Surgical treatment of liver metastases of colorectal cancer: Strategies and controversies in 2006.
To review the latest strategies and controversies in the surgical treatment of liver metastases of colorectal cancer systemically and comprehensively. A medline based literature search on relevant topics was performed in PubMed for key articles concerning the novel strategies and controversies in the management of liver metastases of colorectal cancer. Some information was obtained from 'Proc Am Soc Clin Oncol' published recently. The findings and discussions were related to our own experiences. Although for well-indicated patients, a consensus has been reached that hepatic resection is the only management that could provide the patients curability, there still exist many controversies, such as the prognostic evaluation, contraindications to hepatic resection, treatment for synchronous liver metastases, the place of laparoscopic surgery, etc. Meanwhile, various strategies to improve the respectabilities are available, including neoadjuvant chemotherapy, portal vein embolization, two stage hepatectomy, and some locally ablative approaches. The current condition is difficult and sometimes confusing for a relevant surgeon when designing treatment protocols for more complex diseases. As the advancing of the management of liver metastases of colorectal cancer, more patients will become candidates for and benefit from potentially curative surgical resections. Optimal effect could only be achieved when used in a manner tailored to the individual patient.


Identifying subpopulations for subgroup analysis in a longitudinal clinical trial.
In a typical clinical trial treatment effects will not be expected to be the same on all of the study participants. As a result, investigators are often tempted to look at the effects of a given treatment in subgroups of patients in order to determine who will benefit the most or the least, especially when the treatment effect in the total sample is insignificant or borderline. This paper aims at demonstrating the application of random effect models as one approach to identify subpopulations suitable for subgroup analysis in a longitudinal study. Data collected from a double-blind randomized controlled trial were used to demonstrate how multilevel modeling using random effects can be used to identify subgroups of postmenopausal women who benefit the most from nonhormonal treatment (gabapentin) of their hot flashes. We estimated subject-specific treatment effects and correlated these effects with patient characteristics at baseline. We found that women with a higher severity of hot flashes score at baseline were more likely to have the greatest reduction in hot flashes score from the treatment. Also, women who had a serum creatinine level higher than the median level at baseline demonstrated a greater response to gabapentin compared to the placebo group. Our proposed method can help researchers identify patient factors that are associated with differential effect. Those factors are potential areas for further clinical investigation or for constructing subgroups for sub-analysis.


Identifying the source of superficial reflux in venous leg ulcers using duplex ultrasound.
Mapping of venous reflux routes associated with medially or laterally located venous leg ulcers and their source of origin. This prospective report presents the results of duplex investigations performed in consecutive leg ulcer patients, all with venous reflux, in a time period over 2 years. A total of 169 patients (183 legs), with chronic venous leg ulcers (CEAP: C6) were examined in a private practice. The data collection integrated an examination that included medical history and clinical diagnoses and incorporated measurements such as body mass index, oscillometric index, and range of motion of the ankle joint. Venous function was assessed with duplex ultrasound, and the cases were described using the advanced CEAP classification. Additionally, a "sourcing" technique was performed with duplex ultrasound investigation of the ulcer bed and the venous system under manual compression and release of the ulcer. The principle of "sourcing" is to follow venous reflux from the ulcer area to its proximal origin. The detected reflux routes were classified either as "axial" or "crossover" type. A total of 20% of the ulcer patients showed no clinically visible varicose veins. One hundred three patients had medial ulcers, 54 lateral ulcers, 21 medial and lateral, and five had gaiter ulcers. Sixty-four (35%) of the medially located ulcers had reflux in the great saphenous vein (GSV), 28 (15%) showed reflux in the medial perforating veins (axial types), and 11 (6%) had reflux in the small saphenous vein (SSV; crossover type). From 54 patients presenting with lateral ulcers, 25 (14%) showed GSV incompetence (crossover type) and only 13 (7%) SSV incompetence (axial type). Sixteen patients showed refluxes penetrating from deep into lateral perforating veins. Crossover reflux routes were detected in 25 of 54 (46%) legs with lateral and in 11 of 103 (11%) legs with medial ulceration (χ2 44.34; P<.001). In venous ulcer patients, an extended examination (CEAP classification) and a special duplex technique ("sourcing") are recommended to identify the specific route responsible for the venous reflux. This seems essential for planning a rational treatment of venous reflux ulcers.


Relationship between cellular morphology and immunocytological findings of spontaneous pituitary tumours in the aged rat.
A total of 339 spontaneous pituitary tumours from 284 aged rats were studied by light microscopy. Based on the cellular morphology in preparations stained by haematoxylin and eosin, tumour cells were classified into 4 types: granular; agranular small; agranular large polygonal; and agranular large slender cells. Eight tumours consisted of mixed neoplastic masses of 2 types of cells. A total of 85 cases representative for each tumour type was used for special staining and immunocytochemistry. All tumours of the granular cell type and some tumours of the agranular large polygonal cell type had granules which stained red by azocarmine and were positive for prolactin. All agranular small cell type tumours were also positive for prolactin and agranular slender cell type tumours were positive for adrenocorticotropic hormone. Only tumours of the agranular large polygonal cell type gave an indefinite or negative reaction for all the various pituitary hormones. These results indicate a relatively good correlation between the cellular morphology and the immunocytochemistry of spontaneous pituitary tumours in aged rats.


Three-stage assembly of the cysteine synthase complex from Escherichia coli.
Control of sulfur metabolism in plants and bacteria is linked, in significant measure, to the behavior of the cysteine synthase complex (CSC). The complex is comprised of the two enzymes that catalyze the final steps in cysteine biosynthesis: serine O-acetyltransferase (SAT, EC 188.8.131.52), which produces O-acetyl-L-serine, and O-acetyl-L-serine sulfhydrylase (OASS, EC 184.108.40.206), which converts it to cysteine. SAT (a dimer of homotrimers) binds a maximum of two molecules of OASS (a dimer) in an interaction believed to involve docking of the C terminus from a protomer in an SAT trimer into an OASS active site. This interaction inactivates OASS catalysis and prevents further binding to the trimer; thus, the system exhibits a contact-induced inactivation of half of each biomolecule. To better understand the dynamics and energetics that underlie formation of the CSC, the interactions of OASS and SAT from Escherichia coli were studied at equilibrium and in the pre-steady state. Using an experimental strategy that initiates dissociation of the CSC at different points in the CSC-forming reaction, three stable forms of the complex were identified. Comparison of the binding behaviors of SAT and its C-terminal peptide supports a mechanism in which SAT interacts with OASS in a non-allosteric interaction involving its C terminus. This early docking event appears to fasten the proteins in close proximity and thus prepares the system to engage in a series of subsequent, energetically favorable isomerizations that inactivate OASS and produce the fully isomerized CSC.


Mechanistic understanding of the increased photoactivity of TiO2 nanosheets upon tantalum doping.
Anatase TiO2 is doped with Ta cations through a hydrothermal route. Based on X-ray photoelectron spectroscopy and X-ray absorption near-edge structure spectroscopy, the Ta dopants exist in the 5+-oxidation state. The oxidation state is insensitive to the Ta loading amount. Extended X-ray absorption fine structure spectroscopy confirms that the local structure around Ta cations is not identical between the Ta-doped samples. The Ta-O distance monotonically increases with the Ta loading amount due to a gradually expanding lattice. The Ta-doped samples show higher activity than pristine TiO2 for photomineralizing recalcitrant organics. The enhanced photocatalytic activity is proposed to be due to an enhanced population of photoexcited electrons, as probed using light-induced IR absorption spectroscopy, and an extended electron lifetime, as probed using time-resolved microwave conductivity, which are associated with the formation of Ti3+ defect states acting as shallow electron traps. The maximum photocatalytic activity is observed for TiO2 doped with 2 mol% of Ta, which shows enhancement of mineralization efficiency (about 3 times) and enhancement of electron population (up to 20 times), as compared to those of pristine TiO2. The fundamental question of why a proper metal doping into TiO2 increases photocatalytic activity is discussed in this study.


Predictive value of serum collagen biomakers on the outcome of acute myocardial infarction treated with percutaneous coronary intervention.
This study was designed to investigate the predictive value of serum collagen biomarkers on the outcomes of acute ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI). Two hundred and ten patients with STEMI were successfully treated with PCI within 6 hrs ofthe onset of chest pain. The levels of serum procollagen type I carboxyterminal peptide (PICP) and procollagen type III peptide (PIIINP) were measured by enzymelinked immunosorbent assay (ELISA) before, 3 and 6 months after PCI. Left ventricular ejection fraction was assessed by echocardiography at 3 and 6 months after PCI. The composite endpoints were death by any cause, recurrent myocardial infarction, heart failure or stroke. At the end of the 12-month follow up, 29 patients (13.8%) experienced an end point. The level of serum PICP in patients with an end point was higher than in patients without an end point 7 days (19.45 ± 2.17 vs 14.95 ± 3.07 ng/mL, P<0.05) or 3 month after the PCI (29.87 ± 3.02 vs 22.14 ± 3.33 ng/mL, P<0.05). The serum PIIINP level in patients with an end point was also higher than those without 7 days after PCI (59.34 ± 4.23 vs 48.78 ± 4.23 ng/mL, P<0.05). Multivariate logistic regression analysis showed day 7 (OR=2.170, 95% CI 1.583-4.345, P=0.01) and 3-month serum PICP (OR=2.340, 95% CI 1.431-4.650, P=0.01) were independent predictors of composite end points. Persistent elevation of serum collagen marker PICP three months after PCI predicts an adverse outcome for patients with acute ST-elevation myocardial infarction.


Contribution of strength characteristics to change of direction and agility performance in female basketball athletes.
Research has often examined the relationship between 1 or 2 measures of strength and change of direction (COD) ability reporting inconsistent relationships to performance. These inconsistencies may be the result of the strength assessment used and the assumption that 1 measure of strength can represent all "types" of strength required during a COD task. Therefore the purpose of this study was to determine the relationship between several lower-body strength and power measures, COD, and agility performance. Twelve (n = 12) elite female basketball athletes completed a maximal dynamic back squat, isometric midthigh pull, eccentric and concentric only back squat, and a countermovement jump, followed by 2 COD tests (505 and T-test) and a reactive agility test. Pearson product-moment correlation and stepwise regression analysis were performed on all variables. The percentage contribution of each strength measure to an athletes total strength score was also determined. Our results demonstrated that both COD tests were significantly correlated to maximal dynamic, isometric, concentric, and eccentric strength (r = -0.79 to -0.89), with eccentric strength identified as the sole predictor of COD performance. Agility performance did not correlate with any measure of strength (r = -0.08 to -0.36), whereas lower-body power demonstrated no correlation to either agility or COD performance (r = -0.19 to -0.46). These findings demonstrate the importance of multiple strength components for COD ability, highlighting eccentric strength as a deterministic factor of COD performance. Coaches should aim to develop a well-rounded strength base in athletes; ensuring eccentric strength is developed as effectively as the often-emphasized concentric or overall dynamic strength capacity.


Incremental detection of coronary artery disease by assessment of non-calcified plaque on coronary CT angiography.
The purpose of this study was to evaluate the improved assessment of coronary atherosclerotic plaque burden by measurement of non-calcified plaque in addition to calcified plaque using CT coronary angiography (CTA). Low to intermediate-risk outpatients with suspected coronary artery disease were prospectively recruited. Patients underwent CTA and calcium scoring in addition to invasive angiography. The presence of plaque (calcified, non-calcified, and mixed) was analysed on a per segment basis (percentage of segments with disease) with stratification by calcium score (CS). Seventy-six patients were enrolled of whom 30 had a CS of 0, 26 had a CS of 1-200, and 20 had a CS of >200. One thousand, one hundred and two segments were analysed using CTA and invasive angiography. The prevalence of segments with calcified or mixed plaque was 3.1% (n=13) for a CS of 0, 15.1% (n=57) for a CS of 1-200, and 50% (n=142) for a CS of >200 (all p<0.0001). The proportion of segments with non-calcified plaque alone was low and similar among the three groups: 5.4% (n=23; CS=0), 8.2% (n=32; CS=1-200), and 8.6% (n=25; CS= >200), (CS=0 versus CS= >200; p=0.04, others p=ns). The relative increase in diseased segments by additional assessment of non-calcified plaque was greatest for patients with a CS of 0 (173%) versus a CS of 1-200 (55%), and a CS of >200 (17%). CTA offers increased relative incremental detection of non-calcified plaque, particularly in those with negative CS; however, the absolute detection of non-calcified plaque in those with negative CS is low. The prognostic significance of non-calcified plaque for the prediction of cardiac events, particularly in patients with low CS, requires continued study.


Monitoring health inequalities when the socio-economic composition changes: are the slope and relative indices of inequality appropriate? Results of a simulation study.
The slope (SII) and relative (RII) indices of inequality are commonly recommended to monitor health inequality policies. As an upwards shift of the educational level distribution (ELD) can be part of those policies, we examine how such a shift affects the SII, the RII and the population attributable fraction (PAF). We simulated 632 distributions of 4 educational levels (ELs) by varying the share (p1 to p4) of each EL, with constant mortality rates (MR) and calculated the corresponding RII, SII and PAF. Second, we decomposed the effect on the three indices of a change affecting both the ELD and the MRs, into the contributions of each component. RIIs and SIIs sharply increase with p4 at fixed p1 values and evolve as reversed U-curves for p1 changing in complement to p4. The RII reaches a maximum, at much higher p4 values than the SII. PAFs monotonically decrease when p4 increases. If improving the educational attainment is part of a policy, an upwards shift of EL should be assessed as a progress; however the RII, and to a lesser extent the SII, frequently translate an increased EL4 share as a worsening. We warn against the use of SII and RII for monitoring inequality-tackling policies at changing socio-economic structures. Rather, we recommend to complement the assessment of changes in absolute and relative pairwise differentials, with changes in PAF and in the socio-economic group shares.


A High-Performance, Low Power Research Hearing Aid featuring a High-Level Programmable Custom 22nm FDSOI SoC.
With advances in algorithmic hearing aid research, the need for high-level programmable, behind-the-ear (BTE) wearable and low-power research platforms is emerging. These can be used to test new algorithms in real-world scenarios. Although various groups are developing different portable solutions, they are not in a BTE form factor. For this reason, the devices must be worn around the neck or somewhere on the body, which causes limited mobility and can lead to inaccurate research results. Therefore, this work presents a fully integrated and functional hearing aid research platform that weighs only 5 grams and can be worn behind the ear. The platform is high-level programmable, features wireless technologies such as near-field magnetic induction (NFMI) and Bluetooth Low Energy (BLE), and integrates two micro-electro-mechanical systems (MEMS) microphones and an external speaker. The audio processor of the system is based on a new custom, low-power 22nm mixed-signal system on chip (SoC). Different real-world use cases, like a dynamic compressor, are used to evaluate the platform. With a total power consumption of 47 mW, the rechargeable device achieves a run-time of six hours. When the wireless interfaces are turned off, the power consumption drops to 31 mW, and the run-time increases to nine hours.Clinical relevance-The proposed research hearing aid demonstration platform can be used portable and outside the clinical setting for algorithmic research. With its behind-the-ear form factor and rechargeable battery, studies can be conducted for several hours without restricting patient movement in real-world scenarios.


The effect of ethanol and heat on the functional hydrophobicity of casein micelles.
Milk proteins are very important ingredients to the food industry. As new uses and applications for these proteins are developed, it becomes more important to understand their physicochemical properties when they are subjected to different treatments. It has been reported that casein micelles dissociate when heated in the presence of ethanol. The changes to the hydrophobicity of milk proteins during that process were evaluated by using the fluorescent hydrophobic probe 1-anilinonaphthalene-8-sulfonic acid (ANS). Raw skim milk, pasteurized skim milk, and whey protein isolate samples with ethanol concentrations of 0 to 60% (vol/vol) were heated from 20 to 60 degrees C. The fluorescence of the samples with and without the addition of ANS was measured at an excitation wavelength of 390 nm and an emission wavelength of 400 to 500 nm. The results showed a decrease in the extrinsic fluorescence of the samples as the ethanol concentration and temperature increased, indicating competitive inhibition of the ANS-hydrophobic site interaction by ethanol. This inhibition was further enhanced by the addition of heat. This resulted in a reduction in the functional hydrophobicity of the milk proteins as ethanol rendered the hydrophobic sites unavailable for interaction.


Redox homeostasis dysregulation in noise-induced hearing loss: oxidative stress and antioxidant treatment.
Noise exposure is an important cause of acquired hearing loss. Studies have found that noise exposure causes dysregulated redox homeostasis in cochlear tissue, which has been recognized as a signature feature of hearing loss. Oxidative stress plays a pivotal role in many diseases via very complex and diverse mechanisms and targets. Reactive oxygen species are products of oxidative stress that exert toxic effects on a variety of physiological activities and are considered significant in noise-induced hearing loss (NIHL). Endogenous cellular antioxidants can directly or indirectly counteract oxidative stress and regulate intracellular redox homeostasis, and exogenous antioxidants can complement and enhance this effect. Therefore, antioxidant therapy is considered a promising direction for NIHL treatment. However, drug experiments have been limited to animal models of NIHL, and these experiments and related observations are difficult to translate in humans; therefore, the mechanisms and true effects of these drugs need to be further analyzed. This review outlines the effects of oxidative stress in NIHL and discusses the main mechanisms and strategies of antioxidant treatment for NIHL.


Pannexin-1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration.
Extracellular ATP signalling is involved in many physiological and pathophysiological processes in several tissues, including adipose tissue. Adipocytes have crucial functions in lipid and glucose metabolism and they express purinergic receptors. However, the sources of extracellular ATP in adipose tissue are not well characterized. In the present study, we investigated the mechanism and regulation of ATP release in white adipocytes, and evaluated the role of extracellular ATP as potential autocrine and paracrine signal. Online ATP release was monitored in C3H10T1/2 cells and freshly isolated murine adipocytes. The ATP release mechanism and its regulation were tested in cells exposed to adrenergic agonists, insulin, glucose load and pharmacological inhibitors. Cell metabolism was monitored using Seahorse respirometry and expression analysis of pannexin-1 was performed on pre- and mature adipocytes. The ATP signalling was evaluated in live cell imaging (Ca2+ , pore formation), glycerol release and its effect on macrophages was tested in co-culture and migration assays. Here, we show that upon adrenergic stimulation white murine adipocytes release ATP through the pannexin-1 pore that is regulated by a cAMP-PKA-dependent pathway. The ATP release correlates with increased cell metabolism and is sensitive to glucose. Extracellular ATP induces Ca2+ signalling and lipolysis in adipocytes and promotes macrophage migration. Importantly, ATP release is markedly inhibited by insulin, which operates via the activation of phosphodiesterase 3. Our findings reveal an insulin-pannexin-1-purinergic signalling crosstalk in adipose tissue and we propose that deregulation of this signalling may contribute to adipose tissue inflammation and type 2 diabetes.


Sulfinamide Formation from the Reaction of Bacillithiol and Nitroxyl.
Bacillithiol (BSH) replaces glutathione (GSH) as the most prominent low-molecular-weight thiol in many low G + C gram-positive bacteria. BSH plays roles in metal binding, protein/enzyme regulation, detoxification, redox buffering, and bacterial virulence. Given the small amounts of BSH isolated from natural sources and relatively lengthy chemical syntheses, the reactions of BSH with pertinent reactive oxygen, nitrogen, and sulfur species remain largely unexplored. We prepared BSH and exposed it to nitroxyl (HNO), a reactive nitrogen species that influences bacterial sulfur metabolism. The profile of this reaction was distinct from HNO oxidation of GSH, which yielded mixtures of disulfide and sulfinamide. The reaction of BSH and HNO (generated from Angeli's salt) gives only sulfinamide products, including a newly proposed cyclic sulfinamide. Treatment of a glucosamine-cysteine conjugate, which lacks the malic acid group, with HNO forms disulfide, implicating the malic acid group in sulfinamide formation. This finding supports a mechanism involving the formation of an N-hydroxysulfenamide intermediate that dehydrates to a sulfenium ion that can be trapped by water or internally trapped by an amide nitrogen to give the cyclic sulfinamide. The biological relevance of BSH reactivity toward HNO is provided through in vivo experiments demonstrating that Bacillus subtilis exposed to HNO shows a growth phenotype, and a strain unable to produce BSH shows hypersensitivity toward HNO in minimal medium cultures. Thiol analysis of HNO-exposed cultures shows an overall decrease in reduced BSH levels, which is not accompanied by increased levels of BSSB, supporting a model involving the formation of an oxidized sulfinamide derivative, identified in vivo by high-pressure liquid chromatography/mass spectrometry. Collectively, these findings reveal the unique chemistry and biology of HNO with BSH in bacteria that produce this biothiol.


Emerging regenerative approaches for periodontal reconstruction: a systematic review from the AAP Regeneration Workshop.
More than 30 years have passed since the first successful application of regenerative therapy for treatment of periodontal diseases. Despite being feasible, periodontal regeneration still faces numerous challenges, and complete restoration of structure and function of the diseased periodontium is often considered an unpredictable task. This review highlights developing basic science and technologies for potential application to achieve reconstruction of the periodontium. A comprehensive search of the electronic bibliographic database PubMed was conducted to identify different emerging therapeutic approaches reported to influence either biologic pathways and/or tissues involved in periodontal regeneration. Each citation was assessed based on its abstract, and the full text of potentially eligible reports was retrieved. Based on the review of the full papers, their suitability for inclusion in this report was determined. In principle, only reports from scientifically well-designed studies that presented preclinical in vivo (animal studies) or clinical (human studies) evidence for successful periodontal regeneration were included. Hence, in vitro studies, namely those conducted in laboratories without any live animals, were excluded. In case of especially recent and relevant reviews with a narrow focus on specific regenerative approaches, they were identified as such, and thereby the option of referring to them to summarize the status of a specific approach, in addition to or instead of listing each separately, was preserved. Admittedly, the presence of subjectivity in the selection of studies to include in this overview cannot be excluded. However, it is believed that the contemporary approaches described in this review collectively represent the current efforts that have reported preclinical or clinical methods to successfully enhance regeneration of the periodontium. Today's challenges facing periodontal regenerative therapy continue to stimulate important research and clinical development, which, in turn, shapes the current concept of periodontal tissue engineering. Emerging technologies--such as stem cell therapy, bone anabolic agents, genetic approaches, and nanomaterials--also offer unique opportunities to enhance the predictability of current regenerative surgical approaches and inspire development of novel treatment strategies.


Environmental monitoring of Aichi virus and human bocavirus in samples from wastewater treatment plant, drain, and River Nile in Egypt.
Wastewater plays a major role in water pollution causing transmission of several viral pathogens, including Aichi virus (AiV) and human bocavirus (HBoV), associated with gastrointestinal illness in humans. In this study, we investigated the presence of AiV and HBoV in aquatic, sludge, sediment matrices collected from Abu-Rawash wastewater treatment plant (WWTP), El-Rahawy drain, Rosetta branch of the River Nile in Egypt by conventional polymerase chain reaction (PCR). AiV RNA was detected in 16.6% (2/12), 8.3% (1/12), 8.3% (1/12), 22% (16/72), 12.5% (3/24), 4% (1/24), and 0/24 (0%) of untreated raw sewage, treated sewage, sewage sludge, drainage water, drain sediment, river water, and river sediment, respectively. On the other hand, HBoV DNA was detected in 41.6% (5/12), 25% (3/12), 16.6% (2/12), 48.6% (35/72), 29% (7/24), 3/24 (12.5%), 4% (1/24) of untreated raw sewage, treated raw sewage, sewage sludge, drainage water, drain sediment, river water, and river sediment, respectively. This study provides data on the presence of these viruses in various types of water samples that are valuable to environmental risk assessment. In addition, the current study demonstrates the importance of environmental monitoring as an additional tool to investigate the epidemiology of AiV and HBoV circulating in a given community.


Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: potential relevance to the pathogenesis of endometriosis.
Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role. The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression. This was a cell/tissue culture study. The study was conducted at an academic center. Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study. Treatment of cultured human endometrial explants and stromal cells with A4 (10 nm) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5'-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens. Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.


[Structural-functional chromosome organization in response to stress].
Published data and the results of experiments conducted at the Laboratory of Genetics of Higher Nervous Activity, Pavlov Institute of Physiology, on the effect of stress on chromosome structure and function are reviewed briefly. Experiments were performed on inbred rats selected for excitation threshold and mutant Drosophila with altered metabolism of secondary mediators.


QTL mapping of resistance to gray leaf spot in ryegrass.
Gray leaf spot (GLS) is a serious fungal disease caused by Magnaporthe grisea, recently reported on perennial ryegrass (Lolium perenne L.), an important turf grass and forage species. This fungus also causes rice blast and many other grass diseases. Rice blast is usually controlled by host resistance, but durability of resistance is a problem. Little GLS resistance has been reported in perennial ryegrass. However, greenhouse inoculations in our lab using one ryegrass isolate and one rice-infecting lab strain suggest presence of partial resistance. A high density linkage map of a three generation Italian x perennial ryegrass mapping population was used to identify quantitative trait loci (QTL) for GLS resistance. Potential QTL of varying effect were detected on four linkage groups, and resistance to the ryegrass isolate and the lab strain appeared to be controlled by different QTL. Of three potential QTL detected using the ryegrass isolate, the one with strongest effect for resistance was located on linkage group 3 of the MFB parent, explaining between 20% and 37% of the phenotypic variance depending on experiment. Another QTL was detected on linkage group 6 of the MFA parent, explaining between 5% and 10% of the phenotypic variance. The two QTL with strongest effect for resistance to the lab strain were located on linkage groups MFA 2 and MFB 4, each explaining about 10% of the phenotypic variance. Further, the QTL on linkage groups 3 and 4 appear syntenic to blast resistance loci in rice. This work will likely benefit users and growers of perennial ryegrass, by setting the stage for improvement of GLS resistance in perennial ryegrass through marker-assisted selection.


Large cell neuroendocrine carcinoma of the mediastinum with alpha-fetoprotein production.
Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immunohistochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.


Soil-borne fungi alter the apoplastic purinergic signaling in plants by deregulating the homeostasis of extracellular ATP and its metabolite adenosine.
Purinergic signaling activated by extracellular nucleotides and their derivative nucleosides trigger sophisticated signaling networks. The outcome of these pathways determine the capacity of the organism to survive under challenging conditions. Both extracellular ATP (eATP) and Adenosine (eAdo) act as primary messengers in mammals, essential for immunosuppressive responses. Despite the clear role of eATP as a plant damage-associated molecular pattern, the function of its nucleoside, eAdo, and of the eAdo/eATP balance in plant stress response remain to be fully elucidated. This is particularly relevant in the context of plant-microbe interaction, where the intruder manipulates the extracellular matrix. Here, we identify Ado as a main molecule secreted by the vascular fungus Fusarium oxysporum. We show that eAdo modulates the plant's susceptibility to fungal colonization by altering the eATP-mediated apoplastic pH homeostasis, an essential physiological player during the infection of this pathogen. Our work indicates that plant pathogens actively imbalance the apoplastic eAdo/eATP levels as a virulence mechanism.


Weakened magnetic braking as the origin of anomalously rapid rotation in old field stars.
A knowledge of stellar ages is crucial for our understanding of many astrophysical phenomena, and yet ages can be difficult to determine. As they become older, stars lose mass and angular momentum, resulting in an observed slowdown in surface rotation. The technique of 'gyrochronology' uses the rotation period of a star to calculate its age. However, stars of known age must be used for calibration, and, until recently, the approach was untested for old stars (older than 1 gigayear, Gyr). Rotation periods are now known for stars in an open cluster of intermediate age (NGC 6819; 2.5 Gyr old), and for old field stars whose ages have been determined with asteroseismology. The data for the cluster agree with previous period-age relations, but these relations fail to describe the asteroseismic sample. Here we report stellar evolutionary modelling, and confirm the presence of unexpectedly rapid rotation in stars that are more evolved than the Sun. We demonstrate that models that incorporate dramatically weakened magnetic braking for old stars can--unlike existing models--reproduce both the asteroseismic and the cluster data. Our findings might suggest a fundamental change in the nature of ageing stellar dynamos, with the Sun being close to the critical transition to much weaker magnetized winds. This weakened braking limits the diagnostic power of gyrochronology for those stars that are more than halfway through their main-sequence lifetimes.


Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy.
With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) <170 microg hr/mL. Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.


Subfascial endoscopic perforator vein surgery in patients with post-thrombotic venous insufficiency--is it justified?
Previous results following subfascial endoscopic perforator vein surgery were reported to be worse in post-thrombotic syndrome than in limbs with primary valvular incompetence. This report comprises a larger patient cohort with longer follow-up. The goal of this study was to determine if subfascial endoscopic perforator vein surgery is justified in patients with post-thrombotic venous insufficiency. The clinical data of 91 consecutive patients who underwent subfascial endoscopic perforator vein surgery with or without superficial reflux ablation over a 7-year period from May 1993 to June 2000 were retrospectively analyzed. Fifty-four females and 37 males (median age, 53 years; range, 20-77) underwent 103 subfascial endoscopic perforator vein surgery procedures. Forty-two limbs were classified as C6 (active ulcer), 34 as C5 (healed ulcer), and 24 as C4 (lipodermatosclerosis). Thirty procedures were performed in post-thrombotic limbs. Concomitant superficial reflux ablation was performed in 74 limbs (72%); saphenous vein stripping had been previously performed in 29 (28%). Deep venous incompetence was present in 89% of limbs; 13% had venous outflow obstruction on plethysmography. Cumulative ulcer healing in post-thrombotic limbs was not significantly different from limbs with primary valvular incompetence; 30-, 60-, and 90-day healing rates were 44%, 72%, and 72% vs 39%, 70%, and 87%, respectively (p = 0.35). On univariate analysis, the presence of ulcer greater than 2 cm in diameter was associated with delayed ulcer healing (p = 0.02). Cumulative ulcer recurrence in all limbs was 4%, 20%, and 27% at 1, 3, and 5 years, respectively. Ulcer recurrence in post-thrombotic limbs was higher than in limbs with primary valvular incompetence at 1, 3, and 5 years; 16%, 47%, and 56% vs 0%, 8%, and 15%, respectively (p = 0.001). Recurrent ulcers were small, superficial, and easier to heal. Clinical improvement was significant even in post-thrombotic limbs; median clinical score decreased from 9.5 to 3 (p = 0.001), and median outcome score was +2 (mean 1.9; range, -1 to 3). Median clinical score in patients with primary valvular incompetence improved from 6 to 1.5 (p = 0.0001). Subfascial endoscopic perforator vein surgery with superficial reflux ablation promoted ulcer healing, improved clinical outcome, and resulted in a low long-term ulcer recurrence rate in limbs with primary valvular incompetence. Despite good clinical outcome in post-thrombotic limbs, ulcer recurrence was high. These results imply that the role of subfascial endoscopic perforator vein surgery with superficial reflux ablation in patients with post-thrombotic limbs continues to be controversial.


BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model.
No effective antiviral therapies are currently available to treat disease after infection with yellow fever virus (YFV). A Syrian golden hamster model of yellow fever (YF) was used to characterize the effect of treatment with BCX4430, a novel adenosine nucleoside analog. Significant improvement in survival was observed after treatment with BCX4430 at 4 mg/kg of body weight per day dosed intraperitoneally (i.p.) twice daily (BID). Treatment with BCX4430 at 12.5 mg/kg/day administered i.p. BID for 7 days offered complete protection from mortality and also resulted in significant improvement of other YF disease parameters, including weight loss, serum alanine aminotransferase levels (6 days postinfection [dpi]), and viremia (4 dpi). In uninfected hamsters, BCX4430 at 200 mg/kg/day administered i.p. BID for 7 days was well tolerated and did not result in mortality or weight loss, suggesting a potentially wide therapeutic index. Treatment with BCX4430 at 12 mg/kg/day i.p. remained effective when administered once daily and for only 4 days. Moreover, BCX4430 dosed at 200 mg/kg/day i.p. BID for 7 days effectively treated YF, even when treatment was delayed up to 4 days after virus challenge, corresponding with peak viral titers in the liver and serum. BCX4430 treatment did not preclude a protective antibody response, as higher neutralizing antibody (nAb) concentrations corresponded with increasing delays of treatment initiation, and greater nAb responses resulted in the protection of animals from a secondary challenge with YFV. In summary, BCX4430 is highly active in a hamster model of YF, even when treatment is initiated at the peak of viral replication.


Effects of hyperglycemia on hepatic gluconeogenic flux during glycogen phosphorylase inhibition in the conscious dog.
The aim of these studies was to investigate the effect of hyperglycemia with or without hyperinsulinemia on hepatic gluconeogenic flux, with the hypothesis that inhibition would be greatest with combined hyperglycemia/hyperinsulinemia. A glycogen phosphorylase inhibitor (BAY R3401) was used to inhibit glycogen breakdown in the conscious overnight-fasted dog, and the effects of a twofold rise in plasma glucose level (HI group) accompanied by 1) euinsulinemia (HG group) or 2) a fourfold rise in plasma insulin were assessed over a 5-h experimental period. Hormone levels were controlled using somatostatin with portal insulin and glucagon infusion. In the HG group, net hepatic glucose uptake and net hepatic lactate output substantially increased. There was little or no effect on the net hepatic uptake of gluconeogenic precursors other than lactate (amino acids and glycerol) or on the net hepatic uptake of free fatty acids compared with the control group. Consequently, whereas hyperglycemia had little effect on gluconeogenic flux to glucose 6-phosphate (G-6-P), net hepatic gluconeogenic flux was reduced because of increased hepatic glycolytic flux during hyperglycemia. Net hepatic glycogen synthesis was increased by hyperglycemia. The effect of hyperglycemia on gluconeogenic flux to G-6-P and net hepatic gluconeogenic flux was similar. We conclude that, in the absence of appreciable glycogen breakdown, the increase in glycolytic flux that accompanies hyperglycemia results in decreased net carbon flux to G-6-P but no effect on gluconeogenic flux to G-6-P.


Role of induced fit in enzyme specificity: a molecular forward/reverse switch.
Enzyme structures solved with and without bound substrate often show that substrate-induced conformational changes bring catalytic residues into alignment, alter the local environment, and position the substrate for catalysis. Although the structural data are compelling, the role of conformational changes in enzyme specificity has been controversial in that specificity is a kinetic property that is not easy to predict based upon structure alone. Recent studies on DNA polymerization have illuminated the role of substrate-induced conformational changes in enzyme specificity by showing that the rate at which the enzyme opens to release the bound substrate is a key kinetic parameter. The slow release of a correct substrate commits it to the forward reaction so that specificity is determined solely by the rate of substrate binding, including the isomerization step, and not by the slower rate of the chemical reaction. In contrast, fast dissociation of an incorrect substrate favors release rather than reaction. Thus, the conformational change acts as a molecular switch to select the right substrate and to recognize and disfavor the reaction of an incorrect substrate. A conformational switch may also favor release rather than reverse reaction of the product.


[Cholelithiasis in the neonatal period].
We report about a four weeks old male infant who developed jaundice with cholangitis and fever caused by cholelithiasis which could be confirmed by sonographic examination. Familiar history revealed several relatives with gallstones.


A wearable electrofluidic actuation system.
We report a wearable electrofluidic actuation system, which exploits the alternating current electrothermal (ACET) effects to engineer biofluid flow profiles on the body. The wearable ACET flow is induced with the aid of corrosion-resistant electrode configurations (fabricated on a flexible substrate) and custom-developed, wirelessly programmable high frequency (MHz) excitation circuitry. Various tunable flow profiles are demonstrated with the aid of the devised flexible ACET electrode configurations, where the induced profiles are in agreement with the ACET theory and simulation. The demonstrated capabilities rendered by the presented system create new degrees of freedom for implementing advanced bioanalytical operations for future lab-on-the-body platforms.


Novel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors.
Epidermal growth factor receptors (EGFRs) have potential to be considered as therapeutic target for cancer treatment especially in cancer patients with overexpression of EGFR. Cetuximab as a first monoclonal antibody and Imatinib as the first small molecule tyrosine kinase inhibitor (SMTKI) were approved by FDA in 1998 and 2001. About 28 SMTKIs have been approved until 2015 and a large number of compound with kinase inhibitory activity are at the different phases of clinical trials. Although Kinase inhibitors target specific intracellular pathways, their tissue or cellular distribution are not specific. So treatment with these drugs causes serious dose dependent side effects. Targeted delivery of kinase inhibitors via dendrimers, polymeric nanoparticles, magnetic nanoparticles and lipid based delivery systems such as liposomes, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can lead to reduction of side effects and improving therapeutic efficacy of the drugs in the target organs. Furthermore formulation of these drugs is challenged by their physicochemical properties such as solubility and dissolution rate. The main approaches in order to increase dissolution rate, are particle size reduction, self-emulsification, cyclodextrin complexation, crystal modification and amorphous solid dispersion. Synergistic therapeutic effect, decreased side effects and drug resistant, reduced cost and increased patient compliance are the advantages associated with using combination therapy especially in the treatment of cancer. Combination of TKIs with chemotherapeutic agents or biopharmaceuticals such as monoclonal antibodies and oligonucleotides and also combination of two TKIs within one formulation is possible by new targeting delivery systems. This article reviews the recent advances in the design and development of delivery systems for TKIs.


Endovascular treatment of ruptured intracranial aneurysms in elderly people.
Endovascular detachable coil is being increasingly used for the treatment of cerebral aneurysms but little information is available about its feasibility and effectiveness in people. We assessed clinical outcomes in elderly patients with ruptured intracranial aneurysms treated with selective embolization. Between 1996 and 2002, 68 patients aged 65-80 years (mean age, 71 years) were treated by selective embolization with coils. Among them, 34 had a Hunt and Hess (HH) grade of I or II; 15, an HH grade of III; and 19, an HH grade of IV or V. All patients except four were treated within 72 hours after initial bleeding; those four patients had an HH grade of IV or V and were treated at 3-6 weeks after their clinical recovery. Clinical outcomes were assessed by using the Modified Glasgow Outcome Scale. Mean duration of follow-up was 20 months (range, 6-36 months). Endovascular treatment resulted in 47 complete occlusions (69%), 15 neck remnants (22%), and six incomplete occlusions (9%). Procedural complications occurred in eight patients (12%). Outcomes were good or excellent in 40 patients (59%), including the four treated 3-6 weeks after initial bleeding. A fair or poor outcome was observed in 14 patients (20.5%), including two with an HH grade of I or II. Of 14 patients (20.5%) who died, 13 (93%) had an HH grade of IV or V. No rebleeding occurred during follow-up. Endosaccular coiling may be proposed in elderly people with ruptured intracranial aneurysms. However, in patients with HH grade IV or V lesions, morbidity and mortality rates remain high, and embolization should be considered only after their clinical recovery.


Contextual influences in V1 as a basis for pop out and asymmetry in visual search.
I use a model to show how simple, bottom-up, neural mechanisms in primary visual cortex can qualitatively explain the preattentive component of complex psychophysical phenomena of visual search for a target among distracters. Depending on the image features, the speed of search ranges from fast, when a target pops-out or is instantaneously detectable, to very slow, and it can be asymmetric with respect to switches between the target and distracter objects. It has been unclear which neural mechanisms or even cortical areas control the ease of search, and no physiological correlate has been found for search asymmetry. My model suggests that contextual influences in V1 play a significant role.


Interleukin-1beta induces interleukin-6 production through the production of prostaglandin E(2) in human osteoblasts, MG-63 cells.
This study was conducted to investigate the mechanism of interleukin-1beta (IL-1beta)-induced IL-6 production in human osteoblasts (MG-63 cells). Stimulation with IL-1beta resulted in the production of IL-6 and prostaglandin E(2) (PGE(2)). IL-6 production gradually increased and peaked 96 h after stimulation. IL-6 mRNA was detected between 4 and 72 h after IL-1beta stimulation. The patterns of PGE(2) production and the expression of cyclooxygenase-2 (COX-2) mRNA were biphasic after stimulation. Actinomycin D, cycloheximide, indomethacin, and NS-398 (COX-2 inhibitor) suppressed the production of IL-6 and PGE(2). Anti-PGE(2) antibody markedly reduced the production of IL-6. In addition, stimulation with 17-phenyl-PGE(2), a PGE receptor-1 (EP-1 receptor) agonist, led to the expression of IL-6 mRNA after pretreatment with IL-1beta. These findings indicate that IL-1beta-induced IL-6 production in MG-63 cells involves the following sequence of steps: IL-1beta-induced COX-2 activation, PGE(2) production, and EP-1 receptor signaling prior to IL-6 production.


Ovarian remnant syndrome in dogs and cats: 21 cases (2000-2007).
To describe signalment, clinical findings, diagnostic tests, and results of treatment of dogs and cats with ovarian remnant syndrome (ORS). Retrospective case series. 19 dogs and 2 cats with ORS. Medical records for animals examined between June 2000 and October 2007 were reviewed for signalment, clinical signs, age at time of ovariohysterectomy (OHE), surgical findings during OHE, experience of the surgeon (veterinary student vs veterinarian), interval from OHE until diagnosis of ORS, results of diagnostic tests, surgical findings, and results of histologic examination of excised tissues. 21 animals (19 dogs and 2 cats) with ORS were identified. The most common clinical signs were those associated with proestrus and estrus. More dogs than cats were affected, and all residual ovarian tissues were found in the region of the ovarian pedicles. The right ovary in dogs was affected significantly more often than the left ovary. Seven animals had neoplasms of the reproductive system. These animals had a significantly longer interval between OHE and diagnosis of ORS than did the 14 animals without neoplasms. Long-term follow-up of 18 animals revealed resolution of clinical signs following exploratory laparotomy. Ovarian remnants were found in typical locations for ovaries and were not considered ectopic tissue; thus, surgical error during OHE was suspected as the cause of ORS. Anatomic differences may account for differences between species, and clinical signs may not be recognized until years after OHE. Surgical removal of residual ovarian tissue resulted in resolution of clinical signs.


[Biological monitoring of environmental benzene exposure in traffic wardens].
Vehicle exhausts are a well known source of aromatic hydrocarbon pollution in urban environments. The paper reports the results of environmental and biological monitoring of benzene exposure in traffic wardens carried out over a 5-hour workshift. Subjects (n = 131) were grouped according to smoking habits and job task as follows: group (A) 52 nonsmoking office workers, (B) 43 nonsmoking outdoor workers, subdivided into (B1) 36 working on foot and (B2) 7 cyclists; (C) 20 smokers office workers, (D) 16 smokers outdoor workers, subdivided into (D1) 11 working on foot and (D1) 5 cyclists. The median indoor environmental benzene concentration (26 micrograms/m3, n = 50) was significantly lower than the outdoor concentration (45 micrograms/m3, n = 43) (p < 0.01); median exposure value of cyclists was 78 micrograms/m3 (n = 12). For biological monitoring, urinary excretion of trans,transmuconic acid was determined in spot samples collected at 7:30 h (MAit) and 12:30 h (MAft). The MAftA median value (63 micrograms/l, range 2-242 micrograms/l) was not statistically different from MAftB (74 micrograms/l, range 15-216 micrograms/l), while the MAftB2 value of 96 micrograms/l was higher than both MAftB1 (71 micrograms/l) and MAftA. In group (B) there was a relationship between airborne benzene levels and MAftB excretion (y = 17.2 + 1.1x, r = 0.62, n = 35, p < 0.01). The influence of smoking on urinary MA excretion was studied by comparing the results obtained in all nonsmokers (AB) with smokers (CD). MAftCD (192 micrograms/l) was significantly higher than MAftAB (69 micrograms/l) (p < 0.01). In smokers, statistically significant relationships were observed between urinary excretion of MAft (y, microgram/l) and cotinine (x, microgram/l) (y = 83 + 0.08x, r = 0.73, n = 23, p < 0.01), and smoking (x, number cigarettes/day) (y = 87.4 + 4.4x, r = 0.53, n = 29, p < 0.01). Comparison between MAft and MAit median excretion values, calculated for each of the 6 exposure groups, showed that MAft was always higher than the corresponding MAit value. A rough estimate of the total dose of benzene ("index of exposure", EI) inhaled by each subject during the 5-hour working shift as a consequence of air pollution and smoking was also made. Considering the entire group of subjects, a significant association was observed between EI and MAft values (y = 43.4 + 0.39x, r = 0.65, n = 104, p < 0.01). Individual values of MA it were correlated with MAft according to the equation y = 43.6 + 0.82x (r = 0.62, n = 105; p < 0.01) and were also positively associated with EI values (y = 42.3 + 0.20x; r = 0.55; n = 74; p < 0.01). In conclusion, the results suggest that the measurement of urinary MA excretion is a poor indicator for assessing environmental benzene exposure at levels below 100 micrograms/m3, such as those seen in this study; MA can however be reliably used as a biomarker for higher exposures such as those, for example, due to smoking.


What is the role of sleep in physician burnout?
The occurrence of physician burnout is widespread among clinicians and academic faculty, who report indicators such as low quality of life and poor work-life balance. Chronic insufficient sleep, whether due to extended work hours, circadian misalignment, or unrecognized sleep disorders, is a critically important risk factor for burnout that is overlooked and under-studied, and interventions to promote healthy sleep may reduce burnout susceptibility among attending physicians. While strategies to reduce burnout among resident and attending physicians have been under-evaluated, evidence suggests a need to address burnout at both individual and organizational levels. Solutions have been offered that are applicable to many stakeholders, including employers; payers; licensing and certification boards; state and federal regulatory agencies; and physicians and researchers. As more studies are undertaken to evaluate how these approaches impact burnout, two questions need to be addressed: (1) What is the role of sleep in the crisis of burnout, specifically among attendings, who are particularly under-studied? (2) Is restoration of healthy sleep the fundamental mechanism by which burnout interventions work? It is essential for key stakeholders to consider the role of sleep, sleepiness, and sleep disorders in order to optimize any efforts to mitigate the present crisis in physician burnout, particularly among attending physicians, an understudied group.


Hirschsprung-associated congenital anomalies.
Between 1976-1993, 302 patients were diagnosed to have Hirschsprung's disease (HD) in Hacettepe University Children's Hospital. All patients have been searched for the occurrence of associated anomalies and other parameters including 1) sex, 2) gestational age, 3) birth weight, 4) length of aganglionic segment, 5) familial occurrence, 6) consanguinity. Forty-nine of 302 patients were proved to have 83 associated congenital anomalies together with HD. Distribution of anomalies was as follows; central nervous system and special senses 28.92%, genitourinary system 26.51%, skeletal 24.09%, gastrointestinal 12.05%, cardiovascular 8.43%. In eleven patients more than one anomaly involving different systems were detected; only one of these patients was female and six of them have shown short segment disease. Down's syndrome was present in 5 patients. Female: male ratio was 1:4.2 for the whole series and 1:6 for the patients with Hirschsprung associated congenital anomalies (HACA). In the HACA group the percentage increased in favor of long-segment and extensive aganglionosis without statistical significance (p>0.05). The majority of patients were term babies and their birth weights were between 2500g < 3500g. Consanguinity was present in 36 families. No affected parents were detected but two sisters and four brothers were proved to have HD. Three pairs of twins, one of which was monozygotic, and all showing discordance were detected. There was no difference between HACA group and HD without HACA in terms of sex, birth weight, length of aganglionic segment and consanguinity. Although HD seemed to be genetically heterogeneous HACA did not have a genetically different origin from that of HD.


Meta-analysis with Robust Variance Estimation: Expanding the Range of Working Models.
In prevention science and related fields, large meta-analyses are common, and these analyses often involve dependent effect size estimates. Robust variance estimation (RVE) methods provide a way to include all dependent effect sizes in a single meta-regression model, even when the exact form of the dependence is unknown. RVE uses a working model of the dependence structure, but the two currently available working models are limited to each describing a single type of dependence. Drawing on flexible tools from multilevel and multivariate meta-analysis, this paper describes an expanded range of working models, along with accompanying estimation methods, which offer potential benefits in terms of better capturing the types of data structures that occur in practice and, under some circumstances, improving the efficiency of meta-regression estimates. We describe how the methods can be implemented using existing software (the "metafor" and "clubSandwich" packages for R), illustrate the proposed approach in a meta-analysis of randomized trials on the effects of brief alcohol interventions for adolescents and young adults, and report findings from a simulation study evaluating the performance of the new methods.


Protective effects of a calcium channel blocker on apoptosis in thymus of neonatal STZ-diabetic rats.
Streptozotocin (STZ) is known to induce insulin-dependent diabetes in experimental animals. In STZ-induced diabetes, atrophy of the thymus is caused by elevated intracellular calcium levels leading to apoptosis. Hyperglycemia is known to result in a decrease in numbers of T cells in the thymus and circulation. Intracellular calcium levels increase in diabetic animals after induction by STZ. Hyperglycemia inhibits Ca2+-ATPase and increases intracellular calcium levels. We have investigated apoptosis in thymus tissue of neonatal STZ (n-STZ)-diabetic rats and the effects of isradipine as a calcium channel blocker (CCB) on apoptosis. Five groups of newborn Wistar rats were used. On the second day after birth, 100 mg/kg STZ was given i.p. to the first two groups. The first group was n-STZ diabetic. To the second group, starting from the 12th week, 5 mg/kg/day isradipine (i.p) was given for 6 weeks. To the third group, the same dose of isradipine was given on the second day, followed by STZ treatment. The fourth group was non-diabetic and treated with 5 mg/kg/day isradipine for six weeks. The fifth group consisted of non-diabetic rats. To the sixth group, dexamethasone (5 mg/kg i.p.) was given to adult rats. For detection of apoptotic cells in paraffin-embedded thymus sections, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay was used. The DNA ladder method was performed for analysis of DNA fragmentation. In the isradipine-treated non-diabetic group, typical apoptotic banding patterns were found, whereas thick bands between 123 and 246 bp length were found in the n-STZ- and n-STZ+isradipine-treated groups. More apoptotic cells were observed in the thymus of isradipine-treated, n-STZ-treated and n-STZ+isradipine-treated groups when compared with the non-diabetic control and isradipine+n-STZ-treated groups. In conclusion, we observed that long-term STZ diabetes results in apoptosis in the thymus. We also found that isradipine administered before STZ has protective effects against apoptosis, whereas isradipine alone induces apoptosis.


Analysis of production objectives and breeding practices of dairy goats in Kenya.
Production objectives and breeding practices of smallholder households participating in dairy goat breeding projects were analysed in relation to their ability to bring about sustainable genetic improvement in the dairy goat flocks in Kenya. A stratified survey involving 311 goat keepers in 4 project sites was used. This employed both qualitative and quantitative research methods to get a holistic view of dairy goats, and take into account the full array of contributions of dairy goats to the smallholder households. Milk production and sales of breeding stock were high priority functions for the objective to create a financial buffer. The breeding objective traits that farmers perceived as being of primary importance were milk yield, growth rate, body size, fertility and disease tolerance. There were logical trade-offs in the choice of these traits by farmers. Female dairy goats were mainly culled due to old age, poor fertility, small body size and poor health. Farmers did not place a large significance on unsatisfactory milk performance when culling female goats, mainly due to the very small production size and the high demand existing for breeding animals. Factors affecting milk yield and flock size presented satisfied a P<0.1 significance level. The performance levels of dairy goats were mainly influenced by breeding strategies and the resource availability at the farm level. The optimisation of genotype x environment interactions remains the biggest challenge given the objectives set by the farmer.


Vibrational Excitation in Some Four-Center Transition States.
The rates of substitution of deuterium for hydrogen in homogeneous gas phase reactions between D(2) and HX (X = H, Cl, NH(2), or HS) were measured at high temperatures by single-pulse shock tube techniques. The magnitudes observed and their dependency on concentration indicate that the rates of exchange are much faster than would be attainable were the deuterium to dissociate and the D atoms to react with HX by atomic displacement to produce H + DX. Also, these rates were not limited by methathesis through four-center transition states generated by sufficiently energetic collisions between the principal reactants. The results are compatible with the assumption that the rates are controlled by the populations of D(2) in about its 6th vibrational energy level.


Immunopathological changes in rheumatoid arthritis and other joint diseases.
A comparative study of the distribution of immunoglobulins G, M, and A and C3 in the synovium and inside synovial fluid leucocytes and of the relative levels of IgG, IgM, AND C3 in paired samples of serum and synovial fluid from both seropositive and seronegative patients with rheumatoid arthritis and other types of non-infective synovitis shows that although there is no distinctive immunopathological feature of rheumatoid arthritis, the incidence of immune complexes containing IgG and IgM with and without detectable C3 in the affected synovium or inside synovial fluid granulocytes is higher in rheumatoid arthritis and especially so in seropositive cases. The mean level of C3 in synovial fluid from patients with rheumatoid arthritis is lower than that from the group without rheumatoid arthritis. In contrast to previous reports, extracellular clumps of IgA could be detected in the affected synovium of a number of affected patients. Aggretated human IgG could be bound by some of the synovial biopsies and synovial fluid leucocytes from both seropositive and seronegative rheumatoid arthritis patients. Antinuclear factor and rheumatoid factor could be detected in the synovial fluid but not in the serum of several patients suggesting either selective sequestration or local synthesis of antinuclear and rheumatoid factors in the affected joints.


Translating advice to eat more vegetables into practice: observations from a 12-month weight loss trial.
This study aimed to identify the main vegetable sources of overweight participants during a 12-month randomised controlled trial for weight loss. Secondary analysis using data from diet history interviews to determine changes to daily vegetable intake amounts and types throughout the trial at 0, 3 and 12 months. Pre-trial 77% participants consumed frozen vegetables. At baseline (n = 113, 85 F), participants reported 345 ± 170 (56-920) g/day vegetables increasing to 498 ± 180 (146-930) g/day at 3 months and remaining stable at 475 ± 169(170-1053) g/day by 12 months (p = 0.001). At baseline, 32 of 34 different vegetable categories were reported, mainly tomato (69.9 g/day) and, potato (58.2 g/day). After 3 months (n = 109), seven vegetables remained in the top 10 reported (contributing 72%). Tomato remained top ranked to 12 months. Following advice to consume more vegetables, consumption increased above the Australian Dietary recommendation of ~375 g/day. Tomatoes remained a mainstay regardless of the time of year, but choices changed with time. Frozen vegetables may be a feasible option.


Characterization of cell cycle specific protein interaction networks of the yeast 26S proteasome complex by the QTAX strategy.
Ubiquitin-proteasome dependent protein degradation plays a fundamental role in the regulation of the eukaryotic cell cycle. Cell cycle transitions between different phases are tightly regulated to prevent uncontrolled cell proliferation, which is characteristic of cancer cells. To understand cell cycle phase specific regulation of the 26S proteasome and reveal the molecular mechanisms underlying the ubiquitin-proteasome degradation pathway during cell cycle progression, we have carried out comprehensive characterization of cell cycle phase specific proteasome interacting proteins (PIPs) by QTAX analysis of synchronized yeast cells. Our efforts have generated specific proteasome interaction networks for the G1, S, and M phases of the cell cycle and identified a total of 677 PIPs, 266 of which were not previously identified from unsynchronized cells. On the basis of the dynamic changes of their SILAC ratios across the three cell cycle phases, we have employed a profile vector-based clustering approach and identified 20 functionally significant groups of PIPs, 3 of which are enriched with cell cycle related functions. This work presents the first step toward understanding how dynamic proteasome interactions are involved in various cellular pathways during the cell cycle.


[Five year surveillance of Entamoeba histolytica and Giardia antigen of stool samples by ELISA method].
The aim of this study is to show the ratio of detection of distribution of E. histolytica ve Giardia in the fecal samples of the patients with diarrhoea complaints admitted to the hospitals and medical centers of our instution between June 2004 and June 2009. In our study, the patient samples were analyzed by E. histolytica antigen ELISA (Cellabs, Entamoeba Celisa Path, Brookvale, NSW Australia) kit and by Giardia antigen (Ridascreen, R-Biopharm AG, Darmstadt, Germany). Further, fecal cultures were performed and the presence of leukocytes and erythrocytes and Entamoeba and Giardia trophozoite and cysts were also examined. During this time in 539 of the 10305 patients (5.2%) Entamoeba histolytica (E. histolytica) and in 343 of 3100 patients (11.1%) Giardia specific antigens were detected. In the microscopical examination Entamoeba cysts were detected in 3% of the E. histolytica antigen positively detected patients and in 2% of the E. histolytica antigen negatively detected patients. Giardia cysts were detected in only 10% of the Giardia antigen positively detected patients. Continuous training of personnel is planned. The physicians were informed and trained to order antigen detection tests along with the direct microscopic examinations in fecal samples to provide the best diagnosis.


The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines.
Cytolethal distending toxins (CDTs) are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo. In the present study, xenograft mouse models of colon and liver cell lines were set up to study the effects of the CdtB subunit of Helicobacter hepaticus. Conditional transgenic cell lines were established, validated in vitro and then engrafted into immunodeficient mice. After successful engraftment, mice were treated with doxycyclin to induce the expression of transgenes (red fluorescent protein, CdtB, and mutated CdtB). For both engrafted cell lines, results revealed a delayed tumor growth and a reduced tumor weight in CdtB-expressing tumors compared to controls. CdtB-derived tumors showed γ-H2AX foci formation, an increase in apoptosis, senescence, p21 and Ki-67 nuclear antigen expression. No difference in proliferating cells undergoing mitosis (phospho-histone H3) was observed. CdtB intoxication was also associated with an overexpression of cytokeratins in cells at the invasive front of the tumor as well as an increase in ploidy. All these features are hallmarks of endoreplication, as well as aggressiveness in cancer. These effects were dependent on the histidine residue at position 265 of the CdtB, underlying the importance of this residue in CdtB catalytic activity. Taken together, these data indicate that the CdtB triggers senescence and cell endoreplication leading to giant polyploid cells in these xenograft mouse models.


Bayesian analysis versus discriminant function analysis: their relative utility in the diagnosis of coronary disease.
Both Bayesian analysis assuming independence and discriminant function analysis have been used to estimate probabilities of coronary disease. To compare their relative accuracy, we submitted 303 subjects referred for coronary angiography to stress electrocardiography, thallium scintigraphy, and cine fluoroscopy. Severe angiographic disease was defined as at least one greater than 50% occlusion of a major vessel. Four calculations were done: (1) Bayesian analysis using literature estimates of pretest probabilities, sensitivities, and specificities was applied to the clinical and test data of a randomly selected subgroup (group I, 151 patients) to calculate posttest probabilities. (2) Bayesian analysis using literature estimates of pretest probabilities (but with sensitivities and specificities derived from the remaining 152 subjects [group II]) was applied to group I data to estimate posttest probabilities. (3) A discriminant function with logistic regression coefficients derived from the clinical and test variables of group II was used to calculate posttest probabilities of group I. (4) A discriminant function derived with the use of test results from group II and pretest probabilities from the literature was used to calculate posttest probabilities of group I. Receiver operating characteristic curve analysis showed that all four calculations could equivalently rank the disease probabilities for our patients. A goodness-of-fit analysis suggested the following relationship between the accuracies of the four calculations: (1) less than (2) approximately equal to (4) less than (3). Our results suggest that data-based discriminant functions are more accurate than literature-based Bayesian analysis assuming independence in predicting severe coronary disease based on clinical and noninvasive test results.


Beta-Caryophyllene Suppresses Ovarian Cancer Proliferation by Inducing Cell Cycle Arrest and Apoptosis.
Ovarian cancer is the fifth most common cause of cancer deaths among women with lesser prognostics. Current treatment options are chemotherapy with platinum and taxane based chemotherapy. β-Caryophyllene (BCP) an essential oil found in many plant species is known to possess an anti-proliferative effect. We aimed to investigate the antiproliferative, cytotoxic, and apoptotic role of BCP against ovarian cancer cells PA-1 and OAW 42. The antiproliferative effect of BCP was determined by MTT assay and cell viability by trypan blue exclusion assay. Cell cycle and live/dead cell analyses were performed by flow cytometry to determine cell cycle distribution and apoptosis, respectively. Results of MTT assay proved the anti-proliferative effect of BCP in a dose and time-dependent manner in ovarian cancer cells. Cell cycle analysis showed that BCP induced S Phase arrest in OAW 42 cells. Results of apoptosis assay confirmed the apoptosis inducing potential of BCP in ovarian cancer cells. The apoptosis is mediated by caspase-3 activation and PARP cleavage. The results of our present study prove that BCP exerts its action partly by inducing cell cycle arrest and apoptosis in ovarian cancer. We conclude that BCP is a potential anti-cancer agent.


Tests of the linearity assumption in the dose-effect relationship for radiation-induced cancer.
The validity of the BEIR linear extrapolation to low doses of the dose-effect relationship for radiation induced cancer is tested by use of natural radiation making use of selectivity on type of cancer, smoking habits, sex, age group, geographic area and/or time period. For lung cancer, a linear interpolation between zero dose-zero effect and the data from radon-induced cancers in miners implies that the majority of all lung cancers among non-smokers are due to radon; since lung cancers in miners are mostly small-cell undifferentiated (SCU), a rather rare type in general, linearity over predicts the frequency of SCU lung cancers among non smokers by a factor of 10, and among non-smoking females age 25-44 by a factor of 24. Similarly, linearity predicts that the majority of all lung cancers early in this century were due to radon even after due consideration is given to cases missed by poor diagnostic efficiency (this matter is considered in some detail). For the 30-40 age range, linearity over predicts the total lung cancer rate at that time by a factor of 3-6; for SCU lung cancer, the over-prediction is by at least a factor of 10. Other causes of lung cancer are considered which further enhance the degree to which the linearity assumption over-estimates the effects of low level radiation. A similar analysis is applied to leukemia induced by natural radiation. It is concluded that the upper limit for this is not higher than estimates from the linearity hypothesis. The use of the selectivities is justified by the fact that the total incidence of lung cancer or leukemia is an upper limit on the rate at which it is caused by natural radiation effects; in determining upper limits it is justifiable to select situations which minimize them.


Highly stretchable anti-freeze hydrogel based on aloe polysaccharides with high ionic conductivity for multifunctional wearable sensors.
Conductive hydrogels have limitations such as non-degradability, loss of electrical conductivity at sub-zero temperatures, and single functionality, which limit their applicability as materials for wearable sensors. To overcome these limitations, this study proposes a bio-based hydrogel using aloe polysaccharides as the matrix and degradable polyvinyl alcohol as a reinforcing material. The hydrogel was crosslinked with borax in a glycerol-water binary solvent system, producing good toughness and compressive strength. Furthermore, the hydrogel was developed as a sensor that could detect both small and large deformations with a low detection limit of 1 % and high stretchability of up to 300 %. Moreover, the sensor exhibited excellent frost resistance at temperatures above -50 °C, and the gauge factor of the hydrogel was 2.86 at 20 °C and 2.12 at -20 °C. The Aloe-polysaccharide-based conductive hydrogels also functioned effectively as a wearable sensor; it detected a wide range of humidities (0-98 % relative humidity) and exhibited fast response and recovery times (1.1 and 0.9 s) while detecting normal human breathing. The polysaccharide hydrogel was also temperature sensitive (1.737 % °C-1) and allowed for information sensing during handwriting.


Selective calcification of pancreatic islets of Langerhans. An unusual association with hypercalcemia and diabetes mellitus.
An unusual and extensive calcification of islets of Langerhans was found at autopsy in a man, 58 years old, who developed myeloma and, subsequently, hypercalcemia and diabetes. Although the islet cell calcification appears to be related to the hypercalcemia, the pathogenesis of the calcification is not clear, as primary metastatic calcification of pancreatic islets due to hypercalcemia does not occur. In support of this, a retrospective study of pancreatic tissue from 52 hypercalcemic patients with parathyroid adenoma and 34 patients with multiple myeloma, who frequently have hypercalcemia, did not reveal islet calcification. The islet calcification is ascribed to primary islet cell degeneration and necrosis, with hypercalcemia playing an augmenting but crucial role. It is considered that the combination of islet degeneration and calcification resulted in the diabetic state.


Survivorship research in advanced gynecological cancer: A scoping review of cohort studies.
Recent calls to action highlight the need to address gaps in our understanding of survivorship for those living with advanced gynecological cancer to support optimal care. To ensure future research fills these knowledge gaps, we need to understand the breadth of existing survivorship research in this patient group, including the outcomes assessed, the populations included and the duration and retention in follow-up. We conducted a systematic scoping review searching PubMed, PsychINFO, and CINAHL during the month of November 2022 to identify prospective cohort studies measuring survivorship outcomes among participants with advanced (stage III-IV) gynecological cancer, or in cohorts in which ≥50% of participants had advanced cancer, or which provide results separately for patients with advanced cancer. Articles were screened, and data extracted using a standard form. We assessed 33 articles from 21 unique studies, which overall included 6023 participants with gynecological cancer. Of these, 45% had cervical cancer, 44% ovarian, 10% endometrial/uterine, and 1% vaginal/vulvar cancer. The most frequently measured survivorship outcome was quality of life. Of the 33 articles, most reported on participant age (n = 31), but relatively few reported on comorbidities (n = 10), physical status (n = 6), ethnic background (n = 4), the country of birth (n = 2), or the area of participant residence (n = 2). None included details on indigenous status. Recruitment proportions ranged from 48% to 100%. Retention proportions ranged from 15% to 97%. Our findings highlight gaps in survivorship research for advanced gynecological cancers and emphasize the need for future studies to include and describe the experiences of diverse and underrepresented groups.


Ambler class A extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. in Canadian hospitals.
This report describes a study carried out to gain baseline information on the molecular characteristics of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp. in Canada. A total of 29,323 E. coli and 5,156 Klebsiella sp. isolates were screened at 12 participating sites. Of these, 505 clinically significant, nonrepeat isolates displaying reduced susceptibility to the NCCLS-recommended beta-lactams were submitted to a central laboratory over a 1-year period ending on 30 September 2000. A total of 116 isolates were confirmed to be ESBL producers. PCR and sequence analysis revealed the presence of TEM-11 (n = 1), TEM-12 (n = 1), TEM-29 (n = 1), TEM-52 (n = 4), CTX-M-13 (n = 1), CTX-M-14 (n = 15), CTX-M-15 (n = 11), SHV-2 (n = 2), SHV-2a (n = 12), SHV-5 (n = 6), SHV-12 (n = 45), and SHV-30 (n = 2). Five novel beta-lactamases were identified and designated TEM-115 (n = 2), TEM-120 (n = 1), SHV-40 (n = 2), SHV-41 (n = 4), and SHV-42 (n = 1). In addition, no molecular mechanism was identified for five isolates displaying an ESBL phenotype. Macrorestriction analysis of all ESBL isolates was conducted, as was restriction fragment length polymorphism analysis of plasmids harboring ESBLs. Although a "clonal" distribution of isolates was observed at some individual sites, there was very little evidence suggesting intrahospital spread. In addition, examples of identical or closely related plasmids that were identified at geographically distinct sites across Canada are given. However, there was considerable diversity with respect to plasmid types observed.


Solvent Free Twin Screw Processed Silybin Nanophytophospholipid: In Silico, In Vitro and In Vivo Insights.
Silybin (SIL) is a polyphenolic phytoconstituent that is commonly used to treat liver disorders. It is difficult to fabricate an orally delivered SIL product due to its low oral bioavailability (0.95%). Therefore, the current research focusses on the development of a novel composition of a phospholipid complex, termed as nanophytophospholipid, of SIL by employing a unique, solvent-free Twin Screw Process (TSP), with the goal of augmenting the solubility and bioavailability of SIL. The optimised SIL-nanophytophospholipid (H6-SNP) was subjected to physicochemical interactions by spectrometry, thermal, X-ray and electron microscopy. The mechanism of drug and phospholipid interaction was confirmed by molecular docking and dynamics studies. Saturation solubility, in vitro dissolution, ex vivo permeation and preclinical pharmacokinetic studies were also conducted. H6-SNP showed good complexation efficiency, with a high practical yield (80%). The low particle size (334.7 ± 3.0 nm) and positively charged zeta potential (30.21 ± 0.3 mV) indicated the immediate dispersive nature of H6-SNP into nanometric dimensions, with good physical stability. Further high solubility and high drug release from the H6-SNP was also observed. The superiority of the H6-SNP was demonstrated in the ex vivo and preclinical pharmacokinetic studies, displaying enhanced apparent permeability (2.45-fold) and enhanced bioavailability (1.28-fold). Overall, these findings indicate that not only can phospholipid complexes be formed using solvent-free TSP, but also that nanophytophospholipids can be formed by using a specific quantity of lipid, drug, surfactant, superdisintegrant and diluent. This amalgamation of technology and unique composition can improve the oral bioavailability of poorly soluble and permeable phytoconstituents or drugs.


Increased expressions of SATB1 and S100A4 are associated with poor prognosis in human colorectal carcinoma.
This study was designed to explore the correlation between expressions of SATB1 and S100A4 and their relationships to the clinicopathologic parameters of colorectal carcinoma (CRC). Expressions of SATB1 and S100A4 were evaluated by immunohistochemistry in a cohort of 131 primary CRC patients undergone surgical resection from 2005 to 2007. SATB1 and S100A4 were positively expressed in 48.9% and 54.2% of CRC cases, respectively. SATB1 and S100A4 expressions in tumor tissues were significantly higher than those in the corresponding normal tissues. A positive correlation was observed between SATB1 and S100A4. Moreover, the levels of SATB1 and S100A4 were both significantly associated with invasion, lymph node status, and TNM stage of CRC, whereas S100A4 expression was also correlated with distant metastasis. Multivariate analysis revealed that SATB1 expression was an independent prognostic indicator for poor survival of CRC. Further survival analysis indicated that co-expression of SATB1 and S100A4 suggested a worse 5-year overall survival rate in CRC patients. Thus, combined analysis of SATB1 and S100A4 expressions may be valuable in determining the development and progression of CRC. Co-expression of SATB1 and S100A4 is an unfavorable prognostic indicator and may be useful in the follow-up of patients with CRC.


Biomechanical changes of the lumbar segment after total disc replacement : charite(r), prodisc(r) and maverick(r) using finite element model study.
The purpose of this study was to analyze the biomechanical effects of three different constrained types of an artificial disc on the implanted and adjacent segments in the lumbar spine using a finite element model (FEM). The created intact model was validated by comparing the flexion-extension response without pre-load with the corresponding results obtained from the published experimental studies. The validated intact lumbar model was tested after implantation of three artificial discs at L4-5. Each implanted model was subjected to a combination of 400 N follower load and 5 Nm of flexion/extension moments. ABAQUS version 6.5 (ABAQUS Inc., Providence, RI, USA) and FEMAP version 8.20 (Electronic Data Systems Corp., Plano, TX, USA) were used for meshing and analysis of geometry of the intact and implanted models. Under the flexion load, the intersegmental rotation angles of all the implanted models were similar to that of the intact model, but under the extension load, the values were greater than that of the intact model. The facet contact loads of three implanted models were greater than the loads observed with the intact model. Under the flexion load, three types of the implanted model at the L4-5 level showed the intersegmental rotation angle similar to the one measured with the intact model. Under the extension load, all of the artificial disc implanted models demonstrated an increased extension rotational angle at the operated level (L4-5), resulting in an increase under the facet contact load when compared with the adjacent segments. The increased facet load may lead to facet degeneration.


Simultaneous cutaneous melanoma and ipsilateral breast cancer with metastasis to the same axilla. A case report with a focus on a multidisciplinary approach.
Treatment of simultaneously occurring primary malignancies with separate lymphatic drainage is a surgical and medical challenge. We present a patient in which multidisciplinary management of coexisting melanoma and breast cancer was mandatory for optimal results. A 67-year-old female had a primary surgical resection for a skin lesion on the back. Histology revealed melanoma with a Breslow thickness of 4.8 mm. According to guidelines, a wide local excision was scheduled. Prior to the surgery, routine mammography revealed simultaneous ipsilateral breast cancer. A preoperative work-up revealed a pathological lymph node in the left axilla. Biopsies found metastasis from malignant melanoma. She had combined surgery with breast-conserving therapy, wide local excision of the skin on the back, and extended axillary clearance of levels I-III. Final histology revealed axillary metastases both from melanoma and breast cancer. Adjuvant therapy was decided based on a multidisciplinary approach. To our knowledge, cases of synchronous primary cutaneous melanoma with biopsy-verified axillary metastases and independent, ipsilateral primary breast carcinoma have not been described. The surgical approach was done according to guidelines. The breast cancer was re-staged based on the histology of the surgical specimen. Adjuvant treatment was a combination of treatment strategies for the two primary malignancies. This case highlights the need for a multidisciplinary approach in treating simultaneous breast cancer and melanoma both with axillary metastasis. The optimal treatment approach was based on close collaboration between surgeons, oncologists, radiologists, and pathologists. Multidisciplinary meetings are mandatory for optimal results.


Genetic recombination between Proteus mirabilis and Providencia alcalifaciens.
Chromosome transfer occurred in plate matings between Proteus mirabilis strain PM5006 and Providencia alcalifaciens strain P29 in either direction with the use of plasmid D or R772 as sex factor. Auxotrophic chromosomal markers of recipients were converted to prototrophy and the galactose fermentation marker of donor PM5006 could also be selected. Recombination frequencies for a group of selected markers in PM5006(D) x P29 matings varied between 3 x 10(-5) (trp+) and 1.2 x 10(-7) (lys+) per donor. In the reverse cross, plasmid D mobilized markers on the P29 chromosome randomly with a recombination frequency of about 1.7 x 10(-7) per donor for all selected P29 markers. R772 produced random mobilization of markers on both chromosomes yielding recombinants at a frequency of about 1.8 x 10(-7) per donor. Unselected markers separated by no more than about 10 min from selected markers on the PM5006 chromosome were cotransferred from P29 by both plasmids. Despite the low degree of DNA homology existing between the two species, all hybrids behaved as stable haploids. Progeny from P29(D or R772) x PM5006 auxotroph matings displayed similar sets of naturally occurring P29 unselected markers irrespective of the selected prototroph allele. In reverse crosses, a similar range of PM5006 naturally occurring unselected markers registered in P29 recipients, although differences existed in the sets of markers mediated by the two plasmids. Weak linkage was detected between PM5006 gal+ allele(s) and some P29 auxotroph markers. Adsorption of donor-specific phages 5006M or PL25 to hybrids could not be demonstrated and many recombinants failed to express some or all of the plasmid markers.


Volitional impairment and the sexually violent predator.
This article discusses psychiatry's limited conceptualization of volitional capacity and its application to sexually violent predator laws by exploring two legal opinions critical to predator case law (Kansas v. Hendricks and Kansas v. Crane). The author reviewed pertinent psychiatric literature on impaired volition to identify potential contributions and limitations that psychiatry may offer the legal field. Assessment of the ego dystonic nature of impaired self-regulation, utilization of recent advances in self-assessment and laboratory evaluation of impulsive behavior, and dimensional categorization of a volitional capacity construct are recommended as an approach to the assessment and understanding of an inability to control concept. This paper concludes that elements of volition may be psychiatrically evaluated in a way that contributes to the Court's understanding of that capacity. However, further study is needed to operationally define volitional capacity and address issues of assessment validity and reliability.


What influences patient decision-making in amyotrophic lateral sclerosis multidisciplinary care? A study of patient perspectives.
Patients with amyotrophic lateral sclerosis (ALS) are required to make decisions concerning quality of life and symptom management over the course of their disease. Clinicians perceive that patients' ability to engage in timely decision-making is extremely challenging. However, we lack patient perspectives on this issue. This study aimed to explore patient experiences of ALS, and to identify factors influencing their decision-making in the specialized multidisciplinary care of ALS. An exploratory study was conducted. Fourteen patients from two specialized ALS multidisciplinary clinics participated in semistructured interviews that were audio recorded and transcribed. Data were analyzed for emergent themes. Decision-making was influenced by three levels of factors, ie, structural, interactional, and personal. The structural factor was the decision-making environment of specialized multidisciplinary ALS clinics, which supported decision-making by providing patients with disease-specific information and specialized care planning. Interactional factors were the patient experiences of ALS, including patients' reaction to the diagnosis, response to deterioration, and engagement with the multidisciplinary ALS team. Personal factors were patients' personal philosophies, including their outlook on life, perceptions of control, and planning for the future. Patient approaches to decision-making reflected a focus on the present, rather than anticipating future progression of the disease and potential care needs. Decision-making for symptom management and quality of life in ALS care is enhanced when the patient's personal philosophy is supported by collaborative relationships between the patient and the multidisciplinary ALS team. Patients valued the support provided by the multidisciplinary team; however, their focus on living in the present diverged from the efforts of health professionals to prepare patients and their carers for the future. The challenge facing health professionals is how best to engage each patient in decision-making for their future needs, to bridge this gap.


Modeling cholesterol metabolism and atherosclerosis.
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among Western populations. Many risk factors have been identified for ASCVD; however, elevated low-density lipoprotein cholesterol (LDL-C) remains the gold standard. Cholesterol metabolism at the cellular and whole-body level is maintained by an array of interacting components. These regulatory mechanisms have complex behavior. Likewise, the mechanisms which underpin atherogenesis are nontrivial and multifaceted. To help overcome the challenge of investigating these processes mathematical modeling, which is a core constituent of the systems biology paradigm has played a pivotal role in deciphering their dynamics. In so doing models have revealed new insights about the key drivers of ASCVD. The aim of this review is fourfold; to provide an overview of cholesterol metabolism and atherosclerosis, to briefly introduce mathematical approaches used in this field, to critically discuss models of cholesterol metabolism and atherosclerosis, and to highlight areas where mathematical modeling could help to investigate in the future. This article is categorized under: Cardiovascular Diseases > Computational Models.