiovascular Diseases.METHODS: The study population consisted of 1925 patients who underwent gastrectomies for stomach cancer between the years 1978 and 1992 and who received follow-up examinations to check for second malignancies. They included 1114 patients who underwent surgery only (group A) and 811 who underwent surgery and received chemotherapy (group B). The observed incidence of second malignancy (O) was compared with the expected incidence (E), calculated by the person-year method, using data from the Cancer Registry in Osaka.RESULTS: The average follow-up period was 7.99 years. The total number of patients with a second malignancy was 127 (men, 97; women, 30); 72 patients had the second malignancy in digestive organs; 27 in respiratory organs; and 28 in other organs. The relative risks of a second malignancy in group A and B patients were 1.05 and 1.02 (differences between the two groups were not significant). The relative risks of a second malignancy in patients who received ACT with 5-fluorouracil, Tegafur and Uracil, and FT207 were 0.79, 1.01, and 1.06, respectively (differences between the groups were not significant).CONCLUSION: The risk of second malignancy after chemotherapy for stomach cancer was not high in comparison with the expected incidence. Adjuvant chemotherapy did not increase the risk of a second malignancy.


A sandwich-based evanescent wave fluorescent biosensor for simple, real-time exosome detection†.
Exosomes are regarded as a promising biomarker for the noninvasive diagnosis and treatment of diseases. The value of exosomes for medical research has promoted the search for a fast, efficient, and sensitive detection method. This study reported a sandwich-based evanescent wave fluorescent biosensor (S-EWFB) for exosome detection. A two-step strategy was implemented to take advantages of the simple binding of fluorescent probes with exosomes via the hydrophobic interaction between the cholesteryl and phospholipid bilayer membrane, as well as real-time detection on an evanescent wave liquid-solid interface based on CD63 aptamer-specific capture to form an exosome@fluorescence probe/aptamer sandwich structure. The one-to-many connection between exosomes and signal molecules and the aptamer-modified evanescent wave optical fiber detection platform reduced the detection limit of exosomes to 7.66 particles/mL, with a linear range of 47.5-4.75 × 106 particles/mL. The entire detection process was simple, rapid, and real-time and lasted about 1 h while requiring no separation and purification. Additionally, this platform showed excellent surface regeneration capability and exhibited good performance during the analysis of tumor and non-tumor-derived exosomes.


Multimodal MRI improves diagnostic accuracy and sensitivity to longitudinal change in amyotrophic lateral sclerosis.
Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord. We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section. We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics. Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.


Social Networks and Atopic Dermatitis: Cross-Sectional Descriptive Study.
Social networks have become key tools for finding and disseminating medical information. To describe the characteristics of social network postings on atopic dermatitis, the content that is posted, and the number of followers of pages, groups, or accounts. We selected pages, groups, or accounts related to atopic dermatitis on Facebook, Twitter, and Linkedin during January and February of 2020. For each site, group, or account we recorded country of origin, year created, purpose, presence of links, provision of a contact email, and number of followers. We also analyzed the topics treated in recent content posts on the pages with the largest numbers of followers in each network. A total of 257 pages, groups, or accounts were included: Facebook, 171; Twitter, 59; and LinkedIn, 27. Facebook had the largest total number of pages and mean (SD) number of followers: 1416.71 (3722.63). Patient support groups accounted for most of the pages (63%), but businesses or product offers had more followers (P <.035). Of the 909 posts of informative content we analyzed, the most frequent topic was "general information about atopic dermatitis" (27.94%). Our findings show the importance of clearly defining the roles and limitations of social media platforms for designing future information campaigns and new patient-centered approaches to reaching patients with atopic dermatitis.


Community matters: Heterogeneous impacts of a sanitation intervention.
Sanitation is at the heart of public health policies in most of the developing world, where around 85% of the population still lack access to safe sanitation. We study the effectiveness of a widely adopted participatory community-level information intervention aimed at improving sanitation. Results from a randomized controlled trial, implemented at scale in rural Nigeria, reveal stark heterogeneity in impacts: the intervention has immediate, strong and lasting effects on sanitation practices in less wealthy communities, realized through increased sanitation investments. In contrast, we find no evidence of impacts among wealthier communities. This suggests that a targeted implementation of CLTS may increase its effectiveness in improving sanitation. Our findings can be replicated in other contexts, using microdata from evaluations of similar interventions.


Developmental outcomes of toddlers of young Latina mothers: Cultural, family, and parenting factors.
Children of adolescent mothers are at risk for poor developmental outcomes. This study is among the first to examine how cultural, family, and parenting factors prospectively predict the cognitive and language development of children of young Latina mothers (N=170; Mage=17.9 years). Mothers were interviewed and observed interacting with their children at 18 months (W1). Children were tested at 18 (W1) and 24 (W2) months. Mothers' cultural orientation (W1) was related to aspects of the childrearing environment (W1), which in turn had implications for the children's development (W2). Specifically, a stronger orientation toward American culture was related to higher mother-reported engagement in parenting by their own mothers (grandmothers), which in turn predicted stronger gains in cognitive and expressive language functioning from W1 to W2. A stronger Latino orientation related to the display of more directiveness and greater mother-reported engagement by the children's biological fathers; directiveness, in turn, predicted fewer gains in cognitive functioning only when father engagement was low and did not predict expressive language development. Finally, mothers' display of more positive affect, a stronger American orientation, and higher grandmother engagement uniquely predicted gains in W2 expressive language functioning. Implications for intervention are discussed.


Efficacy and safety of tumor-treating fields in recurrent glioblastoma: a systematic review and meta-analysis.
Tumor-treating fields (TTF) is a novel cancer treatment that uses alternating electric fields to interfere with tumor cell mitosis. It has been approved by the U.S. food and drug administration for the treatment of recurrent glioblastoma (rGBM). We designed this meta-analysis to evaluate the efficacy and safety of TTF in the treatment of rGBM. The study was based on the PRISMA guideline. Systematic retrieval was performed in PubMed, Cochrane Library, and Embase databases. The outcomes were overall survival (OS) hazard ratio (HR), 1-year survival rate, and cutaneous toxicity. These studies included a total of 1048 rGBM patients who received TTF treatment. The overall survival time between the TTF group and the control group was HR 0.75 ([95%CI 0.63 to 0.89]; P = 0.001). Pooled 1-year overall survival rate and incidence of cutaneous toxicity were 0.47 and 0.48, respectively. Data were insufficient to evaluate the effect of MGMT methylation status and tumor recurrence times on heterogeneity. TTF therapy is effective for recurrent glioblastoma. However, most relevant trials should assess rGBM patient baseline characteristics such as age, KPS, MGMT methylation status, and number of tumor recurrence,. In addition, the risk of rashes caused by long-term wearing of devices should also be considered.


Co-existence of cholecystokinin- or gastrin-like peptides with other peptides in the hypophysis and the hypothalamus.
The presence of cholecystokinin and gastrin has been reported in the hypothalamohypophyseal system. These peptides present a peculiar distribution in the hypothalamic nuclei, the median eminence, and the neurohypophysis. CCK and gastrin have close relationships with other peptides like oxytocin, CRF, vasopressin, and the enkephalins; these relationships vary in different projecting areas and in different types of hypothalamic neurons. The functional role of G-CCK in neurosecretion seems to be linked to the role of these closely associated peptides and certainly deserves further investigation.


Analysis of CRSsNP Proteome Using a Highly Multiplexed Approach in Nasal Mucus.
Chronic rhinosinusitis without nasal polyps (CRSsNP) represents a phenotype of CRS, whose immunological mechanisms are still unclear. So far there are neither suitable biomarkers to determine the course of the disease nor an individual therapy. The purpose of this study was to characterize the CRSsNP endotype by identifying and validating non-invasive proteomic biomarkers. A highly-multiplexed proteomic array consisting of antibodies against 2000 proteins was used to identify proteins that are differentially expressed in the nasal mucus of the CRSsNP and control groups (n = 7 per group). The proteins identified to be most differentially expressed were validated in matched nasal mucus samples using western blots and enzyme-linked immunosorbent assay (ELISA). Validation was also done in a second cohort using western blots (CRSsNP n = 25, control n = 23) and ELISA (n = 30 per group). Additionally, immunohistochemistry in CRSsNP and control tissue samples was performed to characterize the selected proteins further. Out of the 2000 proteins examined, 7 from the most differentially expressed proteins were chosen to be validated. The validation results showed that 4 proteins were significantly upregulated in CRSsNP mucus, including macrophage inflammatory protein-1beta (MIP-1β), resistin, high mobility group box 1 (HMGB1), and forkhead box protein 3 (FOXP3). Cartilage acidic protein 1 (CRTAC1) was not significantly upregulated. Two proteins were significantly downregulated including scavenger receptor class F member 2 (SCARF2) and P-selectin. All proteins selected are mainly associated with inflammation, cell proliferation/differentiation, apoptosis and cell-cell or cell-matrix interaction. Proteomic analysis of CRSsNP and control mucus has confirmed known and revealed novel disease-associated proteins that could potentially serve as a new biosignature for CRSsNP. Analysis of the associated pathways will specify endotypes of CRSsNP and will lead to an improved understanding of the pathophysiology of CRSsNP. Furthermore, our data contribute to the development of a reproducible, non-invasive, and quantitative "liquid biopsy" for rhinosinusitis.


Efficacy of body ventilation system for reducing strain in warm and hot climates.
This study determined whether a torso-vest forced ambient air body ventilation system (BVS) reduced physiological strain during exercise-heat stress. Seven heat-acclimated volunteers attempted nine, 2-h treadmill walks at 200 W m(-2) in three environments, -40 degrees C, 20% rh (HD), 35 degrees C, 75% rh (HW), and 30 degrees C, 50% rh, (WW) wearing the Army Combat Uniform, interceptor body armor (IBA) and Kevlar helmet. Three trials in each environment were BVS turned on (BVS(On)), BVS turned off (BVS(Off)), and no BVS (IBA). In HD, BVS(On) significantly lowered core temperature (T (re)), heart rate (HR), mean skin temperature (T (sk)), mean torso skin temperature (T (torso)), thermal sensation (TS), heat storage (S), and physiological strain index (PSI), versus BVS(Off) and IBA (P < 0.05). For HW (n = 6), analyses were possible only through 60 min. Exercise tolerance time (min) during HW was significantly longer for BVS(On) (116 +/- 10 min) versus BVS(Off) (95 +/- 22 min) and IBA (96 +/- 18 min) (P < 0.05). During HW, BVS(On) lowered HR at 60 min versus IBA, T (sk) from 30 to 60 min versus BVS(Off) and IBA, and PSI from 45 to 60 min versus BVS(Off) and at 60 min versus IBA (P < 0.05). BVS(On) changes in T (re) and HR were lower in HD and HW. During WW, BVS(On) significantly lowered HR, T (sk), and T (torso) versus BVS(Off) and IBA (P < 0.05) during late exercise. Sweating rates were significantly lower for BVS(On) versus BVS(Off) and IBA in both HD and WW (P < 0.05), but not HW. These results indicate that BVS(On) reduces physiological strain in all three environments by a similar amount; however, in hot-dry conditions the BVS(Off) increases physiological strain.


Heart failure outcomes in low-risk patients with atrial fibrillation: a case-control study of 680 523 Swedish individuals.
Knowledge of long-term outcomes in patients with atrial fibrillation (AF) remains limited. We sought to evaluate the risk of new-onset heart failure (HF) in patients with AF and a low cardiovascular risk profile. Data from the Swedish National Patient Register were used to identify all patients with a first-time diagnosis of AF without underlying cardiovascular disease at baseline between 1987 and 2018. Each patient was compared with two controls without AF from the National Total Population Register. In total, 227 811 patients and 452 712 controls were included. During a mean follow-up of 9.1 (standard deviation 7.0) years, the hazard ratio (HR) for new-onset HF was 3.55 [95% confidence interval (CI) 3.51-3.60] in patients compared with controls. Women with AF (18-34 years) had HR for HF onset 24.6 (95% CI 7.59-80.0) and men HR 9.86 (95% CI 6.81-14.27). The highest risk was within 1 year in patients 18-34 years, HR 103.9 (95% CI 46.3-233.1). The incidence rate within 1 year increased from 6.2 (95% CI 4.5-8.6) per 1000 person-years in young patients (18-34 years) to 142.8 (95% CI 139.4-146.3) per 1000 person-years among older patients (>80 years). Patients studied had a three-fold higher risk of developing HF compared with controls. Young patients, particularly women, carry up to 100-fold increased risk to develop HF within 1 year after AF. Further studies in patients with AF and low cardiovascular risk profile are needed to prevent serious complications such as HF.


Influence of Frequently Used Chemical Insecticides on Mycoflora Carried by Common Housefly, Musca domestica L.
The housefly, Musca domestica L. (Diptera: Muscidae), is a major medical and veterinary insect pest. It serves as a vector of many pathogenic microorganisms causing spoilage of food and diseases in human and animals. Use of chemical insecticides is adapted as a principal tool to manage housefly. Insecticides have many unforeseen ecological consequences including effects on non-target organisms. In the present study, we have assessed the effects of 10 different synthetic insecticides on the growth of mycoflora associated with the external body of the housefly by using poison food technique. Our results reveled that all synthetic insecticides enhanced the growth. Surprisingly, in most of the cases, mycelial growth of fungi was significantly increased at high concentration as compared with lower concentration. This study provides useful information about the dangerous effects of synthetic insecticides on environment by increasing the spread of various non-target pathogenic, mycotoxigenic, and food spoiling fungi, carried by houseflies.


Early Diagnosis: A Seeming Misfortune for Osteosarcoma of Mandible-Rare Case Report.
Osteosarcoma is a mesenchymal malignant tumour of long bones; it is the second most common malignancy of bone after multiple myeloma but it rarely affects jaw, accounting only for 4-8% of all osteosarcomas (Baumhoer et al. in Oral Oncol 50(2):147-153, 2014). The rare occurrence of tumour makes it challenging to diagnose either by radiographic or histopathologic examination. Here we presented a rare case of chondroblastic variant of osteosarcoma of body of mandible in a 54 year old female.


Inhibition of corneal neovascularization in rats by systemic administration of sorafenib.
To evaluate the effect of orally administered sorafenib on corneal neovascularization in rat models. In male Sprague-Dawley rats, a silver nitrate applicator was placed on the central cornea in both eyes to elicit angiogenesis. Rats were divided into 3 groups, the control group and the 2 sorafenib-treated groups (low dose, 30 mg · kg(-1) · day(-1); high dose, 60 mg · kg(-1) · day(-1)). The area of corneal neovascularization was measured by image analysis. Vascular endothelial growth factor receptor 2 (VEGFR2) messenger RNA expression was measured in rat corneas by reverse transcription-polymerase chain reaction, and the expression of phosphorylated extracellular signal-regulated kinase (ERK) was measured by Western blot analysis 1 week after cauterization. The area of corneal neovascularization was significantly reduced by 44% in the 30 mg · kg(-1) · day(-1) group and by 66% in the 60 mg · kg(-1) · day(-1) group, compared with the control group (P = 0.014 and P < 0.0001). Corneal VEGFR2 messenger RNA expression was higher in the control group than in the sorafenib-treated groups. The expression of phosphorylated ERK in rat corneas was suppressed in the sorafenib-treated groups but not in the control group. Oral administration of a multikinase inhibitor (sorafenib) significantly reduced the development of experimental corneal neovascularization in a dose-dependent manner. This inhibitory effect is probably related to the suppression of ERK phosphorylation by sorafenib.


Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.
Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.


Biosynthesis of cytochrome c oxidase by isolated rat liver mitochondria.
When isolated mitochondria which have been labeled with [3H]leucine are solubilized and treated with anti-serum specific for cytochrome c oxidase, labeled polypeptides which correspond to the three largest polypeptides of this enzyme are immunoprecipitated. This indicates that the three largest polypeptides of cytochrome c oxidase which have Mr of 66,000, 39,000, and 23,000 are synthesized by isolated mitochondria whereas the three smallest ones which have Mr of 14,000, 12,500, and 10,000 are not. The smallest polypeptides are probably synthesized on cytoplasmic ribosomes as has been demonstrated in other systems by in vivo studies. These results are the first demonstration that isolated mammalian mitochondria are capable of synthesizing some of their own polypeptide components. The antiserum used in this study was prepared to highly purified cytochrome c oxidase (12.4 nmol of heme a + a3/mg of protein) from rat liver mitochondria. This antiserum gives a single precipitin line when tested by the Ouchterlony double diffusion technique. Its specificity has been demonstrated by the fact that it: 1) only precipitates heme a + a3, not hemes b, c, or c1, when added to solubilized mitochondria, 2) inhibits cytochrome c oxidase activity at least 85%, and 3) precipitates only those polypeptides found in purified cytochrome c oxidase when added to solubilized mitochondria labeled in vivo.


Effect of Acer tegmentosum bark on atopic dermatitis-like skin lesions in NC/Nga mice.
Atopic dermatitis (AD) is a chronic and relapsing inflammatory condition characterized by pruritic and eczematous skin lesions that requires safe and effective pharmacological therapy. The bark of Acer tegmentosum Maxim trees has been used in Korean folk and traditional medicine to treat abscesses, surgical bleeding, liver diseases, and AD. To investigate the therapeutic effect of A. tegmentosum, on a mouse model of Dermatophagoides farinae (Df)-induced AD. Development of AD-like skin lesions was induced by repetitive skin contact with barrier-disrupted backs of NC/Nga mice with Df body ointment, and the effects of A. tegmentosum were evaluated on the basis of histopathological skin assessment results, ear swelling, and cytokine production in the dorsal skin. The component of A. tegmentosum, salidroside, inhibited the production of TSLP in KCMH-1 cells, which indicated that its production could be pharmacologically regulated. Topical application of A. tegmentosum for 1 week after Df body ointment challenge significantly reduced ear swelling and improved dorsal skin lesions. Suppression of dermatitis by combined therapy was accompanied by a decrease in the skin level of Th2 cytokines, such as interleukin (IL)-4, IL-5 and IL-13, plasma levels of thymus and activation-regulated chemokine, and IgE. Induction of thymic stromal lymphopoietin, which leads to a systemic Th2 response, was also reduced in in vivo and in vitro by A. tegmentosum and salidroside. Our findings suggest that A. tegmentosum treatment has a significant therapeutic effect on Df-induced AD-like skin lesions on NC/Nga mice through inhibition of thymic stromal lymphopoietin and IgE via a mechanism that may inhibit Th2-mediated immune responses. These results suggest that A. tegmentosum and salidroside may be useful tools for the treatment of AD.


Pharmacokinetic optimisation of oral antifungal therapy.
The range of oral antifungal therapy has been expanded recently by the introduction of itraconazole, and terbinafine. These agents have a broader spectrum of activity than griseofulvin and flucytosine, and induce less liver toxicity than ketoconazole. Treatment with these agents may be optimised by application of pharmacokinetic principles. Griseofulvin, ketoconazole and itraconazole should be administered with food to ensure adequate absorption. Maximal absorption of griseofulvin is achieved by administration of the drug as a solid solution in polyethylene glycol. Absorption of azole antifungal agents is impaired by high gastric pH, which is observed in some patients with acquired immunodeficiency syndrome. It is also impaired by frequent vomiting, which commonly occurs in patients with neutropenia. Furthermore, antacids, H2-antagonists and sucralfate interfere with absorption of ketoconazole. The newer oral antifungals are more slowly eliminated and associated with less pronounced drug interactions than ketoconazole. As with ketoconazole, itraconazole and fluconazole influence cyclosporin metabolism. These effects are of clinical relevance and necessitate cyclosporin dosage reduction. However, the cyclosporin dosage reduction required during coadministration of itraconazole and fluconazole (50 to 55%) is less than that required when ketoconazole is concomitantly administered (85%). Monitoring of cyclosporin concentrations during coadministration with these agents is necessary to avoid nephrotoxicity. Drug monitoring is also advisable when phenytoin, carbamazepine or rifampicin (rifampin) are administered concomitantly with azoles, due to a mutual influence on drug metabolism. The antifungal activity of itraconazole is not related exclusively to free drug concentrations. Therefore, the low protein binding of fluconazole does not place this agent at an advantage over itraconazole in the treatment of fungal meningitis. However, terbinafine may be superior to itraconazole for the treatment of tinea unguium, another recalcitrant fungal disease, because terbinafine more rapidly penetrates the nail plate. During repeated use, itraconazole concentrations increase slowly in the nail plate. Steady-state concentrations are reached in the stratum corneum only after several weeks' administration. Following cessation of treatment, terbinafine, itraconazole and ketoconazole concentrations in keratinised tissues decline slowly. This allows a short duration of drug treatment. Some clinical trials suggest that low concentrations of flucytosine, griseofulvin and itraconazole are associated with treatment failure. Flucytosine-induced myelotoxicity also appears to be concentration dependent. This adverse reaction may be caused by fluorouracil (which is produced by metabolism of flucytosine by enterobacillary flora in the gut) rather than by the parent compound.


Chinese herbal medicine for Henoch-Schönlein purpura in children without renal damage: a systematic review of randomized controlled trials.
Henoch-Schönlein Purpura (HSP) is the most common necrotizing vasculitis affecting children. Traditional Chinese herbal medicine (CHM) was widely used. We aim to explore the evidence of effectiveness and safety of CHM for HSP in children without renal damage. Randomized controlled trials (RCTs) comparing CHM with conventional medications were searched from five databases. Eligible data were pooled using random-effects model using RevMan 5.2 Subgroup analysis for different co-interventions and sensitivity analysis for reducing heterogeneity were implemented. GRADE approach was adopted. We included 15 trials with 1112HSP children (age 1-16 years old), disease duration one day to three months. The overall methodological quality of included trials is relatively low. Adjunctive oral CHM treatments reduced renal damage (6 trials, RR 0.47, 95%CI 0.31-0.72, I(2)=0%), and subsiding time (days) of purpura (5 trials, mean difference (MD) -3.60, 95%CI -4.21 to -2.99, I(2)=23%), joint pain (5 trials, MD -1.04, 95%CI -1.33 to -0.74, I(2)=1%) and abdomen pain (5 trials, MD -1.69, 95%CI -2.51 to -0.86, I(2)=74%). Subgroup and sensitivity analysis did not change the direction of results. No severe adverse events reported. Orally taken adjunctive CHM treatments are effective for children suffering HSP in terms of reducing renal damage and subsiding time of purpura, and could possibly reduce subsiding pain of joint and abdomen. No reliable conclusion regarding safety is possible based on the safety data retrieved. Further rigorous trials are warranted.


Measurement of gait speed in older adults to identify complications associated with frailty: A systematic review.
Several frailty screening tests in older cancer patients were developed but their statistical performance is low. We aimed to assess whether measurement of usual gait speed (GS) alone could be used as a frailty screening test in older cancer patients. This systematic review was conducted on "pub med" between 1984 and 2014 and included reviews and original studies. Eligibility criteria were: GS over a short distance, alone or included in composite walking tests (Timed Get Up and Go test: TGUG, Short Physical Performance Battery: SPPB) in older people (aged 65 and over) living in a community setting and predictive value of GS on medical complications associated with frailty. 46 articles were finally selected. GS alone is consensual and recommended for screening sarcopenia in elderly. A slow GS is predictive of early death, disability, falls and hospitalization/institutionalization in older people living in a community setting. GS alone is comparable to composite walking tests that do not provide additional information on the medical complications associated with frailty. Despite few studies in geriatric oncology, GS seems to predict overall survival and disability. We suggest GS over 4m (at a threshold of 1m/s) as a new frailty screening test in older cancer patients (65 and over) to guide the implementation of a comprehensive geriatric assessment during the initial management phase or during follow-up. Prospective cohort studies are needed to validate this algorithm and compare it with other screening tool.