Site and mechanism of action of dynorphin A-(1-13) and N-methyl-D-aspartate on ACTH release in fetal sheep.
Dynorphin A (Dyn A) stimulates the release of ACTH in fetal sheep, a response that involves N-methyl-D-aspartate (NMDA) receptors but not the secretogogues corticotropin-releasing hormone or arginine vasopressin. We now find that neither Dyn A-(1-13) (0.5 mg/kg, i.v.) nor NMDA (4 mg/kg, i.v.) elicits ACTH release in postnatal lambs. This led us to hypothesize that Dyn A-(1-13) and NMDA might act to release placental ACTH. However, the ability of Dyn A-(1-13), NMDA, and the kappa-opioid receptor agonist U-50488H (1 mg/kg, i.v.) to release ACTH was lost after either fetal hypophysectomy (n = 4) or hypothalamo-pituitary disconnection (n = 4). These results indicate that neither the placenta nor the fetal pituitary is the site of action for these agonists and suggest a hypothalamic or suprahypothalamic site of action. Furthermore, the release of ACTH by Dyn A-(1-13) and NMDA was abolished after pretreatment with indomethacin, suggesting that they might cause the release of a prostanoid, possibly from the placenta, that subsequently acts at the hypothalamus or serves as a permissive factor in the action of Dyn A-(1-13) and NMDA at the hypothalamus.


How does thought suppression impact upon beliefs about uncontrollability of worry?
According to Wells' metacognitive model of generalised anxiety disorder (GAD; [Wells, A. (1995). Meta-cognition and worry: A cognitive model of generalised anxiety disorder. Behavioural and Cognitive Psychotherapy, 23, 301-320]), GAD patients attempt to suppress intrusions that trigger worry. Wells postulates that these attempts are rarely effective and may increase the frequency of worry triggers. These apparent failures are interpreted as evidence for loss of mental control, thereby exacerbating beliefs about worry uncontrollability. The current study tested these predictions. Sixty-two high worriers completed a naturalistic experiment comprising two sessions separated by 1 week. In Session 1, participants recorded their beliefs about worry in general, including its uncontrollability. They then selected a current worry and recorded how often it came to mind over the following week. The Suppression group (N=32) suppressed their chosen worry during the week. The Mention group (N=30) simply monitored its occurrence. In Session 2, Session 1 measures were repeated. Contrary to prediction, the Suppression group reported a significant increase in worry controllability in general. No shift was demonstrated by the Mention group. In addition, relative to the Mention group, the Suppression group reported more success at suppressing their chosen worries, spent less time thinking about them, and found them more controllable and less distressing. Findings are discussed within the context of Wells' model.


mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.
High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.


Covalent coupling of a PIM-1 oncogene targeted PNA with an antennapedia derived peptide.
Peptide nucleic acids (PNA) are promising antisense molecule for blocking gene expression in cell culture or in vivo. Nevertheless because they are poor efficient to pass the cellular membrane, it is necessary to use a vectorisation agent to observe an inhibitory effect. We describe the coupling of the rhodamine labeled 17-mer antisense PNA to a fusogenic peptide from antenapedia via S-S linkage, the studies of the penetration of this complex into fibroblast cells and its inhibitory effect on pim1 targeted protononcogene.


The clinical role of multimodality imaging in the detection of prostate cancer recurrence after radical prostatectomy and radiation therapy: past, present, and future.
Detection of the recurrence sites in prostate cancer (PCa) patients affected by biochemical recurrence after radical prostatectomy (RP) and radiation therapy (RT) is still a challenge for clinicians, nuclear medicine physicians, and radiologists. In the era of personalised and precision care, this task requires the integration, amalgamation, and combined analysis of clinical and imaging data from multiple sources. At present, multiparametric Magnetic Resonance Imaging (mpMRI) and choline-positron emission tomography (PET) are giving encouraging results; their combination allows the effective detection of local, lymph nodal, and skeletal recurrences at low PSA levels. Future diagnostic perspectives include the clinical implementation of PET/MRI scanners, multimodal fusion imaging platforms for retrospective co-registration of PET and MR images, real-time transrectal ultrasound/mpMRI fusion imaging, and novel organ-specific PET radiotracers.


[Effect of Electroacupunctrue on ERp57 in NAFLD Rats].
To investigate the effect of electroacupunctrue on ERp57 in non-alcoholic fatty liver disease (NAFLD) rats, and study the therapeutic mechanism of electroacupunctrue in patients with NAFLD. Sixty male SD rats were randomly divided into common diet group (n = 15) and high-fat diet group (n = 45). 5 weeks later, two rats from the two groups were executed and confirmed that the model was successful. Then 10 rats in common diet group were chosen as control group (Control), and 40 rats in high-fat diet group were randomly chosen and divided into diet group 1 (D1), diet group 2 (D2), electroacupuncture group 1 (EA) and electroacupuncture group 2 (EA2) (n = 10 each). D1 and EA1 were fed by high fat diet; D2 and EA2 were fed with common diet. In EA1 and EA2, filiform needle acupuncture was applied to ST36, SP6 and Liv3 and electroacupunctrue was applied to one-side of ST36, SP6 for 20 min once daily for 4 weeks. The rats in each group were weighed per-week. After the treatment the changes of blood lipid and liver functions of these rats were observed. ERp57 gene expression and protein expression were detected by RT-PCR and Western blot, and expression of ERp57 downstream SREBP-1c was detected. The body mass of D1 increased slowly and were lower than D2 and EA1 (P < 0.05); the body weights of EA2 increased rapidly and were higher than EA1 (P < 0.05), but without significant difference with D2 (P > 0.05). The contents of blood lipid, liver functions and the expression of ERp57 and SREBP-1c were significantly higher than those in Control, D2 and EA1 (P < 0.05). While compared to D2 and EA1 respectively, the index mentioned above in EA2 decreased more significantly (P < 0.05). Electroacupunctrue can decrease expression of ERp57 to improve endoplasmic reticulum stress (ERS) of rats with NAFLD and then decrease expression of SREBP-1c to regulate rat lipid, which could be one of mechanism to cure NAFLD.


Genetic differentiation of continental and island populations of Bombus terrestris (Hymenoptera: Apidae) in Europe.
Ten microsatellite loci and a partial sequence of the COII mitochondrial gene were used to investigate genetic differentiation in B. terrestris, a bumble bee of interest for its high-value crop pollination. The analysis included eight populations from the European continent, five from Mediterranean islands (six subspecies altogether) and one from Tenerife (initially described as a colour form of B. terrestris but recently considered as a separate species, B. canariensis). Eight of the 10 microsatellite loci displayed high levels of polymorphism in most populations. In B. terrestris populations, the total number of alleles detected per polymorphic locus ranged from 3 to 16, with observed allelic diversity from 3.8 +/- 0.5 to 6.5 +/- 1.4 and average calculated heterozygosities from 0.41 +/- 0.09 to 0.65 +/- 0.07. B. canariensis showed a significantly lower average calculated heterozygosity (0.12 +/- 0.08) and observed allelic diversity (1.5 +/- 0.04) as compared to both continental and island populations of B. terrestris. No significant differentiation was found among populations of B. terrestris from the European continent. In contrast, island populations were all significantly and most of them strongly differentiated from continental populations. B. terrestris mitochondrial DNA is characterized by a low nucleotide diversity: 0.18% +/- 0.07%, 0.20% +/- 0.04% and 0.27% +/- 0.04% for the continental populations, the island populations and all populations together, respectively. The only haplotype found in the Tenerife population differs by a single nucleotide substitution from the most common continental haplotype of B. terrestris. This situation, identical to that of Tyrrhenian islands populations and quite different from that of B. lucorum (15 substitutions between terrestris and lucorum mtDNA) casts doubts on the species status of B. canariensis. The large genetic distance between the Tenerife and B. terrestris populations estimated from microsatellite data result, most probably, from a severe bottleneck in the Canary island population. Microsatellite and mitochondrial DNA data call for the protection of the island populations of B. terrestris against importation of bumble bees of foreign origin which are used as crop pollinators.


Immunotherapy of human malignant melanoma with oil-attached BCG cell-wall skeleton.
A first case of malignant melanoma treated with oil-attached BCG cell-wall skeleton (BCG-CWS) is reported. The patient, a 70-year-old farmer, with metastatic malignant melanoma was treated intralesionally with oil-attached BCG-CWS or was given intradermally with oil-attached BCG-CWS together with irradiated autologous and allogeneic tumor cells. Four months after the start of the immunotherapy with oil-attached BCG-CWS, Primary tumor and metastatic inguinal lymph nodes regressed markedly without any significant complications. Lymphocytosis in the peripheral blood was usually observed after injection of oil-attached BCG-CWS.


Tuning and dissecting electronic and steric effects in ammonium receptors: nonactin vs artificial receptors.
Ion selective electrodes (ISE) based on three different tripodal receptors (5, 6, and 7) have been investigated for sensing ammonium ion. Each receptor is based on three pyrazole groups that can accept three H-bonds from the bound ammonium ion. The receptor based on 4-bromo-3,5-dimethylpyrazole (6) is the most sensitive with a detection limit for ammonium ion of 2.5 x 10(-5) M at pH 8. The detection limits for the receptors based on 2,3-dimethylpyrazole (5) and unsubstitued pyrazole (7) are 1.0 x 10(-4) and 2.0 x 10(-4) M, respectively. The selectivities of the receptors 5, 6, and 7 for sensing ammonium ion over potassium ion (logK(NH)4+(/K)+) are -2.8, -2.3, and -1.7, respectively. In contrast, the detection limit and the selectivity of a nonactin-based ISE are 2.2 x 10(-5) M and -1.3, respectively. Crystallographic studies reveal that 6 accepts three H-bonds from the bound ammonium and singly protonated receptor 5 forms three H-bonds with the bound water molecule.


Hypercholesterolemia increases the production of leukotriene B4 in neutrophils by enhancing the nuclear localization of 5-lipoxygenase.
Neutrophils can synthesize leukotriene B4 (LTB4) by activating the 5-lipoxygenase (5-LO)signaling pathway. LTB4 is a pro-inflammatory mediator associated with the etiology and progression of atherosclerosis. It can increase function and number of neutrophils in an autocrine manner. Since hypercholesterolemia is associated with an increase in the number and function of neutrophils, we hypothesized that this effect could be mediated through increased production of LTB4 in neutrophils. Hypercholesterolemia was modeled in Wistar rats by feeding them with a high cholesterol diet. The induction of hypercholesterolemia caused an increase in the plasma levels of LTB4, following lipopolysaccharide stimulation. This effect was recapitulated in vitro, both in the presence and absence of stimulation with the activator of 5-LO, A23187. Neutrophils in hypercholesterolemia rats expressed similar total levels of 5-LO as control rats, but displayed increased nuclear localization of 5-LO, as well as elevated levels of phosphorylated 5-LO and ERK1/2. In vitro, MβCD/cholesterol complexes enriched cholesterol in neutrophils, resulted in similar changes in 5-LO/LTB4. In addition, these alterations could be inhibited with the ERK inhibitor PD98059. Hypercholesterolemia increases LTB4 production in neutrophils by increasing the nuclear localization of 5-LO, which is the result of its phosphorylation by activated ERK1/2.


[Stroke prevention by statins].
The correlation between stroke incidence and serum lipid level has been equivocal, and conventional lipid-lowering agents such as fibrates were ineffective for stroke prevention. Recent clinical trials for HMG-CoA reductase inhibitors(statins) have demonstrated 20-30% reduction in the risk of cerebrovascular events and mortality in the population with previous coronary heart disease(CHD). The beneficial effect of statins was most evident for thromboembolic stroke, and no significant increase in hemorrhagic events was noted. Equal reduction in stroke risk was observed between hyper- and normocholesterolemic populations, indicating the non-lipid mechanisms of statins. The efficacy and safety of statin treatment make it a promising approach for the management of both CHD and non-CHD patients at high risk of stroke, especially the elderly.


The efficacy of generating three independent anti-HIV-1 siRNAs from a single U6 RNA Pol III-expressed long hairpin RNA.
RNA Interference (RNAi) effectors have been used to inhibit rogue RNAs in mammalian cells. However, rapidly evolving sequences such as the human immunodeficiency virus type 1 (HIV-1) require multiple targeting approaches to prevent the emergence of escape variants. Expressed long hairpin RNAs (lhRNAs) have recently been used as a strategy to produce multiple short interfering RNAs (siRNAs) targeted to highly variant sequences. We aimed to characterize the ability of expressed lhRNAs to generate independent siRNAs that silence three non-contiguous HIV-1 sites by designing lhRNAs comprising different combinations of siRNA-encoding sequences. All lhRNAs were capable of silencing individual target sequences. However, silencing efficiency together with concentrations of individual lhRNA-derived siRNAs diminished from the stem base (first position) towards the loop side of the hairpin. Silencing efficacy against HIV-1 was primarily mediated by siRNA sequences located at the base of the stem. Improvements could be made to first and second position siRNAs by adjusting spacing arrangements at their junction, but silencing of third position siRNAs remained largely ineffective. Although lhRNAs offer advantages for combinatorial RNAi, we show that good silencing efficacy across the span of the lhRNA duplex is difficult to achieve with sequences that encode more than two adjacent independent siRNAs.


Outcome appraisal of patients with limited brain metastases (BMs) from non small cell lung cancer (NSCLC) treated with different local therapeutic strategies: a single institute evaluation.
To evaluate the outcome of patients with non-small-cell lung cancer (NSCLC) with limited brain metastases (BMs) treated with local approaches omitting whole-brain radiation therapy (WBRT). Surgery was performed in case of a single, large BM, controlled extracranial disease and Karnofsky Performance Status (KPS) 90-100; stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiosurgery (HSRS) was performed in all other cases. The prescribed dose was 24 Gy/1 fraction for lesions <2.5 cm, and a median of 30 Gy (24-40 Gy) in 3-5 fractions for lesions >2.5 cm. 156 patients treated for 228 BMs were retrospectively evaluated. The median age was 62 years. The majority of patients had a KPS 90-100, recursive partitioning analysis Class II, diagnosis-specific graded prognostic assessment score 2.5-3 and 1-2 BMs. Surgical resection was performed in 18 cases, and SRS/HSRS was performed in 210 cases. The 1-2-year local control was 87.2 ± 3.0% and 72.8 ± 5.0%; the 1.2-year brain distant failure was 30.8 ± 4.0% and 58.1 ± 6.0%; the 1-2-year overall survival was 60.9 ± 3.9% and 31.4 ± 4.0%. On univariate and multivariate analysis, the following factors influenced survival: age (p = 0.01), the presence of lymph node involvement (p = 0.03), KPS (p << 0.01), the presence of extracranial metastases at the time of BM treatment (p < 0.01), the number of BMs (p = 0.02) and the treatment performed (p < 0.01). The choice of an adequate local treatment can impact on survival in patients with limited BMs from NSCLC. A careful evaluation of prognostic and predictive factors is a pivotal additional aid. Advances in knowledge: Radiosurgery or surgery followed by radiosurgery on the tumour bed in place of WBRT proved to be an effective treatment influencing outcome. Surgical resection followed by SRS on the tumour bed has to be considered for lesions ≥15 mm, in patients with good KPS, age ≤70 years, adenocarcinoma histology and oligometastatic disease.


Permissive and instructive induction of adult rodent prostatic epithelium by heterotypic urogenital sinus mesenchyme.
Adult rodent (rat and mouse) prostatic ducts (PR) were recombined heterospecifically with fetal urogenital sinus mesenchyme (UGM) (mouse UGM plus rat PR or rat UGM plus mouse PR), and the resultant tissue recombinants were grafted under the renal capsule of male athymic mice. For recombination with mouse UGM the ductal tips of each of the 4 rat prostatic lobes [ventral (VP), lateral type 1 (L1), lateral type 2 (L2), and dorsal prostate (DP)] were used. For recombination with rat UGM the ductal tips of each of the 2 mouse prostatic lobes [ventral (VP) and dorso-lateral prostate (DLP)] were used. After 1 month of growth in vivo, the DNA content of UGM+PR recombinants increased substantially (6.1- to 76.8-fold increase) over the combined DNA content of the isolated UGM and PR prior to grafting. Immunocytochemical, polyacrylamide gel electrophoretic and Western blot analyses demonstrated that irrespective of the initial source of the adult prostatic duct, the epithelium of UGM + PR recombinants continued to express its normal lobe-specific secretory proteins as well as secretory proteins specific to other prostatic lobes. For example, rat ventral and lateral type 2 prostate do not normally express DP-1, a rat dorsal-prostatic-specific protein, but after recombination with mouse UGM the induced prostatic epithelium expressed DP-1 as well as C3, a rat ventral-prostatic-specific protein. Sensitive reverse transcriptase-polymerase chain reaction techniques (RT-PCR) verified the expression of mRNA for C3 and DP-1 in such tissue recombinants. Analogous results were obtained for UGM + PR tissue recombinants constructed with prostatic ductal tips from rat L1, L2 and DP and mouse VP and DLP. These findings demonstrate that adult rodent prostatic epithelium retains a responsiveness to its connective tissue environment, and that fetal UGM can permissively induce prostatic ductal growth and morphogenesis while instructively inducing the expression of a new spectrum of prostatic secretory proteins.


Preoperative diagnosis and staging of gallbladder carcinoma by EUS.
EUS has recently been shown to be efficacious for the preoperative assessment of depth of invasion of gallbladder carcinoma. This study assessed the value of EUS for determining T stage (International Union Against Cancer). Preoperative EUS findings in 41 patients with gallbladder carcinoma were analyzed retrospectively. EUS images were classified according to the shape of the tumor and the adjacent gallbladder wall structure as follows: type A, pedunculated mass with preserved adjacent wall structures; type B, sessile and/or broad-based mass with a preserved outer hyperechoic layer of the gallbladder wall; type C, sessile and/or broad-based mass with a narrowed outer hyperechoic layer; type D, sessile and/or broad-based mass with a disrupted outer hyperechoic layer. EUS and histopathologic findings were compared, including the depth of invasion of the tumor in the resection specimen. The 4 categories of EUS images of gallbladder carcinoma correlated with the histologic depth of invasion and T stage. Accuracies for the EUS classification as type A corresponding to pTis, type B to pT1, type C to pT2, and type D to pT3-4 were, respectively, 100%, 75.6%, 85.3%, and 92.7%. Preoperative EUS imaging accurately depicts T stage of gallbladder carcinoma and allows for effective therapeutic decision making.


Radiation dose reconstruction from L-band in vivo EPR spectroscopy of intact teeth: Comparison of methods.
In vivo EPR tooth dosimetry is a more challenging problem than in vitro EPR dosimetry because of several potential additional sources of variation associated with measurements that are made in the mouth of a living subject. For in vivo measurement a lower RF frequency is used and, unlike in the in vitro studies, the tooth cannot be processed to optimize the amount and configuration of the enamel that is measured. Additional factors involved with in vivo measurements include the reproducibility of positioning the resonator on the surface of the tooth in the mouth, irregular tooth geometry, and the possible influence of environmental noise. Consequently, in addition to using the theoretical and empirical models developed for analyzing data from measurements of teeth in vitro, other unconventional and more robust methods of dose reconstruction may be needed. The experimental parameter of interest is the peak-to-peak amplitude of the spectrum, which is correlated to the radiation dose through a calibration curve to derive the reconstructed dose. In this study we describe and compare the results from seven types of computations to measure the peak-to-peak amplitude for estimation of the radiation induced signal. The data utilized were from three sets of in vivo measurements of irradiated teeth. Six different teeth with different doses were placed in the mouth of a volunteer in situ and measurements of each tooth were carried out on three different days. The standard error of dose prediction (SEP) is used as a figure of merit for quantifying precision of the reconstruction. We found that many of the methods gave fairly similar results, with the best error of prediction resulting from a computation based on a Lorentzian line model whose center field corresponds to the known parameter of the radiation-induced EPR spectra of teeth, with corrections from a standard sample that was measured as part of the data acquisition scheme. When the results from the three days of measurement were pooled, the SEP decreased dramatically, which suggests that one of the principal sources of variation in the data is the ability to precisely standardize the measurements conditions within the mouth. There are very plausible ways to accomplish improvements in the existing procedures.


Prediction and analysis of atmospheric visibility in five terrain types with artificial intelligence.
Scattering visiometers are widely used to measure atmospheric visibility; however, visibility is difficult to measure accurately because the extinction coefficient decays exponentially with visual range according to the Koschmid's law. Moreover, models for predicting visibility are lacking due to the lack of accurate visibility observations to verify. This study formulated an artificial intelligence method for measuring atmospheric visibility in five topographical regions: hills, basins, plains, alluvial plains, and rift valleys. Four air pollution factors and five meteorological factors were selected as independent variables for predicting visibility by using three artificial intelligence models, namely a support vector machine (SVM) model, a multilayer perceptron (MLP) model, and an extreme gradient boosting (XGBoost) model. The GridSearchCV function was used to automatically tune model hyperparameters to determine the optimal parameter values of the three models for the five target areas. The predictions of the aforementioned three models underwent considerable considerably scale shrinking relative to observed values. The inappropriately low predicted visibility values might have been caused by the use of inaccurate observations for training. To solve this problem, formulas of scale ratio and downshift were used to adjust the predicted values. Statistical measurements of model performance measures by five quantitative methods (e.g., correlation coefficient, mean absolute error) showed that adjusted predictions were in strong agreement with the observation data for the five target areas. Therefore, the adjusted prediction has high reliability. Because of obvious differences in the topography, weather, and air quality of the five target areas, different models provided optimal predictions for different areas. In densely populated western Taiwan, the MLP model is most suitable for predicting visibility on hills whereas the XGBoost model is most suitable for predicting visibility on basins and plains. In eastern Taiwan, the SVM model is most suitable for predicting visibility on alluvial plains and rift valleys. Thus, the optimal prediction model should be identified according to the conditions in each area. These results can inform decision-making processes or improve visibility predicting in specific areas.


OPCML gene promoter methylation and gene expression in tumor and stroma cells of invasive cervical carcinoma.
To investigate the CpG island methylation and the mRNA expression of OPCML gene in patients with cervical carcinoma, we collected tumor and stroma cells from 36 invasive cervical carcinoma samples and 16 normal cervical tissues as well as Hela cells. Methylation specific PCR was used to detect promoter CpG island methylation status, and fluorescence quantitative RT-PCR was used to detection of OPCML gene expression. Our data showed that OPCML gene promoter methylation may play an important role in the carcinogenesis of cervical carcinoma and OPCML gene may be a cervical carcinoma-associated candidate TSG (tumor suppressor gene).


Supplemented dialysis: amino acid-based solutions in peritoneal dialysis.
Peritoneal dialysis is associated with several metabolic and nutritional abnormalities, some of which are related to the use of glucose-based solutions. Furthermore, the catabolic effects of uremia per se, protein and amino acid losses into the dialysate, peritonitis and poor appetite contribute to amino acid abnormalities, negative nitrogen balance and a high prevalence of malnutrition in peritoneal dialysis patients. To overcome these problems the use of amino acid instead of glucose as an osmotic agent has been proposed. Short-term studies have shown that amino acid-based solutions in peritoneal dialysis may supplement in excess the daily losses of amino acids during dialysis with glucose-based solutions. The amino acid solutions produce similar ultrafiltration and solute transport as the standard glucose solutions although the period of effective ultrafiltration is rather short. However, it should be noted that some studies have reported that the transport of small and large solutes may increase in patients using amino acid solutions. During the early 1980s several investigators have developed and tested different amino acid solutions for peritoneal dialysis. The initial clinical experience from Toronto with amino acid solutions containing large amounts of non-essential amino acids and inadequate amount of buffer were in general discouraging. The patients, who were not always malnourished and tended to have a low energy intake, developed increased BUN levels, acidosis, no improvement in nutritional status or amino acid abnormalities and, in some cases, anorexia. In 1985 a new 1% amino acid solution, containing an increased buffer amount and amino acids (mainly essential) in proportions which take the amino acid abnormalities in uremic patients into account, became available. The use of this solution resulted in some improvement in amino acid pattern and nutritional parameters, but acidosis and increased BUN levels remained problems. The experiences from these and previous studies showed that: (1) the improvement of the composition of amino acid solutions was beneficial; (2) a further increase of the buffer amount was needed; (3) patients included should have signs of protein malnutrition combined with low dietary protein intake to benefit from intraperitoneal amino acid supply, and (4) energy intake should be sufficient to prevent amino acids to end up as energy source. For this purpose a new improved 1.1% amino acid solution has been developed containing a further increase of some essential amino acids and an increased amount of lactate (40 mmol/l). This solution has been tested in malnourished patients eating 0.8 g protein/kg/day and 25-30 kcal/kg/day.(ABSTRACT TRUNCATED AT 400 WORDS)


Novel evidence suggesting Clostridium difficile is present in human gut microbiota more frequently than previously suspected.
Prevalence rate of Clostridium difficile in healthy human adults is believed to be very low. Our RT-PCR system using glass powder, which can eliminate PCR inhibitors, detected C. difficile toxin B mRNA in 16 of 30 fecal samples (53.3%) from healthy human adults. In contrast, we failed to detect toxin B in the same fecal samples by PCR using DNA templates extracted with phenol-chloroform. Our results suggest that PCR inhibitors in feces carried through phenol-chloroform extraction procedure might suppress the sensitivity of PCR and that C. difficile is actually present in human gut microbiota more frequently than previously suspected.


Activation of the human immunodeficiency virus long terminal repeat in THP-1 cells by a staphylococcal extracellular product.
Staphylococcal strains can release a factor that strongly activates the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in THP-1 cells transfected with the HIV-1 LTR-driven luciferase reporter gene (THP-1 LTRluc). The factor is present in the overnight culture fluid and is readily released from the organisms into aqueous medium by vigorous mixing. Staphylococcal extracellular material is a complex mixture of polysaccharide and protein containing peptidoglycan and teichoic acid, released in part by cell wall turnover. The importance of the carbohydrate component is emphasized by concanavalin A (Con A) inhibition of staphylococcal product-induced LTR activation but not of activation by phorbol 12-myristate 13-acetate or tumor necrosis factor. The effect of Con A was decreased or abolished by sugars in the order methyl alpha-D-mannopyranoside > methyl alpha-D-glucopyranoside > mannose > glucose = fructose > N-acetylglucosamine. Wheat germ agglutinin was less inhibitory than Con A; in this instance N-acetylglucosamine decreased inhibition, whereas methyl alpha-D-mannopyranoside or methyl alpha-D-glucopyranoside did not. The induction of luciferase activity in THP-1 LTRluc by the staphylococcal extracellular product also was inhibited by fetal bovine and normal human serum. A comparison of 31 staphylococcal isolates (9 Staphylococcus aureus, 11 Staphylococcus epidermidis, 2 Staphylococcus haemolyticus, 4 Staphylococcus hominis, 2 Staphylococcus capitis, 2 Staphylococcus warneri, 1 Staphylococcus saprophyticus) revealed wide variation in LTR activating activity that did not correlate closely with slime production. Our findings, using induction of luciferase in THP-1 LTRluc as a model for upregulation of HIV infection, raise the possibility that staphylococci, as well as certain other microorganisms, release carbohydrate-containing exopolymers, which can activate the HIV-1 LTR, thus influencing progression of HIV infection.


Rate of inter-herd transmission of classical swine fever virus by different types of contact during the 1997-8 epidemic in The Netherlands.
In this study we quantified the rate at which classical swine fever had been transmitted by several different types of inter-herd contact during the 1997-8 epidemic in The Netherlands. During that epidemic 428 CSFV-infected pig herds were detected, 403 of which were include in this study. The estimated rates of transmission were 0.065 per shipment of live pigs, 0.011 per contact by a pig transportation lorry, 0.0068 per person contact, 0.0007 per dose of semen, 0.0065 per contact with a potentially contaminated pig assembly point, 0.027 per week per infected herd within a radius of 500 metres and 0.0078 per week per infected herd at a distance between 500 and 1000 metres. These transmission rates can be used to optimize the strategy to stop future epidemics of CSF in The Netherlands. In addition, the analysis demonstrated in this paper, can be used to quantify CSFV transmission rates from other epidemics.


Consensus for the Fip35 folding mechanism?
Recent advances in computational power and simulation programs finally delivered the first examples of reversible folding for small proteins with an all-atom description. But having at hand the atomistic details of the process did not lead to a straightforward interpretation of the mechanism. For the case of the Fip35 WW-domain where multiple long trajectories of 100 μs are available from D. E. Shaw Research, different interpretations emerged. Some of those are in clear contradiction with each other while others are in qualitative agreement. Here, we present a network-based analysis of the same data by looking at the local fluctuations of conventional order parameters for folding. We found that folding occurs through two major pathways, one almost four times more populated than the other. Each pathway involves the formation of an intermediate with one of the two hairpins in a native configuration. The quantitative agreement of our results with a state-of-the-art reaction coordinate optimization procedure as well as qualitative agreement with other Markov-state-models and different simulation schemes provides strong evidence for a multiple folding pathways scenario with the presence of intermediates.


Analysis of Contact Allergens in Polyvinyl Chloride Examination Gloves in the United States.
Background: Polyvinyl chloride (PVC) gloves are recommended as a safe alternative for patients with rubber accelerator allergy. However, allergic contact dermatitis to other chemicals in PVC gloves has been reported. Objective: To analyze single-use PVC medical examination gloves in the United States for the presence of potential contact allergens. Methods: Using liquid chromatography-mass spectrometry, 20 unique PVC gloves were analyzed in triplicate for 6 chemicals: benzisothiazolinone, bisphenol A, mono(2-ethylhexyl) maleate, tricresyl phosphate, triphenyl phosphate, and triphenyl phosphite. Results: All 20 PVC gloves contained detectable quantities of benzisothiazolinone (range, 0.001-1.48 parts per million [ppm]), bisphenol A (0.01-0.11 ppm), triphenyl phosphate (0.01-2.11 ppm), and triphenyl phosphite (0.001-0.22 ppm). Eighteen (90%) gloves contained mono(2-ethylhexyl) maleate (0.001-0.14 ppm) and 3 (15%) contained tricresyl phosphate (0.001-0.002 ppm). Conclusions: Known allergens were present in all 20 PVC gloves. However, the detected levels were mostly low and their relationship with sensitization and elicitation thresholds requires further study.


Hemodynamic and morphological differences in cerebral aneurysms between before and after rupture.
Although it has been proposed that aneurysm morphology is different after rupture, detailed research of the morphological changes using 3D imaging acquired before and after rupture has not been conducted because of the difficulty of data collection. Similarly, hemodynamic changes due to morphological alterations after rupture have not been analyzed. The aim of this study was to investigate the changes in morphology and hemodynamics observed after aneurysm rupture. For 21 cerebral aneurysms (21 patients) that ruptured during observation, 3D geometry of the aneurysms and parent arteries were reconstructed based on the angiographic images before and after their rupture. In addition, using the reconstructed geometry, blood flow was simulated by computational fluid dynamics (CFD) analysis. Morphological and hemodynamic parameters were calculated both before and after rupture, and their changes from before to after were compared. In the morphological parameters, statistically significantly higher values were observed after rupture in height (before: 5.5 ± 2.1 mm, after: 6.1 ± 2.0 mm; p < 0.0001), aspect ratio (p = 0.002), aneurysm volume (p = 0.04), and undulation index (p = 0.005). In terms of hemodynamic changes, the mean normalized wall shear stress (NWSS) decreased significantly (before: 5.4 × 10-1 ± 2.9 × 10-1, after: 4.4 × 10-1 ± 2.8 × 10-1; p < 0.001) as well as the other NWSS parameters, including maximum and minimum NWSS, which were associated with stagnant flow due to the morphological changes after rupture. Aneurysm morphology was found to change after rupture into an elongated and irregular geometry, accompanied by an increase in aneurysm volume. These morphological changes were also associated with statistically significant hemodynamic alterations that produced low wall sheer stress by stagnant flow. The authors' results also provide the opportunity to explore and develop a risk evaluation method for aneurysm rupture based on prerupture morphology and hemodynamics by further exploration in this direction.


[Hypovitaminosis D and burn injury].
Vitamin D deficiency is common in adults and even in children, appearing to be more frequent than expected.Accumulating data about the pleiotropic effects of vitamin D have raised renewed interest in this hormone. Severe burn injury represents a unique trauma leading to major systemic dysfunctions such as bone loss, mineral disruptions, myopathy, or immunosuppression. Moreover, burn patients are at high risk of hypovitaminosis D. In this context, vitamin D supplementation could help counteract post-burn sequelae. The aim of the present review is to summarize the current knowledge on vitamin D with a special focus on burn related hypovitaminosis D.


The role of self-interest in unethical pro-organizational behavior: A nomological network meta-analysis.
To date, the unethical pro-organizational behavior (UPB) literature has been guided by a prosocial perspective, which argues that people engage in UPB primarily to benefit the employers with whom they identify and have a positive social exchange. According to this perspective, employees who are characteristically self-interested are less likely to engage in UPB. However, recent evidence suggests self-interest may play a larger role in motivating UPB than originally theorized. To clarify this controversy, we offer two different, but not necessarily mutually exclusive, perspectives of UPB-one in which UPB is driven primarily by prosocial motives and one in which it is driven primarily by self-interest. We tested which of these accounts of UPB was more strongly supported by comparing UPB's relationships with two nomological networks: one containing relatively prosocially motivated constructs and the other containing relatively self-interest-motivated constructs. Two of the eight hypotheses from the prosocial perspective were supported, while seven of the eight hypotheses from the self-interest perspective were supported. Additionally, the average absolute value of UPB's correlations with prosocial perspective constructs was .09, while the comparable average correlation with self-interest perspective constructs was .33. Thus, the results favored the self-interest perspective. We discuss how these findings change our theoretical understanding of UPB by acknowledging both its prosocial and self-interest motivations, and we accordingly propose a revised definition for UPB that allows for both of these motivations. We also examined more broadly the relationship between UPB and other constructs to provide a comprehensive meta-analytic overview of this literature. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Elbow pain.
Nonarticular causes of elbow pain include muscle strains, ligamentous injuries, epicondylitis, olecranon bursitis, and compressive neuropathies. Overuse and trauma commonly cause these conditions. The history and physical examination differentiate them from an intra-articular process such as synovitis. Laboratory analysis of fluid aspirated from a swollen olecranon bursa is necessary to differentiate infection or gout. X-rays are useful in avulsion fracture, osteochondritis dissecans, and epiphyseal separation. Electromyography with nerve conduction velocities can localize the site of nerve entrapment. Treatment, in general, consists of prevention from further overuse, protection by rest and splinting to allow healing, pharmacologic intervention to reduce inflammation, relieve pain and combat infection, and physical therapy to restore motion and function. Surgery may be necessary to repair torn muscle, to release the wrist extensors in refractory lateral epicondylitis, and to decompress an entrapped nerve.


Treating suicidality in depressive illness. Part I: current controversies.
To consider 2 current controversies about the treatment of depressed suicidal patients: 1) whether they are undertreated by physicians and 2) whether the increase in antidepressant prescribing in recent years is responsible for the observed fall in suicide rates in some countries. Systematic review of the literature. Analysis of Canadian data. There is evidence that depressive illness in suicidal persons has been undertreated, but there has been improvement, possibly in response to enhanced public and professional awareness. There continues to be public resistance to taking antidepressants and (among men) to seeking professional help for suicidal depression. Because of inconsistencies, the epidemiologic evidence (although sometimes compelling) remains inconclusive for attributing the decline in suicide rates in some countries to the increase in new-generation antidepressants supply. Physicians should aggressively pursue recognition and treatment of depression and suicidality but not put their entire faith in medication. Suicide is the product of complex factors that become the person's individual predicament, some of them beyond the capacity of antidepressant drugs to control. The physician should endeavour to assist the patient either to alter the personal predicament or to come to terms with it, as well as prescribing medication appropriately.


Familial amyloid polyneuropathy in a Sri Lankan family.
A woman who presented with features of peripheral sensory, motor and autonomic neuropathy and amyloid deposits in the vitreous due to familial amyloid polyneuropathy (FAP) is described. Her father had died of a similar illness and one of her brothers and her two children had lesions suggestive of early amyloid deposits in the vitreous. Reports of familial amyloidosis are rare from Asian countries and it has not been reported in Sri Lanka previously.


A Service Or a Right: Informed Consent for HIV-Positive Latin American Men in Japan.
Since April 1996, Japanese health care providers who practise informed consent have been financially rewarded. Although there is no precedent for this financial gain, there are no detailed studies. Focused on a group of Latin American men living with HIV/AIDS, this paper clarifies the actual practices of informed consent at Japanese medical facilities. Twenty HIV-positive men were interviewed in order to investigate how they obtained medical treatment and how they were informed about their physical condition. From April to September 2002 and during August 2003 and 2004, a set of six interviews were conducted with each male, who were 28-37 years old. Participants were acquired through a hospital and a non-governmental organization, and by snowball sampling. The interviews showed that most of the informants received information concerning medical treatment, but they were advised neither about alternative treatments nor about the feasibility of seeking a third party's advice. Informed consent and communication between the informants and physicians were obstructed by language and structural, as well as cultural barriers. In conclusion, this paper adds a new dimension to the understanding of informed consent as the authors regard the practice as an educational process for health care providers and patients.


Fascicular turnover flap in the reconstruction of facial nerve defects: an experimental study in rats.
The purpose of this study was to assess the utility of a fascicular turnover flap for facial nerve repair and to investigate its possible application in the field of facial nerve repair using a rat model of facial paralysis. Twenty-four Wistar rats were used in this study. A left vibrissal muscle palsy model was established via excision of the buccal and marginal branches through a periauricular incision. In Group 1, the nerve gap was not reconstructed. In Group 2, the nerve gap of the marginal mandibular branch was reconstructed using an autograft, and in Group 3, the gap was reconstructed using a fascicular turnover flap. At 12 weeks after the operation, the nerve regeneration was assessed based on clinical, histopathological and electrophysiological evaluations. The functional recovery of the vibrissal muscle was observed with a fascicular turnover flap. The functional recovery of whisker movement was almost same between Groups 2 and 3 (p = .57). The histopathological examinations almost same result between Groups 2 and 3 (p = .17). The compound muscle action potential after reconstruction was also almost same between Groups 2 and 3 (p = .99). We found that the fascicular turnover flap could be applied to facial nerve gap reconstruction. However, further evaluations will be necessary to clarify its indication and mechanism in human.


Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity.
Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.


A Pilot Study of Non-invasive Sacral Nerve Stimulation in Treatment of Constipation in Childhood and Adolescence.
Background/Aims: Constipation shows both, a high prevalence and a significant impact. However, it is often perceived as minor and treatment choices are limited. The neuromodulation approach is a valuable option to be considered. This study assesses the use of non-invasive sacral nerve stimulation to reduce constipation in children. Methods: Between February 2013 and May 2015, pediatric patients with chronic constipation were treated with this non-invasive neuromodulation procedure, adapted from classical sacral nerve stimulation. A stimulation device attached to adhesive electrodes on the lower abdomen and back generated an electrical field with a stable frequency of 15 Hz via variable stimulation intensity (1-10 V). The effect of therapy was evaluated in routine check-ups and by specialized questionnaires. Results: The study assessed non-invasive sacral nerve stimulation in 17 patients (9 boys, 8 girls, mean age 6.5 years). They underwent stimulation with 6-9 V for a mean of 11 h per day (range 0.5-24 h) over a mean of 12.7 weeks. Improvement of constipation was achieved in more than half of the patients (12/17) and sustained in almost half of these patients (5/12). Complications were minor (skin irritation, electrode dislocation). Conclusions: Non-invasive sacral nerve stimulation appears to be effective in achieving improvement in pediatric patients with chronic constipation. As an additional external neuromodulation concept, this stimulation may represent a relevant addition to currently available therapeutic options. Further studies are needed to confirm these results.


Chinese Ethnicity Is Associated With Concomitant Cartilage Injuries in Anterior Cruciate Ligament Tears.
Chinese ethnicity is associated with the presence of knee osteoarthritis. This raises the possibility that it may similarly be associated with concomitant meniscus and cartilage injuries in patients with anterior cruciate ligament (ACL) tears. There are currently no published data on the effect of Chinese ethnicity in this regard. The primary aim was to determine whether Chinese ethnicity is associated with concomitant intra-articular injuries in patients with ACL tears and to verify the correlation of age, sex, body mass index, mechanism of injury, cause of injury, and presence of bone contusions on magnetic resonance imaging with such injuries. A secondary purpose was to determine the optimal time frame for surgical reconstruction in patients with identified risk factors for concomitant injuries. Cohort study; Level of evidence, 3. The medical records of 696 patients from a multiethnic population who underwent ACL reconstruction from January 2013 to August 2016 were retrospectively analyzed. Univariate and multivariate logistic regression analyses were performed to identify patient factors that were associated with medial meniscus tears, lateral meniscus tears, and cartilage injuries. Further univariate analysis was conducted to determine the earliest time point for surgery, after which the rate of concomitant injuries was significantly higher. Over half (69.1%, n = 481) of our study population sustained at least 1 other concomitant knee injury. Meniscus tears were most frequently associated with ACL tears (24.1% medial, 25.6% lateral, and 15.5% medial and lateral meniscus tears). Cartilage injuries were present in 18.4% of our cohort. Chinese ethnicity was associated with concomitant cartilage injuries. Increased age (≥30 years) was significantly associated with cartilage injuries and male sex with medial and lateral meniscus tears. Among patients with these factors, significantly fewer medial meniscus tears and cartilage injuries were noted when surgery was carried out within 12 months of the index trauma. This is one of the first studies to have identified an association between Chinese ethnicity and concomitant cartilage injuries in ACL tears. This study also found an association between increased age and an increased prevalence of cartilage injuries. Male sex was associated with both medial and lateral meniscus tears. Definitive surgery should be performed within 12 months of the index injury to minimize further intra-articular injuries.


Improvement of Split Skin Graft Quality Using a Newly Developed Collagen Scaffold as an Underlayment in Full Thickness Wounds in a Rat Model.
Frequently, full thickness skin defects were treated through split skin graft (SSG) transplantation. However, this is usually associated with a reduction of skin quality and scarring. In this context, a newly developed collagen cell carrier (CCC) has been evaluated as an underlayment in SSG transplantations in a rat model. Twenty-eight standardized full thickness skin defects were generated on the back of 28 adult male Lewis rats. The wounds were randomized and treated with SSG transplantation solitarily (n = 14) or SSG transplantation using CCC as an underlayment (n = 14). For skin quality analysis, a histological evaluation was performed 3 months postoperative in regard to epidermal cell count and epidermal and dermal thickness. Wounds treated with SSG and CCC demonstrated a thicker epidermis and significantly higher epidermal cell count compared to SSG solitarily. At the time of evaluation, epidermal thickness of SSG and CCC was comparable to untreated, healthy skin (no statistically significant differences). As split skin grafting is frequently associated with skin quality reduction, the presented results reveal the beneficial effects of CCC in terms of skin graft quality improvement. This may offer unique opportunities in wound management and encourages further evaluation of CCC in surgical applications and regenerative medicine.


[Clinico-electrophysiologic study of the anti-arrhythmic action of trimecaine].
The antiarrhythmic activity of trimecaine hydrochloride administered orally and intramuscularly was studied in 58 patients with coronary heart disease accompanied by ventricular and supraventricular rhythm disorders. In 73.9% of the cases the drug exhibited antiarrhythmic action which was reflected in a longer period of the recovery of sinus node function, inhibited conduction in the atrioventricular node and a decreased time of intraatrial conduction. Side effects were observed in 17.3% of the cases mostly with the oral drug; they tended to abate spontaneously 2-4 h after trimecaine hydrochloride withdrawal.


Delayed breast reconstruction with implants after invasive breast cancer does not impair prognosis.
We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women <70 years who underwent breast reconstruction with implants after mastectomy after invasive breast cancer during 1978 to 1992, on average 2.2 years (range, 3 days-9.4 years) after mastectomy. The reconstructed women were closely matched to breast cancer patients without reconstruction on age and calendar time of diagnosis, tumor size, regional lymph node involvement, and adjuvant radiation therapy. Overall, 580 reconstructed women and 1158 individually matched controls were followed-up for disease-free survival within the first 10 years and for overall survival for an average of 20.1 year (range, 12.8-27.5 years). Disease-free survival was significantly improved hazard ratio 0.78; 95% confidence interval 0.64-0.95 and overall survival was nonsignificantly improved (hazard ratio, 0.90; 95% confidence interval 0.76-1.06) among the breast reconstructed women. This is likely because of differences in socioeconomic and health factors.


Bone mineral density in adolescent girls with anorexia nervosa--a cross-sectional study.
The total body and lumbar spine bone mineral density (BMD) were measured in order to determine the prevalence and possible risk factors of decreased BMD in anorexia nervosa (AN). Sixty-one in-patient girls with DSM III-R AN: age 14.7+/-2.16 years; duration of AN 12.9+/-15.1 months; percentage of ideal body weight 70+/-8.7%; body mass index score -1.62+/-0.79. Total body (in 61 patients) and lumbar spine BMD (in 43 patients), content of lean and fat tissue mass were measured by DXA during the first month of treatment. Low total body BMD was found in 23.7% and low lumbar spine BMD in 36.6% of patients. There was a negative correlation between BMD and age, age of menarche, degree of undernourishment, duration of AN and amenorrhea. A step-wise linear regression analysis revealed that age of menarche was the most important factor related to BMD in this group.


Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation.
Safe parameters for electrical cortical stimulation in humans are difficult to estimate from the animal experimental literature. We therefore examined the light microscopic histology at a total of 11 sites of direct subdural electrical stimulation, taken as part of anterior temporal lobectomies in 3 patients. Stimulations had been done through 3.175 mm diameter electrodes, with 0.3 msec square wave pulses of alternating polarity at 50 pulses/sec. In 2 patients, one site each had been used as a common reference for stimulation, receiving over 251 stimulation trials, most of 2-5 sec duration, at currents of 12.5-15.0 mA, 1 day prior to resection. The maximum charge per phase was 4.0-4.4 microC; the maximum charge density was 52-57 microC per geometric cm2 per pulse at the electrode surfaces. Comparison of hematoxylin and eosin, periodic acid-Schiff, and cresyl violet-stained material from the electrode sites with that from other regions did not show any histologic abnormalities attributable to the electrical stimulation. The relatively brief and intermittent periods utilized for human stimulation testing do not appear to cause structural damage at the light microscopic level at charge densities that exceed the threshold for damage established in animal studies with more continuous, chronic stimulation schedules.


The prognostic role of blood lymphocyte subset distribution in patients with resected high-risk primary or regionally metastatic melanoma.
The aim of this study was to investigate whether the profile of peripheral blood lymphocyte subsets of patients with high-risk malignant melanoma is associated with prognosis. Blood samples were systematically obtained from 31 patients with high-risk melanoma eligible for the Nordic Melanoma Cooperative Group adjuvant interferon study. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using CD3, CD4, CD8, CD56, and CD69 monoclonal antibodies. Patients with low proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells before treatment had an improved disease-free survival compared to those with high proportions [77.7 vs. 16.8 mo, hazard ratio (HR) 0.25, confidence interval (CI) 0.09-0.71, P=0.005 and 77.2 vs. 16.0 mo, HR: 0.25, CI 0.086-0.73, P=0.001, respectively]. Low pretreatment levels of these cell populations also correlated with a better overall survival (79.2 vs. 22.6 mo, HR: 0.17, CI 0.05-0.52, P=0.0005 and 78.2 vs. 21.4 mo, HR: 0.2, CI 0.07-0.59, P=0.001, respectively). In the multivariate analysis both the pretreatment proportion of CD3+CD4+CD69+ cells (P=0.01, HR: 0.21, CI 0.07-0.67) and CD3+CD56+ cells (P=0.01, HR: 0.22, CI 0.062-0.65) were independent prognostic factors for overall survival. Our data show that both the proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells seem to have a prognostic potential in the natural course of melanoma. These results need to be confirmed in larger studies.


The application of digestive tract lactic acid bacteria with high esterase activity for zearalenone detoxification.
Zearalenone (ZEA) is an estrogenic mycotoxin produced by several Fusarium species and frequently contaminates cereals used for food or animal feed. This study attempted to select lactic acid bacteria (LAB) with high esterase activity from the digestive tract, with the goal of using these bacteria for ZEA detoxification. No ZEA activity-related biotransformation products were observed in three isolates (B1, B2 and D10) during incubation in the presence of ZEA. All three LAB strains were Lactobacillus plantarum, but the API 50 CHL results suggested that the three isolates were different strains. Increased esterase activity was associated with an increase in cell growth, and the ZEA-detoxifying capabilities of isolates rely on the concentration of bacteria in the culture medium. The lipolytic activity and ZEA removal assay indicated that ZEA degradation by the supernatant fraction was dependent on esterase activity; the supernatant of B2 strain showed the highest ZEA degradation ability and did not release the binding ZEA back into the medium. The D10 strain showed fast ZEA binding ability during the late log phase but began to release the bound ZEA back into the medium after the early stationary phase. All isolates showed good acid and bile salt tolerance ability but all strains showed low adhesion ability to epithelial cells. Based on the ZEA removal characterization and ability of the isolates, it is suggested that the isolates could be applied to ZEA detoxification of contaminated feed, but the with the requirement of high cell number for ZEA binding and limited degradation time before absorption of ZEA in the digestive tract. © 2018 Society of Chemical Industry.


Neural mechanisms underlying binocular fusion and stereopsis: position vs. phase.
The visual system utilizes binocular disparity to discriminate the relative depth of objects in space. Since the striate cortex is the first site along the central visual pathways at which signals from the left and right eyes converge onto a single neuron, encoding of binocular disparity is thought to begin in this region. There are two possible mechanisms for encoding binocular disparity through simple cells in the striate cortex: a difference in receptive field (RF) position between the two eyes (RF position disparity) and a difference in RF profile between the two eyes (RF phase disparity). Although there have been studies supporting each of the two encoding mechanisms, both mechanisms have not been examined in a single study. Therefore, the relative roles of the two mechanisms have not been determined. To address this issue, we have mapped left and right eye RFs of simple cells in the cat's striate cortex using binary m-sequence noise, and then we have estimated RF position and phase disparities. We find that RF position disparities are generally limited to small values that are not sufficient to encode large binocular disparities. In contrast, RF phase disparities cover a wide range of binocular disparities and exhibit dependencies on orientation and spatial frequency in a manner expected for a mechanism that encodes binocular disparity. These results indicate that binocular disparity is mainly encoded through RF phase disparity. However, RF position disparity may play a significant role for cells with high spatial frequency selectivity, which are constrained to small RF phase disparities.


Extrahepatic manifestations of HCV: the role of direct acting antivirals.
Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations. This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions. Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.


Global range expansion history of pepper (Capsicum spp.) revealed by over 10,000 genebank accessions.
Genebanks collect and preserve vast collections of plants and detailed passport information, with the aim of preserving genetic diversity for conservation and breeding. Genetic characterization of such collections has the potential to elucidate the genetic histories of important crops, use marker-trait associations to identify loci controlling traits of interest, search for loci undergoing selection, and contribute to genebank management by identifying taxonomic misassignments and duplicates. We conducted a genomic scan with genotyping by sequencing (GBS) derived single nucleotide polymorphisms (SNPs) of 10,038 pepper (Capsicum spp.) accessions from worldwide genebanks and investigated the recent history of this iconic staple. Genomic data detected up to 1,618 duplicate accessions within and between genebanks and showed that taxonomic ambiguity and misclassification often involve interspecific hybrids that are difficult to classify morphologically. We deeply interrogated the genetic diversity of the commonly consumed Capsicum annuum to investigate its history, finding that the kinds of peppers collected in broad regions across the globe overlap considerably. The method ReMIXTURE-using genetic data to quantify the similarity between the complement of peppers from a focal region and those from other regions-was developed to supplement traditional population genetic analyses. The results reflect a vision of pepper as a highly desirable and tradable cultural commodity, spreading rapidly throughout the globe along major maritime and terrestrial trade routes. Marker associations and possible selective sweeps affecting traits such as pungency were observed, and these traits were shown to be distributed nonuniformly across the globe, suggesting that human preferences exerted a primary influence over domesticated pepper genetic structure.


Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma.
Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma.


Preictal activity of subicular, CA1, and dentate gyrus principal neurons in the dorsal hippocampus before spontaneous seizures in a rat model of temporal lobe epilepsy.
Previous studies suggest that spontaneous seizures in patients with temporal lobe epilepsy might be preceded by increased action potential firing of hippocampal neurons. Preictal activity is potentially important because it might provide new opportunities for predicting when a seizure is about to occur and insight into how spontaneous seizures are generated. We evaluated local field potentials and unit activity of single, putative excitatory neurons in the subiculum, CA1, CA3, and dentate gyrus of the dorsal hippocampus in epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Average action potential firing rates of neurons in the subiculum, CA1, and dentate gyrus, but not CA3, increased significantly and progressively beginning 2-4 min before locally recorded spontaneous seizures. In the subiculum, CA1, and dentate gyrus, but not CA3, 41-57% of neurons displayed increased preictal activity with significant consistency across multiple seizures. Much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity, whereas preictal firing of neurons in the dentate gyrus was independent of theta. In addition, some CA1 and dentate gyrus neurons displayed reduced firing rates preictally. These results reveal that different hippocampal subregions exhibit differences in the extent and potential underlying mechanisms of preictal activity. The finding of robust and significantly consistent preictal activity of subicular, CA1, and dentate neurons in the dorsal hippocampus, despite the likelihood that many seizures initiated in other brain regions, suggests the existence of a broader neuronal network whose activity changes minutes before spontaneous seizures initiate.


Measurement of skeletal muscle radiation attenuation and basis of its biological variation.
Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance (MR) imaging, MR spectroscopy and computed tomography (CT). CT uses computer-processed X-rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre-defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from -190 to -30 Hounsfield units (HU)] and muscle (-29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle (radio) density] is reported. Inconsistent criteria for the upper and lower HU cut-offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation.


A New Surgical Approach for Aortic Root Aneurysm and Small Aortic Annulus.
Reconstruction of the aortic root in patients with aortic root aneurysm and small aortic annulus is an intricate surgical procedure. Here, we describe our technique performed in 2 patients, that involved aortic root enlargement with grafting in conjunction with annular implantation of the composite graft with a prosthetic mechanical valve, which allowed us to avoid incompatibility. This novel method offers an alternative combined surgical approach for patients with small aortic annulus and aortic root aneurysm that preserves the structure of the valved conduit at the level of the aortic annulus.


Catalysis of Extracellular Deamination by a FAD-Linked Oxidoreductase after Prodrug Maturation in the Biosynthesis of Saframycin A.
The biosynthesis of antibiotics in bacteria is usually believed to be an intracellular process, at the end of which the matured compounds are exported outside the cells. The biosynthesis of saframycin A (SFM-A), an antitumor antibiotic, requires a cryptic fatty acyl chain to guide the construction of a pentacyclic tetrahydroisoquinoline scaffold; however, the follow-up deacylation and deamination steps remain unknown. Herein we demonstrate that SfmE, a membrane-bound peptidase, hydrolyzes the fatty acyl chain to release the amino group; and SfmCy2, a secreted oxidoreductase covalently associated with FAD, subsequently performs an oxidative deamination extracellularly. These results not only fill in the missing steps of SFM-A biosynthesis, but also reveal that a FAD-binding oxidoreductase catalyzes an unexpected deamination reaction through an unconventional extracellular pathway in Streptmyces bacteria.


Percutaneous treatment of late complications of the Bentall procedure.
Aortic pseudo-aneurysm following the Bentall procedure is a rare but potentially severe complication. Surgical reintervention represents a high risk. We report on two cases with different pseudo-aneurysm types which were successfully treated using two different percutaneous techniques. © 2017 Wiley Periodicals, Inc.


Early diagnosis of bacterial and fungal infection in chronic cholestatic hepatitis B.
To investigate the early diagnostic methods of bacterial and fungal infection in patients with chronic cholestatic hepatitis B. One hundred and one adult in-patients with chronic hepatitis B were studied and divided into 3 groups: direct bilirubin (DBil)/total bilirubin (TBil) > or = 0.5, without bacterial and fungal infection (group A, n=38); DBil/TBil <0.5, without bacterial and fungal infection (group B, n=23); DBil/TBil> or = 0.5, with bacterial or fungal infection (group C, n=40). The serum biochemical index and pulse rate were analyzed. Level of TBil, DBil, alkaline phosphatase (ALP) and DBil/ALP in group A increased compared with that in group B. The level of ALP in group C decreased compared with that in group A, whereas the level of TBil, DBil and DBil/ALP increased (ALP: 156+/-43, 199+/-68, respectively, P<0.05; TBil: 370+/-227, 220+/-206, respectively, P<0.01; DBil: 214+/-143, 146+/-136, respectively, P<0.01; DBil/ALP: 1.65+/-1.05, 0.78+/-0.70, respectively, P<0.001). The level of DBil and infection affected DBil/ALP. Independent of the effect of DBil, infection caused DBil/ALP to rise (P<0.05). The pulse rate in group A decreased compared with that in group B (63.7+/-6.4, 77.7+/-11.4, respectively, P<0.001), and the pulse rate in group C increased compared with that in group A (81.2+/-12.2, 63.7+/-6.4, respectively, P<0.001). The equation (infection=0.218 pusle rate +1.064 DBil/ALP -16.361), with total accuracy of 85.5%, was obtained from stepwise logistic regression. Pulse rate (> or =80/min) and DBil/ALP (> or =1.0) were used to screen infection. The sensitivity was 62.5% and 64.7% respectively, and the specificity was 100% and 82.8% respectively. Bacterial and fungal infection deteriorate jaundice and increase pulse rate, decrease serum ALP and increase DBil/ALP. Pulse rate, DBil/ALP and the equation (infection=0.218 pusle rate+1.064 DBil/ALP-16.361) are helpful to early diagnosis of bacterial and fungal infection in patients with chronic cholestatic hepatitis B.


Top 10 Myths Regarding the Diagnosis and Treatment of Cellulitis.
Cellulitis is commonly treated in the emergency department (ED). Patients who present with cellulitis incur significant health care costs and may be overtreated with antibiotics. The accurate diagnosis and treatment of cellulitis plays an important role in cost-effective, high-quality medical care, as well as appropriate antibiotic utilization. We aim to describe common fallacies regarding cellulitis. We present 10 myths that result in misdiagnosis, overtreatment, or inappropriate empiric management of cellulitis. Clinical presentation, including swelling and redness, is explored in depth, along with incidence of community-acquired methicillin-resistance Staphylococcus aureus, management of tick bites, and effective antibiotic therapy for cellulitis. Patients are often treated for cellulitis unnecessarily or inappropriately. Awareness of these myths will help guide providers in clinical decision making in order to effectively tailor treatment for these infections. Cellulitis is not as simple as it might seem, and is commonly misdiagnosed in the ED. Noninfectious causes of local symptoms, including lymphedema, venous stasis, and deep vein thrombosis need to be considered. Cellulitis should be treated with empiric antimicrobial therapy based on patient risk factors and regional susceptibility patterns. This review will assist providers in managing cellulitis and avoiding treatment errors that lead to high costs, unwanted side effects for patients, and overuse of antibiotics.


Clinical impact of tumor-infiltrating CD45RO⁺ memory T cells on human gastric cancer.
Memory T cells survive for months and even years and are critical for host defense in humans. They have been recently suggested to play a significant role in tumor immunity. In this study, we aimed to investigate the clinical impact of tumor-infiltrating memory T cells on human gastric cancer. We evaluated CD45RO(+)T cells infiltrating into primary gastric cancer tissues by immunohistochemistry in 101 patients with gastric cancer. Patients were classified into 2 groups (CD45RO(+Hi) and CD45RO(+Lo)) based on the number of positively stained T cells. There was no significant correlation observed between CD45RO status and post-operative prognosis in early gastric cancer. By contrast, in advanced cancer, the post-operative overall and disease-free survival of patients with CD45RO(+Hi) were significantly improved compared to those of patients with CD45RO(+Lo). In addition, CD45RO status in the primary tumors significantly correlated with the development of post-operative recurrence, particularly peritoneal recurrence. Furthermore, the local expression of interferon-γ (IFN-γ) in the CD45RO(+Hi) tumors was significantly higher than that in the CD45RO(+Lo) tumors, suggesting that CD45RO(+) T cells induced local immune activation. Multivariate analysis indicated that the CD45RO(+) status was an independent prognostic factor in advanced gastric cancer. In conclusion, tumor-infiltrating CD45RO(+) memory T cells are functional and have significant prognostic value in human gastric cancer. Our data suggest that adaptive immune response is clinically critical in gastric cancer.


Characterizing heart failure with preserved and reduced ejection fraction: An imaging and plasma biomarker approach.
The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls. Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization. Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784). HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.


Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing--remitting experimental autoimmune encephalomyelitis.
Cortical pathology, callosal atrophy and axonal loss are substrates of progression in multiple sclerosis (MS). Here we describe cortical, periventricular subcortical lesions and callosal demyelination in relapsing-remitting experimental autoimmune encephalomyelitis in SJL mice that are similar to lesions found in MS. Unlike the T-cell infiltrates that peak during acute disease, we found that microglia activation persists through the chronic disease phase. Microglia activation correlated with abnormal phosphorylation of neurofilaments in the cortex and stripping of synaptic proteins in cortical callosal projecting neurons. There was significant impairment of retrograde labeling of NeuN-positive callosal projecting neurons and reduction in the labelling of their transcallosal axons. These data demonstrate a novel paradigm of cortical and callosal neuropathology in a mouse model of MS, perpetuated by innate immunity. These features closely mimic the periventricular and cortical pathology described in MS patients and establish a model that could be useful to study mechanisms of progression in MS.


Effect of Anti-Clouding Agent on the Fate of 3-Monochloropropane-1,2-Diol Esters and Glycidyl Esters in Palm Olein during Repeated Frying.
Issues on 3-monochloropropane-diol-1,2-diol (MCPD) esters and glycidyl esters in refined oil have gained much attention when these heat-induced contaminants are associated with health implications. Oil that undergoes the frying process could influence the fates of 3-MCPD esters and glycidyl esters, especially with the addition of an anti-clouding agent. In this study, we investigated the effect of polyglycerol fatty acid esters (PGE) on the transients of 3-MCPD esters and glycidyl esters in palm olein (POo) during intermittent frying. Thermal resistance of POo fortified with PGE (0.1% to 0.4%) was assessed for 8 h of daily frying operations at 180 °C across five consecutive days. The addition of PGE decelerated the reduction of 3-MCPD esters and glycidyl esters with the progression of frying. The presence of these compounds coincided with the amount of oil taken up by the fried product. The inclusion of PGE in POo also induced higher augmentation of polar compound fractions, i.e., oxidised triacylglycerols (OxTAG) and polymerised triacylglycerols (PTAG), but gave comparable free fatty acid (FFA), p-anisidine value (AnV), total chloride and fatty acid composition (FAC) with control oil (POo). The results also showed that the presence of chloride in POo did not onset further formation of 3-MCPD esters and glycidyl esters throughout the frying period. As the behaviours of 3-MCPD esters and glycidyl esters were affected by PGE, only a sufficient amount should be added into POo to ensure oil clarity at a realistic period.


Multifunctional Fiber-Based Optoacoustic Emitter as a Bidirectional Brain Interface.
A bidirectional brain interface with both "write" and "read" functions can be an important tool for fundamental studies and potential clinical treatments for neurological diseases. Herein, a miniaturized multifunctional fiber-based optoacoustic emitter (mFOE) is reported thatintegrates simultaneous optoacoustic stimulation for "write" and electrophysiology recording of neural circuits for "read". Because of the intrinsic ability of neurons to respond to acoustic wave, there is no requirement of the viral transfection. The orthogonality between optoacoustic waves and electrical field provides a solution to avoid the interference between electrical stimulation and recording. The stimulation function of the mFOE is first validated in cultured ratcortical neurons using calcium imaging. In vivo application of mFOE for successful simultaneous optoacoustic stimulation and electrical recording of brain activities is confirmed in mouse hippocampus in both acute and chronical applications up to 1 month. Minor brain tissue damage is confirmed after these applications. The capability of simultaneous neural stimulation and recording enabled by mFOE opens up new possibilities for the investigation of neural circuits and brings new insights into the study of ultrasound neurostimulation.


Significance of a low serum ferritin level in elderly in-patients.
Iron deficiency, defined as a serum ferritin level less than or equal to 50 micrograms/l was found in 28 (11%) of 252 consecutive elderly in-patients (mean age 81 years). Sixteen among them were anaemic and only five had a microcytic anaemia. In a separate study, 15 anaemic and 13 non-anaemic iron-deficient elderly in-patients were investigated in order to evaluate the prevalence of gastrointestinal symptoms and lesions in both groups. In nine of the anaemic and seven of the non-anaemic patients a potential cause for the iron deficiency was established. Most anaemic and non-anaemic patients lacked the symptoms described as suggestive of underlying gastrointestinal pathology. Thus, a ferritin level less than or equal to 50 micrograms/l justifies a gastrointestinal investigation if the general condition allows for it as well in anaemic as in non-anaemic elderly hospitalized patients. Therefore, serum ferritin should be part of the routine biochemical investigation of elderly in-patients.


Secondary electrospray ionization coupled to high-resolution mass spectrometry reveals tryptophan pathway metabolites in exhaled human breath.
Many studies and personalized medicine in general require frequent measurements and/or rapid results of biomarker levels. Here we show that 20 low volatility metabolites of the tryptophan pathway can be detected in exhaled human breath. This real-time and non-invasive method offers an attractive alternative to blood analysis.


Prognostic Role of Serum Levels of Uric Acid in Amyotrophic Lateral Sclerosis.
It has been suggested that oxidative stress is one of the pathomechanisms underlying amyotrophic lateral sclerosis (ALS), and thus antioxidants such as uric acid (UA) that could reduce oxidative stress might be beneficial in the prevention or treatment of this disease. The objective of this study was to prospectively investigate serum UA levels in Korean ALS patients and to relate them to disease progression. ALS patients and healthy controls who were individually well-matched for sex, age, and body mass index (BMI) underwent blood testing for serum UA levels, and analyzed whether UA levels were correlated with the disease status of the patients, as defined by the ALS Functional Rating Scale-Revised (ALSFRS-R). The study included 136 ALS patients and 136 matched controls. The UA level was lower in the ALS patients (4.50±1.17 mg/dL, mean±SD) than in the controls (5.51±1.22 mg/dL; p<0.001). Among the ALS patients, the level of UA acid was inversely correlated with the rate of disease progression (decrease in ALSFRS-R score). Kaplan-Meier analysis revealed that a better survival rate was more strongly correlated with top-tertile levels of serum UA than with bottom-tertile levels (log-rank test: p=0.035). ALS patients had lower serum UA levels than did healthy individuals. UA levels in ALS were negatively correlated with the rate of disease progression and positively associated with survival, suggesting that UA levels contribute to the progression of ALS. UA levels could be considered a biomarker of disease progression in the early phase in ALS patients.


Dendritic resonance in rat neocortical pyramidal cells.
Dendritic integration of synaptic signals is likely to be an important process by which nerve cells encode synaptic input into spike output. However, the response properties of dendrites to time-varying inputs are largely unknown. Here, I determine the transfer impedance of the apical dendrite in layer V pyramidal cells by dual whole cell patch-clamp recordings in slices of rat somatosensory cortex. Sinusoidal current waveforms of linearly changing frequencies (0.1-25 Hz) were alternately injected into the soma or apical dendrite and the resulting voltage oscillations recorded by the second electrode. Dendrosomatic and somatodendritic transfer impedances were calculated by Fourier analysis. At near physiological temperatures (T approximately 35 degrees C), the transfer impedance had a maximal magnitude at low frequencies (f(res) approximately 6 Hz). In addition, voltage led current up to approximately 3 Hz, followed by a current lead over voltage at higher frequencies. Thus the transfer impedance of the apical dendrite is characterized by a low-frequency resonance. The frequency of the resonance was voltage dependent, and its strength increased with dendritic distance. The resonance was completely abolished by the I(h) channel blocker ZD 7288. Dendrosomatic and somatodendritic transfer properties of the apical dendrite were independent of direction or amplitude of the input current, and the responses of individual versus distributed inputs were additive, thus implying linearity. For just threshold current injections, action potentials were generated preferentially at the resonating frequency. I conclude that due to the interplay of a sag current (I(h)) with the membrane capacitance, layer V pyramids can act as linear band-pass filters with a frequency preference in the theta frequency band.


Course and Outcome of Children with Convulsive Status Epilepticus Admitted to a Pediatric Intensive Care Unit.
Introduction The objective of this study was to describe the course and the outcomes of children with convulsive status epilepticus and to evaluate the differences between two groups of children with new-onset seizures and known seizure disorders. Methods This is a retrospective, single-center study. Children with convulsive status epilepticus admitted to our tertiary care pediatric intensive care unit were included in the study. Medical records were reviewed to obtain the demographic- and seizure-related variables. Results Among 139 children with status epilepticus, 69.7% (n = 99) had a known seizure disorder. Focal seizures were present in 23.9% of children, and 34.6% required intubation; there was an overall mortality rate of 1.2%. The children with new-onset seizures were younger and received electroencephalography (EEG) and neuroimaging more often compared to children with known seizure disorders (p < 0.05). However, an abnormal EEG was more common among children with known seizure disorders (p < 0.001). Conclusions Sub-therapeutic anti-epileptic drugs levels were common among children with known seizure disorders presenting with status epilepticus. Gender, race, insurance status, type of seizures, intubation requirement, lengths of stay, and mortality were not significantly different between the two groups.


Development and optimization of single and combined detoxification processes to improve the fermentability of lignocellulose hydrolyzates.
In this work, an enzyme catalyzed detoxification process of lignocellulose hydrolyzates with immobilized laccase from Trametes versicolor was developed and optimized. Further, the immobilized laccase significantly reduced the amount of toxic phenolic compounds in the xylan rich fraction (XRF) by polymerization within 1h. The insoluble products precipitated onto the carrier surface and could be reversible resolubilized by an aqueous ethanol solution. Consequently, an in situ product removal could be realized. The reusability of the immobilized laccase could be additionally shown. The reaction kinetics could be described by a reversible Michaelis Menten equation giving the prerequisite for scaling up the process. In a second step, the organic acids, hydroxymethylfurfural and phenolic acids could be further removed by employing an anion exchanger. Both, the laccase and the laccase+anion exchanger treatment enhanced successfully the fermentability of an organosolv wheat straw fraction.


Prolonged sinus tachycardia caused by human herpesvirus 6 (HHV6) encephalomyelitis after allogeneic bone marrow transplantation.
A 19-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia received an allogeneic hematopoietic cell transplant with unrelated bone marrow. On day 20, the patient developed impaired consciousness and disorientation. Examination of the cerebrospinal fluid showed 2×10(4) copies/mL of HHV6B. HHV6 encephalitis was diagnosed, as had HHV6 myelitis based on symptoms that included lancinating pain/pruritus in the lower limbs and dysuria/dyschezia. Concurrently, he showed sinus tachycardia. Even after clearance of the HHV6 genome from the plasma and CSF was achieved by treatment with foscarnet, sinus tachycardia persisted for another 100 days. We suspected prolonged sinus tachycardia due to dysautonomia caused by HHV6 encephalomyelitis.


Incarcerated adolescent girls: personality, social competence, and delinquency.
The aim of this study was to gain greater insight into the relationship of delinquency to personality and social competence in incarcerated girls. It was hypothesized that agreeableness and conscientiousness would correlate negatively with delinquency, and that the sensation-seeking aspect of extroversion would correlate positively. Two theoretical views were used to predict the relationship between social competence and delinquency: (a) delinquency as an expression of lack of social competence (i.e., social deficit), and (b) delinquency as socially competent and rationally analyzed behavior. The first view implies a negative correlation between delinquency and social competence, while the second indicates a positive one. The participants were thirty-three 12- to 18-year-old incarcerated girls. An adaptation of the Self-Reported Delinquency Scale was used for measuring delinquency; personality was measured using the Five-Factor Personality Inventory; and the Scale for Interpersonal Behavior was used to measure social competence. Agreeableness was not found to correlate with the overall delinquency score or with any specific type of delinquency or crime. The more crimes the girls reported, the less conscientious they were, and the more neurotic and open they were. The correlation between delinquency and extroversion was not statistically significant. A higher level of delinquency was accompanied by higher social competence when negative self-assertion was required (i.e., a low level of tension was felt in expressing negative feelings that were appropriate to the situation). In other social situations, however, the girls reported more situation-inappropriate feelings of tension. It was concluded that some personality factors and aspects of social competence can predict delinquency.


Exposure to biomass smoke extract enhances fibronectin release from fibroblasts.
COPD induced following biomass smoke exposure has been reported to be associated with a more fibrotic phenotype than cigarette smoke induced COPD. This study aimed to investigate if biomass smoke induced extracellular matrix (ECM) protein production from primary human lung fibroblasts in vitro. Primary human lung fibroblasts (n=5-10) were stimulated in vitro for up to 72 hours with increasing concentrations of biomass smoke extract (BME) or cigarette smoke extract (CSE) prior to being assessed for deposition of ECM proteins, cytokine release, and activation of intracellular signalling molecules. Deposition of the ECM proteins perlecan and fibronectin was upregulated by both CSE (p<0.05) and BME (p<0.05). The release of the neutrophilic chemokine IL-8 was also enhanced by BME. ERK1/2 phosphorylation was significantly upregulated by BME (p<0.05). Chemical inhibition of ERK signalling molecules partially attenuated these effects (p<0.05). Stimulation with endotoxin had no effect. This study demonstrated that BME had similar effects to CSE in vitro and had the capacity to directly induce fibrosis by upregulating production of ECM proteins. The mechanisms by which both biomass and cigarette smoke exposure cause lung damage may be similar.


Acute methylene chloride intoxication--a case report on domestic poisoning.
Acute intoxication by methylene chloride has primarily been reported from occupational settings. However, it may occur through domestic exposure, by the use of aerosol sprays, degreasers and paint removers. We describe an unusual case of an accidental domestic methylene chloride intoxication through the use of aerosol spray, resulting in an HbCO of 30%.