Conventional cementation technique for Targis restorations.
Ivoclar can now recommend a clinical and laboratory procedure for the conventional cementation of Targis single- and multiple-unit full-coverage restorations. The ability to bond restorations utilizing enamel/dentin bonding systems and dual-cure resin cements (Variolink II, Ivoclar Vivadent, Amherst, NY) has minimized microleakage and postoperative sensitivity, provided stronger restorations, and reinforced remaining tooth structure. Unfortunately, the benefits of the adhesive technique can often be compromised by existing or pre-existing clinical conditions. This challenge has limited the broad use of adhesive, metal-free restorations in many clinical situations. Targis restorations can now be successfully cemented utilizing zinc phosphate or conventional glass ionomer cements. This article describes the technique through a case presentation.


[Prevalence of lymphoma subtypes in Shanxi according to latest WHO classification].
To analyze the prevalence of lymphoma subtypes in Shanxi according to the latest World Health Organization (WHO) classification, and to compare the figures with those in other parts of the world. The hematoxylin and eosin-stained sections of 447 lymphoma cases from the archive files of Shanxi Tumor Hospital were reviewed. Immunohistochemical study was performed using a panel of antibodies, including ALK1, bcl-6, CD (1a, 3, 4, 5, 7, 8, 10, 15, 20, 23, 30, 43, 56, 68, 79a and 99), cyclin D1, EMA, IgD, kappa, lambda, LMP1, PAX5, TdT and Vs38C. In addition, in-situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was carried out. All cases were then reclassified according to the latest WHO classification of lymphoma. Of the 447 cases studied, 385 cases (86.1%) were confirmed to be non-Hodgkin lymphoma (NHL), while 62 cases (13.9%) belonged to classic Hodgkin lymphoma (HL). Of the NHL cases, 68.3% were of B-cell lineage and 30.6% were of T and/or NK-cell lineage. Histiocytic neoplasm accounted for only 0.8% (3 cases). As for the subtyping of NHL, diffuse large B-cell lymphoma was commonest (35.1%), followed by peripheral T-cell lymphoma, NOS (12.0%), extranodal marginal zone B-cell lymphoma (MALT lymphoma) (11.7%), follicular lymphoma (8.6%), T-lymphoblastic lymphoma (7.0%), anaplastic large cell lymphoma (4.2%), B-small lymphocytic lymphoma (3.6%) and mantle cell lymphoma (2.6%). Amongst the 263 cases of B-cell lymphoma, 105 cases (39.9%) expressed immunoglobulin light chain (kappa in 52 cases and lambda in 53 cases) in paraffin sections. Regarding markers for EB virus infection, 14 cases of the B-cell lymphoma gave positive findings with both EBER in-situ hybridization and LMP-1 immunohistochemistry, while 6 of the T/NK-cell lymphoma expressed LMP-1 and 19 showed positive signals for EBER. In NHL, there was discordance in EBER in-situ hybridization and LMP-1 immunohistochemical results. As for HL, EB virus positivity was noted in 37 of the 62 cases (59.7%), including 7 cases of lymphocyte-rich HL, 11 cases of mixed cellularity HL and 19 cases of nodular sclerosis HL. In classic HL, there was complete concordance of results by both EBER in-situ hybridization and LMP-1 immunohistochemistry. The prevalence of diffuse large B-cell lymphoma in Shanxi is similar to that in America, Australia, Japan and Korea. The incidence of follicular lymphoma however is much lower than America and Australia.


Uncommon presentation, rare complication and previously undescribed oncologic association of pheochromocytoma; the great masquerader.
We describe the case of a 67-year-old man presenting with ventricular tachycardia (VT) and systolic heart failure secondary to a left adrenal phaeochromocytoma. After treatment with amiodarone, the patient's VT resolved. However, his course was complicated by femoral deep venous thrombosis secondary to an incidentally discovered dedifferentiated liposarcoma of the thigh, for which he was prescribed a course of enoxaparin. The patient was discharged with plans for adrenalectomy following achievement of sufficient preoperative heart rate and blood pressure control with alpha-adrenergic receptor blockade, but re-presented to an outside facility in haemorrhagic shock, where he ultimately expired. Autopsy determined his death to be caused by spontaneous haemorrhage of the phaeochromocytoma. Cardiac manifestations, complications and oncological associations of phaeochromocytoma are discussed.


Effectiveness of indonesian honey on the acceleration of cutaneous wound healing: an experimental study in mice.
The purpose of this study was to investigate the effectiveness of Indonesian honey in wound healing compared to Tegaderm hydrocolloid dressing and Manuka honey. Three groups of male mice were treated to produce 2 circular, full-thickness skin wounds on the dorsum. They were then randomly allocated to receive daily Indonesian honey, Manuka honey, or hydrocolloid (control). Macroscopic findings were observed from day 0 to 14 after wounding. Microscopic findings on days 3, 7, 11, and 14 after wounding were obtained. The ratios of wound areas for honey groups on day 3 were smaller than those of the control group. Wound areas of honey groups gradually decreased to almost the same wound area as the control group on day 14, while the control group wound area peaked on day 5 and rapidly decreased until day 14. On day 3, myofibroblasts and new blood capillaries in wound tissue of honey groups were observed, but were not seen in the control group. After day 7, microscopic findings were almost the same among the 3 groups. These results indicate that Indonesian honey is almost as effective for wound healing as Manuka honey and hydrocolloid dressing. .


Immunoglobulin E and eosinophil-dependent protective immunity to larval Onchocerca volvulus in mice immunized with irradiated larvae.
Mice immunized with irradiated Onchocerca volvulus third-stage larvae developed protective immunity. Eosinophil levels were elevated in the parasite microenvironment at the time of larval killing, and measurements of total serum antibody levels revealed an increase in the immunoglobulin E (IgE) level in immunized mice. The goal of the present study was to identify the role of granulocytes and antibodies in the protective immune response to the larval stages of O. volvulus in mice immunized with irradiated larvae. Immunity did not develop in mice if granulocytes, including both neutrophils and eosinophils, were eliminated, nor did it develop if only eosinophils were eliminated. Moreover, larvae were killed in naïve interleukin-5 transgenic mice, and the killing coincided with an increase in the number of eosinophils and the eosinophil peroxidase (EPO) level in the animals. To determine if EPO was required for protective immunity, mice that were genetically deficient in EPO were immunized, and there were no differences in the rates of parasite recovery in EPO-deficient mice and wild-type mice. Two mouse strains were used to study B-cell function; micro MT mice lacked all mature B cells, and Xid mice had deficiencies in the B-1 cell population. Immunity did not develop in the micro MT mice but did develop in the Xid mice. Finally, protective immunity was abolished in mice treated to eliminate IgE from the blood. We therefore concluded that IgE and eosinophils are required for adaptive protective immunity to larval O. volvulus in mice.


Adult emergency department referrals from urgent care centers.
Although urgent care centers (UCCs) can often evaluate and treat minor injuries/illnesses, patients may present with life threatening conditions that require immediate recognition, stabilization, and transfer to a higher level of care, beyond the capabilities of most UCCs. To describe adult ED referrals from UCCs and to determine the percentage of referrals considered critical, complex, and simple. A prospective study was conducted between 8/2016-8/2017 on patients >18 years referred directly to our ED from surrounding UCCs. Referrals were categorized based on investigations/procedures performed or medications/consultations received in the ED. We analyzed 317 patient encounters; 23 (7.3%) considered critical, 254 (80.1%) complex, and 40 (12.6%) simple. The most common chief complaints for all ED referrals were abdominal pain (62 encounters), chest pain (28), shortness of breath (16), eye pain/injury (16), and leg pain/swelling (15). 68% of patients received laboratory diagnostic investigations and 69% received radiologic investigations. 37% of patients required consultation from a subspecialist. 78% of patients were discharged home. The most common primary diagnoses for all ED referrals were nonspecific abdominal pain (27 encounters), laceration (22), fracture (20), nonspecific chest pain (12), cellulitis (12), and pneumonia (12). The most common primary diagnoses for critical referrals were appendicitis (7) and fracture (3). Many adult ED referrals in our sample were considered complex and few were considered critical. Individual UCCs should evaluate their current states of ED referrals, and develop educational and preparedness strategies based on the epidemiology of adult emergencies that may occur.


Fast and high-resolution purification of a PEGylated protein using a z2 laterally-fed membrane chromatography device.
PEGylated proteins comprise a class of value-added biopharmaceuticals. High-resolution separation techniques are required for the purification of these molecules. In this study, we discuss the application of a newly developed z2 laterally-fed membrane chromatography (or z2LFMC) device for carrying out high-resolution purification of a PEGylated protein drug. The device used in the current study contained a stack of anion exchange (Q) membranes. The membrane bed-height of this z2LFMC device being small, it could be operated at very high flow rates, at relatively low back pressures. The primary goal was to speedily and efficiently separate a mono-PEGylated protein from impurities present in the PEGylation reaction mixture. A resin-based anion exchange column having the same ligand and bed-volume was used as the control device. The purification performance of the z2LFMC device and the control column were compared terms of resolution, recovery and purity. The z2LFMC device outperformed the control column in terms of every metric compared in this study. Higher purity (85.4% as opposed to 77.9%) and higher recovery (28% greater) of the target mono-PEGylated protein were obtained using the z2LFMC device at 20-time higher speed. These results clearly demonstrate that the z2LFMC device could be a faster and more efficient alternative to resin-based columns for purification of biopharmaceuticals.


Carbohydrate inhibition of chlamydial infectivity.
The effects of exogenous carbohydrates on chlamydial infectivity were tested. It was shown that the addition of certain carbohydrates reduced the infectivity of Chlamydia psittaci in cell culture. The greatest inhibitory effects were observed by monosaccharides, disaccharides and trisaccharides, respectively. The addition of ATP, but not AMP, enhanced the inhibitory effect.


Interleukin-32 Gamma Stimulates Bone Formation by Increasing miR-29a in Osteoblastic Cells and Prevents the Development of Osteoporosis.
Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32γ in bone remodeling and the hypothetical correlation between IL-32γ and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32γ showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32γ TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32γ levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32γ plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32γ and DKK1 as bone metabolic markers.


A modification of the connective tissue graft procedure for the treatment of type II and type III ridge deformities.
Various grafting procedures have been developed for reconstruction of partially edentulous ridge deformities prior to prosthetic rehabilitation. The majority of these procedures have been applicable to reconstruction of Type I (buccolingual) ridge deformities. Type II and Type III defects present a more difficult challenge because of the need for apicocoronal augmentation and replacement of greater volumes of lost tissue. The onlay and subepithelial connective tissue grafts have been predominately used for the treatment of these type of defects, however, each procedure presents certain limitations. This report describes a simple modification of the connective tissue graft that enhances its ability to augment tissue for Type II and Type III deformities. The technique is an effective and predictable procedure for advanced ridge deformities.


Synthesis of α-methylstilbenes using an aqueous Wittig methodology and application toward the development of potent human aromatase inhibitors.
The development of aqueous Wittig methodology for the synthesis of α-methylstilbenes using tripropylphosphine-derived phosphonium salts is described. The Wittig olefination reaction was high yielding and allowed isolation of stilbenes by simple filtration and washing with water. The novel phosphonium salts employed were accessed via a highly efficient, regioselective addition of hydrogen bromide to styrenes. Application of the α-methylstilbenes toward the synthesis of a collection of stilbenoid-triazoles is reported and their inhibition of CYP450 19A1 (aromatase) investigated. The overall structure-activity profile provided additional evidence on the aryl halide-ketone bioisostere hypothesis and identified 6c as a potent inhibitor of aromatase in vitro (Ki = 8 nM).


Long-term Bisphosphonates for Osteoporosis: A Factor Effecting Fracture Pattern?
The incidence of fragility hip fractures, intracapsular and extracapsular, has been increasing worldwide. Fracture stability is important for treatment decision-making and is related to the expected rate of complications. It is unclear whether metabolic therapy explains the increased incidence of unstable fractures. To investigate the possible association between treatment with bisphosphonates and the various patterns encountered with intertrochanteric hip fractures. Patients with fragility hip fractures who were treated in our department between 2013 and 2014 were included in this study. They were classified into three groups: group 1 had a stable extracapsular fracture, group 2 had an unstable extracapsular fracture, and group 3 had an intracapsular fracture. Collated data included: osteoporosis preventive therapy and duration, fracture-type, history of previous fractures, and vitamin D levels. Of 370 patients, 87 were previously treated with bisphosphonates (18.3% prior to fracture in group 1, 38.3% in group 2, and 13.8% in group 3). Of those treated with bisphosphonates, 56.3% had an unstable fracture, 21.8% had a stable fracture, and the rest an intracapsular fracture. In contrast, only 27.9% of patients who were not treated with bisphosphonates had an unstable fracture and 30.0% had stable fractures. Our findings show a higher proportion of complex and unstable fractures among patients with fragility hip-fractures who were treated with bisphosphonates than among those who did not receive this treatment. The risk for complex and unstable fracture may affect the preferred surgical treatment, its complexity, length of surgery, and rehabilitation.


The nature of the chemical bond and the role of non-dynamical and dynamical correlation in Be2.
In the spin-coupled generalized valence bond (SCGVB) description of Be2, there is a pair of electrons in highly overlapping "inner" orbitals corresponding to a traditional σ bond, but this bond is compromised by Pauli repulsion arising from its overlap with a second "outer" pair. The presence of this outer pair of electrons leads to a repulsive potential energy curve at long range and a bound, but metastable molecule at short range. To obtain further insights into the nature of the bond in Be2, we determined the non-dynamical and dynamical correlation contributions to the potential energy curve of Be2 using four different choices for the zero-order wave function: Restricted Hartree-Fock (RHF), SCGVB, valence-CASSCF(4,4), and valence-CASSCF(4,8). The SCGVB and valence-CASSCF(4,4) wave functions yield similar breakdowns of the total correlation energy, with non-dynamical correlation being the more important contribution. For the RHF and valence-CASSCF(4,8) wave functions, dynamical correlation is critical, without which the potential energy curve is purely repulsive. High accuracy calculations on the HBen-1Be-BeBen-1H molecule as a function of n (n = 1-6) suggest that the intrinsic strength of a Be-Be σ bond uncompromised by Pauli repulsion is on the order of 62-63 kcal/mol, and its length is 2.13-2.14 Å, ∼60 kcal/mol stronger and ∼0.35 Å shorter than in Be2.


PRSice: Polygenic Risk Score software.
A polygenic risk score (PRS) is a sum of trait-associated alleles across many genetic loci, typically weighted by effect sizes estimated from a genome-wide association study. The application of PRS has grown in recent years as their utility for detecting shared genetic aetiology among traits has become appreciated; PRS can also be used to establish the presence of a genetic signal in underpowered studies, to infer the genetic architecture of a trait, for screening in clinical trials, and can act as a biomarker for a phenotype. Here we present the first dedicated PRS software, PRSice ('precise'), for calculating, applying, evaluating and plotting the results of PRS. PRSice can calculate PRS at a large number of thresholds ("high resolution") to provide the best-fit PRS, as well as provide results calculated at broad P-value thresholds, can thin Single Nucleotide Polymorphisms (SNPs) according to linkage disequilibrium and P-value or use all SNPs, handles genotyped and imputed data, can calculate and incorporate ancestry-informative variables, and can apply PRS across multiple traits in a single run. We exemplify the use of PRSice via application to data on schizophrenia, major depressive disorder and smoking, illustrate the importance of identifying the best-fit PRS and estimate a P-value significance threshold for high-resolution PRS studies. PRSice is written in R, including wrappers for bash data management scripts and PLINK-1.9 to minimize computational time. PRSice runs as a command-line program with a variety of user-options, and is freely available for download from http://PRSice.info firstname.lastname@example.com or email@example.com Supplementary data are available at Bioinformatics online.


PILL series. The solitary pulmonary nodule.
The solitary pulmonary nodule on chest X-ray (CXR) is a common problem in pulmonary medicine. Its presence raises the question of lung cancer. As five-year survival after resection of a solitary bronchogenic carcinoma can be as high as 80%, prompt evaluation is crucial. This should begin with a cancer risk assessment based on clinical and radiographic factors. The risk and benefits of surgery should next be assessed, and together with the patient's preferences, a management plan can be decided upon. Surgery is recommended for patients at high risk of malignancy with a low surgical risk, while careful observation is adopted for patients at low risk of malignancy coupled with a high surgical risk. Further diagnostic tests may be warranted to aid in this decision process. Although CXR is not useful for lung cancer screening, low-dose computed tomography imaging is increasingly recommended for individuals at high risk for lung cancer.


Antibiotics and antiseptics for surgical wounds healing by secondary intention.
Following surgery, incisions are usually closed by fixing the edges together with sutures (stitches), staples, adhesives (glue) or clips. This process helps the cut edges heal together and is called 'healing by primary intention'. However, a minority of surgical wounds are not closed in this way. Where the risk of infection is high or there has been significant loss of tissue, wounds may be left open to heal by the growth of new tissue rather than by primary closure; this is known as 'healing by secondary intention'. There is a risk of infection in open wounds, which may impact on wound healing, and antiseptic or antibiotic treatments may be used with the aim of preventing or treating such infections. This review is one of a suite of Cochrane reviews investigating the evidence on antiseptics and antibiotics in different types of wounds. It aims to present current evidence related to the use of antiseptics and antibiotics for surgical wounds healing by secondary intention (SWHSI). To assess the effects of systemic and topical antibiotics, and topical antiseptics for the treatment of surgical wounds healing by secondary intention. In November 2015 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We also searched three clinical trials registries and the references of included studies and relevant systematic reviews. There were no restrictions with respect to language, date of publication or study setting. Randomised controlled trials which enrolled adults with a surgical wound healing by secondary intention and assessed treatment with an antiseptic or antibiotic treatment. Studies enrolling people with skin graft donor sites were not included, neither were studies of wounds with a non-surgical origin which had subsequently undergone sharp or surgical debridement or other surgical treatments or wounds within the oral or aural cavities. Two review authors independently performed study selection, risk of bias assessment and data extraction. Eleven studies with a total of 886 participants were included in the review. These evaluated a range of comparisons in a range of surgical wounds healing by secondary intention. In general studies were small and some did not present data or analyses that could be easily interpreted or related to clinical outcomes. These factors reduced the quality of the evidence.Two comparisons compared different iodine preparations with no antiseptic treatment and found no clear evidence of effects for these treatments. The outcome data available were limited and what evidence there was low quality.One study compared a zinc oxide mesh dressing with a plain mesh dressing. There was no clear evidence of a difference in time to wound healing between groups. There was some evidence of a difference in measures used to assess wound infection (wound with foul smell and number of participants prescribed antibiotics) which favoured the zinc oxide group. This was low quality evidence.One study reported that sucralfate cream increased the likelihood of healing open wounds following haemorrhoidectomy compared to a petrolatum cream (RR: 1.50, 95% CI 1.13 to 1.99) over a three week period. This evidence was graded as being of moderate quality. The study also reported lower wound pain scores in the sucralfate group.There was a reduction in time to healing of open wounds following haemorrhoidectomy when treated with Triclosan post-operatively compared with a standard sodium hypochlorite solution (mean difference -1.70 days, 95% CI -3.41 to 0.01). This was classed as low quality evidence.There was moderate quality evidence that more open wounds resulting from excision of pyomyositis abscesses healed when treated with a honey-soaked gauze compared with a EUSOL-soaked gauze over three weeks' follow-up (RR: 1.58, 95% CI 1.03 to 2.42). There was also some evidence of a reduction in the mean length of hospital stay in the honey group. Evidence was taken from one small study that only had 43 participants.There was moderate quality evidence that more Dermacym®-treated post-operative foot wounds in people with diabetes healed compared to those treated with iodine (RR 0.61, 95% CI 0.40 to 0.93). Again estimates came from one small study with 40 participants. There is no robust evidence on the relative effectiveness of any antiseptic/antibiotic/anti-bacterial preparation evaluated to date for use on SWHSI. Where some evidence for possible treatment effects was reported, it stemmed from single studies with small participant numbers and was classed as moderate or low quality evidence. This means it is likely or very likely that further research will have an important impact on our confidence in the estimate of effect, and may change this estimate.


Identification of an avirulent Entamoeba histolytica strain with unique tRNA-linked short tandem repeat markers.
Highly polymorphic, non-coding short tandem repeats (STR) are scattered between the tRNA genes in Entamoeba histolytica in a unique tandemly arrayed organization. STR markers that correlate with the virulence of individual E. histolytica strains have recently been reported. Here we evaluated the usefulness of tRNA-linked STR loci as genetic markers in identifying virulent and avirulent strains of E. histolytica from 37 Japanese E. histolytica samples (12 diarrheic/dysenteric, 20 amebic liver abscess (ALA), and 5 asymptomatic cases). Twenty three genotypes, assigned by combining the STR sequence types from all 6 STR loci, were identified. One to 8 new STR sequence types per locus were also discovered. Genotypes found in asymptomatic isolates were highly polymorphic (4 out of 5 genotypes were unique to this group), while in symptomatic isolates, almost half of the genotypes were shared between diarrhea/dysentery and ALA. One asymptomatic isolate (KU27) showed unique STR patterns in 4 loci. This strain, though associated with the typical pathogenic zymodeme II, failed to induce amebic liver abscess by animal challenge, which suggests that inherently avirulent E. histolytica strains exist, that are associated with unique genotypes. Furthermore, STR genotyping and in vivo challenge of 2 other asymptomatic isolates (KU14 and KU26) verified the covert virulence of these strains.


Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer.
CXCL12/CXCR4 signaling, being important in the homing of cancer cells to lungs, bone and other organs, is a promising therapeutic target. Our purpose was to determine whether a peptide-based antagonist of CXCR4 would reduce primary tumor growth and/or metastasis in a preclinical mouse model of inflammatory breast cancer. We improved an existing model of inflammatory breast cancer for this study by luciferase transfection of SUM149 cells and the monitoring of such cells in mice by imaging and the luciferase assay. We implanted 2 x 10(6) SUM49-Luc cells along with matrigel into the left thoracic mammary fat pad of nude mice to produce tumors. Our mouse model exhibited important features of inflammatory breast cancer, namely, aggressive local disease, local metastases and distant metastases. To evaluate the efficacy of a CXCR4 antagonist CTCE-9908, by itself or in combination with paclitaxel, we treated groups of ten mice each with CTCE-9908 (25 mg/kg, injected subcutaneously 5 days/week), control peptide SC-9908, paclitaxel (10 mg/kg, injected subcutaneously twice a week), and CTCE-9908 plus paclitaxel concurrently. We assessed all mice weekly by whole-body luciferase imaging to quantify relative primary tumor burden and distant metastases. At the end of the experiment, we quantified primary tumors by weight and lung metastases by luciferase activity assay on tissue lysates. Paclitaxel, a known chemotherapeutic, inhibited primary tumor growth in our model (P < 0.05). CTCE-9908 did not significantly inhibit primary tumor growth or lung metastases as compared to control groups, without or with paclitaxel (P > 0.05). However, CTCE-9908 as a single therapy inhibited organ-specific metastasis to leg (P < 0.05 by chi-squared test and by two-sample t-test).


Variability of orthopedic physician fracture location identification: Implications for bone stimulator treatment.
Aseptic non-union is a significant complication in approximately 5% of long-bone fractures. External bone stimulation treatment is often attempted before more invasive surgical interventions. Bone stimulators can have favorable results, but have a limited 1.7cm therapeutic radius. This study evaluated the accuracy by which clinicians locate a fracture on a cadaveric model. This has implications for the clinician's ability to accurately counsel patients on daily bone stimulator placement. Additionally, physicians (orthopedic attending surgeons and residents) were compared with pre-clinical (M1 and M2) medical students to evaluate if higher levels of training improved accuracy. Orthopedic physicians and pre-clinical medical students will localize a radiographic fracture within 1.7cm less than 100% of the time, which represents the ideal consistency for patient care. Furthermore, orthopedic physicians will achieve a higher percentage accuracy than pre-clinical medical students. The sample included 20 orthopedic physicians and 16 pre-clinical medical students. Upper (radius) and lower (tibia) extremity cadaver models were prepared by inducing a single, transverse diaphyseal fracture. Plain reference radiographs of each model were obtained. Participants placed a radiopaque marker onto each model at the perceived fracture location, and radiographs were taken to document placement. Perpendicular marker-to-fracture distance was measured to the nearest mm along each bone's long axis using the PACS system. Placement within the therapeutic radius was achieved by 70-80% of physicians, and 69-75% of medical students. In the remaining participants, improper placement distances were lower among physicians than among medical students (radius: 2.1±0.5 vs. 3.6±0.9cm, p=0.02; tibia: 2.6±0.5 vs 3.5±0.5cm, p=0.89). In two cadaveric fracture models, up to 30% of orthopedic surgeons perceived a fracture location to be outside a bone stimulator's 1.7cm therapeutic radius. This finding suggests that physicians and their patients may benefit from additional methods for specifying the location of a non-union before commencing daily bone stimulator treatment. Level IV, prospective cohort study-evidence from a well-designed prospective cohort study.


Developmental cycle of Coxiella burnetii: structure and morphogenesis of vegetative and sporogenic differentiations.
Coxiella burnetii is a gram-variable obligate intracellular bacterium which carries out its development cycle in the phagolysosome of eucaryotic cells. Ultrastructural analysis of C. burnetii, in situ and after Renografin purification, by transmission electron microscopy of lead-stained thin sections has revealed extreme pleomorphism as demonstrated by two morphological cell types, a large cell variant (LCV) and a small cell variant (SCV). Potassium permanganate staining of purified rickettsiae revealed a number of differences in the internal structures of the cell variants. (i) The outer membrane of the sCV and LCV were comparable; however, the underlying dense layer of the SCV was much wider and more prominent than that of the LCV. The periplasmic space of the SCV was not readily visualized, whereas the periplasmic space of the LCV was apparent and resembled that of other gram-negative bacteria. (ii) Complex internal membranous intrusions which appeared to originate from the cytoplasmic membrane were observed in the SCV. The LCV did not harbor an extensive membranous system. (iii) Some LCVs contained a dense body in the periplasmic space. This endogenous structure appeared to arise in one pole of the LCV as an electrondense "cap" formation with the progressive development of a dense body approximately 130 to 170 nm in diameter which was eventually surrounded by a coat of at least four layers. Our observations suggest that the morphogenesis of C. burnetii is comparable, although not identical, to cellular differentiation of endospore formation. A developmental cycle consisting of vegetative and sporogenic differentiation is proposed.


Selection of affibody molecules to the ligand-binding site of the insulin-like growth factor-1 receptor.
Affibody molecules binding to the site of hormone interaction in IGF-1R (insulin-like growth factor-1 receptor) were successfully selected by phage-display technology employing a competitive-elution strategy during biopanning, whereby release of receptor-bound phagemids was accomplished by competition with IGF-1 (insulin-like growth factor-1). In non-competitive selections, the elution of receptor-bound phagemids was performed by imidazole or low-pH incubation, which also resulted in the isolation of affibody molecules that could bind to the receptor. An ELISA-based assay showed that the affibody molecules generated by IGF-1 competition during elution, in addition to affibody molecules generated in the non-competitive selections, could compete with IGF-1 for binding to the receptor. The affinities of the isolated variants to IGF-1R-overexpressing MCF-7 cells were determined and ranged from high nanomolar to 2.3 nM. The most promising variant, Z4:40, was shown to recognize IGF-1R efficiently in several different contexts: in analyses based on flow cytometry, fluorescence microscopy and receptor pull-down from cell extracts. In addition, when Z4:40 was added to the medium of MCF-7 cells that were dependent on IGF-1 for efficient growth, it was found to have a dose-dependent growth-inhibitory effect on the cells. Applications of affibody-based reagents for quantitative and qualitative analyses of IGF-1R status, as well as applications of affibody-based reagents for therapy, are discussed.


Bicycling Exercise Helps Maintain a Youthful Metabolic Cost of Walking in Older Adults.
The decline of walking performance is a key determinant of morbidity among older adults. Healthy older adults have been shown to have a 15-20% lower walking economy compared with young adults. However, older adults who run for exercise have a higher walking economy compared with older adults who walk for exercise. Yet, it remains unclear if other aerobic exercises yield similar improvements on walking economy. The purpose of this study was to determine if regular bicycling exercise affects walking economy in older adults. We measured metabolic rate while 33 older adult "bicyclists" or "walkers" and 16 young adults walked on a level treadmill at four speeds between (0.75-1.75 m/s). Across the range of speeds, older bicyclists had a 9-17% greater walking economy compared with older walkers (p = .009). In conclusion, bicycling exercise mitigates the age-related deterioration of walking economy, whereas walking for exercise has a minimal effect on improving walking economy.


Functional Characterization of Class I Trehalose Biosynthesis Genes in Physcomitrella patens.
The function of trehalose metabolism in plants during growth and development has been extensively studied, mostly in the eudicot Arabidopsis thaliana. So far, however, not much is known about trehalose metabolism in the moss Physcomitrella patens. Here, we show that in P. patens, two active trehalose-6-phosphate synthase enzymes exist, PpTPS1 and PpTPS2. Expression of both enzymes in Saccharomyces cerevisiae can complement the glucose-growth defect of the yeast tps1∆ mutant. Truncation of N-terminal extension in PpTPS1 and PpTPS2 resulted in higher TPS activity and high trehalose levels, upon expression in yeast. Physcomitrella knockout plants were generated and analyzed in various conditions to functionally characterize these proteins. tps1∆ and tps2∆ knockouts displayed a lower amount of caulonema filaments and were significantly reduced in size of gametophores as compared to the wild type. These phenotypes were more pronounced in the tps1∆ tps2∆ mutant. Caulonema formation is induced by factors such as high energy and auxins. Only high amounts of supplied energy were able to induce caulonema filaments in the tps1∆ tps2∆ mutant. Furthermore, this mutant was less sensitive to auxins as NAA-induced caulonema development was arrested in the tps1∆ tps2∆ mutant. In contrast, formation of caulonema filaments is repressed by cytokinins. This effect was more severe in the tps1∆ and tps1∆ tps2∆ mutants. Our results demonstrate that PpTPS1 and PpTPS2 are essential for sensing and signaling sugars and plant hormones to monitor the balance between caulonema and chloronema development.


Screening for future cardiovascular disease using age alone compared with multiple risk factors and age.
Risk factors such as blood pressure and serum cholesterol are used, with age, in screening for future cardiovascular disease (CVD) events. The value of using these risk factors with age compared with using age alone is not known. We compared screening for future CVD events using age alone with screening using age and multiple risk factors based on regular Framingham risk assessments. Ten-year CVD risk was estimated using Framingham risk equations in a hypothetical sample population of 500,000 people aged 0-89 years. Risk estimates were used to identify individuals who did and did not have a CVD event over a ten-year period. For screening using age alone (age screening) and screening using multiple risk factors and age (Framingham screening) we estimated the (i) detection rate (sensitivity); (ii) false-positive rate; (iii) proportion of CVD-free years of life lost in affected individuals with positive results (person-years detection rate); and (iv) cost per CVD-free life year gained from preventive treatment. Age screening using a cut-off of 55 years detected 86% of all first CVD events arising in the population every year and 72% of CVD-free years of life lost for a 24% false-positive rate; for five yearly Framingham screening the false-positive rate was 21% for the same 86% detection rate. The estimated cost per CVD-free year of life gained was £2,000 for age screening and £2,200 for Framingham screening if a Framingham screen costs £150 and the annual cost of preventive treatment is £200. Age screening for future CVD events is simpler than Framingham screening with a similar screening performance and cost-effectiveness. It avoids blood tests and medical examinations. The advantages of age screening in the prevention of heart attack and stroke warrant considering its use in preference to multiple risk factor screening.


Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria.
Pruritus, or itching, is the most common symptom of dermatologic disease. Psychologic factors can affect pruritus, and in an earlier study of inpatients with moderate to severe psoriasis, we observed that the degree of depressive psychopathology directly correlated with pruritus severity. In this study we investigated the relation between pruritus and depression among a group of patients (N = 252) with a wide range of pruritic skin disorders, including outpatients with mild to moderate psoriasis (N = 77), atopic dermatitis (N = 143) and chronic idiopathic urticaria (N = 32). All patients self-rated the severity of their pruritus on a 10-point scale and completed a battery of psychologic ratings, including the Carroll Rating Scale for Depression (CRSD). We observed a direct correlation (Pearson's r = .34, p < .0001) between pruritus severity and the CRSD score. The correlations between pruritus severity and CRSD scores for each individual diagnostic group were as follows: psoriasis: Pearson's r = .32, p = .004; atopic dermatitis: Pearson's r = .21, p = .013; and chronic idiopathic urticaria: Pearson's r = .34, p = .06. When the subjects with pruritus scores less than 5.5 were compared with subjects with pruritus scores greater than 5.5, significant differences (p < .05) in depression scores were found for all three dermatoses by the Mann-Whitney U test. The depressed clinical state may reduce the threshold for pruritus.


Potential carbon mitigation and income in developing countries from changes in use and management of agricultural and forest lands.
The many opportunities for mitigating atmospheric carbon emissions in developing countries include reforesting degraded lands, implementing sustainable agricultural practices on existing lands and slowing tropical deforestation. This analysis shows that over the next 10 years, 48 major tropical and subtropical developing countries have the potential to reduce the atmospheric carbon burden by about 2.3 billion tonnes of carbon. Given a central price of $10 per tonne of carbon and a discount rate of 3%, this mitigation would generate a net present value of about $16.8 billion collectively for these countries. Achieving these potentials would require a significant global effort, covering more than 50 million hectares of land, to implement carbon-friendly practices in agriculture, forest and previously forested lands. These estimates of host-country income potentials do not consider that outside financial investment may or may not be available. Our calculations take no account of the additional benefits of carbon sequestration in forest soils undergoing reforestation, increased use of biomass and reduced use of fossil-fuel inputs and reduced agricultural emissions. In all events, realizing these incomes would necessitate substantially greater policy support and investment in sustainable land uses than is currently the case.


Spherical hexagonal tellurium nanocrystals: fabrication and size-dependent structural phase transition at high pressure.
Single-crystalline spherical nearly monodisperse tellurium (Te) nanocrystals (NCs) with average diameters of 20 and 90 nm, respectively, have been fabricated for the first time by a facile solution sonochemistry process. The structural characterizations show that the as-synthesized Te NCs have pure hexagonal structure, as revealed by x-ray diffraction (XRD), selected-area electron diffraction (SAED), energy-dispersive x-ray (EDX) spectroscopy, and high-resolution transmission electron microscopy (HRTEM) methods. The size-dependent structural phase transition of Te NCs up to the high pressure of 20 GPa has been investigated in a diamond anvil cell using resistance measurement at room temperature, and compared with the behavior of bulk Te under identical conditions. The experimental results indicate that 20 nm Te NCs, 90 nm NCs, and bulk Te all undergo two phase transitions up to 20 GPa, their respective transition pressures being about 7.2 and 10.3 GPa, 5.9 and 8.8 GPa, and 4.0 and 6.8 GPa. This indicates that the phase transition pressures are higher for the smaller NCs. In this paper we discuss the size-dependent structural phase transitions, the sluggishness of the phase transition process, and the fluctuating properties of the phase transition products at high pressure. The present work might open an avenue to real-time detection of the dynamics of the phase transition in bulk and nanoscale materials at high pressure, and also could serve as a guide to tailoring the microscopic properties of materials.


Phase transition properties of aqueous dispersions of homologues of all-trans 2,3-dipalmitoylcyclopentano-1-phosphocholine.
In a previous publication, (Singer, M.A., Jain, M.K., Sable, H.Z., Pownall, H.H., Mantulin, W.W., Lister, M.D. and Hancock, A.J. (1983) Biochim. Biophys. Acta, 731, 373-377), we reported the properties of aqueous dispersions of the six diastereo-isomers of cyclopentanoid analogues of dipalmitoylphosphatidylcholine. Two of these isomers displayed unusually high enthalpies of transition, about double that of dipalmitoylphosphatidylcholine. One of the high enthalpy isomers whose configuration is all-trans has now been modified by the insertion of extra methylene residues (n = 3 through 9) between the nitrogen and phosphorus atoms of the headgroup. Vesicles were formed from these lipids and studied by 22Na permeability measurements, differential scanning calorimetry, fluorescence polarization, 31P-NMR, and freeze-fracture electron microscopy. Vesicles composed of lipids with n = 2 or 3 exhibit a sharp transition at 46 degrees C or 49 degrees C, respectively, and a high enthalpy with no detectable sub- or pretransitions. Lipids with n greater than 3 exhibit a main transition between 38 and 43 degrees C with enthalpies less than 10 kcal/mol and after prolonged coding (more than 3 days at 4 degrees C) a broad endotherm at about 20 +/- 3 degrees C with enthalpies greater than 4 kcal/mol. These same dispersions display a permeability peak at 20-25 degrees C and a second increase in 22Na efflux in the temperature range 30-40 degrees C. The results of 31P-NMR measurements suggest that the acyl chains in 2,3-dipalmitoylcyclopentano-1-phosphocholine (n = 2) bilayers have restricted rotation below the main phase transition temperature.


Effect of surgeon specialization on long-term survival following colon cancer resection at an NCI-designated cancer center.
Recent studies have documented improved outcomes for patients undergoing colorectal cancer resection at NCI cancer centers compared to hospitals without this designation. Proposed contributory factors include a higher proportion of surgeons with specialty training in colorectal surgery and surgical oncology. The purpose of this study was to assess whether surgeon specialization is associated with differences in overall survival following colon cancer resection at an NCI cancer center. We conducted a retrospective review of patients undergoing colectomy for colon cancer from 1994 to 2009 at Duke University Medical Center. Patients were divided into two groups based on specialization status of the attending surgeon, and several clinicopathologic variables were compared. A multivariate analysis was then performed examining variables influencing overall survival. Total of 395 patients were included in the study, with 335 patients operated on by specialty-trained surgeons and 60 patients operated on by non-specialists. Overall, the two groups were similar with respect to demographic and pathologic variables. On multivariate analysis, surgeon specialization was found to be an independent predictor of improved overall survival [HR 0.43 (CI: 0.25-0.75), P = 0.003]. Surgeon specialization appears to be associated with improved overall survival in the setting of an NCI-designated cancer center.


Morphologic Changes in Postaxial Polydactyly of the Foot: A Standardized Quantitative Analysis Using the Watanabe-Fujita Classification.
Postaxial polydactyly of the foot is one of the most common congenital abnormalities. A wide forefoot, short toe, and lateral joint deviation are associated with aesthetic and functional outcomes. This study used the Watanabe-Fujita classification to characterize the preoperative and postoperative skeletal morphology of postaxial polydactyly of the foot. This retrospective study included 42 patients (51 feet) with postaxial polydactyly treated at age 1 year. Radiographs taken at ages 0 and 3 to 4 years were used for morphologic analysis. The length of the reconstructed toe, the distance between the fourth and fifth metatarsals, and joint deviation angles were measured. The length measures were standardized using the length of the third metatarsal. Morphologic characteristics were compared based on the Watanabe-Fujita classification at ages 0 and 3 to 4 years. Long-term outcomes were also evaluated in patients followed up for longer than 6 years. The fifth-ray proximal phalangeal subtype had the shortest toe length both at ages 0 and 3 to 4 years. Proximal phalangeal joint lateral deviation improved postoperatively in 78% of patients with the fifth-ray middle phalangeal subtype, regardless of reconstruction type. There was no significant change in proximal phalangeal joint deviation between ages 3 to 4 years and 7 years or older. A residual metatarsal was associated with lateral metatarsophalangeal joint deviation and a wide intermetatarsal distance, and required revision surgery. Morphologic changes of postaxial polydactyly of the foot were successfully characterized using the Watanabe-Fujita classification. This classification could be useful for planning surgical strategies and anticipating morphologic outcomes. Therapeutic, IV.


Bleeding profile of a flexible extended regimen of ethinylestradiol/drospirenone in US women: an open-label, three-arm, active-controlled, multicenter study.
Unscheduled bleeding may affect satisfaction and compliance with extended oral contraceptive (OC) regimens. The bleeding patterns of two variants of a flexible dosing regimen designed to manage intracyclic bleeding problems during extended cycles were compared with that of a conventional OC regimen. This was a 1-year, open-label, active-controlled, Phase 3 study conducted in the USA. Healthy women (18-45 years) received an ethinylestradiol (EE) 20 mcg/drospirenone 3 mg OC in two flexible extended regimens or in a conventional 24/4 (i.e., 28-day) regimen. The primary regimen [management of intracyclic bleeding (flexible(MIB)) regimen] was an extended dosing regimen that required subjects to initiate 4-day tablet-free intervals after 3 days of breakthrough bleeding/spotting. An alternative extended regimen [active period control (flexible(APC)) regimen] allowed subjects to initiate a 4-day tablet-free interval irrespective of the occurrence of bleeding. Bleeding profiles were compared between treatments. Efficacy and safety outcomes were also assessed. The full analysis set comprised 1864 women (flexible(MIB), N=1406; flexible(APC), N=232; conventional 24/4, N=226). Over 1 year, subjects in the flexible(MIB) group experienced significantly fewer (mean±SD, 40±30) bleeding/spotting days than those in the conventional 24/4 group (52±35). The corresponding value in the flexible(APC) group was 47±33 days. The pregnancy rate in the flexible(MIB) group was 1.65 per 100 woman-years (95% confidence interval, 0.96-2.65). All three regimens were well tolerated. A flexible(MIB) dosing regimen of EE 20 mcg/drospirenone 3 mg is associated with good contraceptive efficacy and fewer bleeding/spotting days than the conventional 24/4 regimen.


Assessing the true learning needs of health care professionals in epilepsy care.
This needs assessment, initiated by the American Epilepsy Society (AES) in cooperation with AXDEV Group Inc. (AXDEV), used a mixed-method approach to explore the educational and clinical practice needs of health care professionals in epilepsy care and to identify significant barriers to caring for people with epilepsy. The multiphase assessment began with key informant interviews with AES educational leaders. In Phase II, 26 stakeholders, including epileptologists, neurologists, professionals in epilepsy care, and people with epilepsy, shared their experiences in epilepsy care during four focus groups at the AES annual meeting. In Phase III, a quantitative online survey based on Phase II results was distributed to 228 respondents, including epileptologists (n=84), neurologists (n=55), professionals in epilepsy care (n=69), and others (n=20). Results of the comprehensive analysis of Phase III quantitative data are presented here. They reveal the unmet needs of health care professionals in this therapeutic domain and are discussed in terms of their implications for epilepsy care.


Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis.
Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production.


Association of hemoglobin levels and brainstem auditory evoked responses in lead-exposed children.
Decreased blood hemoglobin (HbB) levels and anemia have been associated with abnormal brainstem auditory evoked responses (BAER). Lead (Pb) exposure has also been associated with anemia and aberrant BAER. This study investigated the relationship between HbB level and BAER wave latency and amplitude in Pb-exposed Andean children. Sixty-six children aged 2 to 15 years (mean age: 9.1; SD: 3.3) living in Pb-contaminated villages were screened for HbB levels, blood Pb (PbB) levels and BAER latencies and amplitudes. The mean HbB level observed in the study group was 11.9 g/dL (SD: 1.4; range: 8.6-14.8 g/dL). The mean HbB level corrected for altitude was 10.3g/dL (SD: 1.4; range: 6.9-13.1 g/dL), and suggestive of anemia. The mean PbB level was 49.3 μg/dL (SD: 30.1; range: 4.4-119.1 μg/dL) and indicative of Pb poisoning. Spearman rho correlation analyses revealed significant associations between the BAER absolute latencies and HbB level, indicating that as the HbB level decreased, the BAER wave latency increased. Children with low HbB levels (≤11 g/dL) showed significantly prolonged absolute latencies of waves I, II, III, IV and V compared to the children with normal HbB levels. Although a significant relationship between HbB and BAER waves was observed, no significant associations between PbB level and BAER parameters were found. Low hemoglobin levels may diminish auditory sensory-neural function, and is therefore an important variable to consider when assessing BAER in children with anemia and/or Pb exposure.


miR-21 may acts as an oncomir by targeting RECK, a matrix metalloproteinase regulator, in prostate cancer.
Prognosis of prostate cancer (PCa) is based mainly in histological aspects together with PSA serum levels that not always reflect the real aggressive potential of the neoplasia. The micro RNA (miRNA) mir-21 has been shown to regulate invasiveness in cancer through translational repression of the Metaloproteinase (MMP) inhibitor RECK. Our aim is to investigate the levels of expression of RECK and miR-21 in PCa comparing with classical prognostic factors and disease outcome and also test if RECK is a target of miR-21 in in vitro study using PCa cell line. To determine if RECK is a target of miR-21 in prostate cancer we performed an in vitro assay with PCa cell line DU-145 transfected with pre-miR-21 and anti-miR-21. To determine miR-21 and RECK expression levels in PCa samples we performed quantitative real-time polymerase chain reaction (qRT-PCR). The in vitro assays showed a decrease in expression levels of RECK after transfection with pre-miR-21, and an increase of MMP9 that is regulated by RECK compared to PCa cells treated with anti-miR-21. We defined three profiles to compare the prognostic factors. The first was characterized by miR-21 and RECK underexpression (N = 25) the second was characterized by miR-21 overexpression and RECK underexpression (N = 12), and the third was characterized by miR-21 underexpression and RECK overexpression (N = 16). From men who presented the second profile (miR-21 overexpression and RECK underexpression) 91.7% were staged pT3. For the other two groups 48.0%, and 46.7% of patients were staged pT3 (p = 0.025). Our results demonstrate RECK as a target of miR-21. We believe that miR-21 may be important in PCa progression through its regulation of RECK, a known regulator of tumor cell invasion.


Comparative analysis of N-terminal cysteine dioxygenation and prolyl-hydroxylation as oxygen-sensing pathways in mammalian cells.
In animals, adaptation to changes in cellular oxygen levels is coordinated largely by 2-oxoglutarate-dependent prolyl-hydroxylase domain (PHD) dioxygenase family members, which regulate the stability of their hypoxia-inducible factor (HIF) substrates to promote expression of genes that adapt cells to hypoxia. Recently, 2-aminoethanethiol dioxygenase (ADO) was identified as a novel O2-sensing enzyme in animals. Through N-terminal cysteine dioxygenation and the N-degron pathway, ADO regulates the stability of a set of non-transcription factor substrates; the regulators of G-protein signaling 4, 5. and 16 and interleukin-32. Here, we set out to compare and contrast the in cellulo characteristics of ADO and PHD enzymes in an attempt to better understand their co-evolution in animals. We find that ADO operates to regulate the stability of its substrates rapidly and with similar O2-sensitivity to the PHD/HIF pathway. ADO appeared less sensitive to iron chelating agents or transition metal exposure than the PHD enzymes, possibly due to tighter catalytic-site Fe2+ coordination. Unlike the PHD/HIF pathway, the ADO/N-degron pathway was not subject to feedback by hypoxic induction of ADO, and induction of ADO substrates was well sustained in response to prolonged hypoxia. The data also reveal strong interactions between proteolytic regulation of targets by ADO and transcriptional induction of those targets, that shape integrated cellular responses to hypoxia. Collectively, our comparative analysis provides further insight into ADO/N-degron-mediated oxygen sensing and its integration into established mechanisms of oxygen homeostasis.


Kernel-based variance component estimation and whole-genome prediction of pre-corrected phenotypes and progeny tests for dairy cow health traits.
Prediction of complex trait phenotypes in the presence of unknown gene action is an ongoing challenge in animals, plants, and humans. Development of flexible predictive models that perform well irrespective of genetic and environmental architectures is desirable. Methods that can address non-additive variation in a non-explicit manner are gaining attention for this purpose and, in particular, semi-parametric kernel-based methods have been applied to diverse datasets, mostly providing encouraging results. On the other hand, the gains obtained from these methods have been smaller when smoothed values such as estimated breeding value (EBV) have been used as response variables. However, less emphasis has been placed on the choice of phenotypes to be used in kernel-based whole-genome prediction. This study aimed to evaluate differences between semi-parametric and parametric approaches using two types of response variables and molecular markers as inputs. Pre-corrected phenotypes (PCP) and EBV obtained for dairy cow health traits were used for this comparison. We observed that non-additive genetic variances were major contributors to total genetic variances in PCP, whereas additivity was the largest contributor to variability of EBV, as expected. Within the kernels evaluated, non-parametric methods yielded slightly better predictive performance across traits relative to their additive counterparts regardless of the type of response variable used. This reinforces the view that non-parametric kernels aiming to capture non-linear relationships between a panel of SNPs and phenotypes are appealing for complex trait prediction. However, like past studies, the gain in predictive correlation was not large for either PCP or EBV. We conclude that capturing non-additive genetic variation, especially epistatic variation, in a cross-validation framework remains a significant challenge even when it is important, as seems to be the case for health traits in dairy cows.


Nanos1 functions as a translational repressor in the Xenopus germline.
Nanos family members have been shown to act as translational repressors in the Drosophila and Caenorhabditis elegans germline, but direct evidence is missing for a similar function in vertebrates. Using a tethered function assay, we show that Xenopus Nanos1 is a translational repressor and that association with the RNA is required for this repression. We identified a 14 amino acid region within the N-terminal domain of Nanos1 that is conserved in organisms as diverse as sponge and Human. The region is found in all vertebrates but notably lacking in Drosophila and C. elegans. Deletion and substitution analysis revealed that this conserved region was required for Nanos1 repressive activity. Consistent with this observation, deletion of this region was sufficient to prevent abnormal development that results from ectopic expression of Nanos1 in oocytes. Although Nanos1 can repress capped and polyadenylated RNAs, Nanos1 mediated repression did not require the targeted RNA to have a cap or to be polyadenylated. These results suggest that Nanos1 is capable of repressing translation by several different mechanisms. We found that Nanos1, like Drosophila Nanos, associates with cyclin B1 RNA in vivo indicating that some Nanos targets may be evolutionarily conserved. Nanos1 protein was detected and thus available to repress mRNAs while PGCs were in the endoderm, but was not observed in PGCs after this stage.


Mercury stable isotopes in seabird eggs reflect a gradient from terrestrial geogenic to oceanic mercury reservoirs.
Elevated mercury concentrations ([Hg]) were found in Alaskan murre (Uria spp.) eggs from the coastal embayment of Norton Sound relative to insular colonies in the northern Bering Sea-Bering Strait region. Stable isotopes of Hg, carbon, and nitrogen were measured in the eggs to investigate the source of this enrichment. Lower δ(13)C values in Norton Sound eggs (-23.3‰ to -20.0‰) relative to eggs from more oceanic colonies (-20.9‰ to -18.7‰) indicated that a significant terrestrial carbon source was associated with the elevated [Hg] in Norton Sound, implicating the Yukon River and smaller Seward Peninsula watersheds as the likely Hg source. The increasing [Hg] gradient extending inshore was accompanied by strong decreasing gradients of δ(202)Hg and Δ(199)Hg in eggs, indicating lower degrees of mass-dependent (MDF) and mass-independent Hg fractionation (MIF) (respectively) in the Norton Sound food web. Negative or zero MDF and MIF signatures are typical of geological Hg sources, which suggests murres in Norton Sound integrated Hg from a more recent geological origin that has experienced a relatively limited extent of aquatic fractionation relative to more oceanic colonies. The association of low δ(202)Hg and Δ(199)Hg with elevated [Hg] and terrestrial δ(13)C values suggested that Hg stable isotopes in murre eggs effectively differentiated terrestrial/geogenic Hg sources from oceanic reservoirs.


Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins.
Aberrant proteins represent an extreme hazard to cells. Therefore, molecular chaperones and proteases have to carry out protein quality control in each cellular compartment. In contrast to the ATP-dependent cytosolic proteases and chaperones, the molecular mechanisms of extracytosolic factors are largely unknown. To address this question, we studied the protease function of DegP, the central housekeeping protein in the bacterial envelope. Our data reveal that DegP processively degrades misfolded proteins into peptides of defined size by employing a molecular ruler comprised of the PDZ1 domain and the proteolytic site. Furthermore, peptide binding to the PDZ domain transforms the resting protease into its active state. This allosteric activation mechanism ensures the regulated and rapid elimination of misfolded proteins upon folding stress. In comparison to the cytosolic proteases, the regulatory features of DegP are established by entirely different mechanisms reflecting the convergent evolution of an extracytosolic housekeeping protease.


Lymphoepithelioma-like carcinoma: a distinct type of gastric cancer.
Lymphoepithelioma-like carcinoma (LELC) is a rare type of gastric carcinoma and has histologic features of intense lymphocytic infiltration. In this study, we attempted to analyze the clinicopathologic characteristics and survival outcome of patients with LELC compared with those with non-lymphoepithelioma-like carcinoma (NLELC). We studied 4282 patients who underwent gastrectomies to treat gastric cancer at the Department of Surgery of the Samsung Medical Center in Seoul, between January 2008 and December 2010. The clinicopathologic features and clinical outcomes of patients with LELC (n = 46) were compared with those with NLELC (n = 4236). In situ hybridization for Epstein-Barr virus (EBV) positivity was performed on the tissue of patients with LELC (n = 46) and NLELC (n = 1247). The patients with LELC are male predominant and had more upper locations, more indeterminate Lauren classifications, lower T stages, less lymphatic invasion, and more positive EBV in situ hybridization compared with those of the NLELC group (80.4% versus 6.5%). Age, histologic type, Lauren type, the location of the tumor, the depth of the invasion, lymph node metastasis, and venous invasion were independent prognostic factors; however, the LELC type itself was not predictive of outcome. The 5-y survival rate of the LELC group (97.7%) was better than that of the NLELC group (89.4%); however, this difference was not statistically significant (P = 0.127). The results of our study suggest that LELC is a less advanced disease than NLELC in terms of depth of invasion and lymphatic invasion at diagnosis. However, our study does not examine LELC as an independent prognostic factor of gastric cancer. Further studies are needed to explore its associations with EBV and a distinct pathway of carcinogenesis from NLELC.


The Molecular Basis for Life in Extreme Environments.
Sampling and genomic efforts over the past decade have revealed an enormous quantity and diversity of life in Earth's extreme environments. This new knowledge of life on Earth poses the challenge of understandingits molecular basis in such inhospitable conditions, given that such conditions lead to loss of structure and of function in biomolecules from mesophiles. In this review, we discuss the physicochemical properties of extreme environments. We present the state of recent progress in extreme environmental genomics. We then present an overview of our current understanding of the biomolecular adaptation to extreme conditions. As our current and future understanding of biomolecular structure-function relationships in extremophiles requires methodologies adapted to extremes of pressure, temperature, and chemical composition, advances in instrumentation for probing biophysical properties under extreme conditions are presented. Finally, we briefly discuss possible future directions in extreme biophysics.


Validation of food diaries as measures of dietary behaviour change.
This study aimed to validate the ability of a 24-h food diary (the DIET-24) to accurately detect change in children's fruit and vegetable consumption at school snack time following implementation of the Food Dudes healthy eating intervention. Participants were 4- to 9-year-old children from two primary schools in England. There were 148 participants in the intervention school and 43 participants in the no intervention control school. For each child, snack-time fruit and vegetable consumption was measured separately by weight (grammes), and compared with teachers' estimates (to the nearest half portion) using the DIET-24. Both consumption measures were taken at T1 (pre-intervention) and T2 (post-intervention). At each time-point, Spearman rank correlations between the two measures were low to moderate, but significant. However, when compared with weighed measures, the DIET-24 did not always accurately detect significant changes in children's fruit and vegetable consumption following the intervention. To provide sensitive measures of behaviour change, it is important that dietary measures assess as accurately as possible the amount of food consumed, rather than, as is often the case, rely on all-or-none portion estimates. This issue is important for the establishment of a reliable evidence-base for healthy eating interventions.


Effect of implantation site on hepatocytes heterotopically transplanted on biodegradable polymer scaffolds.
We investigated the engraftment of heterotopically transplanted hepatocytes in three sites: the subcutaneous space, the small intestinal mesentery, and the omentum to determine the optimal location for tissue-engineered liver constructs. Hepatocytes were isolated from inbred Lewis rats and placed on polymer constructs. Cell-polymer constructs were implanted into the subcutaneous space of the abdominal wall, the small intestinal mesentery, and the omentum of Lewis rats. One group of rats had undergone previous portacaval shunt. Animals were killed 2 or 4 weeks after implantation and the constructs were analyzed for engraftment, using computer-assisted morphometric analysis. Engraftment was greatest in the omentum with less engraftment in the mesentery. There was minimal engraftment in the subcutaneous space in all specimens. Prior portacaval shunt increased engraftment in the mesentery and the omentum, but not the subcutaneous space. The omentum is the most favorable bed for engraftment of hepatocyte-polymer tissue-engineered constructs and the addition of a portacaval shunt increases survival of transplanted hepatocytes in the omentum and mesentery.


Arsenic-Loaded Biomimetic Iron Oxide Nanoparticles for Enhanced Ferroptosis-Inducing Therapy of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) has a poor response to most available systemic therapies due to intrinsic or acquired resistance to apoptosis. Ferroptosis-based therapy is expected to circumvent those limitations. Therefore, the rational design of ferroptosis-based therapies with targeted delivery of ferroptosis inducers for HCC is in need. In this study, we found that arsenic trioxide (ATO) can efficiently induce ferroptosis in HCC cells, and this effect could be reversed by the iron chelator deferoxamine. On this basis, a drug delivery system was constructed to enhance the therapeutic efficacy of ATO by camouflaging ATO-loaded magnetic nanoparticles (Fe3O4) with HCC cell membranes, termed AFN@CM. After AFN@CM treatment, glutathione peroxidase 4 was strongly inhibited and intracellular lipid peroxide species were significantly increased in HCC cells. In addition, enhanced ferroptosis and tumor suppression were observed both in vitro and in vivo. The bio-safety of AFN@CM was also demonstrated by the in vivo toxicity evaluation. In addition, benefiting from the cell membrane coating, AFN@CM showed enhanced accumulation at tumor sites and achieved continuous tumor elimination in the mouse model. In conclusion, AFN@CM exhibited satisfactory therapeutic efficacy in the treatment of HCC and provided a desirable ferroptosis-based strategy for safe and reliable HCC therapeutics.


Technical note: the midline and endocranial volume of the Taung endocast.
The Taung endocast is one of the best-preserved and most important known in paleoanthropology. Although the endocast is undistorted and preserves distinctive landmarks, Taung has proved a difficult endocast, because it is only about 60% complete. To reconstruct Taung it is necessary to first use the available anatomical landmarks to define the midline of the endocast. It is only with a proper description of the midline that it is possible to reconstruct the endocast and obtain an accurate measurement of Taung's endocranial volume. Holloway (Science 168 (1970) 966-968) determined a conservative estimate for Taung of 404 ml. More recently this estimate has been revised downward by Falk and Clarke (Am J Phys Anthropol 134 (2007) 529-534) to 382 ml, giving Taung the smallest endocast for A. africanus. Certain challenges exist with the reconstruction of any endocast, particularly a hemi-endocast such as Taung. A virtual reconstruction of Taung must assume perfect symmetry, a feature called into question here in Taung's most recent reconstruction by Falk and Clarke (2007). Holloway's (1970) reconstruction of Taung provides a guidepost for a conservative approach to endocast reconstructions, and the most reliable measurement of Taung's true endocranial volume.


[The forensic chemical study of synthetic detergents].
Six color reactions were developed and thin-layer chromatography conditions defined for identification of components of some synthetic detergents in preparations and cadaveric material. Sensitivity of toxic components identification in biologic objects is 0.1 mg for alkylbenzolsulfonate and 0.25 mg of sodium silicate per 100 g of the object.


Seeking Parity for Women in Academic Medicine: A Historical Perspective.
In this Invited Commentary, the author applies a historical lens to explore a fundamental paradox in U.S. medical education: the fact that long after women gained parity with men in matriculation to medical school, women remain highly underrepresented in leadership positions in academic medicine. The reasons for this are many and complex, but at the core are the subtle but hurtful indignities ("microinequities") experienced by women physicians and an academic culture that expects single-minded dedication to work, regardless of the costs to faculty members' personal lives. Achieving parity for women in academic leadership will require changing the culture of medical schools and teaching hospitals to correct these 2 fundamental obstacles. In recent years, many medical schools and teaching hospitals have made efforts to improve opportunities and satisfaction for women trainees and physicians, enacting reforms to improve work-life balance for all faculty. It is plausible to imagine a future in which flexible time frames to achieve tenure and promotion are universally available to both women and men, with high scholarly standards firmly maintained. If this occurs, it will represent a profound legacy for women in academic medicine, for their generations of professional sacrifice and advocacy for a more equitable culture will have changed its culture.


Explanatory Model of Perceived Stress in the General Population: A Cross-Sectional Study in Peru During the COVID-19 Context.
The COVID-19 pandemic had negatively impact mental health worldwide. High prevalence of stress had been previously reported in populations during this context. Many theoretical frameworks had been proposed for explaining the stress process, we aim to proposed and explanatory model for the genesis of perceived stress in Peruvian general population. We conducted an online survey in Peruvian general population assessing sociodemographic variables and evaluating mental health conditions by using The Perceived Stress Scale (PSS-10), Positive Affect and Negative Affect Scale (PANAS), Generalized Anxiety Disorder scale (GAD-7), Patient Health Questionnaire (PHQ-9), and a numerical rating scale (NRS) for fear of COVID-19. Correlation analysis was conducted for the variables of interest. Two regression models were constructed to explore related factor to the dimensions of perceived stress. Finally, a structural regression model was performed with the independent variables. Data of 210 individuals was analyzed. Ages ranged from 15 to 74 years and 39% were women. Additionally, 65.2% of the participants had at least one mental health conditions (depression, anxiety, or stress symptoms). Perceived self-efficacy and positive affect (PA) were correlated, as perceived helplessness with anxious symptoms and negative affect (NA). Regression analysis showed that sex, anxiety symptoms, and NA explained perceived helplessness while positive and NA explained self-efficacy. The structural regression model analysis identified that fear of COVID-19 (composed of fear of infecting others and fear of contagion), predicted mental health conditions (i.e., depressive or anxiety symptoms); also, mental health conditions were predicted by PA and NA. Perceived helplessness and Perceived self-efficacy were interrelated and represented the perceived stress variable. We proposed an explanatory model of perceived stress based on two correlated dimensions (self-efficacy and helplessness) in the Peruvian general population during the context of the COVID-19 pandemic, with two out of three individuals surveyed having at least one mental health condition.


Genetic analysis of glutathione S-transferase A1 polymorphism in the Chinese population and the influence of genotype on enzymatic properties.
Genetic polymorphisms of human glutathione S-transferases (hGSTs) have important implications for drug efficacy and cancer susceptibility. hGSTA1 is the most abundant subfamily of hGSTs. The aim of this study was to investigate the distribution of hGSTA1 genetic polymorphism in the Chinese population and whether there exists the potential activity alterations caused by this polymorphism. Therefore, genomic DNA was extracted from peripheral blood of 140 healthy Chinese people and 11 normal liver tissues obtained from patients who had undergone liver surgery. Two variants in the promoter region of the hGSTA1 gene were identified by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). Activities toward selected substrates of the wild type (hGSTA1*A) and variant (hGSTA1*B) were measured spectrometrically using S-9 fractions from liver samples. Delta5-androstene-3,17-dione (AD), cumene hydroperoxide (CuOOH), and 1-chloro-2,4-dinitrobenzene (CDNB) were used as marker substrates toward hGSTA1, hGSTA, and hGST, respectively. The kinetic parameters (Km, Vmax, and Vmax/Km) of hGSTA1 were determined with different concentrations of AD. The results showed that, in the study population, the proportions of hGSTA1*A/*A, hGSTA1*A/*B, and hGSTA1*B/*B genotypes were 75.0, 24.3, and 0.7%, respectively, and the allele frequencies of hGSTA1*A and hGSTA1*B were detected to be 87.1 and 12.9%, respectively. The variant hGSTA1 showed a significantly decreased activity for AD isomerization as compared to the wild type. Kinetic analyses revealed that the V(max) value of the variant hGSTA1 was 48% of that of the wild type despite a Km value of 62% (p < 0.01). This means that the Vma)/Km) in the variant hGSTA1 was 76%. These data indicate that the distribution of hGSTA1 gene is polymorphic in Chinese and is different from those in other racial populations. The promoter sequence polymorphism of the hGSTA1 gene is associated with decreased Km and Vmax values of the enzyme in individuals with the variant allele. This variant is also associated with a decrease in hGSTA1 activity toward preferred substrates. This altered activity, however, is accompanied by significant individual variation in the variant population.


Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages.
Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment.


Steady-state and time-resolved fluorescence studies indicate an unusual conformation of 2-aminopurine within ATAT and TATA duplex DNA sequences.
2-Aminopurine (2-AP), a fluorescent analog of adenine, has been widely used as a probe for local DNA conformation, since excitation and emission characteristics and fluorescence lifetimes of 2-AP vary in a sequence-dependent manner within DNA. Using steady-state and time-resolved fluorescence techniques, we report that 2-AP appears to be unusually stacked in the internal positions of ATAT and TATA in duplex DNA. The excitation wavelength maxima for 2-AP within these contexts were red shifted, indicating reduced solvent exposure for the fluorophore. Furthermore, in these contexts, 2-AP fluorescence was resistant to acrylamide-dependent collisional quenching, suggesting that the fluorophore is protected by its stacked position within the duplex. This conclusion was further reinforced by the presence of a secondary peak at 275 nm in the fluorescence excitation spectra that is indicative of efficient excitation energy transfer from nearby non-fluorescent DNA bases. Fluorescence anisotropy decay and internal angular 'wobbling' motion measurements of 2-AP within these alternating AT contexts were also consistent with the fluorophore being highly constrained and immobile within the base stack. When these fluorescence characteristics are compared with those of 2-AP within other duplex DNA sequence contexts, they are unique.


Hiding in Plain View: Colloidal Self-Assembly from Polydisperse Populations.
We report small-angle x-ray scattering experiments on aqueous dispersions of colloidal silica with a broad monomodal size distribution (polydispersity, 14%; size, 8 nm). Over a range of volume fractions, the silica particles segregate to build first one, then two distinct sets of colloidal crystals. These dispersions thus demonstrate fractional crystallization and multiple-phase (bcc, Laves AB_{2}, liquid) coexistence. Their remarkable ability to build complex crystal structures from a polydisperse population originates from the intermediate-range nature of interparticle forces, and it suggests routes for designing self-assembling colloidal crystals from the bottom up.


Association of Cigarette Smoking with Aberrant Methylation of the Tumor Suppressor Gene RARβ2 in Papillary Thyroid Cancer.
Aberrant gene methylation is often seen in thyroid cancer, a common endocrine malignancy. Tobacco smoking has been shown to be associated with aberrant gene methylation in several cancers, but its relationship with gene methylation in thyroid cancer has not been examined. In the present study, we investigated the relationship between smoking of patients and aberrant methylation of tumor suppressor genes for TIMP3, SLC5A8, death-associated protein kinase, and retinoic acid receptor β2 (RARβ2) in papillary thyroid cancer (PTC), the most common type of thyroid cancer. The promoter methylation status of these genes was analyzed using quantitative real-time methylation-specific PCR on bisulfite-treated genomic DNA isolated from tumor tissues and correlated with smoking history of the patients. Among the four genes, methylation of the RARβ2 gene was significantly associated with smoking and other three genes showed a trend of association. Specifically, among the 138 patients investigated, 13/42 (31.0%) ever smokers vs. 10/96 (10.4%) never smokers harbored methylation of the RARβ2 gene (P = 0.003). This association was highly significant also in the subset of conventional variant PTC (P = 0.005) and marginally significant in follicular variant PTC (P = 0.06). The results demonstrate that smoking-associated aberrant methylation of the RARβ2 gene is a specific molecular event that may represent an important mechanism in thyroid tumorigenesis in smokers.


The Impact of Individual Differences on a Bilingual Vocabulary Approach for Latino Preschoolers.
The purpose of this study was twofold: First, we replicated in a new sample our previous findings that a culturally and linguistically responsive (CLR) bilingual approach for English vocabulary instruction for preschool Latino dual language learners was effective. Subsequently, we investigated whether the positive effect of CLR instruction varies as a function of individual child characteristics, including baseline vocabulary levels and gender. Using a randomized pretest-posttest follow-up group design, we first replicated our previous study (N = 42) with a new sample by randomly assigning 35 Spanish-speaking Latino preschoolers to a CLR bilingual group or an English-only group. The preschoolers received small-group evidence-informed shared readings targeting 30 English words 3 times a week for 5 weeks in their preschools. Vocabulary outcomes were measured using both standardized and researcher-developed measures. We subsequently conducted further studies with the combined sample size of 77 children to examine the variability in intervention effects related to child gender and baseline vocabulary levels. The direct replication study confirmed findings of our earlier work suggesting that the CLR bilingual approach promoted greater gains in L1 and L2 vocabulary than in an English-only approach. The extension studies revealed that the effect of the CLR bilingual vocabulary approach on English and Spanish vocabulary outcomes was not impacted by gender or vocabulary status at baseline. This study provides additional evidence of the benefits of strategically combining L1 and L2 for vocabulary instruction over an English-only approach. Our findings also suggest that preschool Latino dual language learners can benefit from a bilingual vocabulary instructional approach regardless of gender or baseline vocabulary levels in L1.


A student-driven mindfulness curriculum for first-year osteopathic medical students: a pilot study.
Medical education is stressful and can adversely affect the health and well-being of students. Although mindfulness-based interventions (MBIs) have been successfully utilized in other settings, little is known about the use of student-led interventions in undergraduate medical education. The objectives of this study are to assess student satisfaction with four student-selected and student-led mindfulness activities incorporated into mandatory small-group sessions, the immediate impact of these activities on student stress levels, and student use of these activities outside the mindfulness sessions. First-year osteopathic medical students voluntarily participated in weekly student-selected and student-led mindfulness activities once a week for 8 consecutive weeks during regularly scheduled class time. Activities included yoga postures, the 4-7-8 breathing technique, progressive muscle relaxation (PMR), and values affirmation. Each activity was completed twice during the 8 weeks. After each session, students could anonymously complete an electronic survey assessing participation, change in stress level, satisfaction with the activity, and mindfulness activities practiced outside the session. Survey questions included dichotomous, Likert-like, and multiple-choice responses. A chi-square test was utilized to analyze student responses from each week about the decrease in stress level, and satisfaction with the mindfulness activity, and student use of the activities outside the classroom. Wilcoxon rank sum tests were utilized to determine associations between outcomes, and a logistic regression model was utilized to determine relationships between the change in stress levels and other outcomes. Of the 154 first-year medical students initially enrolled in the 2021-2022 academic year, 14 (9.1 %) to 94 (61.0 %) actively participated in the weekly mindfulness activities. Students indicated that the 4-7-8 breathing technique was the activity most practiced outside the mindfulness sessions (32.3 %, 43/133 total responses) across all weeks. The mindfulness activity with the highest percentage of reported decrease in stress level was the yoga postures in week 5 (94.8 %, 36/38), and both weeks of the yoga activities had the highest reported student satisfaction (95.7 %, 90/94 for week 1; 92.1 %, 35/38 for week 5). For students who answered the change in stress level question, the stress level decrease was related to participation in the weekly activity for weeks 1 through 7 (all p<0.03). For students who participated in mindfulness sessions, the odds of reporting a reduction in the stress level were 16.6 times (95 % CI, 6.8-47.2; p<0.001) that of students who did not participate. For those satisfied with the activities, the odds of reporting a reduction in stress level were 6.7 (95 % CI, 3.3-13.9; p<0.001). Results suggested that the student-selected and student-led mindfulness activities may successfully reduce medical student stress in students who actively participate. However, additional research is needed to determine how to optimize mindfulness curricula implementation.


Real-Time Exploration of Large Spatiotemporal Datasets Based on Order Statistics.
In recent years sophisticated data structures based on datacubes have been proposed to perform interactive visual exploration of large datasets. While powerful, these approaches overlook the important fact that aggregations used to produce datacubes do not represent the actual distribution of the data being analyzed. As a result, these methods might produce biased results as well as hide important features in the data. In this paper, we introduce the Quantile Datacube Structure (QDS) that bridges this gap by supporting interactive visual exploration based on order statistics. To achieve this, QDS makes use of an efficient non-parametric distribution approximation scheme called p-digest and employs a novel datacube indexing scheme that reduces the memory usage of previous datacube methods. This enables interactive slicing and dicing while accurately approximating the distribution of quantitative variables of interest. We present two case studies that illustrate the ability of QDS to not only build order statistics based visualizations interactively but also to perform event detection on very large datasets. Finally, we present extensive experimental results that validate the effectiveness of QDS regarding memory usage and accuracy in the approximation of order statistics for real-world datasets.


Analysis of factors associated with the tumorigenic potential of 12 tumor clones derived from a single rat colon adenocarcinoma.
We analyzed several factors which could influence the immunogenicity of colon tumor cells, using a series of clones derived from a single chemically induced rat adenocarcinoma cell line. These clones display variable tumorigenic potential in syngeneic immunocompetent animals, and it has been established that in this model the tumorigenicity of the cells depends on their ability to escape immune surveillance. The results show an absence of relationship between tumorigenicity and expression of MHC-class-I antigens, cell adhesion to rat fibroblasts or fibroblast extracellular matrix. The secretion of latent and active TGF beta I appeared to be quite variable from one clone to the other, but was unrelated to tumorigenicity. Unexpectedly, some regressive clones produced elevated levels of this cytokine, suggesting that in this model, spontaneous secretion of TGF beta I is not sufficient to impair the immune system of the host. In contrast, the more tumorigenic clones were more resistant than less tumorigenic ones to cytotoxicity mediated by NK or LAK cells. They also showed arrest of cell proliferation after reaching confluence, something not observed in the less tumorigenic clones. Finally, the strongest relationship with tumorigenicity was found for expression of blood-group carbohydrate antigens. Increased expression of blood-group-H antigen and, conversely, decreased expression of beta-galactoside precursors of this antigen correlated with increased tumorigenicity.


Improvement of Functional Outcomes in Patients with Stroke who Received Alteplase for Over 15 Years: Japan Stroke Data Bank.
The nationwide verification of intravenous thrombolysis (IVT) was rarely performed after the extension of the therapeutic time window of alteplase or after the expansion of mechanical thrombectomy (MT). We aimed to examine the long-term change in accurate real-world outcomes of IVT in patients with acute ischemic stroke (AIS) using the Japan Stroke Databank, a representative Japan-wide stroke database. We extracted all patients with AIS who received IVT with alteplase between October 11, 2005, the approval date for alteplase use for AIS in Japan, and December 31, 2020. Patients were categorized into three groups using two critical dates in Japan as cutoffs: the official extension date of the therapeutic time window for IVT to within 4.5 h of symptom onset and the publication date of the revised guideline, where the evidence level of MT was heightened. We assessed the yearly trend of IVT implementation rates and the secular changes and three-group changes in clinical outcomes at discharge. Of 124,382 patients with AIS, 9,569 (7.7%) received IVT (females, 41%; median age, 75 years). The IVT implementation rate has generally increased over time and plateaued in recent years. The proportion of favorable outcomes (modified Rankin Scale score of 0-2) increased yearly over 15 years. The results of the changes in the outcomes of the three groups were similar to those of the annual changes. We revealed that IVT implementation rates in patients with AIS increased, and the functional outcome in these patients improved over 15 years. Therefore, the Japanese IVT dissemination strategy is considered appropriate and effective.


High-throughput lipophilicity measurement with immobilized artificial membranes.
We report on a new, high-throughput assay designed to measure octanol/water partition coefficients in early drug discovery. The assay is carried out in 96-well microtiterplates and measures the diffusion of compounds between two aqueous compartments separated by a thin octanol liquid layer. Octanol/water partition coefficients are derived from the apparent permeability (P(a)) values using a calibration curve. The assay can measure partition coefficients within the range -2 to + 8; thus, a dynamic range of 10 log units can be covered in one single run. Unlike chromatographic methods, the technology is not restricted to neutral and weakly basic compounds, and, as no stationary phase is involved, the data can be strictly compared with values obtained from traditional methods such as shake-flask/HPLC or dual-phase potentiometric titration.


The association between alcohol, betel nut, and cigarette use with hepatitis C virus infection in Taiwan.
Hepatitis C virus (HCV) infection may cause chronic liver disease, liver cirrhosis, and liver cancer. It has been reported to associate with habits including alcohol, betel nut and cigarette use. We aimed to investigate the association between alcohol, betel nut, and cigarette use with HCV infection in Taiwan and to explore their effects. A total of 121,421 participants were enrolled from the Taiwan Biobank. They were stratified into two groups according to whether they had (n = 2750; 2.3%) or did not have (n = 118,671; 97.7%) HCV infection. All participants were also classified into four groups according to the number of habits, including a history of alcohol drinking, betel nut chewing, and cigarette smoking. There were 85,406 (no habit), 24,299 (one habit), 8659 (two habits), and 3057 (three habits) participants in the four groups, respectively. Multivariable analysis showed that the participants who had an alcohol drinking history (odds ratio [OR] 1.568; 95% confidence interval [CI] 1.388-1.773; p < 0.001), betel nut chewing history (OR 1.664; 95% CI 1.445-1.917; p < 0.001), cigarette smoking history (OR 1.387; 95% CI 1.254-1.535; p < 0.001), were significantly associated with HCV infection. Furthermore, the participants were classified into four groups according to the number of habits as follows: 85,406 (no habit), 24,299 (one habit), 8659 (two habits), and 3057 (three habits). The HCV infection rates in these four groups were 2.11%, 2.14%, 3.23%, and 4.78%, respectively. Compared to the participants with no or one habit, those with two habits had a higher HCV infection rate (all p < 0.001). In addition, compared to the participants who had no, one or two habits, those who had three habits also had higher HCV infection rates (all p < 0.001). The participants who had three habits had the highest prevalence of HCV infection. In an era when most HCV can be cured, understanding the epidemiology link between habits and HCV may help the case finding.