[Formulation and process optimization of doxorubicin-loaded PLGA nanoparticles and its in vitro release].
Doxorubicin-loaded PLGA nanoparticles (DOX-PLGA NPs) was prepared by double emulsion (W/O/W) solvent evaporation method with the biodegradable materials-poly (lactic-co-glycolic acid) (PLGA) used as carrier materials. Single-factor test was used to investigate the influence of the type and ratio of the organic phase, the amount of surfactant, PLGA concentration, the ratio of external water phase and oil phase (W/O), the ratio of doxorubicin and PLGA, ultrasonic time and stirring time on the preparation of nanoparticles. The best formulation and preparation conditions were optimized by orthogonal test based on single-factor test, evaluation indicator as particle size and entrapment efficiency, and the results were analyzed by overall desirability. And the in vitro release behaviors of the nanoparticles were studied as well. The size distribution, zeta potential, morphology of DOX-PLGA NPs were characterized by laser light scattering and transmission electron microscopy; encapsulation efficiency and releasing behavior of DOX-PLGA NPs in vitro were investigated by ultraviolet spectrophotometry. The results show that the DOX-PLGA NPs are regularly spherical in shape with the mean size of (189.2 +/- 5.3) nm, and the zeta-potential of the NPs is about (-28.32 +/- 0.52) mV. Drug loading and encapsulation efficiency are estimated to be (73.16 +/- 0.43) % and (1.51 +/- 0.07) %, respectively. The cumulative percentage of the drug released is 90.34%, and the in vitro release behavior made up of initial burst release and sustained-release could be described by the bidirectional kinetic equation. The results indicate that hydrophilic small-molecule drugs could be successfully entrapped into PLGA-NPs. With optimization of the formulation and preparation conditions, we obtained uniform and stable DOX-PLGA NPs with sustained release character in vitro and pH-sensitive property, which could provide the experimental basis for the development of a new anti-tumor sustained-release formulation.


Secondary non-resectable liver tumors: A single-center living-donor and deceased-donor liver transplantation case series.
During the last decades, deceased-donor liver transplantation (DDLT) has gained a place in the therapeutic algorithm of well-selected patients harbouring non-resectable secondary liver tumors. Living-donor LT (LDLT) might represent a valuable means to further expand this indication for LT. Between 1985 and 2016, twenty-two adults were transplanted because of neuroendocrine (n = 18, 82%) and colorectal metastases (n = 4, 18%); 50% received DDLT and 50% LDLT. In LDLT, 4 (36%) right and 7 (64%) left grafts were used; the median graft-to-recipient-weight ratios (GRWR) were 1.03% (IQR 0.86%-1.30%) and 0.59% (IQR 0.51%-0.91%), respectively. Median post-LT follow-up was 64 months (IQR 17-107) in the DDLT group and 40 months (IQR 35-116) in the LDLT group. DDLT and LDLT recipients were compared in terms of overall survival, graft survival, postoperative complications and recurrence. The 1- and 5-year actuarial patient survivals were 82% and 55% after DDLT, 100% and 100% after LDLT, respectively (P < 0.01). One- and 5-year actuarial graft survivals were 73% and 36% after DDLT, 91% and 91% after LDLT (P < 0.01). The outcomes of right or left LDLT were comparable. Donor hepatectomy proved safe, and one donor experienced a Clavien IIIb complication. Bilirubin peak was significantly lower after left hepatectomy compared with that after right hepatectomy [1.3 (IQR 1.2-2.2) vs. 3.3 (IQR 2.3-5.2) mg/dL; P = 0.02]. The more recent LDLT series compared favorably to our DDLT series in the treatment of secondary liver malignancies. The absence of portal hypertension and the use of smaller left grafts make recipient and donor surgeries safe. The safety of the procedures and lack of interference with the scarce allograft pool are expected to lead to a more frequent use of LDLT in the field of transplant oncology.


Nasal endoscopy and CT study of Pharaonic and Roman mummies.
In ancient Egypt mummifications were first carried out around 3000 BC. The visceral organs (lungs, stomach, liver and bowel) were removed from the body, cleansed, desiccated and placed in four canopic jars. The brain was removed from the body but was not preserved. Exactly how removal of the brain was accomplished is not clear. This study investigated the route of brain removal during mummification. Nasal endoscopy was carried out on 20 Pharaonic and Roman mummies. CT examination was performed on 2 mummy heads. In all mummies a communication between the cranial and nasal cavities was found passing through the posterior ethmoids and cribriform plates. The cranial cavity was empty. Our results demonstrate that brain removal during mummification was performed endonasally by trained personnel with a good knowledge of anatomy, using special instruments capable of creating a clean-cut endonasal craniotomy.


Second-language experience and speech-in-noise recognition: effects of talker-listener accent similarity.
Previous work has shown that the intelligibility of speech in noise is degraded if the speaker and listener differ in accent, in particular when there is a disparity between native (L1) and nonnative (L2) accents. This study investigated how this talker-listener interaction is modulated by L2 experience and accent similarity. L1 Southern British English, L1 French listeners with varying L2 English experience, and French-English bilinguals were tested on the recognition of English sentences mixed in speech-shaped noise that was spoken with a range of accents (French, Korean, Northern Irish, and Southern British English). The results demonstrated clear interactions of accent and experience, with the least experienced French speakers being most accurate with French-accented English, but more experienced listeners being most accurate with L1 Southern British English accents. An acoustic similarity metric was applied to the speech productions of the talkers and the listeners, and significant correlations were obtained between accent similarity and sentence intelligibility for pairs of individuals. Overall, the results suggest that L2 experience affects talker-listener accent interactions, altering both the intelligibility of different accents and the selectivity of accent processing.


Effectiveness of the ToothSOS App as a training tool for the emergency management of traumatic dental injuries among non-dentists.
Traumatic dental injuries (TDIs) are a major and urgent problem in oral health. Therefore, non-dentists need to be conscious of the emergency management of TDIs. The aim of this study was to assess the effectiveness of the ToothSOS App on the level of knowledge about emergency management of TDIs among people who are not dental professionals. One hundred and five non-dentists, aged 22-57 years, participated in this study and were given training on TDIs. The ToothSOS App launched by the IADT was used as a training tool. A 25-question survey was conducted three times; before the ToothSOS App was downloaded and reviewed (T0 ), immediately after (T1 ), and one month later (T2 ). There was a statistically significant difference among the three time periods (p < .001) in terms of the knowledge about the management of TDIs, and the knowledge increased significantly (p < .001) at both T1 and T2 after reviewing the ToothSOS App. On a scale from 0 to 10, the mean correct scores increased from 2.85 ± 2.15 (median [min-max]: 2[0-10]) to 8.23 ± 2.21 (median [min-max]: 9 [1-10]) (effect size: 2.5) at T1 and to 7.40 ± 2.34 (median [min-max]: 8 [1-10]) (effect size: 2.1) at T2 . The ToothSOS App as a training tool was effective to increase the knowledge level of individuals about the emergency management of TDIs.


Effects of nutritional management intervention on gestational weight gain and perinatal outcome.
To evaluate whether nutritional management intervention can prevent excessive weight gain during pregnancy and improve perinatal outcomes. This cross-sectional study included 276 pregnant women undergoing prenatal care between June 2010 and December 2011 at the Obstetrics and Gynecology Department of the Second Affiliate Hospital of the ChongQing University of Medical Sciences, Chongqing, China. Of them, 131 women received individualized nutritional management in addition to routine prenatal care (intervention group), and 145 women received only routine prenatal care (control group). The primary study outcome was gestational weight gain (GWG). Secondary outcomes included birth weight, Apgar score, and incidence of pregnancy complications. Baseline demographic characteristics of the 2 groups were the same. The average GWG was higher in the control group (12.57+/-4.62 kg) compared with the intervention group (7.58+/-1.59 kg; p=0.000). The incidence rate of preeclampsia was 3.1% and gestational diabetes was 3.8% for the intervention group, compared with 11% for preeclampsia and 14.5% gestational diabetes for the control group (p<0.05). The incidence rates of premature rupture of membranes, preterm labor, birth weight, birth of a newborn, and major congenital anomalies did not significantly differ between the 2 groups. Nutritional management intervention prevented excessive GWG and improved perinatal outcomes. These results support the hypothesis that nutritional management intervention can decrease the rate of complications experienced by expecting mothers.


Recurrent abdominal pain in childhood: an approach to common disorders.
Recurrent abdominal pain is a challenging clinical problem for which the rewards are the return of the ill or disabled child to an active life. I hope that the approach outlined here will hasten recovery, reduce iatrogenesis, and potentially lessen lifelong pain in these children.


Population growth with variable family size.
"The Sharpe-Lotka continuous time deterministic model of population growth is developed to take account of some possible forms of mother-daughter fertility association.... Model specific results relating the intergenerational fertility effect to the long term population growth rate and magnitude are established. The quantitative implications of the theory are illustrated by a consideration of a general bilinear form of A and in this context numerical results illustrating the finite time growth and also the long term distribution of fertility levels in the stable female population are obtained. In particular, it is shown that different fertility specific subpopulations can coexist indefinitely."


A novel bioassay for quantification of surface Cannabinoid receptor 1 expression.
The cannabinoid receptor type 1 (CB1) plays critical roles in multiple physiological processes such as pain perception, brain development and body temperature regulation. Mutations on this gene (CNR1), results in altered functionality and/or biosynthesis such as reduced membrane expression, changes in mRNA stability or changes in downstream signaling that act as triggers for diseases such as obesity, Parkinson's, Huntington's, among others; thus, it is considered as a potential pharmacological target. To date, multiple quantification methods have been employed to determine how these mutations affect receptor expression and localization; however, they present serious disadvantages that may arise quantifying errors. Here, we describe a sensitive bioassay to quantify receptor surface expression; in this bioassay the Gaussia Luciferase (GLuc) was fused to the extracellular portion of the CB1. The GLuc activity was assessed by coelenterazine addition to the medium followed by immediate readout. Based on GLuc activity assay, we show that the GLuc signals corelate with CB1 localization, besides, we showed the assay's functionality and reliability by comparing its results with those generated by previously reported mutations on the CNR1 gene and by using flow cytometry to determine the cell surface receptor expression. Detection of membrane-bound CB1, and potentially other GPCRs, is able to quickly screen for receptor levels and help to understand the effect of clinically relevant mutations or polymorphisms.


Clinical characteristics of Crohn s disease in Qatar.
To assess the clinical characteristics of Crohn's disease (CD) in Qatar. This is a retrospective descriptive study. We studied 50 CD patients admitted to Hamad General Hospital over a period of 8 years from January 1995 to December 2002. We retrospectively collected and analyzed the demographic and clinical data. We made the diagnostic classification of definite CD in accordance with the criteria based on the International Classification of Disease ninth revision [ICD-9]. We based the obtained information on the following parameters: the age at the time of admission, gender and Crohn's risk factor profiles. Of the studied population, 60% were males and 40% females. Sixty-two percent were Qataris and 38% expatriates. Most of the subjects were <40 years of age (80%). Fifty-two percent had ileo-colonic disease, 24% colonic and 24% ileal disease. The majority of the Crohn's patients had the symptom of abdominal pain (84%), followed by weight loss (80%) and diarrhea (70%). Pallor sign was most frequent in patients with inflammatory CD (76.9%) and obstructive CD (66.7%), whereas we found the anal signs in patients with fistulas (84.2%). The study showed a relatively high frequency of ileo-colonic Crohn's disease compared to colonic and ileal diseases. We observed that the most frequent symptom is abdominal pain.


Mobility of "HSPG-bound" LPL explains how LPL is able to reach GPIHBP1 on capillaries.
In mice lacking glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), the LPL secreted by adipocytes and myocytes remains bound to heparan sulfate proteoglycans (HSPGs) on all cells within tissues. That observation raises a perplexing issue: Why isn't the freshly secreted LPL in wild-type mice captured by the same HSPGs, thereby preventing LPL from reaching GPIHBP1 on capillaries? We hypothesized that LPL-HSPG interactions are transient, allowing the LPL to detach and move to GPIHBP1 on capillaries. Indeed, we found that LPL detaches from HSPGs on cultured cells and moves to: 1) soluble GPIHBP1 in the cell culture medium; 2) GPIHBP1-coated agarose beads; and 3) nearby GPIHBP1-expressing cells. Movement of HSPG-bound LPL to GPIHBP1 did not occur when GPIHBP1 contained a Ly6 domain missense mutation (W109S), but was almost normal when GPIHBP1's acidic domain was mutated. To test the mobility of HSPG-bound LPL in vivo, we injected GPIHBP1-coated agarose beads into the brown adipose tissue of GPIHBP1-deficient mice. LPL moved quickly from HSPGs on adipocytes to GPIHBP1-coated beads, thereby depleting LPL stores on the surface of adipocytes. We conclude that HSPG-bound LPL in the interstitial spaces of tissues is mobile, allowing the LPL to move to GPIHBP1 on endothelial cells.


The role of clinical decision support tools to reduce blood pressure variability in critically ill patients receiving vasopressor support.
Current monitoring systems for patients receiving vasopressor support generally rely on bedside monitors with audible alarms that are activated when blood pressure declines below pre-established thresholds, which can result in fluctuations that may increase risk of myocardial ischemia. This pilot study evaluated the effects of three bedside monitors on mean arterial blood pressure and percentage of time at mean arterial pressure among critically ill patients. The monitors were the standard display with audible alarm or one of two types of clinical decision support systems including Intellivue Horizon Trends (Philips Healthcare, Andover, MA) and Horizon Trends and ST Map (Philips Healthcare). Patients in the two groups monitored with Horizon Trends had significantly higher mean arterial pressure (72.8 ± 7.0 mm Hg) compared with those monitored with the standard monitor (68.1 ± 6.8 mm Hg; P= .004). Patients monitored with Horizon Trends also spent a significantly higher percentage of time within their target mean arterial pressure range compared with those in the standard monitor group (P = .031). These findings suggest that further study is needed to assess the impact of clinical decision support tools on management of blood pressure variability in critically ill patients receiving vasopressor therapy.


Increasing Primary Care Access Close to Home for Residents of Remote Communities in Northern Alberta.
Residents of Canada's rural and remote communities know the challenges associated with accessing consistent healthcare. Alberta Health Services uses telehealth technology to minimize travel for rural and remote residents who require follow-up with specialists, however until recently, telehealth was only used in specialty care. This article describes a pilot project introduced in two remote northern Alberta communities to determine the feasibility and sustainability of using telehealth in the delivery of primary healthcare. Included in the article are descriptions of each phase of the project from seeking stakeholder approval through interpretation of findings and continuation of the project after it was determined successful. Jurisdictions interested in attempting their own telehealth program will be interested in the challenges and successes identified during the process. Although the project was successful, further studies are needed to determine if similar findings could be expected in other communities and populations.


Pharmacokinetic evaluation of C-3 modified 1,8-naphthyridine-3-carboxamide derivatives with potent anticancer activity: lead finding.
To develop naphthyridine derivatives as anticancer candidates, pharmacokinetic (PK) evaluations of 10 novel derivatives of 1,4-dihydro-4-oxo-1-proparagyl-1,8-naphthyridine-3-carboxamide, with potent anticancer activity were done using in vitro ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic--pharmcodynamic (PK/PD) assays. Only derivatives 5, 6, 9 and 10 showed better metabolic stability, solubility, permeability, partition coefficient and cytochrome P450 (CYP) inhibition values. PK of derivatives 5, 6, 9 and 10 in rat showed comparable PK profile for derivative 5 (C0 = 6.98 µg/mL) and 6 (C0 = 6.61 µg/mL) with no detectable plasma levels for derivatives 9 and 10 at 5.0 mg/kg i.v. dose. PK/PD assay of derivatives 5 and 6 in tumor-bearing mice (TBM) showed comparable PK but tumor plasma index (TPI) of derivative 6 (4.02) was better than derivative 5 (2.50), suggesting better tumor uptake of derivative 6. Derivative 6, as lead compound, showed highest tumor growth inhibition (TGI) value of 33.6% in human ovary cancer xenograft model.


Excellent immunological recovery following CODOX-M/IVAC, an effective intensive chemotherapy for HIV-associated Burkitt's lymphoma.
: To retrospectively describe the recovery of cellular immunity and the clinical outcome of 30 patients with HIV-associated Burkitt's lymphoma (HIV-BL), who were treated with the intensive chemotherapy CODOX-M/IVAC and HAART as part of their standard care. : Seventy-three percent of the patients had high-risk disease, defined by stage, performance status, extranodal sites and lactate dehydrogenase. The median CD4 cell count at diagnosis of HIV-BL was 171/ml (range: 4-848) and the plasma HIV viral load was undetectable in five of 29 patients. : Nine patients died during treatment (disease progression, three; toxicity, five; central nervous system lesion not biopsied, one). Response rate was 70% (complete response/complete response uncertain, 17; partial response, 4). After a median follow-up of 22 months (range: 6-72), 18 patients remain alive without disease progression. The 3-year overall survival and event-free survival were 52 and 75%, respectively. Viral load was undetectable in 88% and CD4 cell count more than 200/ml in 58% of patients assessed 6 months after completing chemotherapy, and in 87 and 80% at 12 months, respectively. : The intensive regimen CODOX-M/IVAC, a feasible and effective chemotherapy, is associated with an excellent immunological recovery in patients with HIV-BL on HAART.


Most likely to succeed: correlates of good versus poor hospital outcome in young adult inpatients.
This paper presents the findings of a study comparing disparate hospital outcomes of a young adult population. Clinical ratings of much improved and unimproved status at the time of discharge were our outcome variables. Major differences in patient characteristics associated with improvement status related to age of onset of disorder and premorbid functioning. Hospital variables yielding significant differences between the cohorts included treatment alliance on the part of patients and families, reduction in symptomatology, and diagnostic classifications. A discriminant function analysis was carried out to identify the combination of variables contributing the most to the variance. Directions for further study are explored.


Reality and dreams: state of the academy.
These remarks were presented at the opening ceremony of the American Academy of Health Behavior (AAHB) annual scientific conference held in Charleston, SC, in February 2005 by the outgoing president of the Academy.


Successful Neuromuscular Blockade Reversal Using Sugammadex and Neostigmine Failed to Prevent Myasthenic Crisis After Emergency Surgery: A Case Report.
Recent literature suggests that the use of sugammadex for the reversal of neuromuscular blocking agents (NMBAs) reduces the risk of postoperative myasthenic crisis (MC) in patients with myasthenia gravis (MG), particularly after thymectomy, but studies are lacking on emergency surgeries. We achieved successful intraoperative reversal of neuromuscular blockade (NMB) using a combination of sugammadex and neostigmine (with glycopyrrolate). However, MC was not avoided and reintubation was required on postoperative day 1. A 65-year-old male with a longstanding history of MG presented to the emergency department with complaints of abdominal pain, diarrhea, vomiting, chills, and fatigue for three days. A computed tomography (CT) scan of the abdomen showed acute appendicitis, for which he underwent a laparoscopic appendectomy on hospital day 1. The patient received successful general anesthesia with a rapid sequence induction using a smaller than average dose of rocuronium, given his history of MG. At the conclusion of the case, sugammadex followed by neostigmine/glycopyrrolate and a subsequent dose of sugammadex were given, with reversal of NMB. The patient was successfully extubated but required reintubation on postoperative day 1 for hypercapnic respiratory failure. Our case report on this patient with MG yields two topics that have not been extensively examined. First, dual therapy with sugammadex and neostigmine/glycopyrrolate may provide significant clinical benefit over individual therapy for NMBA reversal, given that their mechanisms of action are different and particularly when sugammadex is given prior to neostigmine/glycopyrrolate. Second, anesthesia literature is lacking on MG patients undergoing emergency surgeries. While sugammadex has been promising in medically optimized non-emergent surgeries, we discuss here a case where sugammadex failed to prevent MC in the emergency surgery setting and a look into what may provide patients with the best chance for avoiding postoperative MC.


Longitudinal serum IgG response to Pseudomonas cepacia surface antigens in cystic fibrosis.
In cystic fibrosis (CF), serum antibody against surface antigens of Pseudomonas aeruginosa is detected only after colonization. Since pulmonary acquisition of P. cepacia usually follows colonization with P. aeruginosa and since P. aeruginosa-colonized patients with CF have demonstrable antibody against outer membrane proteins of P. cepacia, it appears that acquisition of the latter organism occurs in the presence of specific serum antibody. To test this hypothesis, serum obtained from six P. aeruginosa-colonized patients 4 and 2 years prior to and 3 months and 2 years after P. cepacia colonization were assayed for total and specific IgG to P. cepacia outer membrane components. Four patients demonstrated 6-fold or greater increases in specific IgG titers to whole outer membranes following colonization. By immunoblot, all patients had demonstrable serum IgG against the 27- and 36-kDa outer membrane proteins of P. cepacia 4 and 2 years prior to colonization. Immunoblots after P. cepacia acquisition demonstrated an intensification of the 28- and 36-kDa bands and the appearance of antibody to a very low molecular weight compound which was not hydrolyzed by proteinase K and was present in purified LPS. These observations suggest that low serum titers of antibody against two P. cepacia outer membrane proteins are present in patients with CF prior to P. cepacia colonization, and that these antibodies fail to protect for intrinsic or extrinsic reasons.


Impact of metformin on tyrosine kinase inhibitor response in chronic myeloid leukemia.
Oral tyrosine kinase inhibitors (TKIs) are first line therapy for chronic myeloid leukemia (CML). A complete cytogenetic response (CCyR) correlates with increased overall survival, however only 66%-88% of patients achieve CCyR after one year of TKI treatment. Because TKI therapy alone cannot eliminate CML stem cells, strategies aimed at achieving faster and deeper responses are needed to improve long-term survival. Metformin is a widely prescribed glucose-lowering agent for patients with diabetes and in preclinical studies, has been shown to suppress cell viability, induce apoptosis, and downregulate the mTORC1 signaling pathway in imatinib resistant CML cell lines (K562R). This study aims to investigate the utility of metformin added to TKI therapy in patients with CML. An observational study at an academic medical center (Salt Lake City, UT) was performed for adults with newly diagnosed, chronic-phase CML to evaluate attainment of CCyR from TKI therapy with or without concomitant metformin use. Descriptive analyses were used to describe baseline characteristics and attainment of response to TKI therapy. Fifty-nine patients were evaluated. One hundred percent (5 of 5) in the metformin group and 73.6% (39 of 54) in the non-metformin group achieved CCyR. Approximately 20% of patients in both groups relapsed (defined by a loss of CCyR during study) after a median 34.5 months of follow-up. Future research is warranted to validate these findings and determine the utility of metformin added to TKI therapy.


Enhanced-view totally extraperitoneal approach in emergency ventral incision hernia repair: a case report.
The rate of emergency operations for incarcerated and strangulated ventral hernias is about 10-15% with worse outcomes than elective surgery. A recent laparoscopic technique called Enhanced view totally extra peritoneal approach (eTEP) was shown to be indicated in elective repair of ventral and incisional hernias and it has been shown to have lower rate of postoperative morbidity compared to the Rives-Stoppa technique, while having the same indications. However the eTEP laparoscopic technique has not been yet reported in emergency ventral hernia repair. We report the case of a 57 years old white male, with history of multiple abdominal interventions by laparotomy, admitted in the emergency department with vomiting and periumbilical pain progressing since 3 days. On clinical examination, we find a strangulated incisional para-umbilical hernia with local cellulitis and tenderness in the right flank. Abdominal CT scan confirm the diagnostic and some signs of thickening of intestinal wall and multiples ventral hernias. The patient was admitted and operated the same day by the eTEP technique without necessity of intestinal resection. The patient was discharged at postoperative day 5. The main complication was the presence of seroma diagnosed and drained by an extra peritoneal laparoscopy after 3 weeks. Total resolution of seroma was confirmed at 1 year follow up. Incarcerated and strangulated ventral hernias are still classically treated by laparotomy.This case report shows for the first time that the eTEP procedure can be applied for abdominal wall surgeries also in emergency setting in selected patients. We hypothesize that this new procedure can be a promising approach leading less postoperative complications and shorter hospital stays.


A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region ("NRR")-Missense Activity in Caenorhabditis elegans.
Genetic analysis of LIN-12/Notch signaling in C. elegans has provided many insights into human biology. Activating missense mutations in the Negative Regulatory Region (NRR) of the ectodomain of LIN-12/Notch were first described in C. elegans, and similar mutations in human Notch were later found to cause T-cell acute lymphoblastic leukemia (T-ALL). The ubiquitin ligase sel-10/Fbw7 is the prototype of a conserved negative regulator of lin-12/Notch that was first defined by loss-of-function mutations that enhance lin-12 NRR-missense activity in C. elegans, and then demonstrated to regulate Notch activity in mammalian cells and to be a bona fide tumor suppressor in T-ALL. Here, we report the results of an RNAi screen of 248 C. elegans protein kinase-encoding genes with human orthologs for enhancement of a weakly activating NRR-missense mutation of lin-12 in the Vulval Precursor Cells. We identified, and validated, thirteen kinase genes whose loss led to increase lin-12 activity; eleven of these genes have never been implicated previously in regulating Notch activity in any system. Depleting the activity of five kinase genes (cdk-8, wnk-1, kin-3, hpo-11, and mig-15) also significantly enhanced the activity of a transgene in which heterologous sequences drive expression of the untethered intracellular domain of LIN-12, suggesting that they increase the activity or stability of the signal-transducing form of LIN-12/Notch. Precedents set by other regulators of lin-12/Notch defined through genetic interactions in C. elegans suggest that this new set of genes may include negative regulators that are functionally relevant to mammalian development and cancer.


Clinical and histological characterization of an aggressive periodontitis case associated with unusual root canal curvatures.
The article presents the histological and clinical characteristics in a severe generalized aggressive periodontitis case associated with multiple root curvatures and the complex therapeutic approach of the severe periodontal destructions. The patient received a complex therapy, including periodontal non-surgical, regenerative and reconstructive approaches, and also endodontic and prosthetic treatments. Recall appointments were fixed at 3-month intervals. One year after the finalization of the active therapy, a hyperplasic, inflamed interdental papilla associated with a recurrent clinical attachment loss was diagnosed at the mesial aspect of the right maxillary second premolar. A biopsy was harvested for histological examination and the recurrent site was treated. The histological study revealed important modifications of the epithelial layer and of the connective tissue of the gingiva. An extremely accentuated pattern of the gingival rete ridges at the epithelial-connective tissue junction, the presence of inflammatory cells infiltrating the epithelial layer and lamina propria and the disorganization of the fascicules of collagen fibers were observed. The inflammatory infiltrate was dominated by plasma and monocytic-like cells as immunohistochemical analyses highlighted. The complex therapeutic approach led to a satisfactory aesthetic and functional outcome. The severe root curvatures may be an unusual trait in this generalized aggressive periodontitis case substantially increasing the amount and the costs of non-periodontal procedures. In this case, the cell make-up of the inflammatory infiltrate and the paucity of collagen in the infiltrated tissue portions are considered to correspond to a fully developed recurrent lesion.


Sputum Active Polymyxin Lipopeptides: Activity against Cystic Fibrosis Pseudomonas aeruginosa Isolates and Their Interactions with Sputum Biomolecules.
The mucoid biofilm mode of growth of Pseudomonas aeruginosa ( P. aeruginosa) in the lungs of cystic fibrosis patients makes eradication of infections with antibiotic therapy very difficult. The lipopeptide antibiotics polymyxin B and colistin are currently the last-resort therapies for infections caused by multidrug-resistant P. aeruginosa. In the present study, we investigated the antibacterial activity of a series of polymyxin lipopeptides (polymyxin B, colistin, FADDI-003, octapeptin A3, and polymyxin A2) against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa cystic fibrosis isolates grown under planktonic or biofilm conditions in artificial sputum and their interactions with sputum component biomolecules. In sputum media under planktonic conditions, the lipopeptides FADDI-003 and octapeptin A3 displayed very promising activity against the polymyxin-resistant isolate FADDI-PA066 (polymyxin B minimum inhibitory concentration (MIC) = 32 mg/L), while retaining their activity against the polymyxin-sensitive strains FADDI-PA021 (polymyxin B MIC = 1 mg/L) and FADDI-PA020 (polymyxin B MIC = 2 mg/L). Polymyxin A2 was only effective against the polymyxin-sensitive isolates. However, under biofilm growth conditions, the hydrophobic lipopeptide FADDI-003 was inactive compared to the more hydrophilic lipopeptides, octapeptin A3, polymyxin A2, polymyxin B, and colistin. Transmission electron micrographs revealed octapeptin A3 caused reduction in the cell numbers in biofilm as well as biofilm disruption/"antibiofilm" activity. We therefore assessed the interactions of the lipopeptides with the component sputum biomolecules, mucin, deoxyribonucleic acid (DNA), surfactant, F-actin, lipopolysaccharide, and phospholipids. We observed the general trend that sputum biomolecules reduce lipopeptide antibacterial activity. Collectively, our data suggests that, in the airways, lipopeptide binding to component sputum biomolecules may reduce antibacterial efficacy and is dependent on the physicochemical properties of the lipopeptide.


EZH2 methyltransferase and H3K27 methylation in breast cancer.
Histone modifications are thought to control the regulation of genetic programs in normal physiology and cancer. Methylation (mono-, di-, and tri-methylation) on histone H3 lysine (K) 27 induces transcriptional repression, and thereby participates in controlling gene expression patterns. Enhancer of zeste (EZH) 2, a methyltransferase and component of the polycomb repressive complex 2 (PRC2), plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Abnormal EZH2 expression has been associated with various cancers including breast cancer. Here, we discuss the contribution of EZH2 and the PRC2 complex in controlling the H3K27 methylation status and subsequent consequences on genomic instability and the cell cycle in breast cancer cells. We also discuss distinct molecular mechanisms used by EZH2 to suppress BRCA1 functions.


The Association between Freedom of Choice and Effectiveness of Home Care Services.
The aim of this paper is to study home care clients' freedom to choose their services, as well the association between the effectiveness of home care services and freedom of choice, among other factors. A structured postal survey was conducted among regular home care clients (n = 2096) aged 65 or older in three towns in Finland. Freedom of choice was studied based on clients' subjective experiences. The effectiveness of the services was evaluated by means of changes in the social-care-related quality of life. Regression analyses were used to test associations. As much as 62% of home care recipients reported having some choice regarding their services. Choosing meals and visiting times for the care worker were associated with better effectiveness. The basic model, which included needs and other factors expected to have an impact on quality of life, explained 15.4% of the changes in quality of life, while the extended model, which included the freedom-of-choice variables, explained 17.4%. The inclusion of freedom-of-choice variables increased the adjusted coefficient of determination by 2%. There was a significant positive association between freedom of choice and the effectiveness of public home care services. Freedom of choice does not exist for all clients of home care who desire it. By changing social welfare activities and structures, it is possible to show respect for clients' opinions and to thereby improve the effectiveness of home care services.


Ultrastructural evaluation of the rat parotid gland in the course of intoxication with lead acetate.
The purpose of this study was to evaluate the ultrastructural changes in the parotid gland of rats exposed to lead. The animals were given lead acetate in drinking water, at a concentration of 50 mg/dm3 Pb for periods of 2, 4 and 6 weeks. The ultrastructural examination showed that lead especially impaired mitochondria, caused accumulation of lipid droplets in the cytoplasm of acinar cells and inhibited the process of exocytosis of secretory granules. In the most extreme cases some acinar cells were destroyed.


[Preoperative embolization of malignancies of the maxillofacial region].
In 28 patients with malignoma of the maxillofacial region catheterization angiography by transfemoral route was applied. In the same act was performed preoperative embolization of the feeding arteries of the expansive formations by temporary embolization material--gel-foam particles. In all the treated patients good vascularization of expansive alterations was achieved as well as their demarcation from the healthy tissues which enables radical extirpation with reduced blood loss during intervention.


Ordinal neural networks without iterative tuning.
Ordinal regression (OR) is an important branch of supervised learning in between the multiclass classification and regression. In this paper, the traditional classification scheme of neural network is adapted to learn ordinal ranks. The model proposed imposes monotonicity constraints on the weights connecting the hidden layer with the output layer. To do so, the weights are transcribed using padding variables. This reformulation leads to the so-called inequality constrained least squares (ICLS) problem. Its numerical solution can be obtained by several iterative methods, for example, trust region or line search algorithms. In this proposal, the optimum is determined analytically according to the closed-form solution of the ICLS problem estimated from the Karush-Kuhn-Tucker conditions. Furthermore, following the guidelines of the extreme learning machine framework, the weights connecting the input and the hidden layers are randomly generated, so the final model estimates all its parameters without iterative tuning. The model proposed achieves competitive performance compared with the state-of-the-art neural networks methods for OR.


Mechanism of Nitrogen Reduction to Ammonia in a Diiron Model of Nitrogenase.
Nitrogenase is a fascinating enzyme in biology that reduces dinitrogen from air to ammonia through stepwise reduction and protonation. Despite it being studied in detail by experimental and computational groups, there are still many unknown factors in the catalytic cycle of nitrogenase, especially related to the addition of protons and electrons and their order. A recent biomimetic study characterized a potential dinitrogen-bridged diiron cluster as a synthetic model of nitrogenase. Using strong acid and reductants, the dinitrogen was converted into ammonia molecules, but details of the mechanism remains unknown. In particular, it was unclear from the experimental studies whether the proton and electron transfer steps are sequential or alternating. Moreover, the work failed to establish what the function of the diiron core is and whether it split into mononuclear iron fragments during the reaction. To understand the structure and reactivity of the biomimetic dinitrogen-bridged diiron complex [(P2P'PhFeH)2(μ-N2)] with triphenylphosphine ligands, we performed a density functional theory study. Our computational methods were validated against experimental crystal structure coordinates, Mössbauer parameters, and vibrational frequencies and show excellent agreement. Subsequently, we investigated the alternating and consecutive addition of electrons and protons to the system. The calculations identify a number of possible reaction channels, namely, same-site protonation, alternating protonation, and complex dissociation into mononuclear iron centers. The calculations show that the overall mechanism is not a pure sequential set of electron and proton transfers but a mixture of alternating and consecutive steps. In particular, the first reaction steps will start with double proton transfer followed by an electron transfer, while thereafter, there is another proton transfer and a second electron transfer to give a complex whereby ammonia can split off with a low energetic barrier. The second channel starts with alternating protonation of the two nitrogen atoms, whereafter the initial double proton transfer, electrons and protons are added sequentially to form a hydrazine-bound complex. The latter split off ammonia spontaneously after further protonation. The various reaction channels are analyzed with valence bond and orbital diagrams. We anticipate the nitrogenase enzyme to operate with mixed alternating and consecutive protonation and electron transfer steps.


Heterologous expression and characterization of the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of Toxoplasma gondii.
We have expressed catalytically active Toxoplasma gondii dihydrofolate-thymidylate synthase (DHFR-TS) and the individual TS and DHFR domains in Escherichia coli using the T7 promoter of pET-15b. DHFR-TS constituted approximately 10% of the total soluble cell protein and was purified using methotrexate-Sepharose chromatography to yield 10 mg of homogeneous DHFR-TS per liter of culture. The DHFR domain was recovered as insoluble inclusion bodies which could be unfolded and refolded to recover soluble, active enzyme. The TS domain was overexpressed as a soluble protein by growing the cells at 24 degrees C; this is the first report of the expression of an active TS domain from a bifunctional enzyme. The kcat and K(m) values for DHFR-TS are similar to those of other previously characterized protozoan DHFRs and TSs. The antimicrobial antifolates, TMP and Pyr, inhibit DHFR activity of the bifunctional protein in accord with their effects in crude enzyme preparations and in vivo systems. Kinetic parameters and Ki values for TMP and Pyr with the isolated DHFR domain were identical to the values for DHFR in the bifunctional enzyme. Evidence of kinetic channeling of the dihydrofolate product of TS to the DHFR domain in the bifunctional enzyme was obtained by kinetic and inhibition studies. Properties such as yield, stability, and activities of the recombinant T. gondii DHFR-TS provide clear advantages over other bifunctional DHFR-TSs as a model for future studies.


Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia.
Loprazolam is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1 mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies. Thus, with its 'intermediate' elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.


[Endoscopic local injection of anticancer drugs bound to carbon particles for treatment of upper digestive tract cancers--clinical trials].
A new dosage formulation consisting of anticancer drugs bound to carbon particles was developed for treating cancers of the upper digestive tract, and is designed to distribute higher levels of anticancer drug to the regional lymph nodes and at the injection site, as compared to a drug in aqueous solution form. Thirteen patients with histologically proven carcinoma (8 with superficial esophageal cancer and 5 with early or proper muscle layer-infiltrating gastric cancer), in whom surgical treatment was contraindicated, received intra- and peritumoral injection of the new dosage formulation (total dose of 35-100 mg of peplomycin or 250-500 mg of methotrexate) guided by esophago- or gastro-fiberscope. Eleven of these 13 patients are currently alive, 12-64 months after therapy, or they died without evidence of recurrence 12-98 months after the treatment. One patient has remained cancer-free for 37 months after a second course of the therapy given to treat a recurrence found 26 months after the first treatment. Another patient has a recurrent tumor 9 months after the therapy and is now going to undergo a second course of treatment. Side effects were not severe and well-tolerable.


Psychology qua psychoanalysis in Argentina: Some historical origins of a philosophical problem (1942-1964).
Contemporary Argentinian psychology has a unique characteristic: it is identified with psychoanalysis. Nonpsychoanalytic theories and therapies are difficult to find. In addition, there is an overt antiscientific attitude within many psychology programs. How should this be explained? In this paper, we claim that a philosophical history of psychology can shed new light on the development of Argentinian psychology by showing that early Argentinian psychoanalysts held positions in the newborn psychology programs and a distinctive stance toward scientific research in general and psychology in particular. In the absence of an explicit and articulate philosophical position, psychoanalysts developed an implicit meta-theory that helped shape the context that led to the institutionalization and professionalization of psychology in Argentina. Although we do not establish or even suggest a monocausal link between their ideas and the current state of Argentinian psychology, we do claim that their impact should be explored. Finally, we discuss some limitations of our study and suggest future complementary investigations.


Aircrew and type 1 diabetes mellitus.
The most stringent clinical criteria cannot guarantee that individuals with Type 1 diabetes mellitus (DM) will preserve awareness of an impending hypoglycemic episode or that a hypoglycemic episode can be prevented. Further, cognition may be impaired for a considerable period of time beyond the correction of any episode. These observations and their implications to operational aircrew with Type 1 DM are discussed.


Efficacy of high-concentration tacalcitol ointment in psoriasis vulgaris after changing from other high-concentration vitamin D3 ointments.
Three high-concentration vitamin D3 ointments are currently available in Japan for the treatment of psoriasis. The aim of the present study is to investigate the efficacy of high-concentration tacalcitol in patients with psoriasis vulgaris who have already been treated with another high-concentration vitamin D3 ointment, calcipotriol or maxacalcitol. The psoriasis area and severity index score was improved in more than half the patients after changing to the tacalcitol ointment. Many patients treated with maxacalcitol once a day achieved greater clinical improvement by changing to high-concentration tacalcitol. In contrast, some patients who had responded to a high-concentration tacalcitol ointment showed exacerbation after changing to maxacalcitol once a day. Interviews with 50 patients (including the 34 patients enrolled in the present study) indicated that high-concentration tacalcitol ointment was an acceptable therapy in terms of the number of daily applications and drug cost. The results of this clinical study suggest that high-concentration tacalcitol ointment meets the preference of many patients who wish to use an ointment once a day.


[Chronic wound as a precancerosis (Ulcus marjolini--Marjolin's ulcer)--a case review].
Marjolin's ulcer is defined as a tumor arising from a chronic wound, scar or chronic inflammation. Commonly, it is histologically diagnosed as a squamous cell carcinoma or a basocellular carcinoma. Its management includes its excisioning including a sufficient circumferential rim and histological examination of the sentinel lymphnode. The authors present a case review of a 51-year-old male with a history of a sacral decubitus, treated for over 40 years. The patient was hospitalized to cover the defect with a skin flap. During the hospitalization, histological examinations of his inguinal lymphnodes and subsequent wound granulations were performed with an identical finding of a squamous cell carcinoma. Based on the findings, the Marjolin's ulcer was diagnosed. The patient underwent the first series of chemotherapy. However, the patient's condition deteriotated. He exited 24 days following establishment of the diagnosis. The aim of this study is to highlight one of the most dangerous complications of chronic wounds. Marjolin's ulcer is a diagnosis, which must be considered in any chronic wound of any etiology, persisting for over 3 months.


Effectiveness of social host and fake identification laws on reducing underage drinking driver fatal crashes.
The public generally assumes that the minimum legal drinking age of 21 (MLDA-21) legislation in the United States is embodied in a single law and therefore all states have the same law. Actually, the MLDA-21 state laws consist of multiple provisions that support the core MLDA-21 laws and include a family of policies directed at controlling underage drinking and underage drinking and driving. Because social host and fake identification laws have recently garnered interest by policy makers in the states, this study was designed to determine their effectiveness. The effective dates for 2 types of social host laws and 3 fake identification laws were documented using the Alcohol Policy Information System (APIS), the Substance Abuse and Mental Health Services Administration's (SAMHSA) 2011 Report to Congress on the Prevention and Reduction of Underage Drinking, and legal research tools. These laws include social host prohibitions (SHPs) and social host civil liability (SHCL), the use of fake identification (FID), retailer support for FID, and transfer/production of FID. We used a pre-post design to evaluate the influence on underage drinking-and-driving fatal crashes of these 5 laws using the Fatality Analysis Reporting System (FARS) data set for the years 1982 through 2010. The data were analyzed using structural equation modeling (SEM) controlling for as many variables as possible. For those drivers younger than aged 21 years, FID supplier laws were associated with significant decreases in FARS ratios after states adopted these laws (-1.0%, P=.030). The 24 states that have adopted FID supplier laws are saving an estimated 14 lives per year in the United States. An additional 16 lives could be saved if the remaining states adopted this law. FID supplier laws prohibit the production of a FID or transfer of an ID or FID to another person. The more stringent the law (i.e., whether a state prohibits only one element [weaker law] compared to both transferring and manufacturing a FID [stronger]) the more effective a deterrent it becomes to supplying a minor with a FID. States without FID supplier laws should consider adopting them.


Sarcodia suiae Water Extract Promotes the Expression of Proinflammatory and Th1-Type Cytokines and Delay the Onset of Mortality in Cobia (Rachycentron canadum) During Photobacterium damselae subsp. damselae Infection.
Cobia (Rachycentron canadum) is a marine fish of high economic value that grows at a fast rate. However, intensive fish farming has led to disease outbreaks in cobia cultures, which is highly costly to the industry. The impact of infectious diseases on cobia production has led to the inappropriate and increased use of chemicals and antibiotics, which negatively affects the environment and human health and promotes the spread of drug-resistant pathogens. Hence, prophylactic measurements, such as the use of immunomodulators, are required to improve the health of cultured animals against pathogens. In this study, we examined the effects of Sarcodia suiae water extract (SSWE) in cobia in vitro and in vivo. We found that treatment with SSWE could significantly increase the expression of cytokines (e.g., IL-1β, IL-6, IL-10, IL-12, and TNF-α) and chemokines (e.g., IL-8) in primary cultured head kidney leukocytes. Intraperitoneal injection of SSWE (20 μg/g body weight) promoted higher expression of IL-6, IL-8, IL-10, IL-12, chemokines (e.g., CC1), and antibodies (e.g., IgT) in head kidney and spleen tissues of the fish compared with other dose levels. Additionally, we describe for the second time (only after India) of the isolation of Photobacterium damselae subsp. damselae (Phdd) from a deadly epizootic in cage-farmed cobia. An intraperitoneal inoculation of SSWE before Phdd challenge showed that SSWE treatment could delay the onset of mortality of cobia. Finally, fish that received SSWE intraperitoneally before infection with Phdd exhibited elevated expression of Th1-type cytokines, namely, IL-8, IL-12, TNF-α, and IFN-γ. At the same time, the expression of Th2-related factors (such as IL-10 in the head kidney, and IgM and IgT in the spleen) were lower for the fish that received SSWE instead of PBS before the Phdd challenge. The results indicate that SSWE treatment facilitates the induction of Th1-type cytokines in cobia to fight against Phdd infection and has the potential to be used as an immunostimulant and vaccine adjuvant for fish.


Pulmonary response after exposure to inhaled nickel hydroxide nanoparticles: short and long-term studies in mice.
Short and long-term pulmonary response to inhaled nickel hydroxide nanoparticles (nano-Ni(OH)(2), CMD = 40 nm) in C57BL/6 mice was assessed using a whole body exposure system. For short-term studies mice were exposed for 4 h to nominal concentrations of 100, 500, and 1000 mg/m(3). For long-term studies mice were exposed for 5 h/d, 5 d/w, for up to 5 months (m) to a nominal concentration of 100 mg/m(3). Particle morphology, size distribution, chemical composition, solubility, and intrinsic oxidative capacity were determined. Markers of lung injury and inflammation in bronchoalveolar lavage fluid (BALF); histopathology; and lung tissue elemental nickel content and mRNA changes in macrophage inflammatory protein-2 (Mip-2), chemokine ligand 2 (Ccl2), interleukin 1-alpha (Il-1α), and tumor necrosis factor-alpha (Tnf-α) were assessed. Dose-related changes in BALF analyses were observed 24 h after short-term studies while significant changes were noted after 3 m and/or 5 m of exposure (24 h). Nickel content was detected in lung tissue, Ccl2 was most pronouncedly expressed, and histological changes were noted after 5 m of exposure. Collectively, data illustrates nano-Ni(OH)(2) can induce inflammatory responses in C57BL/6 mice.


A longitudinal study on mandibular implants supporting an overdenture: the influence of retention mechanism and anatomic-prosthetic variables on periimplant parameters.
The aim of this 5-year longitudinal study was to investigate the influence of the retention mechanism for overdenture fixation on the periimplant parameters of mandibular implants. Ninety edentulous patients, each with two interforaminal implants supporting an overdenture, participated in the study. They had received either a straight or slightly bent round clip bar, a U-shaped rigid bar with or without distal extensions, or single-ball anchors. Anatomic-morphologic and prosthetic variables were assessed related to the implant position and the type of overdenture retention. The degree of mandibular atrophy was determined using cephalometric radiographs. The angle beta between the virtual axis connecting both implants and the mandibular hinge axis was measured on mounted casts. A supporting surface was identified between bent clip bars and U-shaped extension bars. Clinical periimplant parameters were recorded, and changes of the probing attachment level after 5 years were analyzed in 70 patients with respect to the retention device and anatomic-morphologic and prosthetic variables. A significant increase of the Plaque Index was observed after 5 years. The mean clinical attachment loss after 5 years was about 0.2 mm. In more than 50%, beta was small, i.e., < or = 5 degrees. For these implants, loss of clinical attachment was significantly lower. The correlation between attachment loss and beta was weak, while no significant correlation was found with regard to the degree of atrophy and surface. In view of the long observation period, it was concluded that the position and retention mechanism of mandibular implants supporting an overdenture have little influence on the long-term stability of the clinical parameters.


Metropolitan fiscal structure and migration.
This abstract examines the degree to which individuals vote with their feet when considering metropolitan fiscal structure. Local (and state) fiscal policies are considered in detail by investigating migration impacts of expenditures and revenues, as well as by examining effects of distribution of expenditures by type and revenues by source. These impacts are considered across 3 dimensions of the migration decision: the decision of a metropolitan resident to move (relocate), the decision to depart the metropolitan area, and the decision to enter such an area. Empirical results indicate that fiscal structure plays an important role within these decisions, and particularly that to depart the metropolitan area.


General deming regression for estimating systematic bias and its confidence interval in method-comparison studies.
Various forms of least-squares regression analyses are used to estimate average systematic error (bias) and its confidence interval in method-comparison studies. When assumptions that underlie a particular regression method are inappropriate for the data, errors in estimated statistics result. In this report, I present an improved method for regression analysis that is free from the usual simplifying assumptions and is generally applicable to linearly related method-comparison data. Theoretical equations based on the Deming approach, further developed by physicists and extended herein, were applied to method-comparison data analysis. Monte Carlo simulations were used to demonstrate the validity of the new procedure and to compare its performance to ordinary linear regression (OLR) and simple Deming regression (SDR) procedures. Simulation studies included three types of data commonly encountered in method-comparison studies: (a) constant within-method SDs for both methods, (b) constant within-method CVs for both methods, and (c) neither SDs nor CVs constant for both methods. For all cases examined, OLR produced unreliable confidence intervals of the estimated bias. However, OLR point estimates of systematic bias were reliable when the correlation coefficient was >0.975. SDR produced reliable estimates of systematic bias for all cases studied, but the confidence intervals of systematic bias were unreliable when SDs of methods varied as a function of analyte concentration. Only iteratively reweighted general Deming regression produced statistically unbiased estimates of systematic bias and reliable confidence intervals of bias for all cases.


[Posterior vitreous detachment induced by intravitreal injection of the combination of chondroitinase ABC and matrix metalloproteinase-3].
To investigate the occurrence of enzymatic induction of posterior vitreous detachment (PVD) by the combination of Chondroitinase ABC (CA) and matrix metalloproteinase-3 (MMP-3), so as to seek a noninvasive and effective pharmacologic approach to facilitate and eventually replace the present mechanical vitreous surgery. Twenty-four pigmented rabbits were randomly assigned to two groups of twelve each, the experimental group was treated with CA (0.2 U) and MMP-3 (10 ng) combination, the control group was received equivalent dose of balanced salt solution (BSS). Clinical examinations and electroretinography were performed before and after injection. Over a different period of time, the rabbits were euthanized and killed and their eyes were examined histologically. The foci of partial synchisis and clinically named PVD were recognized for the first time three days after injection. Complete liquefaction was found in every eye of experimental group, and in which, 5/8 eyes developed clinically detected PVD one week after injection Histologic section showed PVD with various extent in 3/7, 7/7, 7/7 eyes of experimental group 30 minutes, 60 minutes and one week after injection respectively, and complete PVD in 0/7, 1/7, 5/7 eyes of experimental group at the same periodic intervals as above. By contrast, no vitreous liquefaction was found and only one eye showed confined partial PVD in the control group. Clinic, electrophysiologic and histologic evaluation in all rabbits revealed no evidence of ocular toxicity. Vitreous 1iquefaction and PVD can be produced shortly after intravitreal injection using a combination of CA and MMP-3, and the two enzymes were cooperative. Synchisis and weakening of vitreoretinal adherence were almost simultaneously. The dose of 0.2 U CA and 10 ng MMP-3 combination proved to be safe and ideal selection to induce PVD.


Intraoperative electromyographic monitoring during periacetabular osteotomy.
Periacetabular osteotomy has become the procedure of choice in many centers for the treatment of symptomatic hip dysplasia. Intraoperative real-time nerve monitoring has been advocated during acetabular fracture repair and complex total hip arthroplasties to prevent iatrogenic sciatic nerve injury. To the authors' knowledge there is no information concerning the use of intraoperative electromyographic monitoring during periacetabular osteotomy. The purpose of the current study was to investigate the use of intraoperative continuous electromyographic monitoring during periacetabular osteotomy in a relatively large consecutive series of patients as a mechanism to prevent nerve injury during surgery and as a prognostic indicator of neurologic function after periacetabular osteotomy. From September 1992 to July 1999, 140 consecutive periacetabular osteotomies were done in 127 patients at the authors' institution. There were 96 females and 31 males, with an average age of 32 years at the time of surgery. All patients had intraoperative electromyographic monitoring of femoral and sciatic innervated muscles. All patients were followed up for a minimum of 1 year, until complete resolution of neurologic deficits, or both. Thirty-six patients (26%) had abnormal electromyographic activity recorded during surgery. Seven patients (5%) had peroneal nerve deficits postoperatively including extensor hallucis longus and tibialis anterior weakness with loss of sensation in the first web space. Abnormal electromyographic activity was observed intraoperatively in five of the seven patients with postoperative deficits. Six of the seven injuries resolved completely. One patient with intraoperative electromyographic activity (0.7%) had a postoperative foot drop that persisted for greater than 1 year. There were no femoral, tibial, or obturator nerve deficits observed. Electromyographic monitoring appears to provide prediction of postoperative neurologic deficit.


Effective construction of quaternary stereocenters by highly enantioselective α-amination of branched aldehydes.
A highly efficient enantioselective α-amination of branched aldehydes with azadicarboxylates promoted by chiral proline-derived amide thiourea bifunctional catalysts was developed for the first time, affording the adducts bearing quaternary stereogenic centers with excellent yields (up to 99%) and enantioselectivities (up to 97% ee).


Inhibitory Effects of a Pectin-Enriched Tomato Cell Wall Fraction on Agrobacterium tumefaciens Binding and Tumor Formation.
A pectin-enriched soluble cell wall fraction (CWF) prepared from suspension cultured tomato cells inhibits binding of Agrobacterium tumefaciens to these cells. It was hypothesized that the CWF contains the plant surface binding site for A. tumefaciens (NT Neff, AN Binns 1985 Plant Physiol 77: 35-42). Experiments described here demonstrate that tomato CWF inhibited tumor formation on potato slices and Agrobacterium binding to intact tomato cells in a dose-dependent fashion. Boiling the fraction reduced both its binding and tumor inhibitory activities. Tumor inhibitory activity was titrated out by increased concentrations of bacterial inocula with no inhibition apparent at 1 x 10(8) bacteria per milliliter. These results indicate that a tomato CWF is enriched for a putative A. tumefaciens binding site which may also be involved in tumor formation in potato.


Health education in mental health services.
In the past few years, we have witnessed numerous efforts to develop health education in psychiatry. Many of them, however, were not successfully implemented. In the Netherlands, a health education method was developed in conjunction with seven mental health providers. The method promotes a more successful implementation.


Pimecrolimus cream 1% for the treatment of papulopustular eruption related to epidermal growth factor receptor inhibitors: a case series and a literature review of therapeutic approaches.
Cutaneous side effects of epidermal growth factor receptor inhibitors (EGFRIs) are very frequent and well known. The aim of our study was to investigate the efficacy and safety of pimecrolimus 1% cream in the treatment of papulopustular eruption caused by EGFRIs and to review the relevant literature on therapeutic approaches. Twenty cancer patients being treated with EGFRIs were included in the study. Nine of the patients showed grade 1 and 11 showed grade 2 papulopustular eruption. All patients were treated with pimecrolimus 1% cream, which was applied twice daily. Patients with grade 2 eruption also received systemic minocycline 100 mg/day. All patients with grade 1 eruption responded to treatment, with 4/9 experiencing complete resolution of the lesions 2 weeks after the initiation of treatment. Five out of 11 patients with grade 2 eruption had more than 50% improvement in erythema and pustules, and 1 had complete resolution of the skin lesions. Two patients did not respond to treatment but were significantly improved after substitution of pimecrolimus 1% cream with metronidazole 1% cream. No side effects were recorded. Our case series shows that pimecrolimus cream may be an effective and safe approach in the management of papulopustular eruption related to EGFRIs.


Structure and chromosomal localization of the human anti-müllerian hormone type II receptor gene.
Using the rat anti-müllerian hormone type II receptor (AMHRII) cDNA as a probe, two overlapping lambda phage clones containing the AMHRII gene were isolated from a human genomic library. Sequence analysis of the exons was performed and the exon/intron boundaries were determined. The coding region was found to consist of 11 exons, divided over 8 kb. The genomic structure resembles that of the related activin type II receptor gene. The AMHRII gene was mapped to human chromosome 12q12-q13. The results reported are essential for identification of AMHRII gene alterations in patients with persistent müllerian duct syndrome.


Emerging treatment options in the management of non-small cell lung cancer.
Lung cancer (LC) has become the leading cancer-related cause of death in the US and in developed European countries in the last decade. Its incidence is still growing in females and in smokers. Surgery remains the treatment of choice whenever feasible, but unfortunately, many patients have an advanced LC at presentation and one-third of potentially operable patients do not receive a tumor resection because of their low compliance for intervention due to their compromised cardiopulmonary functions and other comorbidities. For these patients the alternative therapeutic options are stereotactic radiotherapy or percutaneous radiofrequency. When surgery is planned, an anatomical resection (segmentectomy, lobectomy, bilobectomy, pneumonectomy, sleeve lobectomy) is usually performed; wedge resection (considered as a nonanatomical one) is generally the accepted option for unfit patients. The recent increase in discovering small and peripheral LCs and/or ground-glass opacities with screening programs has dramatically increased surgeons' interest in limited resections. The role of these resections is discussed. Also, recent improvements in molecular biology techniques have increased the chemotherapic options for neoadjuvant LC treatment. The role and the importance of targeted chemotherapy is also discussed.


Inguinal hernia repair: see one, do one, teach one?
Clinical management of inguinal hernias has been the subject of recent debate, and guidelines have been produced by The Royal College of Surgeons of England. There is evidence that the results of hernia repair by trainees are inferior to those of more experienced surgeons, but there are no published data on the amount of training and supervision currently experienced by junior surgeons. Thirty-two questionnaires were returned by trainees (21 senior house officers and 11 registrars) from hospitals in the south of England, giving details of teaching and supervision for 3,013 hernia repairs recorded in their log books. Trainees had assisted at 2-90 (median 8) repairs before operating themselves, and had then been supervised during 2-46 (median 9) repairs before being allowed to operate unsupervised. They had assisted subsequently at a further 0-100 (median 9) repairs, and had received supervision during a further 0-42 (median 6) repairs after their first unsupervised repair. The majority (79 per cent) felt adequately trained at the time of their first unsupervised repair. Senior house officers had significantly more experience than registrars in the Shouldice and Lichtenstein techniques, suggesting that these methods have gained ground recently in surgical training. These results show substantial variation in the amount of training and supervision given for inguinal hernia repair. In general, however, trainees experienced a good progression through assisting, supervision, and subsequent reinforcement by further work with senior surgeons after being allowed to operate unsupervised.


Advanced Glycation End Products Predict Loss of Renal Function and Correlate With Lesions of Diabetic Kidney Disease in American Indians With Type 2 Diabetes.
We examined associations of advanced glycation end products (AGEs) with renal function loss (RFL) and its structural determinants in American Indians with type 2 diabetes. Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan. Participants remained under observation after the trial concluded. Glomerular filtration rate (GFR) was measured annually. Kidney biopsies were performed at the end of the trial. Five AGEs were measured in serum collected at enrollment and at kidney biopsy. RFL was defined as ≥40% decline of measured GFR from baseline. Of 168 participants (mean baseline age 41 years, HbA1c 9.2%, GFR 164 mL/min, and albumin-to-creatinine ratio 31 mg/g), 104 reached the RFL end point during median follow-up of 8.0 years. After multivariable adjustment, each doubling of carboxyethyl lysine (hazard ratio [HR] 1.60 [95% CI 1.08-2.37]) or methylglyoxal hydroimidazolone (HR 1.30 [95% CI 1.02-1.65]) concentration was associated with RFL. Carboxyethyl lysine, carboxymethyl lysine, and methylglyoxal hydroimidazolone correlated positively with cortical interstitial fractional volume (partial r = 0.23, P = 0.03; partial r = 0.25, P = 0.02; and partial r = 0.31, P = 0.003, respectively). Glyoxyl hydroimidazolone and methylglyoxal hydroimidazolone correlated negatively with total filtration surface per glomerulus (partial r = -0.26, P = 0.01; and partial r = -0.21, P = 0.046, respectively). AGEs improve prediction of RFL and its major structural correlates.


Interactive intermediates are formed during the urea unfolding of rhodanese.
Structural transitions have been studied on the pathway for urea denaturation of rhodanese. Unlike guanidinium hydrochloride, urea gives no visible precipitation. Increasing urea concentrations cause a transition in which the enzyme activity is completely lost by 4.5 M urea, and there is a shift of the intrinsic fluorescence maximum from 335 nm for the native enzyme to 350 nm. There is a maximum exposure of organized hydrophobic surfaces at 4.5 M urea as reported by the fluorescence of 1,1'-bi(4-anilino)naphthalene-5,5'-disulfonic acid. Above 4.5 M urea, this probe reports the progressive loss of organized hydrophobic surfaces. The polarization of the intrinsic fluorescence falls with increasing urea concentrations in a complex transition showing that rhodanese flexibility increases in at least two phases. Rhodanese becomes increasingly susceptible to digestion by subtilisin between 3.5 and 4.5 M urea, giving rise to large fragments. At urea concentrations > 5 M, rhodanese is completely digested. There is a small increase in the rate of sulfhydryl accessibility between 3.5 and 4.5 M urea, but there is a large increase in the sulfhydryl accessibility above 4.5 M urea. Dimethyl suberimidate cross-linking shows the presence of associated species in 3-5 M urea, but there are few cross-linkable species at lower or higher urea concentrations. These results are consistent with a model in which urea unfolding of rhodanese is associated with the initial production of a species having organized regions of structure with exposed hydrophobic surfaces separated by flexible elements.


Psychosocial effect of common skin diseases.
To increase awareness of the psychosocial effect of acne, atopic dermatitis, and psoriasis. A literature review was based on a MEDLINE search (1966 to 2000). Selected articles from the dermatologic and psychiatric literature, as well as other relevant medical journals, were reviewed and used as the basis for discussion of how skin disease affects patients' lives and of appropriate management. Studies in the medical literature provide mainly level III evidence predominantly based on descriptive studies and expert opinion. Dermatologic problems can result in psychosocial effects that seriously affect patients' lives. More than a cosmetic nuisance, skin disease can produce anxiety, depression, and other psychological problems that affect patients' lives in ways comparable to arthritis or other disabling illnesses. An appreciation for the effects of sex, age, and location of lesions is important, as well as the bidirectional relationship between skin disease and psychological distress. This review focuses on the effects of three common skin diseases seen by family physicians: acne, atopic dermatitis, and psoriasis. How skin disease affects psychosocial well-being is underappreciated. Increased understanding of the psychiatric comorbidity associated with skin disease and a biopsychosocial approach to management will ultimately improve patients' lives.


Localisation and mobility of trace metal in silver fir needles.
Trace metals (TM: Co, Ni, Cu, Zn, Cd, and Pb) as well as Al, Mn, and Fe content was measured in needles of a remote silver fir stand in the south of France. TM localisation and behaviour in needles was evaluated by measuring total and internal content of needles of different ages. Measured concentrations fell within background values. Al, Fe, Co, and Pb were trapped in wax following atmospheric particulate deposition. Contrasting accumulation and migration behaviours of the different elements studied were observed. The wax contained less than 10% Mn, Al, Ni, Co, and Zn and 15-45% Fe, Cu, and Cd in the young needles. Lead was mostly located in the wax (50-80%), and this proportion decreased with needle age. Only the internal content of Pb and Fe increased significantly with needle age. Finally, due to atmospheric deposition accumulation, higher input fluxes of Fe, Cu, Cd, and Pb can be expected in forest soil.


Human immunodeficiency virus: the eighth gene.
Human T-lymphotropic virus type III (HTLV-III/LAV) has been shown to contain at least four extra genes in addition to the three essential genes (gag, pol, env) for replication of most retroviruses. These genes are expressed by complex splicing mechanisms and utilization of overlapping reading frames. We now demonstrate that there is an eighth gene which encodes a protein which is immunogenic and recognized by sera of some HTLV-III seropositive people. The gene is highly conserved among all known HTLV-III isolates and exhibits a polymorphism at the 3' end which distinguishes several molecular clones of the HTLV-IIIB cell line from those of other HTLV-III/LAV isolates. The function of this gene is unknown.


Using Structural and Functional Brain Imaging to Investigate Responses to Acute Thermal Pain.
Despite a fundamental interest in the relationship between structure and function, the relationships between measures of white matter microstructural coherence and functional brain responses to pain are poorly understood. We investigated whether fractional anisotropy (FA) in 2 white matter regions in pathways associated with pain is related to the functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to thermal stimulation. BOLD fMRI was measured from 16 healthy male subjects during painful thermal stimulation of the right arm. Diffusion-weighted images were acquired for each subject and FA estimates were extracted from the posterior internal capsule and the cingulum (cingulate gyrus). These values were then included as covariates in the fMRI data analysis. We found BOLD response in the midcingulate cortex (MCC) to be positively related to FA in the posterior internal capsule and negatively related to FA in the cingulum. Our results suggest that the MCC's involvement in processing pain can be further delineated by considering how the magnitude of the BOLD response is related to white matter microstructural coherence and to subjective perception of pain. Considering relationships to white matter microstructural coherence in tracts involved in transmitting information to different parts of the pain network can help interpretation of MCC BOLD activation. Relationships between functional brain responses, white matter microstructural coherence, and subjective ratings are crucial for understanding the role of the MCC in pain. These findings provide a basis for investigating the effect of the reduced white matter microstructural coherence observed in some pain disorders on the functional responses to pain.


In situ preservation of the partathyroid glands in total thyroidectomy: a propensity score matched analysis.
Severe hypocalcemia due to parathyroid gland damage may be a serious complication after thyroidectomy. In order to save parathyroid integrity we developed a no-touch parathyroid (NTP) thyroidectomy technique. We performed a total extracapsular thyroidectomy with NTP technique in consecutive 50 cases of benign goiter between July 2014 and June 2015. Parathyroid glands were firstly indentified, then they were separated from the thyroid avoiding manipulation or trauma and preserving their vascularization. Traditional scissors were preferentially used for dissection around the glands. Patients operated with NTP technique were matched by a propensity score to a control group. NTP was feasible in all foreseen patients except one. Propensity score selected a group of 23 patients/group for matching. No mortality has been observed in either group. Operative time were comparable between groups. Blood loss were significantly less abundant in the NTP group. No laryngeal permanent paralysis was experienced. Hospital stay was shorter yet not significantly in NTP group. Neither hypocalcemic crisis nor permanent hypoparathyroidism were described in either group. Serum calcium levels (NTP Vs control) were significantly higher in NTP group at day 1 (p=0.03) and day 2 (p=0.002), respectively. Similarly, intact parathormone dosages were significantly higher at day 1 (p=0.004) and day 7 (p=0.001), respectively. We conclude that NTP thyroidectomy is a feasible in the majority of the patientsand, allows a significant reduction of blood loss without prolonging the operative time. After the procedureboth values of calcemia and intact parathormonewere stable and no hypocalcemic crisis was experienced. Parathyroid, Hypoparathyroidism, Hypocalcemia, Total thyroidectomy.


Median nerve electrophysiologic parameters and psychomotor performance in carpal tunnel syndrome.
Psychomotor performance (PMP) involving a repeated, rapid pinch and release task was correlated with median nerve electrophysiologic parameters for control subjects (16 hands) and subjects with carpal tunnel syndrome (CTS) (14 hands). The psychomotor task was used because of its functional resemblance to many work related activities. A strain gauge dynamometer was repeatedly pinched to a predetermined force level using the index finger and thumb and then released as rapidly as possible, while measuring the actual isometric force exerted. Discrete visual and auditory feedback was provided. Median and ulnar nerve motor latencies and amplitudes, as well as median antidromic sensory latencies and amplitudes, and transcarpal latencies and amplitudes were obtained. CTS subjects had longer median motor and sensory latencies and were weaker than controls, however median motor and sensory amplitudes were not statistically different. A strong relationship was observed between electrophysiologic variables and PMP, which could not be accounted for by age differences alone. It is unclear whether the measured differences in PMP are related to sensory or motor deficits.


[Hodgkin's disease in childhood--northern Israel cancer center experience, 1971-1990].
Records of children treated for Hodgkin's disease between 1971-1990 were analyzed retrospectively, and 102 cases of children younger than 18 years when diagnosed were reviewed. There were 54 boys and 48 girls, with male predominance in those younger than 10 years. 44 patients were of Arab ancestry and 58 were Jewish; the incidence was similar in both groups. Most common were the nodular sclerosing and mixed cellularity types, the latter more common in the younger age group. The outcome of various treatments was evaluated. At diagnosis, 64% were in stages I or II and 34% in stages III or IV. 20 of those in stages I-II received radiotherapy (RT) alone, 10 chemotherapy (CT) alone, and 35 combined CT and RT. Survival rates and median disease-free intervals were statistically similar with all 3 modalities. However, relapse rates were higher with either RT or CT alone (35% and 38%, respectively) than with combined therapy (14%). We conclude that combined CT and RT is superior to RT or CT alone.


Field data analysis of boar semen quality.
This contribution provides an overview of approaches to correlate sow fertility data with boar semen quality characteristics. Large data sets of fertility data and ejaculate data are more suitable to analyse effects of semen quality characteristics on field fertility. Variation in fertility in sows is large. The effect of semen factors is relatively small and therefore impossible to find in smaller data sets. Large data sets allow for statistical corrections on both sow- and boar-related parameters. Remaining sow fertility variation can then be assigned to semen quality parameters, which is of huge interest to AI (artificial insemination) companies. Previous studies of Varkens KI Nederland to find the contribution to field fertility of (i) the number of sperm cells in an insemination dose, (ii) the sperm motility and morphological defects and (iii) the age of semen at the moment of insemination are discussed in context of the possibility to apply such knowledge to select boars on the basis of their sperm parameters for AI purposes.


Theophylline metabolism in preterm neonates during the first weeks of life.
The effects of prenatal steroids on theophylline metabolism in infants of 27-32 weeks gestation was studied. Although in utero exposure to betamethasone was associated with a more mature theophylline metabolite pattern in the first days of life, initial elimination half-life (t1/2 beta) did not differ significantly between groups. By the second or third week of life the metabolite pattern was similar in all infants. The decline in t1/2 beta seen during theophylline treatment was not directly related to increased metabolite formation. These data suggest that other factors, such as renal clearance, are more important in determining the pharmacokinetics of theophylline in neonates than is hepatic metabolism.


Informed consent.
Information to make patients fully aware of all the details of treatments is an important part of the medical practice before obtaining patient's signature in the consent form. Explanation may be detailed enough to make patients understand the process of treatment. However, sometime it may not be inclusive enough to cover all major statements that give pros and cons of the treatment. Perhaps detailed explanation may reveal too much information that may discourage patients to receive treatments and cause fear, anxiety, and hopelessness. If health care personnels do not mention all the risks involved in medical treatments, they may be subjected to an accusation of concealing the truth that should be made known to patients. This is one of many ways of looking at the problems. There is no easy answer to the problem of what 'appropriate' explanation should be. Most of our patients are from all walks of life which are not medical profession, and they do not have knowledge to understand technical terms. How should we approach patients in order to be safe from an accusation of that we are not over supporting, not giving the patients false hope? Therefore, we would like to present a guideline for informing and explaining to the patients under the following headings (15): 1. Diseases or major symptoms which are diagnosed. 2. The necessity to receive treatments for the benefits of patients or fetus. 3. If possible, determine the duration of treatments. 4. Methods of treatment, evaluation, and schedule for next appointment. 5. Inform about necessary investigations. 6. Inform about complications of risks, and cost of investigations 7. Usefulness and results of investigations. 8. If options of treatments are available, they should be explained in details, the pros and cons, the risks, and the costs, etc. 9. Maintaining medical confidentiality and the use of patient chart by medical personnel and other related health care providers, for instance, hospital staffs from all levels, medical students, technical medical students, and social workers, etc.


Innovative computer-aided methods for the discovery of new kinase ligands.
Recent evidence points to significant roles played by protein kinases in cell signaling and cellular proliferation. Faulty protein kinases are involved in cancer, diabetes and chronic inflammation. Efforts are continuously carried out to discover new inhibitors for selected protein kinases. In this review, we discuss two new computer-aided methodologies we developed to mine virtual databases for new bioactive compounds. One method is ligand-based exploration of the pharmacophoric space of inhibitors of any particular biotarget followed by quantitative structure-activity relationship-based selection of the best pharmacophore(s). The second approach is structure-based assuming that potent ligands come into contact with binding site spots distinct from those contacted by weakly potent ligands. Both approaches yield pharmacophores useful as 3D search queries for the discovery of new bioactive (kinase) inhibitors.


Increased free light chains in the urine from patients with multiple sclerosis.
We quantitated free kappa (kappa) and lambda light (L) chains in coded urine specimens from subjects with clinically definite multiple sclerosis (MS) (N = 56), other neurologic diseases (OND) (N = 30), and age-matched normal controls (N = 28). Urine from MS patients showed statistically significant increases in free L chains compared with the other groups, although there was overlap between MS patients and OND patients. The ratio of kappa/creatinine was significantly greater in the relapsing-remitting MS group than in patients with clinically stable MS, OND, and normal controls. Elevated free L chains were usually independent of urinary albumin and beta 2-microglobulin levels. Serial studies showed that urinary free kappa/creatinine ratios were elevated during periods of clinical worsening in seven of eight MS patients and subsequently decreased during clinical recovery. The measurement of free L chains in urine obtained at intervals from MS patients may be useful as a marker to monitor disease activity.


Effect of heterogeneous Fenton-like pre-treatment on anaerobic granular sludge performance and microbial community for the treatment of traditional Chinese medicine wastewater.
The effect of a heterogeneous Fenton-like pre-treatment on the anaerobic processes, characteristics and microbial community of sludge was investigated for traditional Chinese medicine (TCM) wastewater containing rhein. When the concentrations of rhein were 50mg/L and 100mg/L, the toxic effect was physiological toxicity for anaerobic granular sludge. Using a single double circle (DC) reactor for the treatment of TCM wastewater containing rhein at concentrations of 15-20mg/L, the chemical oxygen demand (COD) removal rate was 69%, and coenzyme F420 was nearly undetectable in the 3D-excitation-emission matrix (EEM) spectra of soluble microbial products (SMP). The abundances of Methanoregula, Methanobacterium, Methanosphaerula were only 5.57%, 2.39% and 1.08% in the DC reactor, respectively. TCM wastewater containing rhein could be successfully treated by the combination of the heterogeneous Fenton-like pre-treatment and the DC reactor processes, and the COD removal rate reached 95%. Meanwhile, the abundances of Methanoregula, Methanobacterium, Methanosphaerula increased to 22.5%, 18.5%, and 13.87%, respectively. For the bacterial community, the abundance of Acidobacteria_Gp6 decreased from 6.99% to 1.07%, while the abundances of Acidobacteria_Gp1 and Acidobacteria_Gp2 increased from 1.61% to 6.55% and from 1.28% to 5.87%, respectively.


Influence of Butyrate Loaded Clinoptilolite Dietary Supplementation on Growth Performance, Development of Intestine and Antioxidant Capacity in Broiler Chickens.
The study was conducted to evaluate the effects of dietary butyrate loaded clinoptilolite (CLI-B) on growth performance, pancreatic digestive enzymes, intestinal development and histomorphology, as well as antioxidant capacity of serum and intestinal mucosal in chickens. Two hundred forty 1-day-old commercial Arbor Acres broilers were randomly assigned to 4 groups: CON group (fed basal diets), SB group (fed basal diet with 0.05% sodium butyrate), CLI group (fed basal diet with 1% clinoptilolite), and CLI-B group (fed basal diet with 1% CLI-B). The results showed that supplementation of CLI-B significantly decreased (P < 0.05) feed conservation ratio at both 21 and 42 days of age, improved the pancreatic digestive enzymes activities (P < 0.05), increased the villus length and villus/crypt ratio (P < 0.05), and decreased the crypt depth of intestine (P < 0.05) as compared to the other experimental groups. Furthermore, the CLI-B environment improved the antioxidant capacity by increasing the antioxidant enzyme activities (P < 0.05) in intestine mucosal, and decreasing the NO content and iNOS activity (P < 0.05) in serum. In addition, CLI-B supplementation had improved the development of intestine and antioxidant capacity of broilers than supplementation with either clinoptilolite or butyrate sodium alone. In conclusion, 1% CLI-B supplementation improved the health status, intestine development and antioxidant capacity in broiler chickens, thus appearing as an important feed additive for the poultry industry.


A homogeneous, recyclable polymer support for Rh(I)-catalyzed C-C bond formation.
A robust and practical polymer-supported, homogeneous, recyclable biphephos rhodium(I) catalyst has been developed for C-C bond formation reactions. Control of polymer molecular weight allowed tuning of the polymer solubility such that the polymer-supported catalyst is soluble in nonpolar solvents and insoluble in polar solvents. Using the supported rhodium catalysts, addition of aryl and vinylboronic acids to the electrophiles such as enones, aldehydes, N-sulfonyl aldimines, and alkynes occurs smoothly to provide products in high yields. Additions of terminal alkynes to enones and industrially relevant hydroformylation reactions have also been successfully carried out. Studies show that the leaching of Rh from the polymer support is low and catalyst recycle can be achieved by simple precipitation and filtration.


Molecular structure and peptidoglycan recognition of Mycobacterium tuberculosis ArfA (Rv0899).
Mycobacterium tuberculosis ArfA (Rv0899) is a membrane protein encoded by an operon that is required for supporting bacterial growth in acidic environments. Its C-terminal domain (C domain) shares significant sequence homology with the OmpA-like family of peptidoglycan-binding domains, suggesting that its physiological function in acid stress protection may be related to its interaction with the mycobacterial cell wall. Previously, we showed that ArfA forms three independently structured modules, and we reported the structure of its central domain (B domain). Here, we describe the high-resolution structure and dynamics of the C domain, we identify ArfA as a peptidoglycan-binding protein and we elucidate the molecular basis for its specific recognition of diaminopimelate-type peptidoglycan. The C domain of ArfA adopts the characteristic fold of the OmpA-like family. It exhibits pH-dependent conformational dynamics (with significant heterogeneity at neutral pH and a more ordered structure at acidic pH), which could be related to its acid stress response. The C domain associates tightly with polymeric peptidoglycan isolated from M. tuberculosis and also associates with a soluble peptide intermediate of peptidoglycan biosynthesis. This enabled us to characterize the peptidoglycan binding site where five highly conserved ArfA residues, including two key arginines, establish the specificity for diaminopimelate- but not Lys-type peptidoglycan. ArfA is the first peptidoglycan-binding protein to be identified in M. tuberculosis. Its functions in acid stress protection and peptidoglycan binding suggest a link between the acid stress response and the physicochemical properties of the mycobacterial cell wall.


Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial.
The EURTAC trial demonstrated the greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic epidermal growth factor receptor (EGFR) mutations (exon 19 deletion or L858R mutation in exon 21) in tumor tissue. To assess the feasibility of using circulating free DNA (cfDNA) from blood samples as a surrogate for tumor biopsy for determining EGFR mutation status and to correlate EGFR mutations in cfDNA with outcome. This prespecified analysis was a secondary objective of the EURTAC trial using patients included in the EURTAC trial from 2007 to 2011 with available baseline serum or plasma samples. Patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, and no prior chemotherapy for metastatic disease and were treated with erlotinib or chemotherapy. EGFR mutations were examined in cfDNA isolated from 97 baseline blood samples by our novel peptide nucleic acid-mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay. Overall survival (OS), progression-free survival (PFS), and response to therapy were correlated with type of EGFR mutations in cfDNA. In samples from 76 of 97 (78%) patients with usable blood samples, EGFR mutations in cfDNA were detected. Median OS was shorter in patients with the L858R mutation in cfDNA than in those with the exon 19 deletion (13.7 [95% CI, 7.1-17.7] vs 30.0 [95% CI, 19.3-37.7] months; P < .001). Univariate analyses of patients with EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter OS (hazard ratio [HR], 2.70 [95% CI, 1.60-4.56]; P < .001) and PFS (HR, 2.04 [95% CI, 1.20-3.48]; P = .008). For patients with the L858R mutation in tissue, median OS was 13.7 (95% CI, 7.1-17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1-46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09-4.52]; P = .03). In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer PFS (HR, 0.41 [95% CI, 0.23-0.74]; P = .003). The peptide nucleic acid-mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay used in this study can be used to efficiently assess EGFR mutations in cfDNA. The L858R mutation in cfDNA may be a novel surrogate prognostic marker. clinicaltrials.gov Identifier: NCT00446225.