Effects of Gamification on the Benefits of Student Response Systems in Learning of Human Anatomy: Three Experimental Studies.
This paper presents three experiments to assess the impact of gamifying an audience response system on the perceptions and educational performance of students. An audience response system called SIDRA (Immediate Audience Response System in Spanish) and two audience response systems with gamification features, R-G-SIDRA (gamified SIDRA with ranking) and RB-G-SIDRA (gamified SIDRA with ranking and badges), were used in a General and Descriptive Human Anatomy course. Students participated in an empirical study. In the academic year 2019-2020, a total of 90 students used RB-G-SIDRA, 90 students employed R-G-SIDRA in the academic year 2018-2019, and 92 students used SIDRA in the academic year 2017-2018. Statistically significant differences were found between final exam grades obtained by using RB-G-SIDRA and SIDRA, U = 39.211 adjusted p = 0.001 and RB-G-SIDRA and R-G-SIDRA U = 31.157 adjusted p = 0.015, thus finding strong evidence with respect to the benefit of the badges used in RB-G-SIDRA. Moreover, in the students' SIDRA systems scores, statistically significant differences were found between RB-G-SIDRA and SIDRA, U = -90.521 adjusted p < 0.001, and between R-G-SIDRA and SIDRA, U = -87.998 adjusted p < 0.001. Significant correlations between individual and team scores were also found in all of the tests in RB-G-SIDRA and G-SIDRA. The students expressed satisfaction, engagement, and motivation with SIDRA, R-G-SIDRA, and RB-G-SIDRA, thus obtaining a final average assessment of 4.28, 4.61, and 4.47 out of 5, respectively. Students perform better academically with gamified versus non-gamified audience response systems. Findings can be used to build a gamified adaptive learning system.


Identification of novel interaction between annexin A2 and keratin 17: evidence for reciprocal regulation.
Keratins are cytoplasmic intermediate filament proteins providing crucial structural support in epithelial cells. Keratin expression has diagnostic and even prognostic value in disease settings, and recent studies have uncovered modulatory roles for select keratin proteins in signaling pathways regulating cell growth and cell death. Elevated keratin expression in select cancers is correlated with higher expression of EGF receptor (EGFR), whose overexpression and/or mutation give rise to cancer. To explore the role of keratins in oncogenic signaling pathways, we examined the regulation of epithelial growth-associated keratin 17 (K17) in response to EGFR activation. K17 is specifically up-regulated in detergent-soluble fraction upon EGFR activation, and immunofluorescence analysis revealed alterations in K17-containing filaments. Interestingly, we identified AnxA2 as a novel interacting partner of K17, and this interaction is antagonized by EGFR activation. K17 and AnxA2 proteins show reciprocal regulation. Modulating expression of AnxA2 altered K17 stability, and AnxA2 overexpression delays EGFR-mediated change in K17 detergent solubility. Down-regulation of K17 expression, in turn, results in decreased AnxA2 phosphorylation at Tyr-23. These findings uncover a novel interaction involving K17 and AnxA2 and identify AnxA2 as a potential regulator of keratin filaments.


Mapping and validation of quantitative trait loci associated with wheat yellow mosaic bymovirus resistance in bread wheat.
Wheat yellow mosaic (WYM) caused by wheat yellow mosaic bymovirus (WYMV) has been growing as one of the most serious diseases affecting wheat production in China. In this study, the association of quantitative trait loci (QTLs) governing WYMV resistance with molecular markers was established using 164 recombinant inbred lines (RILs) derived from 'Xifeng Wheat' (highly resistant) × 'Zhen 9523' (highly susceptible). Phenotypic data of WYMV resistance of the RILs were collected from 4-year, two-location replicated field trials. A molecular marker-based linkage map, which was comprised of 273 non-redundant loci and represented all the 21 wheat chromosomes, was constructed with the JoinMap 4.0 software. Using the Windows QTL Cartographer V2.5 software, three QTLs associated with WYMV resistance, QYm.njau-3B.1, QYm.njau-5A.1 and QYm.njau-7B.1, were detected on chromosomes 3BS, 5AL, and 7BS, respectively. The favorable allele effects were all contributed by 'Xifeng Wheat'. Among the three QTLs, QYm.njau-3B.1 and QYm.njau-5A.1 were detected in all the four trials and the overall mean, and could explain 3.3-10.2% and 25.9-53.7% of the phenotypic variation, respectively, while QYm.njau-7B.1 was detected in one trial and the overall mean and explained 4.9 and 3.3% of the phenotypic variation, respectively. A large portion of the variability for WYMV response was explained by a major QTL, QYm.njau-5A.1. The relationship of the molecular markers linked with QYm.njau-5A.1 and the WYMV resistance was further validated using a secondary F(2) population. The results showed that three markers, i.e., Xwmc415.1, CINAU152, and CINAU153, were closely linked to QYm.njau-5A.1 with the genetic distances of 0.0, 0.0, and 0.1 cM, respectively, indicating they should be useful in marker-assisted selection (MAS) wheat breeding for WYMV resistance. A panel of germplasm collection consisting of 46 wheat varieties with known WYMV response phenotypes was further used to validate the presence and effects of QYm.njau-5A.1 and the above three markers. It was found that QYm.njau-5A.1 was present in 12 of the 34 WYMV-resistant varieties.


[SLAP lesions as a cause of posterior instability].
SLAP lesions disrupt the perilabral architecture, but so far there have been no reports about posterior instability due to SLAP lesions. In a prospective study of 30 patients with recurrent posterior instability, we found SLAP lesions as a reason for instability in three cases. The purpose of this study is to point out that SLAP lesions can be a cause of posterior instability. Thirty patients with clinical posterior shoulder instability underwent diagnostic arthroscopy before operative stabilization procedures, three of whom (three males, aged 29-51 years) showed a SLAP lesion (once case each of types II, III, and IV) as a cause of posterior instability. All three patients had a history of a fall on the outstretched arm. All patients underwent arthroscopic refixation of the labrum. After arthroscopic refixation of the SLAP lesions, two patients were completely stable (SLAP II and III), whereas one patient (SLAP IV) reported microinstability during overhead activity but complete stability during activity of daily living. The same patient complained about moderate pain in extreme external-flexion rotation with slightly reduced range of motion in external-flexion position. All other patients were free of pain and showed free range of motion. Our results demonstrate that SLAP lesions can be a cause for posterior shoulder instability. In our cases, posterior shoulder instability caused by SLAP lesions was successfully treated by arthroscopic refixation of the torn biceps anchor. When treating posterior shoulder instability, SLAP lesions should be taken into account.


Body Mass Index and Repeat Revascularization After Percutaneous Coronary Intervention: A Meta-analysis.
The effect of obesity on restenosis in patients who undergo percutaneous coronary intervention (PCI) has not been fully understood. We undertook a meta-analysis for the effects of body mass index (BMI) on repeat revascularization in these patients. A systematic search was conducted for published studies in OVID/MEDLINE, EMBASE, and the Cochrane library databases from 1980 to October, 2014. We identified studies that provided estimates for repeat revascularization on the basis of BMI in patients who underwent PCI. Summary estimates of risk ratios (RRs) were obtained for 5 prespecified BMI groups: underweight, normal weight, overweight, obese, and severely obese. A total of 13 studies with 49,002 patients were included in the final analyses. In contrast to a J-shaped association for mortality, a linear association was observed across BMI categories for repeat revascularization. Using normal weight as the reference, underweight was associated with a similar risk of repeat revascularization (RR, 0.93; 95% confidence interval [CI], 0.67-1.31), overweight, obesity, and severe obesity were all associated with incrementally greater risk of repeat revascularization (overweight: RR, 1.08; 95% CI, 1.02-1.14; obesity: RR, 1.10; 95% CI, 1.03-1.18; severe obesity: RR, 1.24; 95% CI, 1.04-1.48). The effect of overweight and obesity vs normal weight was consistent across stent types (drug-eluting stent and bare-metal stent) and definitions of repeat revascularization (target lesion revascularization, target vessel revascularization, and all revascularization). Our data revealed a linear relationship between BMI categories and repeat revascularization for patients who underwent PCI. The risk was lowest among underweight or normal weight patients, and highest among severely obese patients.


Structure, internal motions and association-dissociation kinetics of the i-motif dimer of d(5mCCTCACTCC).
At slightly acidic pH, the association of two d(5mCCTCACTCC) strands results in the formation of an i-motif dimer. Using NMR methods, we investigated the structure of [d(5mCCTCACTCC)]2, the internal motion of the base pairs stacked in the i-motif core, the dimer formation and dissociation kinetics versus pH. The excellent resolution of the 1H and 31P spectra provided the determination of dihedral angles, which together with a large set of distance restraints, improve substantially the definition of the sugar-phosphate backbone by comparison with previous NMR studies of i-motif structures. [d(5mCCTCACTCC)]2 is built by intercalation of two symmetrical hairpins held together by six symmetrical C*C+ pairs and by pair T7*T7. The hairpin loops that are formed by a single residue, A5, cross the narrow grooves on the same side of the i-motif core. The base pair intercalation order is C9*C9+/5mC1*5mC1+/C8*C8+/C2*C2+/T7.T7/C6*C6+/C4*C4+. The T3 bases are flipped out in the wide grooves. The core of the structure includes four long-lived pairs whose lifetimes at 15 degrees C range from 100 s (C8*C8+) to 0.18 s (T7*T7). The formation rate and the lifetime of [d(5mCCTCACTCC)]2 were measured between pH 6.8 and 4.8. The dimer formation rate is three to four magnitude orders slower than that of a B-DNA duplex. It depends on pH, as it must occur for a bimolecular process involving non cooperative association of neutral and protonated residues. In the range of pH investigated, the dimer lifetime, 500 s at 0 degrees C, pH 6.8, varies approximately as 10(-pH).


High performance liquid chromatographic determination of platinum in blood and urine samples of cancer patients after administration of cisplatin drug using solvent extraction and N,N'-bis(salicylidene)-1,2-propanediamine as complexation reagent.
A high performance liquid chromatographic (HPLC) procedure has been developed for the determination of cisplatin, based on the pre-column derivation of platinum(II) with reagent N,N'-bis(salicylidene)-1,2-propanediamine (H2SA2pn). The neutral platinum complex was extracted, concentrated in an organic solvent and then injected (5 microl) on a reverse phase HPLC column, Varian Micro-Pak SP C-18, 5 microm (150 mm x 4.0 mm i.d.). The complex was eluted isocratically using a ternary mixture of methanol/acetonitrile/water (40/30/30, v/v/v) at a flow rate of 1.0 ml/min and was determined by a UV detector set at 254 nm after elution. A detection limit was found to be 4.0 ng per injection. The amounts of platinum in blood serum and urine of cancer patients after administration of cisplatin were observed in a range of 221-298 ng/ml and 43-97 ng/ml with relative standard deviation (R.S.D.) of 3.6-4.6% and 3.5-4.8%, respectively. Preliminary metabolism profiles of Pt concentrations in blood and urine from the patients were established.


Stronger impacts of long-term relative to short-term exposure to carbon nanomaterials on soil bacterial communities.
Environmental impacts of carbon nanomaterials (CNMs) have been attracting increasing concerns in recent years. Knowledge on how short-term exposure to CNMs influences soil microbial communities is available. However, little is known about the possible difference in effects of long-term versus short-term exposure of CNMs on soil microbial communities. In this study, we systematically compared effects of fullerene (C60), single-walled carbon nanotubes (SW), and graphene (GR) on soil bacterial communities over short (30 d) and long (360 d) term exposure durations. Our findings revealed that short-term exposure to all CNMs significantly increased the alpha diversity of soil bacterial communities. SW and GR exposure for 360 d relative to that for 30 d more significantly decreased their alpha diversity. Compared to short-term exposure, a long term exposure to CNMs more strongly altered the beta diversity of soil bacterial communities. LEfSe analysis showed that, GR relative to C60 and SW exposure more strongly altered soil bacterial community composition especially for long-term duration at various taxonomic levels; more taxa were also identified by LEfSe analysis as biomarkers upon long-term GR exposure. More OTUs were affected by long-term GR exposure. These differences resulted from both distinct physicochemical properties of various CNMs and their exposure durations.


Lysosomal enzyme changes in young and aged control and entorhinal-lesioned rats.
In the hippocampus of young and aged rats, lysosomal acid phosphatase and beta-glucuronidase were localized by enzyme histochemistry to the pyramidal and granule cells and to the mossy fiber zone (acid phosphatase only). Following a unilateral entorhinal lesion, enhancement in enzyme staining was observed within GFA (glial fibrillary acidic) protein-positive astrocytes and in cells resembling microglia and oligodendroglia in the ipsilateral dentate outer molecular layer and the hippocampal stratum lacunosum-moleculare. In young animals, these changes, first detected on day 2 post-lesion, were maximum on days 4 and 10 post-lesion and declined subsequently. The aged animals exhibited a delayed time-course of enzyme changes with minimal increases on days 2 and 4 post-lesion and greater increases on days 10 and 30 and gradual diminution thereafter. The delayed lysosomal response in the aged animal paralleled a reduction in the induction of glial cells following the lesion. Our findings suggest that the previously reported impairment in the clearing of degeneration debris in the aged animal is mediated by reduced glial induction and delayed glial lysosomal activation.


Cytogenetic findings in a supratentorial ependymoma.
Cytogenetic studies on a supratentorial ependymoma from a 3-year-old girl showed a t(10;11;15)(p12.2;q13.1;p12) and loss of one X chromosome. To our knowledge, this is the first ependymoma reported with relatively simple karyotypic changes.


High-rate nitrogen removal and its behavior of granular sequence batch reactor under step-feed operational strategy.
Alternating anoxic/oxic (A/O) combined with the step-feed granular sequence batch reactor (step-feed SBR) was operated in laboratory scale to investigate nitrogen removal. The results showed that when the total inorganic nitrogen (TIN) and chemical oxygen demand (COD) levels were 55 and 320 mg/L in the influent, the TIN removal efficiencies were 89.7-92.4% in the step-feed mode and 48.1-59.5% in the conventional alternating A/O single-feed mode within a 360 min cycle. The pH and dissolved oxygen (DO) were used to optimize the process of denitrification and nitrification in the step-feed mode. The optimized operational condition was achieved by shortening the cycle time to 207 min, resulting in a nitrogen removal rate of 0.27 kg N/m3 d, which was much higher than those achieved using activated sludge systems. The dominant community in the aerobic granules was coccus-like bacteria, and filamentous bacteria were hardly found. Granules were well maintained throughout the 90 days of continuous step-feed operation.


Experimental porphyria induced by 3-(2,4,6-trimethylphenyl)-thioethyl)-4 methylsydnone.
Administration of 3-[2-(2,4,6-trimethylphenyl)-thioethyl]-4-methylsydnone (TTMS) induces hepatic porphyria in rats, mice and dogs. The protoporphyrin pigment in livers of rats and mice is found mainly in bile ducts and leads to bile duct proliferation and portal inflammation. Dog livers contain protoporphyrin predominantly in bile canaliculi. The birefringence of the pigment appears to be associated with bilamellar components within the pigment. The markedly depressed catalase activity in livers of rats does not increase after clofibrate administration. The catalase activity of mouse liver is depressed slightly and responds to clofibrate treatment.


A conserved Neurite Outgrowth and Guidance motif with biomimetic potential in neuronal Cell Adhesion Molecules.
The discovery of conserved protein motifs can, in turn, unveil important regulatory signals, and when properly designed, synthetic peptides derived from such motifs can be used as biomimetics for biotechnological and therapeutic purposes. We report here that specific Ig-like repeats from the extracellular domains of neuronal Cell Adhesion Molecules share a highly conserved Neurite Outgrowth and Guidance (NOG) motif, which mediates homo- and heterophilic interactions crucial in neural development and repair. Synthetic peptides derived from the NOG motif of such proteins can boost neuritogenesis, and this potential is also retained by peptides with recombinant sequences, when fitting the NOG sequence pattern. The NOG motif discovery not only provides one more tile to the complex puzzle of neuritogenesis, but also opens the route to new neural regeneration strategies via a tunable biomimetic toolbox.


Radiation induced brain injury: assessment of white matter tracts in a pre-clinical animal model using diffusion tensor MR imaging.
We aim to study radiation induced white matter injury in a pre-clinical model using Diffusion tensor MR imaging (DTI). Nineteen 12-week old Sprague-Dawley rats were irradiated to the right hemisphere using a linear accelerator. The dose distribution map was coregistered to the DTI map to generate the actual radiation dose to each white matter tract. Rats underwent longitudinal DTI scans at five time points from 4 to 48 weeks post-radiation with histological evaluations. Fractional anisotropy (FA) of the external capsule, fornix, cerebral peduncle, anterior commissure, optic tract and optic nerve was evaluated. Radiation dose was highest at the ipsilateral external capsule and fornix (29.4 ± 1.3 and 29.8 ± 1.1 Gy, respectively). Optic nerve received 50 % dose to the external capsule and other white matter tracts received 80 % dose. Significantly lower FA was firstly found in the ipsilateral external capsule at 4 weeks post-radiation and in the ipsilateral fornix at 40 weeks post-radiation compared to the contralateral side. Significantly lower FA was found in contralateral optic nerve compared to ipsilateral optic nerve at 48 weeks post-radiation despite ipsilateral optic nerves receiving higher radiation dose than contralateral optic nerve (p = 0.021). No differences were found in other white matter regions until 48 weeks. Histology indicated demyelination, axonal degeneration and coagulative necrosis in all injured white matter. DTI can serve as a promising tool for assessment of radiation induced white matter injury and regional radiosensitivity of white matter tracts.


Clinical outcomes of fractionated stereotactic radiosurgery in treating perioptic meningiomas and schwannomas: A single-institutional experience.
Application of radiosurgery to the newly diagnosed or post-operative residual perioptic lesions has been proved to improve tumor control. However, risk of vision injury induced by radiosurgery may increase substantially if the radiation dose is too high or tumor is close to the optic apparatus. The purpose of this study was to evaluate the safety and the effectiveness of fractionated stereotactic radiosurgery (FSRS) for perioptic tumors. We retrospectively analyzed 60 consecutive patients with 53 meningiomas and 7 schwannomas treated with FSRS between October 2007 and February 2020. We administered a marginal dose of 6-7 Gy (mean 6.8 Gy) per fraction and delivered 3 fractions in 3 consecutive days. The median tumor volume was 6.31 cm3 (range 0.3-58.23 cm3). The mean minimum lesion-optic distance (MLOD) is 0.85 mm (range 0-3 mm). After mean follow-up period of 69.6 months (range 6.82-156.32 months; median 58.9 months), the tumor control rates at 1, 3, 5, 8 and 13 years were 98.3%, 93.4%, 90.60%, 88.4% and 88.4%, respectively. Four out of the 60 tumors (6.7%) experienced a transient volume increase after FSRS. None of the patients developed visual impairment related to radiation induced optic neuropathy (RION) after FSRS. In conclusion, FSRS offers an alternative treatment option in treating perioptic meningiomas and schwannomas with acceptable tumor control rates and good visual preservation in the present study.


Treatment of stage 4s neuroblastoma--report of 10 years' experience of the French Society of Paediatric Oncology (SFOP).
Stage 4s neuroblastoma (NB) is usually associated with a favourable outcome, despite a large tumour burden, as spontaneous regression frequently occurs. However, in some infants rapid disease progression can be observed with severe functional impairment. Thus, for all patients the potential risks of cytotoxic therapy must be weighed against the benefits of early medical intervention. We have retrospectively reviewed the charts of 94 infants treated for stage 4s NB in centres of the French Society of Paediatric Oncology between 1990 and 2000, and describe the different first-line treatment approaches that were, successively, liver irradiation, chemotherapy using a cyclophosphamide-vincristine regimen, and chemotherapy using a carboplatin-etoposide regimen. The overall survival was 88% (+/-7.6%), with a mean follow-up of 64 months. Elevated serum neuron-specific enolase (>100 nmol ml(-1)), ferritin (>280 ng ml(-1)) and urinary dopamine levels (>2500 nmol mmol(-1) creatinine) were associated with a poor outcome, as were the genetic markers N-myc amplification and chromosome 1p deletion (P<0.0005 and P=0.0016, respectively). Patients who required medical intervention at diagnosis fared worse than those who received supportive treatment only (P<0.005). The clinical evolution observed with the different successive treatment approaches suggests that if infants do require therapy, the prompt initiation of a more intensive regimen such as carboplatin-etoposide may be more beneficial.


[Mastoid bone graft in implantology. A case report].
In implantology, autogenous bone remains currently a useful-material to rebuild horizontal and vertical osseous defects. Usually, it is the needed osseous volume that indicates the grafting procedure, intraoral one for small and middle volume and extraoral one for severely atrophied jaws. The originality of this case report is to show an alternative to usual grafting procedure borrowed from ENT surgeons: osseous mastoid graft. A 63-year-old patient with maxillary sinus pathology underwent during same surgical time maxillary sinus curetting and osseous grafting to finalize the dental treatment. Mastoid cortical bone is a source of bone usable in oral implantology. Its use has been proved to be reliable in oto-surgery. Mastoid bone harvesting implies the presence of ENT surgeon; it is nevertheless interesting to know this site from a biological point of view and because of its functional and economical aspects.


Isoelectric focusing studies of bacteriorhodopsin.
Purified bacteriorhodopsin (BR) samples show a minimum of four isoelectric forms in immobilized pH gradient isoelectric focusing gels. The bands occur as doublets with isoelectric points (pI) centered at 5.20 (principal species) and 5.60. In typical preparations additional bands may be observed at 4.90, 5.07 and 5.50. Purple membrane (PM) was proteolyzed with papain to calibrate the pI shift produced by changing the number of charges on the protein. Asp-242 is removed during the first cleavage between residues 239 and 240 resulting in the loss of a single negative charge and a shift of the principal doublet by +0.35 pH units to pI 5.55. The second papain cleavage occurs between residues 231 and 232 which removes Glu-232, -234 and -237 and shifts the pI by +0.60 pH units to pI 6.10. The +0.60 pH shift upon the second papain cleavage is consistent with the loss of two negative charges and is supported by prior evidence that at least one of the three glutamate residues lost during the second proteolysis step is protonated and neutral in the intact protein. The native and proteolyzed products of BR retain the characteristic 550 nm absorption maxima for solubilized BR. A model for the structural origin of the pI heterogeneity of BR species in proteolyzed PM is presented.


Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease.
To evaluate the relation between age, prostate-specific antigen (PSA) level, and the probability of detecting curable prostate cancer. A consecutive surgical series of radical prostatectomies was performed in 492 men with nonpalpable (Stage T1c) disease, who formed the study cohort (mean age 58 years). The cohort was systematically classified into three age groups ([1] 40 to 50 years [n = 69]; [2] 51 to 60 years [n = 227]; [3] 61 to 73 years [n = 196]) and five pretreatment PSA groups ([1] 2.5 to 4.0 ng/mL [n = 36]; [2] 4.1 to 6.0 ng/mL [n = 100]; [3] 6.1 to 8.0 ng/mL [n = 122]; [4] 8.1 to 10.0 ng/mL [n = 76]; [5] greater than 10.0 ng/mL [n = 135]). The percent probability of curable cancer was determined by logistic regression analysis. Curable cancer was defined as organ-confined tumor or a tumor with capsular penetration of low grade (Gleason score less than 7), with negative margins and no involvement of seminal vesicles or lymph nodes. A comparison within age groups and within PSA groups revealed that the probability of curable cancer was more closely associated with age than PSA level. Although the probability of curable cancer was closely related to PSA level across a wide range of PSA values (0.4 to 52 ng/mL), there was only minimal difference (2% to 4%) in the probability of curable cancer within the range of PSA values from 2.5 to 6.0 ng/mL for all ages. Age is a strong predictor of the probability of curable cancer. Thus, early detection efforts in younger men are more likely to lead to a decrease in prostate cancer mortality. These data suggest that the use of PSA thresholds below 4.0 ng/mL as an indicator of prostate cancer is unlikely to improve the probability of detecting curable cancer.


Cellular hypersensitivity to gangliosides and myelin basic protein in multiple sclerosis.
Peripheral blood lymphocytes from patients with multiple sclerosis (MS), other neurological diseases and healthy controls were investigated for the presence of cell-mediated hypersensitivity to brain gangliosides and myelin basic protein using an active E-rosette assay. Sensitivity to myelin basic protein and gangliosides was found in MS patients in acute relapse and with progressive disease, whereas no sensitivity was found in MS patients in remission. Patients with other neurological diseases showed no response to gangliosides, but sensitization to myelin basic protein was found in a patient with leucoencephalopathy and in 4 of 6 stroke patients. Healthy controls did not respond to either antigen. In MS patients a positive correlation was seen between lymphocyte responses to myelin basic protein and to gangliosides. The data suggest that in comparison to gangliosides, myelin basic protein is a weaker stimulator of active rosette-forming cells. Moreover, cellular hypersensitivity to myelin basic protein is not MS-specific and may be present as a consequence of brain damage. However, cellular hypersensitivity to gangliosides appears to be more specific to MS and may be important in the pathogenesis of the disease.


Experiencing recovery: findings from a qualitative study into mental illness, self and place.
Community-managed mental health organisations are important vehicles for "place-based" recovery-oriented services in regional areas. However, the community-based sector is not well described in data collections and more research is needed to identify the specific contributions that such services can make to recovery. This situation has become more acute in Australia with the restructure of mental health services under the new National Disabilities Insurance Scheme (NDIS). The project aimed to understand more about what is effective in the service system; what impacts living in a regional location might have on a person's lived and service system experience and what people find helpful and supportive in their recovery journeys. A one-year qualitative study utilising photovoice and written narrative with group workshops, individual interviews and a capstone exhibition experience. Research findings were consistent with recovery principles but also revealed elements not commonly emphasised in the recovery literature. Four main themes were distilled: belonging and being connected; survival, resilience and hope; living a contributing life and compassionate service provision. The effectiveness of recovery-oriented service delivery needs to be secured under the individualised funding structure of the new NDIS and expanded for the specific needs of people living in regional communities.


Th2-type innate immune responses mediated by natural helper cells.
Natural helper (NH) cells are a newly identified innate lymphocyte population that responds to a combination of interleukin (IL)-2 and either IL-25 or IL-33 to produce large amounts of T helper cell type 2 (Th2) cytokines. NH cells have been identified in fat-associated lymphoid clusters (FALCs), produce Th2 cytokines constitutively without any stimulation, and support the self-renewal of B1 cells and IgA production by B cells. Large amounts of IL-5 and IL-13 produced upon helminth infection or in response to IL-33 can induce eosinophilia and goblet cell hyperplasia in the lung and intestine; these cytokines, which activate NH cells, play important roles in antihelminth immunity and allergic diseases such as asthma.


Regorafenib: a guide to its use in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib and sunitinib.
Regorafenib (Stivarga(®)), a new inhibitor of multiple kinases, is indicated as third-line treatment in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib and sunitinib in the USA. In a phase III trial in patients with progressive GIST after failure of standard therapies, regorafenib plus best supportive care increased median progression-free survival by >5-fold relative to best supportive care alone. Although regorafenib is associated with several specific drug-related adverse events, it is reasonably well tolerated if recommendations for dose modifications (i.e. treatment interruption, dose reductions and/or permanent treatment discontinuation based on tolerability) and other precautions are followed.


Possible Interaction of Opioidergic and Nitrergic Pathways in the Anticonvulsant Effect of Ivermectin on Pentylenetetrazole-Induced Clonic Seizures in Mice.
Ivermectin (IVM) is an antiparasitic drug that primarily works by the activation of GABAA receptors. The potential pharmacological pathways behind the anti-convulsant effect of IVM haven't yet been identified. In this study, intravenous injection of pentylenetetrazole (PTZ)-induced clonic seizure in mice was investigated in order to assess the possible influence of IVM on clonic seizure threshold (CST). We also look at the function of the Opioidergic and nitrergic pathways in IVM anticonvulsant action on clonic seizure threshold. IVM (0.5, 1, 5, and 10 mg/kg, i.p.) raised the PTZ-induced CST, according to our findings. Furthermore, the ineffective dose of nitric oxide synthase inhibitors (L-NAME 10 mg/kg, i.p.), and (7-NI 30 mg/kg, i.p.) or opioidergic system agonist (morphine 0.25 mg/kg, i.p.) were able to amplify the anticonvulsive action of IVM (0.2 mg/kg, i.p.). Moreover, the anticonvulsant effect of IVM was reversed by an opioid receptor antagonist (naltrexone 1 mg/kg, i.p.). Furthermore, the combination of the ineffective dose of morphine as an opioid receptor agonist with either L-NAME (2 mg/kg, i.p.) or 7-NI (10 mg/kg, i.p.) and with an ineffective dose of IVM (0.2 mg/kg, i.p.) had a significant anticonvulsant effect. Taken together, IVM has anticonvulsant activity against PTZ-induced clonic seizures in mice, which may be mediated at least in part through the interaction of the opioidergic system and the nitric oxide pathway.


No thoracic radiation myelitis after spinal cord dose > or = 50.4 Gy using 1.2. Gy b.i.d. fractionation in patients with Stage III non-small cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy.
We investigated a risk of developing radiation myelitis during four prospective studies using hyperfractionated radiation therapy (HFX RT) with and without concurrent chemotherapy (CHT) during which a portion of thoracic spinal cord received a dose > or = 50.4 Gy given via 1.2 Gy b.i.d. fractionation. Of 536 patients with Stage III non-small cell lung cancer (NSCLC) which were treated on three prospective randomised Phase III studies and one Phase II study, 336 patients received irradiation dose > or = 50.4 Gy to a portion of their spinal cord and survived >1 year after the beginning of therapy. None of these 336 patients developed thoracic radiation myelitis. Therefore, the influence of potentially contributing factors on the occurrence of radiation myelitis, such as cord length, interfraction interval, or administration of concurrent CHT was not possible to investigate. These results give new insight about the influence of total dose/dose per fraction/interfraction interval with or without concurrent CHT on the thoracic spinal cord toxicity.


Treatment of proximal humeral fractures using anatomical locking plate: correlation of functional and radiographic results.
To correlate the functional outcomes and radiographic indices of proximal humerus fractures treated using an anatomical locking plate for the proximal humerus. Thirty-nine patients with fractures of the proximal humerus who had been treated using an anatomical locking plate were assessed after a mean follow-up of 27 months. These patients were assessed using the University of California Los Angeles (UCLA) score and their range of motion was evaluated using the method of the American Academy of Orthopedic Surgeons on the operated shoulder and comparative radiographs on both shoulders. The correlation between radiographic measurements and functional outcomes was established. We found that 64% of the results were good or excellent, according to the UCLA score, with the following means: elevation of 124°; lateral rotation of 44°; and medial rotation of thumb to T9. The type of fracture according to Neer's classification and the patient's age had significant correlations with the range of motion, such that the greater the number of parts in the fracture and the greater the patient's age were, the worse the results also were. Elevation and UCLA score were found to present associations with the anatomical neck-shaft angle in anteroposterior view; fractures fixed with varus deviations greater than 15° showed the worst results (p < 0.001). The variation in the neck-shaft angle measurements in anteroposterior view showed a significant correlation with the range of motion; varus deviations greater than 15° were not well tolerated. This parameter may be one of the predictors of functional results from proximal humerus fractures treated using a locking plate.


New anti-influenza A viral norsesquiterpenoids isolated from feces-residing Streptomyces sp.
Three novel norsesquiterpenoids, (2R,4S,8aR)-8,8a,1,2,3,4-hexahydro-2-hydroxy-4,8a-dimethyl-2(2H)-naphthalenone (1), (1S,3S,4S,4aS,8aR)-4,8a-dimethyloctahydronaphthalene-1,3,4a(3H)-triol(2), (4S,4aS,8aS)-octahydro-4a-hydroxy-4, 8a-dimethyl-1(2H)-naphthalenone (3), as well as six other known analogues (4-9), were isolated from the culture broth of Streptomyces sp. XM17, an actinobacterial strain inhabiting the fresh feces of the giant panda Ailuropoda melanoleuca. The chemical structures of 1-3 were elucidated comprehensively by NMR spectroscopic and MS analyses, furthermore, the stereochemical configurations were resolved by NOESY experiments, along with ECD spectral and single-crystal X-ray crystallographic analyses. These compounds were then tested for their antiviral activities using the "pretreatment of virus" approach, which showed that most of these compounds were potent in inhibiting the entry of influenza A virus, with IC50 values ranging from 5 to 49 nM and selectivity indices all above 500.


Time-courses of size-fractionated phosphate uptake: are larger cells better competitors for pulses of phosphate than smaller cells?
Time-course experiments of phosphate uptake by size-fractionated phytoplankton were conducted in oligotrophic Kennedy and Sproat Lakes. The objective was to determine if large phytoplankton obtained more phosphate than smaller cells, when the nutrient was present at higher concentrations. Studies at Kennedy Lake revealed that uptake rates in the 0.2-3.0 μm fraction were very sensitive to the time they were exposed to elevated concentrations; rates determined over the 60-120 min interval were less than 30% of those recorded over the 0-60 min interval. In contrast, there was little difference in uptake rates over these intervals for cells>3.0 μm. At Sproat Lake phosphate incorporation into the two size fractions was followed after the aerial fertilization of the lake with inorganic nutrients. Following nutrient addition the proportion of phosphate entering the>3.0 μm size fraction increased from ca. 35% to ca. 85%. Despite these observations, it is doubtful that larger cells are able to sequester enough phosphate from pulses to realize the same specific growth rates as their smaller counterparts.


Subcellular fractionation, partial purification and characterization of neutral triacylglycerol lipase from pig liver.
The subcellular distributions of acidic (pH 4.5) and neutral (pH 7.5) longchain triacylglycerol lipases (glycerol ester hydrolase, EC 188.8.131.52) of pig liver have been determined. The distribution of the acidic lipase closely paralleled that of the lysosomal marker enzyme, cathepsin D. Approx. 60% of the neutral lipolytic activity resided in the soluble fraction;the distribution of this activity failed to parallel that of marker enzymes for mitochondria, lysosomes, microsomes, or plasma membranes. A method has been developed for purification of the neutral lipase from the soluble fraction by ultracentrifugation. An approximate 90-fold purification was achieved, with recovery of 16% of the initial activity. The partially purified neutral lipase exhibited a pH optimum between 7.25 and 7.5. It required 30 mM emulsified triolein for optimal activity and ceased to liberate fatty acids after 30 min of incubation. The enzymatic activity was destroyed by heating at 60 degrees C. Neutral lipase was inhibited by sodium deoxycholate, Triton X-100 and iodoacetamide. The activity was not inhibited by sodium taurocholate, EDTA, heparin and diethyl-p-nitrophenyl phosphate. Neutral lipase failed to exhibit activity in assay systems specific for lipoprotein lipase, monoolein hydrolase, tributyrinase, and methyl butyrate esterase and showed little or no capacity to hydrolyze chyle chylomicrons or plasma very low density lipoproteins. It is suggested that the function of neutral lipase may be to supply the liver with fatty acids liberated from endogenously synthesized or stored triacylglycerols.


Resorption of foliar nutrients in a regenerating southern Appalachian forest.
Leaves were sampled in a successional, southern Appalachian forest to estimate autumn foliar nutrient dynamics. Resorption of N and P in a successional forest equaled, or exceeded, resorption estimates for a more mature control forest. Foliar nutrient leaching was not sufficient to account for changes in autumn leaf N, P, Ca and Mg concentrations. The resorption process conserves nutrients by reducing nutrient losses from leaching and litter-fall, thereby closing the nutrient cycle in successional forests. We hypothesize that rapid recovery of primary productivity early in forest regeneration is the result of maximum nutrient resorption of limiting nutrients. Implications of these results for successional nutrient cycling theory are discussed.


Exploring sequence space: harnessing chemical and biological diversity towards new peptide leads.
From their early roots in natural products, peptides now represent an expanding class of novel drugs. Their modular structures make them ideal candidates for pooled library screening approaches. Key technologies for library generation and screening, such as SICLOPPS, phage display and mRNA display, give unparalleled access to tight binding peptides. Through combination with genetic code reprogramming and chemical modifications, access to more natural product-like libraries, spanning non-canonical peptide space, is readily achievable. Recent advances in these fields enable introduction of diverse non-standard motifs, such as cyclisation and backbone methylations. Peptide discovery platforms now allow robust access to potent, highly functionalised peptides against virtually any protein of interest, with typical binding constants in the nanomolar range. Application of these optimised platforms in a drug discovery setting has the potential to significantly accelerate identification of new leads.


ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma.
We recently undertook expression profiling of all 19 human ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin motifs) in malignant and non-neoplastic breast tissue and showed that 11 of the ADAMTS genes are dysregulated in breast carcinoma. We identified a subgroup of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma. Further RNA expression analysis by real-time PCR on a different cohort of 229 patients with breast cancer has identified ADAMTS8 as a predictor of poor overall survival (OS) (hazard ratio (HR) = 2.20, 95% C.I. = 1.29-3.74, p = 0.004) and confirmed ADAMTS15 as a predictor of prolonged relapse-free survival (RFS) (HR = 0.54, 95% C.I. = 0.32-0.89, p = 0.016). We explored the differences in survival of the 4 groups that could be categorized based on the expression levels of ADAMTS8 and ADAMTS15. For both RFS and OS, the group with high ADAMTS8 and low ADAMTS15 expression had a particularly poor prognosis. This group had a 3-fold higher chance of recurrence (HR = 3.03, 95% C.I. = 1.49-6.15, p = 0.001) and a greater than 5-fold higher chance of death (HR = 5.40, 95% C.I. = 2.16-13.5, p < 0.001) than the most favorable prognostic group. This prediction of poor prognosis by ADAMTS8 and ADAMTS15 expression was found to be independent of other classical clinicopathological factors. Results observed in FVB-PyMT mice, a robust transgenic model of highly metastatic breast carcinoma, fitted the expectation that relatively high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 seen in human breast carcinoma are associated with a poor clinical outcome. In summary, ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma.


Chlamydia trachomatis infections increase the risk for ectopic pregnancy: a population-based, nested case-control study.
Chlamydia trachomatis (CT) as a risk factor for ectopic pregnancy (EP) has mainly been established through seroepidemiologic cross-sectional studies. The goal of this study was to obtain EP risk estimates for women diagnosed with CT using women with negative tests as the reference group. We linked prospectively collected CT laboratory data (1990-2003) to EP hospital data (discharge and outpatient registries) in a nested case-control study. Six hundred sixteen women with CT test(s) before first EP were eligible as cases. Three controls were matched to each case for year of birth, age at first test, and number of prior tests. Previous CT infection was associated with elevated EP risk (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0-2.0). In stratified analysis, the association was only significant for the youngest women (born 1970-1984) who had a nearly complete CT testing history (OR, 2.1; 95% CI, 1.3-3.2). A history of diagnosed CT infection is associated with a 2-fold increased EP risk.


Stimulatory effect of EGF and inhibitory effect of sialoadenectomy on growth of an EGF receptor-hyperproducing human gastric cancer xenograft in nude mice.
We recently established epidermal growth factor (EGF) receptor-hyperproducing human gastric cancer xenografts in nude mice. The present study was designed to examine whether the growth of a xenograft having 1,098 +/- 276 fmol/mg protein of EGF receptor would either be stimulated by the administration of EGF or inhibited by the removal of the submandibular glands (sialoadenectomy) which contain a large amount of EGF. A miniosmotic pump containing 2 micrograms or 20 micrograms of EGF was implanted on the back of the animals in the EGF stimulation experiments. The tumor growth was stimulated by the administration of EGF (P < 0.01), and the doubling time of the tumor was reduced relative to the controls (P < 0.01). Both the mitotic indices and the bromodeoxyuridine (BrdU)-labeling indices of the tumor were higher than those of the controls (P < 0.01). Tumor growth inhibited by the sialoadenectomy (P < 0.05) while the tumor doubling time was prolonged compared with the sham-operated mice (P < 0.05). These results suggest that the growth of a human gastric cancer xenograft may be modulated by EGF.


Characterization and function of autoreactive T-lymphocyte clones isolated from normal, unprimed mice.
Self-Ia-reactive cloned T-cell lines, designated PK, were established by long-term culture of T cells from normal DBA/2 mice with irradiated syngeneic splenic adherent cells (SAC), rich in macrophages and dendritic cells. The cell lines were Thy 1+, Lyt 1+, Lyt 2-, produced IL-2 following stimulation with syngeneic spleen cells, and did not exhibit alloreactivity when screened against six different H-2 haplotypes. Of the five cloned PK cell lines tested, four were I-Ed restricted while one was I-Ad restricted as determined by genetic mapping and blocking studies carried out with monoclonal anti-Ia sera. Extensive specificity studies suggested that the PK cells reacted to syngeneic Ia molecules alone and not to foreign antigens such as fetal calf serum (FCS) used in the culture medium, in association with self-Ia. SAC pulsed with FCS or other protein antigens such as turkey gamma-globulin (TGG) were tested for their ability to induce proliferation of autoreactive T cells and other antigen-specific T cells using culture conditions consisting of serumless medium and interleukin 2 (IL-2). The data showed that the autoreactive T cells proliferated better in response to antigen-unpulsed SAC, while FCS-specific and TGG-specific cell lines, developed independently, proliferated only in response to FCS- or TGG-pulsed SAC, respectively, but not to antigen-unpulsed SAC. These results clearly distinguished the autoreactive T-cell clones from the antigen-specific T-cell clones. Preliminary studies carried out to investigate the functions of autoreactive T cells suggested that these cells helped in the in vitro differentiation of alloantigen-specific cytotoxic T lymphocytes (CTL) from CTL precursors obtained from the thymus and augmented syngeneic, allogeneic, and antigen-specific immune responses in vitro. The autoreactive T cells were also capable of inducing both proliferation and differentiation of antigen-specific populations of B cells in the absence of antigen. The present investigation suggests that autoreactive, non-antigen-reactive T cells can be cloned from normal, unimmunized mice and that such cell lines may provide a powerful tool for analyzing the role of the syngeneic mixed lymphocyte reaction in induction and maintenance of both T-and B-cell immune responses.


Agonadal presumptive XX/XY leukochimeric pig.
XX/XY chimeric pigs are uncommon and their reproductive anatomy is variable and unpredictable. A piglet was identified by its enlarged vulva as a possible intersex. Venous blood was collected at 1.5 and 9 months for karyotyping and determination of testosterone and estrone sulphate concentrations. At 1 year euthanasia was performed. The reproductive tract was carefully dissected and examined histologically. As the animal matured the vulva did not develop relative to the size of the animal. Lymphocyte cultures indicated a 70% XX/30% XY chimera. The reproductive tract consisted of a strand of tissue enveloped by fascia. Histological study revealed presumptive Wolffian derivatives, coiled bilateral ducts along the tract, and a Müllerian derivative, a medially located duct in the caudal third of the tract. No gonads were found. Plasma levels of estrone sulfate and testosterone were negligible. In utero exposure to exogenous androgens from a male co-twin or weak endogenous adrenal androgens may account for the enlarged vulva at birth and retention of the androgen dependent Wolffian duct primordia. An atesticular state is supported by retention of the Müllerian duct primordia and the negligible peripheral sex steroids.


Case report: imaging features in a renal transplant patient with calcineurin inhibitor-induced pain syndrome (CIPS).
Post-transplant distal limb bone marrow edema syndrome or calcineurin inhibitor-induced pain syndrome (CIPS) is generally a self-limiting but debilitating acute pain syndrome that has been reported in 2-14 % of renal transplant recipients. The disease is extensively described in the transplant literature in patients receiving the calcineurin inhibitors cyclosporine and tacrolimus. We present a case of CIPS arising in a patient 73 days after renal allograft, review the imaging findings, and discuss proposed etiologies and differential diagnoses. To the authors' knowledge, CIPS has not been characterized as a distinct entity in the radiology literature.


Expression of the U1 RNA gene repeat during early sea urchin development: evidence for a switch in U1 RNA genes during development.
The majority of the genes for U1 RNA are organized in tandemly repeated units in the sea urchin. To assess the level of expression of these genes in the sea urchin Lytechinus variegatus, we measured the transcription of sequences 3' to the gene. The tandemly repeated U1 genes are expressed in morula and continue to be expressed at high rates until 2 hr after hatching, at which time the rate of expression of all the U1 genes and the tandemly repeated U1 genes declines sharply. By the gastrula stage the synthesis of total U1 RNA has declined by a factor of 8. The major tandemly repeated genes are inactive by this time, although other U1 genes remain active. The sequence of U1 RNA synthesized late in embryonic development differs from the sequence of U1 RNA encoded by the tandemly repeated set of U1 RNA genes, indicating that there must be other U1 RNA genes that are active late in embryonic development.


Feeding and mandibular distraction osteogenesis in children with Pierre Robin sequence: a case series of functional outcomes.
In addition to upper airway obstruction, many patients with micrognathia and Pierre Robin sequence also have swallowing abnormalities and reflux. Many studies have demonstrated the effectiveness in alleviating the airway symptoms with mandibular distraction osteogenesis, but very few studies have focused on feeding and reflux outcomes. A retrospective chart review was performed to identify patients with Pierre Robin sequence who underwent mandibular distraction osteogenesis with completed pre- and post-operative upper gastroesophageal series and videofluoroscopic swallow assessments. All six children in our series demonstrated significant improvements in both airway obstructive symptoms and feeding abnormalities. More specifically, all patients showed clinical and objective improvements in reflux and swallowing function after distraction surgery. Objective and symptomatic improvements in swallowing function and reflux disease can be seen after mandibular distraction osteogenesis in children with Pierre Robin sequence.


Cytoprotective effect of acetaminophen against taurocholate-induced damage to rat gastric monolayer cultures.
Acetaminophen has recently been reported to protect against drug damage to gastric mucosa in vivo. The present study tested acetaminophen protection in cultured rat gastric mucous cells against sodium taurocholate-induced damage and assessed the role of endogenous prostaglandins. Cell damage was assessed by phase-contrast microscopy and quantitated by Chromium-51 release assay which positively correlated with the trypan blue dye exclusion test (r = 0.98). The effect of acetaminophen on the production of PGE2 and 6-keto-prostaglandin F1a (6KF) was also studied. Sodium taurocholate caused cell death in a dose-dependent manner as indicated by increased 51Cr release. Preincubation with 5 mM acetaminophen significantly reduced 51Cr release caused by 5 mM sodium taurocholate, producing a 40% increase in cell survival. This cytoprotection was not blocked by indomethacin. PGE2 and 6KF of the media did not change after preincubation with nondamaging concentrations of acetaminophen or taurocholate. These results indicate that: (1) acetaminophen exerts a direct protective effect on gastric mucous cells cultured in vitro independent of indirect factors such as blood flow and (2) this protection is not associated with increased prostaglandin production.


Intermediate filaments in the Xenopus oocyte: the appearance and distribution of cytokeratin-containing filaments.
Cytokeratins have previously been shown to exist in the Xenopus oocyte cortex. Using three monoclonal antibodies against cytokeratins, we follow the appearance of cytokeratin-containing filaments, and their changes in distribution during oocyte differentiation and maturation. Cytokeratin-containing filaments are shown to change dramatically in distribution in the oocyte during its ontogeny.


New predictors of early impaired placentation preceding miscarriage before 10 weeks of gestation in IVF pregnancies: A prospective study.
In a recent study of 10,011 pregnant women, 95% of miscarriages occurred before routine ultrasound scan at 11-14 weeks. Our study aimed to identify early first trimester parameters which may predict miscarriage before 10 weeks of gestation for in vitro fertilization (IVF) pregnancies. A cohort of 115 healthy IVF patients with a singleton viable embryo in early first trimester were studied in a tertiary university-affiliated medical center (April 2017-June 2018). Calculations included gestational age (GA); ultrasound evaluation of crown-rump length (CRL), mean gestational sac diameter (GSD) and volume (GSV), mean yolk sac diameter (YSD) and volume (YSV); fetal heart rate (FHR), mean uterine arteries pulsatility index (UtA-PI); and maternal blood placental protein 13 (PP13) levels. Patients were divided into three groups by GA; and early miscarriage versus ongoing pregnancy after GA 10 weeks. Early fetal loss occurred in 14.8% of patients; miscarriage group had higher discrepancy between calculated and measured GA (P < 0.001), lower GSD and GSV (P = 0.005 and P = 0.02, respectively), significantly different YSD and YSV, and lower GSD/YSD and GSV/YSV ratios (P = 0.001 and P = 0.003, respectively). UtA-PI/CRL ratio was higher in patients with miscarriage at GA 46-48 days and GA >48 days (P = 0.034 and P = 0.026, respectively). PP13/CRL ratio was higher in patients with miscarriage at GA >48 days (P = 0.041). In IVF pregnancies with live embryo at first ultrasound scan, high UtA-PI/CRL and maternal blood PP13/CRL ratios may indicate impaired placentation preceded early pregnancy loss. A larger cohort is needed to further verify these predictions.


Electrochemical DNA hybridization sensors applied to real and complex biological samples.
DNA hybridization biosensors, also known as genosensors, are analytical devices for the detection of specific DNA "target" sequences in solution, upon hybridization of the targets with complementary "probes" immobilized on a solid substrate. Electrochemical genosensors hold great promise to serve as devices suitable for point-of-care diagnostics and multiplexed platforms for fast, simple and inexpensive nucleic acids analysis. Although a lot of progress has been made in the past few years, the performance of genosensors in complex biological samples has been assayed in only a small fraction of published research articles. This review covers such a group of reports, from the year 2000 onwards. Special attention is played in the nature and complexity of the samples and in the way matrix effects were treated and specificity controls were performed.


Unusual Fusobacterium Nucleatum Infection Presenting as a Liver Abscess Associated With Cephalic Vein Thrombosis.
Pyogenic liver abscesses are uncommon entities with potentially devastating consequences requiring immediate diagnosis and treatment. Fusobacterium nucleatum is an anaerobic, gram-negative oral commensal that has been seldom reported as a cause of liver abscess, particularly in immunocompetent hosts. We describe a case of an 80-year-old female patient presenting with a fusobacterium liver abscess associated with thrombosis of the left cephalic vein.


High time-resolved variations of proteins in PM2.5 during haze pollution periods in Xi'an, China.
Proteinaceous matter is an important component of PM2.5, which can cause adverse health effects and also influence the air quality and climate change. However, there is little attention to high time-resolved variations and potential role of aerosol proteins during haze pollution periods. In this study, PM2.5 samples were first collected by a medium flow sampler in autumn and winter in Xi'an, China. Then three high time-resolved monitoring campaigns during haze pollution periods were conducted to determine the evolving characteristics of total protein concentration and explore the interactive relationship between protein and other chemical compositions. The results showed that the average protein concentration in PM2.5 in Xi'an (5.46 ± 3.32 μg m-3) was higher than those in most cities of China, and varied by seasons and air pollution conditions. In particular, the protein concentration in PM2.5 increased with the increase of air quality index (AQI). The continuous variations of aerosol proteins during the haze pollution periods further showed that PM2.5, atmospheric humidity and long-distance air mass transport exerted the significant impacts on the protein components in aerosols. Based on the present observation, it is suggested that aerosol proteins might affect the generation of secondary aerosols under haze weather conditions. The present results may provide a new possible insight into the variations and the role of aerosol proteinaceous matter during the formation and development of haze pollution.


Unravelling the effects of complexation of transition metal ions on the hydroxylation of catechol over the whole pH region.
Catechol pollutants (CATPs) serving as chelating agents could coordinate with many metal ions to form various CATPs-metal complexes. Little information is available on the effects of complexation of metal ions on CATPs degradation. This work presents a systematical study of •OH-mediated degradation of catechol and catechol-metal complexes over the whole pH range in advanced oxidation processes (AOPs). Results show that the pH-dependent complexation of metal ions (Zn2+, Cu2+, Ti4+ and Fe3+) promotes the deprotonation of catechol under neutral and even acidic conditions. The radical adduct formation (RAF) reactions are both thermodynamically and kinetically favorable for all dissociation and complexation species, and OH/O- group-containing C positions are more vulnerable to •OH attack. The kinetic results show that the complexation of the four metal ions offers a wide pH range of effectiveness for catechol degradation. At pH 7, the apparent rate constant (kapp) values for different systems follow the order of catechol+Ti4+ ≈ catechol+Zn2+ > catechol+Cu2+ > catechol+Fe3+ > catechol. The mechanistic and kinetic results would greatly improve our understanding of the degradation of CATPs-metal and other organics-metal complexes in AOPs. The toxicity assessment indicates that the •OH-based AOPs have the ability for decreasing the toxicity and increasing the biodegradability during the processes of catechol degradation.


Glycogen storage disease: recommendations for treatment.
A workshop was held on "Aspects of treatment of patients with glycogen storage disease" within the framework of the Concerted Action "Inborn errors of metabolism" of the European Communities. Consensus was reached on the main issues of treatment of patients with deficiency of glucose-6-phosphatase, glucose-6-phosphate translocase, debranching enzyme, liver phosphorylase and phosphorylase-b-kinase. The resulting recommendations are reported.


Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study.
Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day -1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia's method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation.


Inflammatory cytokines tumour necrosis factor-α and interleukin-8 enhance airway smooth muscle contraction by increasing L-type Ca2+ channel expression.
Inflammation elevates intracellular calcium concentrations ([Ca2+ ]i ) in airway smooth muscle (ASM). The L-type Ca2+ channel (L-VDCC) plays an important role in regulating Ca2+ influx in ASM. However, the role of L-VDCC in the inflammatory cytokine-induced pathology of ASM remains unclear. In the present study, we used calcium imaging and isometric tension measurements to assess the role of L-VDCC in agonist-induced [Ca2+ ]i rise and the associated contractions in mouse ASM, and we used immunoblotting to identify L-VDCC protein expression levels in mouse ASM after exposure to tumour necrosis factor alpha (TNF-α) or interleukin-8 (IL-8). Our results showed that high-K+ - or carbachol-induced contractions of mouse ASM were significantly greater after pretreatment with TNF-α or IL-8 for 24 hours. Both verapamil and nifedipine, L-VDCC inhibitors, abolished this increased contraction induced by TNF-α or IL-8 pretreatment. Moreover, TNF-α treatment enhanced carbachol-induced Ca2+ influx in ASM cells, and this effect was abrogated by verapamil. Additionally, immunoblotting results showed that preincubation of mouse ASM with TNF-α or IL-8 also enhanced L-VDCC protein expression. On the basis of these findings, we concluded that proinflammatory cytokines, such as TNF-α and IL-8, increase the expression level of L-VDCC, which in turn contributes to augmented agonist-induced ASM contractions. This effect of inflammation on L-VDCC expression in ASM may be associated with airway hyper-responsiveness and involved in the development of asthma.


Perforator flaps in hand reconstruction: the effect of blood vessel twisting.
Perforator flaps increasingly find acceptance and use in hand reconstructive surgery. A propeller flap is an island flap that moves from one orientation to another by rotating around its vascular pedicle. It is now possible to design propeller flaps based on a single perforator, so-called "perforator-based propeller flaps," but they are more prone to vascular impairment when twisted more than 90°. We present a prospective study conducted in the Plastic and Reconstructive Surgery Department of the Rehabilitation Hospital over 17 months. All perforator-based propeller flaps that were used for hand reconstruction were analyzed. The parameters studied included the size and location of the defect, the size and shape of the flap, the perforator (length and location) that was used, the degree of twisting of the perforator, the degree of perforator dissection, the management of the donor site, and flap survival area. In this study we investigated the circulatory impairment induced by twisting of the pedicle on a true perforator flap. All flaps survived completely with the exception of partial skin necrosis in few cases. Some of these cases required debridement and skin grafting. Perforator-based propeller flaps provide a reliable option for covering small- to medium-size hand complex tissue defects. They have the advantages of using similar tissues in reconstruction, not damaging another area, they do not require main vessels sacrifice, and the donor site can be generally directly closed.


Stage-dependent ethoxyresorufin-O-deethylase (EROD) in vivo activity in medaka (Oryzias latipes) embryos.
Using medaka (Oryzias latipes) embryos, this study aimed to quantitatively characterize the stage-dependent in vivo ethoxyresorufin-O-deethylase (EROD) as indicator of cytochrome P4501A (CYP1A) activity. Embryos were challenged for 24-h to an agonist (β-naphthoflavone [BNF], 2.5, 5, 10, and 20 μg L(-1)) or to its combination (2.5 μg L(-1)) with an antagonist (α-naphthoflavone [ANF], 25, 50, 100, and 200 μg L(-1)), initiated at four different developmental time points (1, 3, 6, and 9 d post-fertilization [dpf]). Respective induction and competitive inhibition were evaluated over fluorescent images of whole embryo (nonorgan-specific [NOS] EROD activity) and gallbladder (organ-specific [OS] EROD activity). Both flavonoids showed signs of stability in solution. Generally speaking, the mean fluorescence intensity (MFI) values for NOS EROD increased with BNF concentration and exposure challenge. BNF co-exposure with ⩾50 μg ANF L(-1) during the 1-2 and 3-4 dpf challenges lowered NOS EROD to undetectably induced levels. Significant increments in MFIs for OS-EROD were seen from exposures to ⩾2.5 μg BNF L(-1), peaking during the 6-7 dpf challenge regardless of BNF concentration. The simultaneous BNF/ANF incubation showed competitive inhibition for OS EROD activity, although levels were generally detectably induced during all challenges and at all ANF concentrations. The morphometric in vivo gallbladder analysis indicated significant dilation in the 10 dpf-old embryos co-exposed to BNF and 200 μg ANF L(-1). This quantitative approach can be used successfully at 4 dpf at the NOS-EROD or OS-EROD levels, although the NOS-EROD response was sensitive enough to induction or inhibition, even at 2 dpf.


Unusually marked hypoxic sensitization to indoloquinone EO9 and mitomycin C in a human colon-tumour cell line that lacks DT-diaphorase activity.
Studies with purified DT-diaphorase have shown that the enzyme is capable of catalyzing a two-electron reduction of the novel indoloquinone EO9 to a DNA-damaging alkylating species. The aim of this study was to determine to what extent DT-diaphorase may be involved in the metabolic activation of EO9 and mitomycin C in both aerobic and hypoxic conditions. Two human colon-carcinoma cell lines were used; HT29 has high levels of DT-diaphorase whilst BE lacks this activity because of a point mutation in the NQOI gene. In aerobic conditions the 2 cell lines show similar sensitivities to a number of cytotoxic drugs including cisplatin, doxorubicin and etoposide. They are equally sensitive to the benzotriazine di-N-oxide SR 4233 but HT29 is more sensitive than BE to mitomycin C and EO9. Sensitivity to SR 4233 is increased by about 100-fold for both cell lines in hypoxic conditions. DT-diaphorase-deficient BE cells show markedly increased sensitivity to mitomycin C and particularly EO9 in hypoxic conditions, whereas DT-diaphorase-rich HT29 cells show little hypoxic sensitization to these agents unless exposed in the presence of dicoumarol. These results suggest that DT-diaphorase can reduce EO9 and mitomycin C to potent cytotoxic species in aerobic conditions, and this activity predominates over the one-electron-reducing enzymes even in hypoxic conditions. In the absence of DT-diaphorase activity, EO9 and mitomycin C are reduced in hypoxic conditions, presumably by one-electron-reducing enzymes, to a similar or greater extent than is achieved with DT-diaphorase.


Microbiota composition data for wild and captive bluestreak cleaner wrasse Labroides dimidiatus (Valenciennes, 1839).
The Labroides dimidiatus is known as the "doctor fish" because of its role in removing parasites and infectious pathogens from the body of other fishes. This important role played both in wild and captive conditions could represent a novel form of parasitic transmission process mediated by the cleaning activity of the fish. Yet, there is a paucity of data on the microflora associated with this fish which is important for tracking disease infection and generally monitoring the health status of the fish. This article, therefore, represents the first dataset for the microbiota composition of wild and captive L. dimidiatus. Wild fish samples and carriage water were gotten in Terengganu Malaysia around the corals of the Karah Island. The captive sample, however, was obtained from well-known ornamental fish suppliers in Terengganu Malaysia. Thereafter, bacteria present on the skin, in the stomach and the aquarium water were enumerated using culture-independent approaches and Next Generation Sequencing (NGS) technology. Data obtained from the three metagenomic libraries using NGS analysis gave 1,426,740 amplicon sequence reads which are composed of 508 operational taxonomic units (OTUs) for wild samples and 3,238,564 valid reads and 828 OTUs for captive samples. All sequence reads were deposited in the GeneBank (Accession numbers SAMN14260247, SAMN14260248, SAMN14260249, SAMN14260250, SAMN14260251, and SAMN14260252). The dataset presented is associated with the research article "16S rDNA-Based Metagenomic Analysis of Microbial Communities Associated with Wild Labroides dimidiatus From Karah Island, Terengganu, Malaysia" [1]. The microbiota data presented in this article can be used to monitor the health and wellbeing of the ornamental fish, especially under captivity, hence preventing possible cross-infection.


Maternal pre-pregnancy BMI downregulates neonatal cord blood LEP methylation.
Neonatal adiposity has many determinants and may be a risk factor for future obesity. Epigenetic regulation of metabolically important genes is a potential contributor. The objective of the study is to determine whether methylation changes in the LEP gene in cord blood DNA are impacted by the maternal environment or affect neonatal adiposity measures. A cross-sectional study of 114 full-term neonates born to healthy mothers with normal glucose tolerance was performed. Cord blood was assayed for leptin and genome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models and semi-partial correlation coefficients were used to analyze associations. False discovery rate was estimated to account for multiple comparisons. Maternal pre-pregnancy BMI was associated with decreased methylation at five CpG sites near the LEP transcription start site in an adjusted model (false discovery rate <0.022 for each site). The association between maternal BMI and cord blood leptin approached significance (r = 0.18, p = 0.054). Cord blood leptin was positively correlated with neonatal adiposity measures including birth weight (r = 0.45, p < 0.001), fat mass (r = 0.47, p < 0.001) and percent body fat (r = 0.44, p < 0.001). Maternal pre-pregnancy BMI is strongly associated with decreased cord blood LEP gene methylation and may mediate the well-known association between maternal pre-pregnancy BMI and neonatal adiposity.


Pentadecafluorooctanoic-acid-free polytetrafluoroethylene and mechanism of PFOA formation by γ-irradiation.
Low-molecular-weight (Mw) polytetrafluoroethylene (PTFE) micropowder is added to wax for use in automotive equipment and printing machines and is produced by radiation-initiated degradation under atmospheric conditions. However, pentadecafluorooctanoic acid (PFOA) is produced as a by-product in concentrations greater than 25 ppb, which is problematic because PFOA does not degrade in the environment. Herein, we clarify the PFOA-formation mechanism and develop a manufacturing process for a novel low-Mw PTFE micropowder that does not contain PFOA (less than 5 ppb). The process uses combined irradiation and heat treatment in an oxygen-free atmosphere. Furthermore, PFOA-free PTFE micropowder can be produced on the 10-kg scale.


The evolution and consequences of snaR family transposition in primates.
The small NF90 associated RNA (snaR) family of small noncoding RNAs (ncRNA) appears to have evolved from retrotransposon ancestors at or soon after pivotal stages in primate evolution. snaRs are thought to be derived from a FLAM C-like (free left Alu monomer) element through multiple short insertion/deletion (indel) and nucleotide (nt) substitution events. Tracing snaR's complex evolutionary history through primate genomes led to the recent discovery of two novel retrotransposons: the Alu/snaR related (ASR) and catarrhine ancestor of snaR (CAS) elements. ASR elements are present in the genomes of Simiiformes, CAS elements are present in Old World Monkeys and apes, and snaRs are restricted to the African Great Apes (Homininae, including human, gorilla, chimpanzee and bonobo). Unlike their ancestors, snaRs have disseminated by multiple rounds of segmental duplication of a larger encompassing element. This process has produced large tandem gene arrays in humans and possibly precipitated the accelerated evolution of snaR. Furthermore, snaR segmental duplication created a new form of chorionic gonadotropin β subunit (CGβ) gene, recently classified as Type II CGβ, which has altered mRNA tissue expression and can generate a novel short peptide.


Accumulating advantages over time: Family experiences and social class inequality in academic achievement.
Children from different family backgrounds enter schooling with different levels of academic skills, and those differences grow over time. What explains this growing inequality? While the social reproduction tradition has argued that family contexts are central to producing class gaps in academic achievement, recent quantitative studies have found that family experiences explain only a small portion of those inequalities. We propose that resolving this inconsistency requires developing a new measure of family experiences that captures the continuity of exposure over time and thus more closely reflects the logic of the social reproduction tradition. Results using data from the Early Childhood Longitudinal Study - Kindergarten cohort (ECLS-K) show that, consistent with previous quantitative research, time-specific measures of family experiences have little explanatory power. However, cumulative family experiences account for most of the growing inequality in academic achievement between children from different social class backgrounds over time. These findings support claims from the social reproduction tradition, and contribute more broadly to the understanding of how family experiences contribute to social inequality.


Incorporating information about cost-effectiveness into evidence-based decision-making: the evidence-based practice center (EPC) model.
There is a pressing need for guidance on how to incorporate economic information into evidence-based decision-making. Such guidance should take account of the quality and relevance of economic evaluations. To summarize lessons learned in integrating information from decision analyses and cost-effectiveness analyses. Several methods used by the Evidence-Based Practice Centers (EPCs) to conduct systematic reviews are applicable to assessing economic studies. We discuss methods to identify key questions for the review of economic studies. Reviews should assess how an economic model incorporates clinical logic and handles uncertainty about effectiveness. As is the case for metaanalysis of interventions, qualitative or quantitative synthesis of economic studies should explore heterogeneity to identify key uncertainties underlying divergent results as well as unsuspected sources of bias. Applying EPC methods to synthesis of economic information can increase their relevance to clinicians and policymakers and inform decisions that require tradeoffs between effectiveness and harms of interventions.


Re-evaluating associations between the Supplemental Nutrition Assistance Program participation and body mass index in the context of unmeasured confounders.
To evaluate the association between participation in the Supplemental Nutrition Assistance Program (SNAP) and body mass index (BMI) in the presence of unmeasured confounding. We applied new matching methods to determine whether previous reports of associations between SNAP participation and BMI were robust to unmeasured confounders. We applied near-far matching, which strengthens standard matching by combining it with instrumental variables analysis, to the nationally-representative National Household Food Acquisition and Purchasing Survey (FoodAPS, N = 10,360, years 2012-13). In ordinary least squares regressions controlling for individual demographic and socioeconomic characteristics, SNAP was associated with increased BMI (+1.23 kg/m2, 95% CI: 0.84, 1.63). While propensity-score-based analysis replicated this finding, using instrumental variables analysis and particularly near-far matching to strengthen the instruments' discriminatory power revealed the association between SNAP and BMI was likely confounded by unmeasured covariates (+0.21 kg/m2, 95% CI: -3.88, 4.29). Previous reports of an association between SNAP and obesity should be viewed with caution, and use of near-far matching may assist similar assessments of health effects of social programs.


Neural Wiskott-Aldrich syndrome protein (N-WASP) is the specific ligand for Shigella VirG among the WASP family and determines the host cell type allowing actin-based spreading.
Shigella, the causative agent of bacillary dysentery, is capable of directing its movement within host cells by forming an actin comet tail. The VirG (IcsA) pro-tein expressed at one pole of the bacterium recruits neural Wiskott-Aldrich syndrome protein (N-WASP), a member of the WASP family, which in turn stimulates actin-related protein (Arp) 2/3 complex-mediated actin polymerization. As all the WASP family proteins induce actin polymerization by recruiting Arp2/3 complex, we investigated their involvement in Shigella motility. Here, we show that VirG binds to N-WASP but not to the other WASP family proteins. Using a series of chimeras obtained by swapping N-WASP and WASP domains, we demonstrated that the specificity of VirG to interact with N-WASP lies in the N-terminal region containing the pleckstrin homology (PH) domain and calmodulin-binding IQ motif of N-WASP. A conformational change in N-WASP was important for the VirG-N-WASP interaction, as elimination of the C-terminal acidic region, which is responsible for the intramolecular interaction with the central basic region of N-WASP, affected the specific binding to VirG. We observed that, in haematopoietic cells such as macrophages, polymorphonuclear leucocytes (PMNs) and platelets, WASP was predominantly expressed, whereas the expression of N-WASP was greatly suppressed. Indeed, unlike Listeria, Shigella was unable to move in macrophages at all, although the movement was restored as N-WASP was expressed ectopically. Thus, our findings demonstrate that N-WASP is a specific ligand of VirG, which determines the host cell type allowing actin-based spreading of Shigella.


The contribution of PCSK9 levels to the phenotypic severity of familial hypercholesterolemia is independent of LDL receptor genotype.
Autosomal dominant familial hypercholesterolemia (FH) is caused by genetic mutations in the LDL receptor (LDLR), its ligand apolipoprotein (apo) B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 levels have been shown to correlate with LDL-cholesterol (LDL-C) levels in FH, the extent to which PCSK9 levels modulate the phenotypic severity of this disease independent of LDLR genotype remains to be clarified. To assess the relationship between LDLR genotype and the plasma levels of PCSK9, LDL-C, and lipoprotein (a) (Lp(a)) in a large cohort of genetically defined FH heterozygotes (HeFH). A total of 292 HeFH carrying one of the nine French-Canadian mutations in the LDLR gene were recruited. The cohort included 226 carriers of a negative-receptor (NR) mutation and 66 carriers of a defective-receptor (DR) LDLR gene mutation. Fifty-six control subjects, who were matched with the HeFH subjects based on gender and body mass index, were also recruited. PCSK9 levels were higher in the HeFH group than in the control group (317.9±107.1 ng/mL vs. 203.3±59.8 ng/mL; P<0.0001). The strength of the association between PCSK9 and LDL-C levels was similar among controls (r=0.37; P=0.005) and HeFH (r=0.31; P<0.0001). Furthermore, a multiple linear regression analysis revealed that the positive correlation between PCSK9 and LDL-C levels remained significant after adjusting for LDLR genotype in the HeFH group. These results suggested that the contribution of PCSK9 levels to the phenotypic severity in FH heterozygotes is independent of LDLR genotype.


Exploring barriers to physical activity of patients at the internal medicine and surgical wards: a retrospective analysis of continuously collected data.
To analyse physical activity of patients during their hospital stay and to explore the relationship between physical activity and barriers to physical activity. This was a secondary analysis of physical activity data for patients admitted to the internal medicine and surgical wards. Physical activity data, collected with a wireless patch sensor, was operationalized as time spent lying, sitting/standing, and walking. Barriers to physical activity included patients' pain levels, the use of urinary catheters, intravenous tubing, oxygen lines, drains, and level of dependence. Regression analysis explored the relationship between physical activity and barriers to physical activity. Physical activity data were collected in 39 patients (aged 27-88, mean 54 years) during hospital stay. Patients were admitted for a median of 10 d (interquartile range [IQR]: 7-15 d). These patients were lying for a median of 12.1 h (7.6-17.7), sitting/standing 11.8 h (6.3-15.7), and walking 0.1 h (0-0.3) per day. Time lying during the day related to pain levels (β = 0.4 h per unit increase in pain, p < 0.01) and drain use (β = 3.1 h, p < 0.01). Patients spent the most time during the hospital stay lying in bed. Improved pain management and decreased drain use may be worth exploring to increase inpatient physical activity.Implications for rehabilitationContinuous monitoring of physical activity in patients during hospital stay is an important tool for health care professionals to improve multidisciplinary care and rehabilitation.Health care professionals should be aware of the necessity of adequate pain management and critically review the use of drains in order to improve physical activity of patients during hospital stay.Patients need extra support of health care professionals to increase physical activity during consecutive days of their hospital stay.


Genetics of gallstone disease.
Gallstone disease (GSD) is one of the most common biliary tract disorders worldwide. The prevalence, however, varies from 5.9-21.9% in Western society to 3.1-10.7% in Asia. Most gallstones (75%) are silent. Approximately half of symptomatic gallstone carriers experience a second episode of biliary pain within 1 year. These individuals are at increased risk of developing acute cholecystitis, acute cholangitis, and biliary pancreatitis. As can be expected, these complications burden health care systems because of their invasive nature and surgical cost. Factors that contribute to gallstone formation include supersaturation of cholesterol in bile, gallbladder hypomotility, destabilization of bile by kinetic protein factors, and abnormal mucins. Epidemiologic studies have implicated multiple environmental factors and some common genetic elements in gallstone formation. Genetic factors that influence gallstone formation have been elaborated from linkage studies of twins, families, and ethnicities. Accumulating evidence suggests that genetic factors play a role in GSD.


Changes in steady-state levels of tryptophan hydroxylase protein in adult rat brain after neonatal 6-hydroxydopamine lesion.
A recently developed technique of immunoautoradiography on nitrocellulose transfers of serial frozen sections was used to determine tryptophan hydroxylase concentration in selected areas of the adult rat brain following neonatal 6-hydroxydopamine destruction of nigrostriatal dopamine neurons. Particular attention was paid to the neostriatum, known to be serotonin-hyperinnervated under these conditions, and to the nucleus raphe dorsalis, containing the cell bodies of origin for these nerve terminals. The hippocampus was also investigated as a territory of structurally intact serotonin innervation arising primarily from the nucleus raphe medianus. Tryptophan hydroxylase protein was measured at successive transverse levels across the entire caudorostral extent of all these regions. Similar measurements of tyrosine hydroxylase protein across the substantia nigra and the neostriatum verified the disappearance of the nigrostriatal dopamine neurons. The average tryptophan hydroxylase tissue concentration in the dorsal third of the serotonin-hyperinnervated neostriatum was up by 36% above control, i.e. significantly less than the number of its serotonin axon terminals or varicosities. This was therefore indicative of a lowering of the tryptophan hydroxylase protein content per serotonin ending. Interestingly, a tight correlation between the respective level-by-level concentrations of tryptophan hydroxylase and tyrosine hydroxylase protein in the control neostriatum allowed the prediction the tryptophan hydroxylase concentration after dopamine denervation with a serotonin hyperinnervation. Tryptophan hydroxylase concentration was also significantly reduced in both the nucleus raphe dorsalis and nucleus raphe medianus, notably at those raphe dorsalis levels known to give rise to the serotonin hyperinnervation of neostriatum. It is hypothesized that the lower steady-state level of tryptophan hydroxylase inside the terminals and cell bodies of hyperinnervating serotonin neurons was the result of a feedback inhibition of the synthesis of the enzyme by its end-product, presumably because of the increased amount of serotonin in these terminals.


Characterization of the novel HLA-DPB1*1348:01 allele by sequencing-based typing.
HLA-DPB1*1348:01 differs from HLA-DPB1*14:01:01:01 by one nucleotide substitution in codon 147 in exon 3.


Low parental socioeconomic position results in longer post-Norwood length of stay.
Length of stay (LOS) has been proposed as a quality metric in congenital heart surgery, but LOS may be influenced by parental socioeconomic position (SEP). We aimed to examine the relationship between post-Norwood LOS and SEP. Patients undergoing a Norwood procedure from 2008 to 2018 for hypoplastic left heart syndrome from a single institution, who were discharged alive before second-stage palliation, were included. SEP was defined by Area Deprivation Index, distance from hospital, insurance status, and immigration status. A directed acyclic graph identified confounders for the effect of SEP on LOS, which included gestational age, hypoplastic left heart syndrome subtype, postoperative cardiac arrest, reoperations, and ventilator days. A negative binomial model was used to assess effect of SEP on LOS. In total, 98 patients were discharged alive at a median 37 days (15th-85th percentile 26-72). The majority of patients were children of US citizens and permanent residents (n = 89; 91%). Private insurance covered 54 (55%), with 44 (45%) covered by Medicaid or Tricare. Median Area Deprivation Index was 54 (15th-85th percentile, 25-87). Median distance traveled was 72 miles (15th-85th percentile, 17-469 miles). For every 10 percentile increase in Area Deprivation Index, LOS increased 4% (incidence rate ratio, 1.04; 95% CI, 1.007-1.077; P = .022). Insurance type, immigration status, and distance traveled did not affect postoperative length of stay. There is a significant relationship between SEP and LOS. Consideration of LOS as a quality indicator may penalize hospitals providing care for patients with lower parental SEP.


Trichothecin inhibits invasion and metastasis of colon carcinoma associating with SCD-1-mediated metabolite alteration.
Lipid metabolic abnormalities have received intensified concerns and increased de novo synthesis of lipids is recognized as a common feature of many human cancers. Nevertheless, the role of lipid metabolism that confers aggressive properties on human cancers still remains to be revealed. Natural compounds represent an abundant pool of agents for the discovery of novel lead compounds. Trichothecin (TCN) is a sesquiterpenoid originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Here, we assess the association of stearoyl-CoA desaturase 1 (SCD-1) over-expression with malignant progression of colorectal cancer (CRC). Based on this association, the effect of TCN on migration and invasion of colon carcinoma cells closely related to the inhibition of SCD-1 is evaluated. We further demonstrate that reduced production of unsaturated fatty acids (FAs) by blocking SCD-1 activity is beneficial for the anti-invasion effect of TCN. The aim of this study was to clarify the mechanistic connection between metabolite alterations induced by metabolic rewiring and the aggressive tumor phenotype and further develop novel pharmacological tools for the intervention of tumor invasion associated with SCD-1-mediated metabolite alterations.


Persistence and metabolism of the diamide insecticide cyantraniliprole in tomato plants.
Plant uptake and metabolism of pesticides are complex and dynamic processes, which contribute to the overall toxicity of the pesticides. We investigated the metabolic fate of cyantraniliprole, a new diamide class of insecticide, during various growth stages of tomato. Cyantraniliprole was the major residue in leaves, flowers, and fruits, with the relative metabolite-to-parent ratios maintained at < 10% up to 28 days after treatment (DAT). Mature leaves contained consistently higher residues of cyantraniliprole than young leaves throughout the study. Flowers contained the highest cyantraniliprole residues up to 21 DAT, then gradually decreased. Immature green fruits had the highest cyantraniliprole residues (5.3 ± 0.7 ng/g; 42 DAT), and decreased toward red ripening stages (1.4 ± 0.2 ng/g; 84 DAT). Metabolism of cyantraniliprole primarily occurred in the foliage, where 21 metabolites were tentatively identified. Flowers and fruits contained 14 and four of these metabolites, respectively. Major transformation pathways were characterized by ring closure, followed by N-demethylation, and glycosylation. Additionally, plant metabolism of cyantraniliprole was also associated with several minor phase-I, phase-II, and breakdown metabolites. The occurrence of these metabolites in plants varied as a function of tissue types and their developmental stages. Our study highlights a tissue-specific biotransformation and accumulation of metabolites of cyantraniliprole in tomato.


Microbial production of medium-chain-length α, ω-diols via two-stage process under mild conditions.
Medium-chain-length α, ω-diols (mcl-diols) are versatile compounds widely used as building blocks of coating materials and polymers. Mcl-diols are currently synthesized through energy intensive chemical process. Recently, esterified diols have been produced from n-alkanes in E. coli by co-expression of the alkane monooxygenase module (AlkBGTL) and the esterification module (Atf1), thereby establishing the technical feasibility of the process. However, esterified diols need to be hydrolyzed for further applications. In this study, we developed bio-catalysts for mcl-diol production from n-alkanes under mild conditions. The engineered P. putida KT2440 with overexpression of Est12 can efficiently hydrolyze esterified diols (C6-C10). Later, the engineered strain was co-cultured with an E. coli strain (AlkBGTL-Atf1) to produce mcl-diols. In a two-stage approach, 5 mM 1,6-hexanediol was produced, 61.5 times of one-stage test, from n-hexane by biocatalysts for the first time. In conclusion, the present work indicates that bio-catalysis offers a green biobased alternative for synthesis of mcl-diols.


A basic fibroblast growth factor improves lower extremity wound healing with a porcine-derived skin substitute.
Although a number of cytokine or growth factor therapies for wound acceleration have been reported, few mentioned the quality of the outcome. The lower extremity is important in esthetics as well as in function, because it is exposed. Recently, a growth factor, namely basic growth factor (bFGF) is widely used for difficult wound healing with a porcine-derived bilayered artificial dermis for better wound closure. Thus, their combination use was tested clinically. Sequential lower extremity reconstruction by an artificial dermis with or without bFGF administration and secondary split-thickness skin grafting was measured for hardness using a durometer, and the moisture parameters assessed such as effective contact coefficient, transepidermal water loss (TEWL), water content and thickness using a moisture meter for at least 6 months after the final procedure and compared with normal skin control. There was significantly less skin hardness using a durometer in bFGF treatment compared with non-bFGF treatment (16.2 +/- 3.83 vs. 29.2 +/- 4.94, p < 0.01). Effective contact coefficient, TEWL, water content, and thickness in non-bFGF treatment were all significantly greater than those in bFGF treatment, whereas water content and thickness in bFGF treatment were comparable with those of the control. The use of bFGF as artificial dermis for extensive and deeper tissue loss coverage demonstrated better reconstruction quality in terms of hardness using a durometer and the function of the stratum corneum by moisture analysis.