Automation of gene assignments to metabolic pathways using high-throughput expression data.
Accurate assignment of genes to pathways is essential in order to understand the functional role of genes and to map the existing pathways in a given genome. Existing algorithms predict pathways by extrapolating experimental data in one organism to other organisms for which this data is not available. However, current systems classify all genes that belong to a specific EC family to all the pathways that contain the corresponding enzymatic reaction, and thus introduce ambiguity. Here we describe an algorithm for assignment of genes to cellular pathways that addresses this problem by selectively assigning specific genes to pathways. Our algorithm uses the set of experimentally elucidated metabolic pathways from MetaCyc, together with statistical models of enzyme families and expression data to assign genes to enzyme families and pathways by optimizing correlated co-expression, while minimizing conflicts due to shared assignments among pathways. Our algorithm also identifies alternative ("backup") genes and addresses the multi-domain nature of proteins. We apply our model to assign genes to pathways in the Yeast genome and compare the results for genes that were assigned experimentally. Our assignments are consistent with the experimentally verified assignments and reflect characteristic properties of cellular pathways. We present an algorithm for automatic assignment of genes to metabolic pathways. The algorithm utilizes expression data and reduces the ambiguity that characterizes assignments that are based only on EC numbers.


Implanted transmitter in maxilla: real or imaginary?
A case report is given of a patient who came to the oral surgery office apparently in pain, but was referred by her general practitioner dentist for an evaluation of a root fragment. The periapical radiograph revealed a "filament" type opacity in the upper right canine area. It was explained to the patient, who opted for its removal. Although, the removed material appeared to be dental amalgam fragments, the patient insisted that it was a transmitter implanted by her gynecologist. The patient was referred for psychiatric therapy but only went for one visit. The tentative diagnosis was schizophrenia.


Machine Learning to Improve Orientation Estimation in Sports Situations Challenging for Inertial Sensor Use.
In sports, inertial measurement units are often used to measure the orientation of human body segments. A Madgwick (MW) filter can be used to obtain accurate inertial measurement unit (IMU) orientation estimates. This filter combines two different orientation estimates by applying a correction of the (1) gyroscope-based estimate in the direction of the (2) earth frame-based estimate. However, in sports situations that are characterized by relatively large linear accelerations and/or close magnetic sources, such as wheelchair sports, obtaining accurate IMU orientation estimates is challenging. In these situations, applying the MW filter in the regular way, i.e., with the same magnitude of correction at all time frames, may lead to estimation errors. Therefore, in this study, the MW filter was extended with machine learning to distinguish instances in which a small correction magnitude is beneficial from instances in which a large correction magnitude is beneficial, to eventually arrive at accurate body segment orientations in IMU-challenging sports situations. A machine learning algorithm was trained to make this distinction based on raw IMU data. Experiments on wheelchair sports were performed to assess the validity of the extended MW filter, and to compare the extended MW filter with the original MW filter based on comparisons with a motion capture-based reference system. Results indicate that the extended MW filter performs better than the original MW filter in assessing instantaneous trunk inclination (7.6 vs. 11.7° root-mean-squared error, RMSE), especially during the dynamic, IMU-challenging situations with moving athlete and wheelchair. Improvements of up to 45% RMSE were obtained for the extended MW filter compared with the original MW filter. To conclude, the machine learning-based extended MW filter has an acceptable accuracy and performs better than the original MW filter for the assessment of body segment orientation in IMU-challenging sports situations.


[Transrectal microwave hyperthermia in the treatment of chronic prostatitis].
The efficacy of transrectal microwave hyperthermia (TMH) was investigated in 124 patients aged 20 to 55 years. Of them, 75 (60.5%) patients had chronic noninfectious and 49 (39.5%) patients infectious prostatitis. In addition to standard pre- and posttreatment examinations the following tests were made: bacteriological and biochemical tests of prostatic secretion, uroflowmetry, transrectal color Dopplerographic mapping. The course of the treatment included 10 one-hour sessions of microwave hyperthermia, drug therapy and prostatic massage. Patients with both forms of chronic prostatitis exhibited disorders of prostatic circulation, activated lipid peroxidation, low concentration of catalase in the organ secretion, defective urodynamics of the lower urinary tracts. More pronounced changes occurred in noninfectious process. Microwave hyperthermia produced clinical improvement, recovery of hemodynamics in the prostate, structure and function of cell membranes in prostatic secretion, positive response of urodynamics. Thus, TMH generated on domestic equipment can be considered as one of the methods of pathogenetically sound treatment of noninfectious and infectious chronic prostatitis.


Steffimycin E, a new anti-mycobacterial agent against Mycobacterium avium complex, produced by Streptomyces sp. OPMA02852.
The marine actinomycete strain OPMA02852, identified as the genus Streptomyces, was found to produce anti-mycobacterial compounds against Mycobacterium avium complex (MAC). One new compound, designated as steffimycin E (1), was isolated together with three known steffimycins (steffimycin (2), 10-dihydrosteffimycin (3), and 8-demethoxysteffimycin (4)) from the culture broth of this producing microorganism by solvent extraction, ODS column chromatography, and preparative HPLC. Compound 1 has a tetracyclic quinone structure with a sugar moiety. Compound 1 exhibited anti-mycobacterial activity against M. intracellulare, M. bovis BCG, and M. smegmatis.


Insulin and IGF-1 mediated inhibition of apoptosis in CHO cells grown in suspension in a protein-free medium.
When Chinese hamster ovary (CHO) cells were grown in suspension and deprived of serum, 40% of them became apoptotic after 72 hours, as determined by flow cytometry analysis of TUNEL-labelled cells. Cell viability, assessed by erythrocin B staining, decreased correspondingly. An increase in the total fraction of cells expressing interleukin converting enzyme (ICE; caspase 1), B-cell lymphoma 2 protein (Bcl-2,) and Bcl-2 associated x protein (Bax) was shown by antibody probing and subsequent flow cytometry. The p53 tumour suppressor gene product level remained low within the cell population. Insulin-like growth factor-1 (IGF-1) inhibited cell death in a concentration-dependent manner, and at 20 ng/ml, cell viability was maintained close to 100% and no apoptotic cells were detected. Also, insulin was shown to inhibit cell death - at 1.0 microg/ml, cell viability was 95%, whereas 10% of the cells stained for apoptosis. At the highest concentrations of IGF-1 and insulin, the expression of ICE, Bcl-2 and Bax was fully suppressed, whereas the p53 product level increased, despite still being detectable in a minority of cells. Under these conditions, IGF-1 may increase p53 expression to restrain abnormal cell proliferation. It is concluded that special attention should be paid to exposure and culture conditions that induce acquired susceptibility to a toxic insult, during the development and validation of cell-based assays.


Food Insecurity, Adolescent Suicidal Thoughts and Behaviors, and Country-Level Context: A Multi-Country Cross-Sectional Analysis.
Preventing adolescent suicide is a global priority. Inequalities in adolescent suicide and attempt rates are reported across countries, including a greater risk in adolescents experiencing food insecurity. Little is known about the extent to which country-level contextual factors moderate the magnitude of socio-economic inequalities in suicidal thoughts and behavior. We aimed to examine the cross-country variability and national moderators of the association between food insecurity and suicidal thoughts and behavior in school-attending adolescents. We analysed data on 309,340 school-attending adolescents from 83 countries that participated in the Global School-based Student Health Survey between 2003 and 2018. We used Poisson regression to identify whether suicidal thoughts and behavior were more prevalent in adolescents experiencing food insecurity compared to food-secure adolescents. Meta-regression and mixed-effects regression were used to determine whether country-level indicators moderated the magnitude of inequality. Suicidal ideation, suicide planning, and suicide attempts were more prevalent in food-insecure adolescents compared to food-secure adolescents in 72%, 78%, and 90% of countries respectively; however, the magnitude of these associations varied between countries. We observed wider inequalities in countries with greater levels of national wealth and universal health coverage and lower prevalence of adolescent food insecurity. Economic inequality had no moderating role. Food insecurity could contribute to the development of adolescent suicidal thoughts and behavior, and this association is likely to be moderated by country-level context. Food insecurity may be a modifiable target to help prevent adolescent suicide, especially in countries where food insecurity is less common.


Adenosine-A2a receptor down-regulates cerebral smooth muscle L-type Ca2+ channel activity via protein tyrosine phosphatase, not cAMP-dependent protein kinase.
Adenosine acting via A2a receptors (A2aR) is a potent cerebral vasodilator that relaxes vascular smooth muscle cells (VSMCs) by a mechanism attributed to activation of cAMP-dependent protein kinase (cAK). We examined effects of adenosine and its mechanism of action on L-type Ca2+ channels in native VSMCs from rat basilar artery. Reverse transcription-polymerase chain reaction and immunofluorescence imaging confirmed transcription and expression of A2aR, and in situ hybridization confirmed presence of mRNA for L-type Cav1.2b channels. In patch-clamp experiments, adenosine down-regulated Ca2+ channel currents in a concentration-dependent manner, with receptor-subtype-specific antagonists [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) versus 1,3-dipropyl-8-cyclopentyl-1,3-dipropylxanthine] showing that this was caused by action of A2aR. Down-regulation of channel currents was mimicked by stimulation of cGMP-dependent protein kinase (cGK; 8-Br-cGMP) and by inhibition of tyrosine kinase (AG-18) but not by stimulation of cAK [forskolin and 8-bromo-cAMP (8-Br-AMP)]. Down-regulation of currents by the A2aR agonist 2-[p-(2-carboxyeth yl)phenylethylamino]-5'-N-ethyolcarboxamidoadenosine (CGS-21680) was blocked by inhibiting protein tyrosine phosphatase (PTP; orthovanodate and dephostatin), but not by inhibiting cGK (KT-5823 and H-7). Western blots of lysate or of immunoisolated Ca2+ channels from arterial segments incubated with CGS-21680 showed 1) increased phosphorylation of vasodilator-stimulated phosphoprotein that was blocked by inhibiting cAK (KT-5720), consistent with activation of cAK by A2aR; and 2) decreased tyrosine phosphorylation of immunoisolated alpha1c subunit of the Ca2+ channel. Our data show that cAK, although activated, was not germane to down-regulation of Ca2+ channel activity by A2aR, and they delineate a novel signaling mechanism involving reduced tyrosine phosphorylation of Ca2+ channels by A2aR probably caused by PTP activation.


Robust pose estimation.
Standard least-squares (LS) methods for pose estimation of objects are sensitive to outliers which can occur due to mismatches. Even a single mismatch can severely distort the estimated pose. This paper describes a least-median of squares (LMedS) approach to estimating pose using point matches. It is both robust (resistant to up to 50% outliers) and efficient (linear in the number of points). The basic algorithm is then extended to improve performance in the presence of two types of noise: 1) type I which perturbs all data values by small amounts (e.g., Gaussian) and 2) type II which can corrupt a few data values by large amounts.


(Bio)electrochemical ammonia recovery: progress and perspectives.
In recent years, (bio)electrochemical systems (B)ES have emerged as an energy efficient alternative for the recovery of TAN (total ammonia nitrogen, including ammonia and ammonium) from wastewater. In these systems, TAN is removed or concentrated from the wastewater under the influence of an electrical current and transported to the cathode. Subsequently, it can be removed or recovered through stripping, chemisorption, or forward osmosis. A crucial parameter that determines the energy required to recover TAN is the load ratio: the ratio between TAN loading and applied current. For electrochemical TAN recovery, an energy input is required, while in bioelectrochemical recovery, electric energy can be recovered together with TAN. Bioelectrochemical recovery relies on the microbial oxidation of COD for the production of electrons, which drives TAN transport. Here, the state-of-the-art of (bio)electrochemical TAN recovery is described, the performance of (B)ES for TAN recovery is analyzed, the potential of different wastewaters for BES-based TAN recovery is evaluated, the microorganisms found on bioanodes that treat wastewater high in TAN are reported, and the toxic effect of the typical conditions in such systems (e.g., high pH, TAN, and salt concentrations) are described. For future application, toxicity effects for electrochemically active bacteria need better understanding, and the technologies need to be demonstrated on larger scale.


Synthesis of the European ALARA network 18th workshop 'ALARA for decommissioning and site remediation'.
The European ALARA Network regularly organises workshops on topical issues in radiation protection. The topic of the 18th workshop was 'ALARA for Decommissioning and Site Remediation'. The workshop was jointly organised with the ISOE Working Group on Decommissioning (ISOE WG-DECOM) and the French Atomic Alternatives Energy and Atomic Energy Commission (CEA). The main objective was to examine the conceptual and practical aspects of the implementation of the optimisation principle (or ALARA principle) in the 'nuclear' and 'non-nuclear' sectors and also for legacy sites. This memorandum presents a synthesis of the presentations and working groups discussion that took place. It also summaries the conclusions from former EAN workshops on the same topic (1997, 2006) to highlight the commonalities and the new topics. The theoretical scheme for applying the ALARA principle is illustrated by the various presentations of decommissioning and remediation (D&R) projects given at the workshop. The theoretical scheme includes, a starting point, the planning and implementation of the D&R strategy (including ALARA analysis) and the definition of an end-state. To lay down the foundations of ALARA, the initial characterisation should be comprehensive; considering not only radiation protection but other risks and circumstances both on site and off site. Decision-making is not trivial because many factors influence the D&R strategy and they can be addressed together using an holistic approach. A general methodology for such an approach in D&R was drafted by the participants. Techniques are apparently industrially mature and dosimetric data suggest that good control has been achieved, however experience shows that the D&R strategy will go through multiple adaptations along the way. The management of wastes remains a challenge in many cases as well as the decision on the end-state leading to question of what is a 'sustainable ALARA end-state?'.


Carbon Dioxide to Methanol: The Aqueous Catalytic Way at Room Temperature.
Carbon dioxide may constitute a source of chemicals and fuels if efficient and renewable processes are developed that directly utilize it as feedstock. Two of its reduction products are formic acid and methanol, which have also been proposed as liquid organic chemical carriers in sustainable hydrogen storage. Here we report that both the hydrogenation of carbon dioxide to formic acid and the disproportionation of formic acid into methanol can be realized at ambient temperature and in aqueous, acidic solution, with an iridium catalyst. The formic acid yield is maximized in water without additives, while acidification results in complete (98 %) and selective (96 %) formic acid disproportionation into methanol. These promising features in combination with the low reaction temperatures and the absence of organic solvents and additives are relevant for a sustainable hydrogen/methanol economy.


A comparison of cerebral activity in the prefrontal region between young adults and the elderly while driving.
The purpose of this study is to investigate the difference of cerebral activity in the prefrontal region between young adults and elderly subjects during driving. The procedure of the experiment was explained to the subjects and informed consent was obtained. Fourteen young male adults (21.6+/-0.76 yrs), seven elderly males (69.9+/-4.91 yrs), and seven elderly females (66.6+/-6.02 yrs) volunteered as subjects for the experiments. Non-invasive measurement of regional cerebral activity was estimated by measuring the deoxygenated hemoglobin, oxygenated hemoglobin, and total hemoglobin of both sides of the prefrontal region using near-infrared spectroscopy (NIRS) and time-resolved spectroscopy (TRS). The distance to the vehicle in front, speed, and braking were recorded and the behavior of the drivers was obtained using a CCD camera and video recorder. Temperature and relative humidity in the experimental car were 23-25 degrees Centigrade and 30-40%RH respectively. Background noise in the car was 50-65 dB (A). The less experienced young adults display a greater increase in prefrontal cerebral activity than do the experienced young adults during driving. Prefrontal cerebral activity in elderly subjects is lower than that in young adults at rest and shows little variation compared with young adults during driving. Less experienced young adults and elderly males display similar behavior patterns in driving, such as not observing the door mirror carefully when changing lane. The less experienced young adults are considered to be less adapted to driving. It is possible to evaluate adaptability for driving by means of measuring cerebral hemodynamic changes while driving.


Autism Narratives in Media Coverage of the MMR Vaccine-Autism Controversy under a Crip Futurism Framework.
While previous studies in health communication have examined online news media regarding autism, there is a lack of research that critically examines how such media representations may stigmatize autism and seeks to eliminate the condition, particularly in the context of the resurging measles, mumps, and rubella (MMR) vaccine-autism controversy. To address this gap in the literature, this study analyzes 153 articles that engage the MMR vaccine-autism controversy from the top 10 online news sources in the U.S. from September 2015 through July 2017. It draws from Kafer's (2013) work in Feminist, Crip, Queer, using a lens of crip futurism to interpret three major narrative themes: a death and survival narrative that purports autism as a worst-case scenario, a societal problem narrative, and a preventative narrative that seeks to eliminate the condition. These themes suggest that online news media narratives about autism surrounding the autism-MMR controversy play into stereotypes about autism, including stigmatization and prioritization of preventive behaviors and cures over supporting the lived experiences of autistic individuals. Continued research on the impact of online media portrayals of autism specifically, and disability in health contexts generally, is called for.


Retailer-led healthy pricing interventions: a pilot study within aquatic and recreation centres in Victoria, Australia.
This study aimed to pilot the feasibility, acceptability and effectiveness of three co-developed healthy food and beverage pricing interventions in a community retail setting. Aquatic and recreation centres in Victoria, Australia were recruited to co-develop and pilot pricing interventions within their onsite cafés, for 15 weeks from January 2019. A mixed method intervention evaluation was conducted. Interviews were conducted with food retail managers to understand the factors perceived to influence implementation, maintenance and effectiveness. Customer surveys assessed support for, and awareness of, interventions. Interrupted time series analysis estimated the impact of pricing interventions on food and beverage sales. Three centres each implemented a unique intervention: (i) discounted healthy bundles ('healthy combination deals'), (ii) offering deals at specific times of the day ('healthy happy hours') and (iii) increasing the prices of selected unhealthy options and reducing the prices of selected healthier options ('everyday pricing changes'). Café team leaders did not identify any significant challenges to implementation or maintenance of interventions, though low staff engagement was identified as potentially influencing the null effect on sales for healthy combination deals and healthy happy hours interventions. Customers reported low levels of awareness and high levels of support for interventions. Everyday pricing changes resulted in a significant decrease in sales of unhealthy items during the intervention period, though also resulted in a decrease in café revenue. Co-developed healthy food and beverage pricing interventions can be readily implemented with broad customer support. Everyday pricing changes have demonstrated potential effectiveness at reducing unhealthy purchases.


Exploring the potential for Ross River virus emergence in New Zealand.
Ross River virus (RRV) is an exotic vector-borne disease considered highly likely to emerge as a future human health issue in New Zealand, with its range expansion from Australia being driven by exotic mosquito introduction and improving conditions for mosquito breeding. We investigated our ability to assess the potential for such emergence using deterministic modeling and making preliminary predictions based on currently available evidence. Although data on actual mosquito densities (as opposed to indices) were identified as a need for predictions to be made with greater confidence, this approach generated a contrasting prediction to current opinion. Only limited potential for RRV emergence in New Zealand was predicted, with outbreaks in the human population more likely of concern in urban areas (mainly should major exotic vectors of the virus establish). The mechanistic nature of the model also allowed the understanding that if such outbreaks do occur, they will most likely be driven by virus amplification in dense human populations (as opposed to the spillover infection from wildlife common in Australia). With implications for biosecurity and health care resource allocation, modeling approaches such as that employed here have much to offer both for disease emergence prediction and surveillance strategy design.


Delineation of immunodominant and cytadherence segment(s) of Mycoplasma pneumoniae P1 gene.
Adhesion of Mycoplasma pneumoniae (M. pneumoniae) to host epithelial cells requires several adhesin proteins like P1, P30 and P116. Among these proteins, P1 protein has been inedited as one of the major adhesin and immunogenic protein present on the attachment organelle of M. pneumoniae. In the present study, we scanned the entire sequence of M. pneumoniae P1 protein to identify the immunodominant and cytadherence region(s). M. pneumoniae P1 gene was synthesized in four segments replacing all the UGA codons to UGG codons. Each of the four purified P1 protein fragment was analyzed for its immunogenicity with anti-M. pneumoniae M129 antibodies (Pab M129) and sera of M. pneumoniae infected patients by western blotting and ELISA. Antibodies were produced against all the P1 protein fragments and these antibodies were used for M. pneumoniae adhesion, M. pneumoniae adhesion inhibition and M. pneumoniae surface exposure assays using HEp-2 cells lines. Our results show that the immunodominant regions are distributed throughout the entire length of P1 protein, while only the N- and C- terminal region(s) of P1 protein are surface exposed and block cytadhesion to HEp-2 cells, while antibodies to two middle fragments failed to block cytadhesion. These results have important implications in designing strategies to block the attachment of M. pneumoniae to epithelial cells, thus preventing the development of atypical pneumonia.


Synergistic anti-tumor effect of 13-cRA and IFN-alpha/beta in mouse renal cell carcinoma.
The synergistic anti-tumor effect of 13-cis retinoic acid (13-cRA) and interferon-alpha/beta (IFN-alpha/beta) was investigated using a highly metastatic mouse renal cell carcinoma cell subline (RenCa/F). Although 13-cRA inhibited tumor growth in vivo as well as in vitro, IFN-alpha/beta did not. Combined administration of 13-cRA and IFN-alpha/beta significantly enhanced the anti-tumor effect of 13-cRA. The retinoic acid receptor (RAR)-alpha and RAR-gamma were expressed in RenCa/F cells. Treatment with IFN-alpha/beta did not influence the expression level of these receptors at the mRNA level, which suggests that the synergism of 13-cRA and IFN-alpha/beta is not mediated through the RAR.


Characterization of CrgA, a new partner of the Mycobacterium tuberculosis peptidoglycan polymerization complexes.
The role(s) in cell division of the Mycobacterium tuberculosis Rv0011c gene product, a homolog of the Streptomyces CrgA protein that is responsible for coordinating growth and cytokinesis in sporogenic aerial hyphae, is largely unknown. We show that an enhanced cyan fluorescent protein-M. tuberculosis CrgA (ECFP-CrgA(MT)) fusion protein is localized to the cell membrane, midcell, and cell pole regions in Mycobacterium smegmatis. Furthermore, the ECFP-CrgA(MT) fusion protein colocalized with FtsZ-enhanced yellow fluorescent protein (EYFP) in M. smegmatis. Bacterial two-hybrid assays indicated strong interactions of M. tuberculosis CrgA with FtsZ, FtsQ, and the class B penicillin-binding proteins, FtsI (PBPB) and PBPA. The midcell localization of CrgA(MT) was severely compromised under conditions of FtsZ depletion, which indicated that CrgA localizes to the midcell region after assembly of the FtsZ ring. M. tuberculosis cells with reduced CrgA levels were elongated and grew more slowly than wild-type cells, which indicated defects in cell division, whereas CrgA overproduction did not show growth defects. A M. smegmatis ΔcrgA strain exhibited a bulged cell morphology, elongated cells with a chain-like phenotype, cells with polar bulbous structures, and a modest growth defect. FtsZ and FtsI levels were not affected in cells producing altered levels of CrgA. Septal and membrane localization of GFP-FtsI was enhanced by CrgA overproduction and was diminished in a ΔcrgA strain, which indicates that one role of CrgA is to promote and/or stabilize FtsI localization. Overall, these data indicate that CrgA is a novel member of the cell division complex in mycobacteria and possibly facilitates septum formation.


The perception of humans by piglets: recognition of familiar handlers and generalisation to unfamiliar humans.
Humans are part of the environment of domestic animals and interact with them daily, providing a good basis for the study of interspecific relationships. Abilities to discriminate and recognise individuals form the basis of these relationships, and they are crucial skills for domestic animals, since individual humans can differ in their behaviour towards them. At the same time, with experience, animals may develop a general memory of humans and generalise their behaviour towards strangers. This study aimed to determine the extent to which weaned piglets can discriminate familiar humans and generalise their past experience when faced with unfamiliar humans. Forty-eight groups of three piglets were submitted to two consecutive 5-day conditioning periods of the same or opposite valence (positive and/or negative) given by one (A) or two (A then B) handlers. The reactivity of piglets to a motionless human and to an approaching human was measured before and after conditioning periods with unfamiliar and familiar handlers. Thereafter, piglets which received treatments with the two handlers A and B were subjected to a choice test between both handlers. The reactivity to an approaching human appeared to better reflect the past experience with familiar handlers since piglets clearly recognised them and adapted their behaviour accordingly. In contrast, reaction of piglets to a motionless human reflected their natural propensity to seek interaction, even after a negative experience. Although piglets were able to extend their memory of humans to an unfamiliar human through generalisation, many factors seemed to interact in this process, especially the complexity of the previous experience (inconsistent vs consistent) and the context in which piglets met the unfamiliar human (motionless vs approaching). We conclude that discrimination and generalisation processes of reactivity to humans do not simply rely on past interactions, but also depend on the context according to the degree of similitude with their past experience.


Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats.
To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer. Isometric tension was recorded. Cumulative concentration-response curves were obtained for (+)-cis-dioxolane (cD), a nonspecific muscarinic agonist, at 10(-8)-10(-4) mol/L, in the presence of tetrodotoxin (TTX, 10(-7) mol/L). Results were normalized to cross sectional area. A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1 (pirenzepine), M2 (methoctramine) and M3 (darifenacin) muscarinic receptor subtypes. The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment. The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. A dose-dependent contractile response observed with bethanechol, was not affected by TTX. The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol. Lack of calcium as well as the presence of the L-type calcium channel blocker, nifedipine, also inhibited the cholinergic contraction, with a reduction in response from 2.5+/-0.4 g/mm2 to 1.2+/-0.4 g/mm(2) (P<0.05). The dose-response curves were shifted to the right by muscarinic antagonists in the following order of affinity: darifenacin (M(3))>methocramine (M(2)) >pirenzepine (M(1)). The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s) involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels. The presence of the residual contractile response after the treatment with nifedipine, suggests that an additional pathway could mediate the cholinergic contraction. The involvement of more than one muscarinic receptor (functionally predominant type 3 over type 2) also suggests more than one pathway mediating the cholinergic contraction in rat antrum.


Lemierre's syndrome.
Lemierre's syndrome is a rare and potentially life-threatening condition that follows an oropharyngeal infection, typically from Fusobacterium necrophorum, and usually affects healthy adolescents or young adults. The characteristic features are septic thrombophlebitis of the internal jugular vein and septic embolism leading to multiorgan involvement, commonly the brain, lungs and bones. We report a man with presenting symptoms suggesting hemicrania continua, whose initial imaging showed no features of dural venous sinus or jugular thrombosis. Two weeks later, he had fever, sore throat, cervical lymphadenopathy and Actinomyces meyeri grew from peripheral blood cultures. Further imaging identified thrombosis of the internal jugular vein and cerebral venous sinuses, with multifocal cavitating lung lesions. Following antibiotics and anticoagulation, he recovered without residual deficits. Lemierre's syndrome when recognised and treated early has a good prognosis but delayed treatment may result in significant morbidity or mortality.


Development of multigene expression signature maps at the protein level from digitized immunohistochemistry slides.
Molecular classification of diseases based on multigene expression signatures is increasingly used for diagnosis, prognosis, and prediction of response to therapy. Immunohistochemistry (IHC) is an optimal method for validating expression signatures obtained using high-throughput genomics techniques since IHC allows a pathologist to examine gene expression at the protein level within the context of histologically interpretable tissue sections. Additionally, validated IHC assays may be readily implemented as clinical tests since IHC is performed on routinely processed clinical tissue samples. However, methods have not been available for automated n-gene expression profiling at the protein level using IHC data. We have developed methods to compute expression level maps (signature maps) of multiple genes from IHC data digitized on a commercial whole slide imaging system. Areas of cancer for these expression level maps are defined by a pathologist on adjacent, co-registered H&E slides, allowing assessment of IHC statistics and heterogeneity within the diseased tissue. This novel way of representing multiple IHC assays as signature maps will allow the development of n-gene expression profiling databases in three dimensions throughout virtual whole organ reconstructions.


Gene expression modulation by chalcopyrite and bornite in Acidithiobacillus ferrooxidans.
Acidithiobacillus ferrooxidans is a mesophilic, acidophilic, chemolithoautotrophic bacterium that obtains energy from the oxidation of ferrous iron (Fe2+), elemental sulfur and reduced sulfur compounds. The industrial interest in A. ferrooxidans resides in its capacity to oxidize insoluble metal sulfides into soluble metal sulfates, thus allowing the recovery of the desired metals from low-grade sulfide ores. In the present work, RNA arbitrarily primed PCR (RAP-PCR) was performed to identify cDNAs differentially expressed in A. ferrooxidans cells grown in the presence of Fe2+ and cells maintained for 24 h in the presence of the copper sulfides bornite and chalcopyrite. Eighteen cDNAs corresponding to genes with known function were identified, and their relative expression was further characterized by real-time quantitative PCR. Bornite had a mild effect on the expression of the 18 genes analyzed. None of these genes was down-regulated and among the few genes up-regulated, it is worth mentioning lepA and def-2 that are involved in protein synthesis. Chalcopyrite presented the most significant changes. Five genes related to protein processing were down-regulated, and another 5 genes related to the transport system were up-regulated. The up- and down-regulation of these genes in the presence of bornite and chalcopyrite could be due to alterations in the ideal pH, presence of copper ions in solution and nutrient limitation. The results suggest that gene expression modulation might be important for the A. ferrooxidans early response to copper sulfides.


Natural products against acute respiratory infections: Strategies and lessons learned.
A wide variety of traditional herbal remedies have been used throughout history for the treatment of symptoms related to acute respiratory infections (ARIs). The present work provides a timely overview of natural products affecting the most common pathogens involved in ARIs, in particular influenza viruses and rhinoviruses as well as bacteria involved in co-infections, their molecular targets, their role in drug discovery, and the current portfolio of available naturally derived anti-ARI drugs. Literature of the last ten years was evaluated for natural products active against influenza viruses and rhinoviruses. The collected bioactive agents were further investigated for reported activities against ARI-relevant bacteria, and analysed for the chemical space they cover in relation to currently known natural products and approved drugs. An overview of (i) natural compounds active in target-based and/or phenotypic assays relevant to ARIs, (ii) extracts, and (iii) in vivo data are provided, offering not only a starting point for further in-depth phytochemical and antimicrobial studies, but also revealing insights into the most relevant anti-ARI scaffolds and compound classes. Investigations of the chemical space of bioactive natural products based on principal component analysis show that many of these compounds are drug-like. However, some bioactive natural products are substantially larger and have more polar groups than most approved drugs. A workflow with various strategies for the discovery of novel antiviral agents is suggested, thereby evaluating the merit of in silico techniques, the use of complementary assays, and the relevance of ethnopharmacological knowledge on the exploration of the therapeutic potential of natural products. The longstanding ethnopharmacological tradition of natural remedies against ARIs highlights their therapeutic impact and remains a highly valuable selection criterion for natural materials to be investigated in the search for novel anti-ARI acting concepts. We observe a tendency towards assaying for broad-spectrum antivirals and antibacterials mainly discovered in interdisciplinary academic settings, and ascertain a clear demand for more translational studies to strengthen efforts for the development of effective and safe therapeutic agents for patients suffering from ARIs.


Occurrence and characterisation of Salmonella enterica subspecies diarizonae serovar 61: k: 1, 5, (7) in sheep in the federal state of Thuringia, Germany.
The occurrence of Salmonella enterica subspecies diarizonae serovar 61: k: 1, 5, (7) (SASd) and other Salmonella organisms in sheep in the German federal state of Thuringia was examined for the first time. Pooled faecal samples from 90 flocks located in this state were monitored. Only SASd was detected in 74 (82.2%) out of the 90 sheep herds, other Salmonella serovars were not identified. A positive correlation was found between the flock size and the detection probability of SASd. Despite the agent's high prevalence, clinical symptoms of a disease exclusively due to SASd have not been observed. The SASd strains were characterised by macrorestriction analysis, antimicrobial testing and the biochemical profile. All strains were sensitive to 13 out of 14 antimicrobial substances and resistant to only sulfamethoxazole. The high number of macrorestriction groups of SASd strains indicated a low clonality of the serovar. Data from sheep derived foods and public health data in Germany strongly suggest that the significance of SASd for public health is considerably lower than that of serovars belonging to Salmonella enterica subspecies enterica. For this reason and because of the low disease-causing potential of SASd in sheep, it is worthwile to consider a reduction in ongoing activities from combating to monitoring serovar 61: k: 1, 5, (7) in the sheep population.


Femoral neck fracture fixation. Clinical decision making.
Femoral neck fractures continue to pose significant decision making problems for the busy practitioner. Indirect factors over which the orthopaedic surgeon has little control include the patient's preinjury medical status, metabolic bone quality, and fracture classification. Direct factors that fall on the decision making ability of the surgeon include surgical timing, capsular hematoma, quality of reduction, and mechanics of fixation. Early, rigid anatomic reduction with 6.5-mm compression screws in patients with few comorbidities will achieve the optimum outcomes using fixation techniques. Anterolateral open approaches afford capsular hematoma decompression and anatomic access for fixation in the young or irreducible fracture pattern.


Determining optimal risk retention in the healthcare industry.
Several methodologies may be used for determining the level of risk that a healthcare organization should retain as part of its overall insurance and risk management program. Approaches used in the past, however, may not be appropriate to use in the 1990s. This article proposes a more comprehensive methodology of risk determination.


Human lactational and ovarian response to endogenous prolactin release.
Radioimmunoassayable prolactin rises in postpartum women during nursing and after intravenous thyrotropin-releasing hormone (TRH). Prolactin release induced by TRH can be dissociated from the postsuckling response. In addition to this, increases in endogenous prolactin secretion are followed by marked breast engorgement and milk letdown, especially after intravenous TRH. In this group of breast-feeding women, vaginal smears remained atrophic even up to 410 postpartum days. Prolactin appears to influence the production of breast milk, and the maintenance of a regular nursing pattern seems to promote the maintenance of ovarian unresponsiveness to circulating gonadotropins.


The role of periodic mortality case review sessions in a primary care teaching clinic.
Maintaining a death register and holding staff discussions about patients who died can aid the physician in audit and research, which will lead to improved care of the terminally ill and the bereaved and to the development of prevention strategies. These issues are important for students and residents as well. To review the value of mortality-case discussions in primary care clinics, particularly teaching clinics. The clinic death register, instituted in 1998, includes age, gender, cause of death, place of death, relevant illnesses, and support provided to the patient before the death. In the half-yearly sessions, the data are reviewed, and individual cases that had an emotional impact on the staff, or information that can bring about changes in future care are discussed by the clinic staff and trainees. In our clinic 233 deaths occurred during a 6 year period (1998-2003). The crude all-cause mortality rate was 7.1/1000. The median age was 80 years old. Neoplastic causes were slightly more frequent than cardiovascular causes of death. Only 15% died at home; 20% lived alone and 70% lived with a spouse or family members before the death. Topics discussed in the mortality review meetings include identifying pre-suicidal patients, when to hospitalize the sick elderly, dealing with the anger of bereaved families, and ensuring proper home care for terminal patients. We recommend keeping a death register and conducting mortality review sessions in order to improve the quality of care, emotional support of the staff, and training students and residents about the complex issues surrounding the death of patients.


Serological response to Helicobacter pylori infection among Latin American populations with contrasting risks of gastric cancer.
Gastric cancer is a rare outcome of chronic Helicobacter pylori infection. Serologic profiles may reveal bacterial, environmental and/or host factors associated with cancer risk. We therefore compared specific anti-H. pylori antibodies among populations with at least twofold differences in gastric cancer mortality from Mexico, Colombia and Chile. Our study included 1,776 adults (mean age 42 years) from three nationally representative surveys, equally divided between residents of high- and low-risk areas. Antibodies to 15 immunogenic H. pylori antigens were measured by fluorescent bead-based multiplex assays; results were summarized to identify overall H. pylori seropositivity. We used logistic regression to model associations between antibody seroreactivity and regional cancer risk (high vs. low), adjusting for country, age and sex. Both risk areas had similar H. pylori seroprevalence. Residents in high- and low-risk areas were seroreactive to a similar number of antigens (means 8.2 vs. 7.9, respectively; adjusted odds ratio, OR: 1.02, p = 0.05). Seroreactivities to Catalase and the known virulence proteins CagA and VacA were each significantly (p < 0.05) associated with residence in high-risk areas, but ORs were moderate (1.26, 1.42 and 1.41, respectively) and their discriminatory power was low (area under the curve < 0.6). The association of Catalase was independent from effects of either CagA or VacA. Sensitivity analyses for antibody associations restricted to H. pylori-seropositive individuals generally replicated significant associations. Our findings suggest that humoral responses to H. pylori are insufficient to distinguish high and low gastric cancer risk in Latin America. Factors determining population variation of gastric cancer burden remain to be identified.


An iterative approach of protein function prediction.
Current approaches of predicting protein functions from a protein-protein interaction (PPI) dataset are based on an assumption that the available functions of the proteins (a.k.a. annotated proteins) will determine the functions of the proteins whose functions are unknown yet at the moment (a.k.a. un-annotated proteins). Therefore, the protein function prediction is a mono-directed and one-off procedure, i.e. from annotated proteins to un-annotated proteins. However, the interactions between proteins are mutual rather than static and mono-directed, although functions of some proteins are unknown for some reasons at present. That means when we use the similarity-based approach to predict functions of un-annotated proteins, the un-annotated proteins, once their functions are predicted, will affect the similarities between proteins, which in turn will affect the prediction results. In other words, the function prediction is a dynamic and mutual procedure. This dynamic feature of protein interactions, however, was not considered in the existing prediction algorithms. In this paper, we propose a new prediction approach that predicts protein functions iteratively. This iterative approach incorporates the dynamic and mutual features of PPI interactions, as well as the local and global semantic influence of protein functions, into the prediction. To guarantee predicting functions iteratively, we propose a new protein similarity from protein functions. We adapt new evaluation metrics to evaluate the prediction quality of our algorithm and other similar algorithms. Experiments on real PPI datasets were conducted to evaluate the effectiveness of the proposed approach in predicting unknown protein functions. The iterative approach is more likely to reflect the real biological nature between proteins when predicting functions. A proper definition of protein similarity from protein functions is the key to predicting functions iteratively. The evaluation results demonstrated that in most cases, the iterative approach outperformed non-iterative ones with higher prediction quality in terms of prediction precision, recall and F-value.


Apoptotic effects of γ-mangostin from the fruit hull of Garcinia mangostana on human malignant glioma cells.
Gliomas are a common type of primary brain tumor with glioblastoma multiforme accounting for the majority of human brain tumors. In this paper, high grade human malignant glioblastomas (MGs) including U87 MG and GBM 8401 were used to evaluate the antitumor effects of γ-mangostin, a xanthone derivative isolated and purified from the hull of the tropical fruit Garcinia mangostana. The γ-mangostin showed potent antiproliferative activity toward MGs in dose- and time-dependent manners. In addition, flow cytometric analysis of cell morphology in the apoptotic cells revealed an increase in hypodiploid cells in γ-mangostin treated U87 MG and GBM 8401 cells, while significant enhancement of intracellular peroxide production was detected in the same γ-mangostin treated cells by DCHDA assay and DiOC(6)(3) stain. g-Mangostin induced apoptosis, which in turn mediates cytotoxicity in human MG cells was prevented by the addition of catalase. Naturally derived medicines and herbal therapies are drawing increasing attention in regard to the treatment of many health issues, and this includes the testing of new phytochemicals or nutrients for brain tumor patients. This has led to γ-mangostin being identified as a potential leading compound for the development of an anti-brain tumor agent.


Left Ventricle to Right Atrial Shunt Associated With Ventricular-Atrial Malalignment, Double Outlet Right Atrium, and Subaortic Membrane.
We describe an asymptomatic 7-year-old boy who was taken to the operating room for repair of a subaortic membrane and possible Gerbode's defect. He was found to have a double outlet right atrium associated with an accessory atrioventricular valve in addition to a small atrial septal defect and subaortic membrane. Regurgitant flow through this accessory valve led to the left ventricle to right atrial shunt that was seen on preoperative ECHO. The atrial septal defect was repaired and a baffle was used to isolate blood flow across the accessory valve from the left atrium to the left ventricle. The patient was discharged on postoperative day 4 and has been doing well 2 years postoperatively.


Emotional Well-Being, Cognitive Load and Academic Attainment.
This article was migrated. The article was marked as recommended. This opinion piece examines some of the literature on the impact of emotional wellbeing on cognitive load and the impact this might have on educational attainment. It discusses cognitive load theory and outlines a brief history of its evolution to our current understanding. The literature on the degree to which negative emotions contribute to cognitive load is explored, followed by the association between cognitive load and educational attainment in the context of cognitive load theory. The article concludes by making a case for increased awareness, highlighting the need for more empirical research and briefly examining the role of some potential interventions to optimise cognitive load in the context of emotional wellbeing and their potential impact on educational attainment.


Do newborn infants of Ethiopian origin spit up more than other newborn infants?
Ethnic differences in the incidence of spitting up have not been reported. The nursing team at our well-baby nursery observed that newborn infants of Ethiopian origin appeared to spit up more than the others. To determine whether there are such ethnic differences and what, if anything, is their clinical relevance. Of the 3663 enrolled infants born at the Hillel Yaffe Medical Center during the 12 month study period, 55 were of Ethiopian origin and their medical records were retrospectively surveyed. The retrieved data were compared with those of 167 randomly selected non-Ethiopian newborns (controls). Exclusion criteria were preterm delivery, admission to the neonatal intensive care unit, and congenital birth defects. Newborn infants of Ethiopian origin spit up 57% more than control infants. The difference in the number of spit ups was more obvious when only the infants who spit up were compared (2.3 +/- 1.7 Ethiopian newborns vs. 1.5 +/- 0.9 controls, P=0.002), although the percentage of infants who spit up was the same in the two groups. There was no difference in weight gain, days of hospitalization, bilirubin levels or nutrition type between the groups. Infants of Ethiopian origin spit up more than the control newborn infants of non-Ethiopian origin, while other clinical parameters were similar. In the absence of other pathological signs, spitting up is a non-relevant clinical condition.


Postural and muscular adaptations to repetitive simulated work.
Complex repetitive tasks are common in the workplace and have been associated with upper extremity disorders. The purpose of this study was to examine the progressive effects of highly repetitive work on joint kinematics and muscle activity of the trunk and upper extremity. Fifteen healthy men performed 60 one-minute cycles of 4 simulated automotive-related tasks. Electromyography of eight muscles and kinematics of the trunk and right upper extremity were collected. Data were analysed at 12-min intervals and divided into a complete work cycle. The time to complete the work cycle decreased by 6.3 s over the trials. Peak shoulder flexion decreased and peak elbow flexion increased during the work cycle. Muscle activity magnitude and variability was influenced by time during the repetitive tasks. This study found adaptations to highly repetitive but light work in only 1 h; redistributing muscle demands within the shoulder over time may reduce muscle fatigue development. Practitioner Summary: While the work was not strenuous, we were able to demonstrate muscular and postural adaptations in a single hour of simulated work. By evaluating both the whole work cycle and the sub-tasks, we aim to develop new methods for evaluating the risk of complex tasks in prolonged repetitive work.


Strong two photon absorption and photophysical properties of symmetrical chromophores with electron accepting edge substituents.
Two photon absorption (TPA) and photophysical properties of three new symmetrical chromophores with electron accepting phthalimide edge substituents have been studied. The three chromophores contain fluorene, alcoxy-substituted divinyl benzene, and carbazole moieties as central cores, respectively. The femtosecond time-resolved fluorescence upconversion spectroscopy and two photon excited fluorescence technique have been carried out. The effect of solvent polarity on TPA and on photophysics has also been determined. Ultrafast fluorescence dynamics, with decay times ranging from 1 to 13 ps, are revealed in polar solvents. This is attributed to the relaxation of the chromophores to the intramolecular charge transfer state. The chromophore bearing fluorene central core, being of the type A-pi-A, is the most efficient concerning TPA. Strong TPA, with a cross section value as high as 2100 GM at an excitation wavelength of 770 nm is found in acetophenone which is a solvent of intermediate polarity. The TPA spectra were also reproduced using a sum over states three-state model. A study of the TPA induced photobleaching of the fluorene molecule, doped in a solid poly(methyl-methacrylate) film, has shown that this material is very promising for efficient TPA optical data storage.


ANTENATAL SUPERVISION. A REVIEW OF OBSTETRICAL CARE WITH SUGGESTIONS FOR REEVALUATION.
Studies by California Maternal Mortality Study Committees over a period of six years have revealed many avoidable inadequacies in the care of pregnant patients. Other reviews have shown a high incidence of non-fatal complications arising early in pregnancy when care is often inadequate. Since antenatal care is justly credited with the vast improvement of the incidence of maternal mortality, maternal morbidity and perinatal salvage, it is time for a reevaluation and upgrading of present-day practices. Responsibility is shared by the medical and auxiliary professions and the community. The public as well as those who care for the expectant mother must have improved educational exposure to achieve better results.


Help-seeking in transit workers exposed to acute psychological trauma: a qualitative analysis.
Traumatic events often occur in workplace settings and can lead to stress reactions such as Post-Traumatic Stress Disorder (PTSD). One such workplace is the transportation industry, where employees are often exposed to trauma. However, extant research shows that a considerable proportion of people with PTSD do not seek specialty mental health treatment. In this qualitative study, we sought to better understand the experience of a traumatic event at work and the barriers and motivating factors for seeking mental health treatment. Twenty-nine Toronto Transit Commission (TTC) employees participated in a one-on-one interview, 18 soon after the traumatic event and 11 after entering a specialized treatment program. Semi-structured, one-on-one interviews were conducting using qualitative description and analyzed using content analysis. Participants described emotional responses after the trauma such as guilt, anger, disbelief as particularly difficult, and explained that barriers to seeking help included the overwhelming amount and timing of paperwork related to the incident as well as negative interactions with management. Motivating factors included family and peer support, as well as financial and emotional issues which persuaded some to seek help. Seeking treatment is a multifactorial process. Implications and recommendations for the organization are discussed.


Progressive but previously untreated CLL patients with greater array CGH complexity exhibit a less durable response to chemoimmunotherapy.
To better understand the implications of genomic instability and outcome in B-cell chronic lymphocytic leukemia (CLL), we sought to address genomic complexity as a predictor of chemosensitivity and ultimately clinical outcome in this disease. We used array-based comparative genomic hybridization (aCGH) with a one-million probe array and identified gains and losses of genetic material in 48 patients treated on a chemoimmunotherapy clinical trial. We identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14, and 17. Higher genomic complexity, as a mechanism favoring clonal selection, was associated with shorter progression-free survival, and predicted a poor response to treatment. Of interest, CLL cases with loss of p53 surveillance showed more complex genomic features and were found both in patients with a 17p13.1 deletion and in the more favorable genetic subtype characterized by the presence of 13q14.1 deletion. This aCGH study adds information on the association between poor trial response and increasing genetic complexity as CLL progresses.


Exploring the environmental preference of weak interactions in (alpha/beta)8 barrel proteins.
The environmental preference for the occurrence of noncanonical hydrogen bonding and cation-pi interactions, in a data set containing 71 nonredundant (alpha/beta)(8) barrel proteins, with respect to amino acid type, secondary structure, solvent accessibility, and stabilizing residues has been performed. Our analysis reveals some important findings, which include (a) higher contribution of weak interactions mediated by main-chain atoms irrespective of the amino acids involved; (b) domination of the aromatic amino acids among interactions involving side-chain atoms; (c) involvement of strands as the principal secondary structural unit, accommodating cross strand ion pair interaction and clustering of aromatic amino acid residues; (d) significant contribution to weak interactions occur in the solvent exposed areas of the protein; (e) majority of the interactions involve long-range contacts; (f) the preference of Arg is higher than Lys to form cation-pi interaction; and (g) probability of theoretically predicted stabilizing amino acid residues involved in weak interaction is higher for polar amino acids such as Trp, Glu, and Gln. On the whole, the present study reveals that the weak interactions contribute to the global stability of (alpha/beta)(8) TIM-barrel proteins in an environment-specific manner, which can possibly be exploited for protein engineering applications.


Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3.
Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 (sgk3(-/-)) and their wild-type littermates (sgk3(+/+)). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular Ca(2+) and entry of extracellular Ca(2+). Influx of extracellular Ca(2+) but not Ca(2+) release from intracellular stores was significantly blunted in sgk3(-/-) BMMCs compared with sgk3(+/+) BMMCs. Antigen stimulation further led to a rapid increase of a K(+)-selective conductance in sgk3(+/+) BMMCs, an effect again blunted in sgk3(-/-) BMMCs. In contrast, the Ca(2+) ionophore ionomycin activated K(+) currents to a similar extent in sgk3(-/-) and in sgk3(+/+) BMMCs. β-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in sgk3(-/-) BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in sgk3(-/-) compared with sgk3(+/+) mice. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk3(-/-) than in sgk3(+/+) mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function.


Variations in T1 and T2 relaxation times of normal appearing white matter and lesions in multiple sclerosis.
To investigate the variation in T1 and T2 relaxation times of normal appearing white matter (NAWM) and lesions in multiple sclerosis (MS) throughout the brain. The magnetic resonance imaging (MRI) sequence fast FLAIR (fluid attenuated inversion recovery) has demonstrated overall increased lesion detection when compared to conventional or fast spin echo (FSE) but fewer lesions in the posterior fossa and spinal cord. The reasons for this are unknown, but may be due to variations in the T1 and T2 relaxation times within NAWM and MS lesions. Ten patients and 10 controls underwent MRI of the brain which involved FSE, fast FLAIR and the measurement of T1 and T2 relaxation times. Of 151 lesions analysed (22 infra-tentorial, 129 supra-tentorial), eight were missed by the fast FLAIR sequence. T1 and T2 relaxation times in normal controls were longer in the infra-tentorial, than supra-tentorial, region. Patient NAWM relaxation times were prolonged compared with control values in both regions. Lesions demonstrated longer relaxation times than either control white matter or patient NAWM in both regions, however this difference was less marked infra-tentorially. The eight posterior fossa lesions not visible on the fast FLAIR sequence were characterised by short T1 and T2 relaxation times which overlapped with the patient NAWM for both T1 and T2 and with control values for T2 relaxation times. Both lesion and NAWM relaxation time characteristics vary throughout the brain. The T1 and T2 relaxation times of infra-tentorial lesions are closer to the relaxation times of local NAWM than supra-tentorial lesions, resulting in reduced contrast between posterior fossa lesions and the background NAWM. Consequently the characteristics of some lesions overlap with those of NAWM resulting in reduced conspicuity. By utilising this information, it may be possible to optimise fast FLAIR sequences to improve infra-tentorial lesion detection.


Contemporaneous Perioperative Inflammatory and Angiogenic Cytokine Profiles of Surgical Breast, Colorectal, and Prostate Cancer Patients: Clinical Implications.
Surgery-induced tumor growth acceleration and synchronous metastatic growth promotion have been observed for decades. Surgery-induced wound healing, orchestrated through growth factors, chemokines, and cytokines, can negatively impact patients harboring residual or metastatic disease. We provide detailed clinical evidence of this process in surgical breast, prostate, and colorectal cancer patients. Plasma samples were analyzed from 68 cancer patients who had not received treatment before surgery or adjuvant therapy until at least four weeks post-surgery. The levels of plasma cytokines, chemokines, and growth factors were simultaneously quantified and profiled using multiplexed immunoassays for eight time points sampled per patient. The immunologic processes are induced immediately after surgery in patients, characterized by a drastic short-term shift in the expression levels of pro-inflammatory and angiogenic molecules and cytokines. A rapid and significant spike in circulating plasma levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), placental growth factor (PLGF), and matrix metalloproteinase-9 (MMP-9) after surgery was noted. The rise in these molecules was concomitant with a significant drop in transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF-AB/BB), insulin-like growth factor-1 (IGF-1), and monocyte chemoattractant protein-2 (MCP-2). If not earlier, each plasma analyte was normalized to baseline levels within 1-2 weeks after surgery, suggesting that surgical intervention alone was responsible for these effects. The effects of surgical tumor removal on disrupting the pro-inflammatory and angiogenic plasma profiles of cancer patients provide evidence for potentiating malignant progression. Our findings indicate a narrow therapeutic window of opportunity after surgery to prevent disease recurrence.


Budesonide induces complete remission in autoimmune hepatitis.
Prednisone and azathioprine represent the standard treatment for autoimmune hepatitis (AIH). However, only 65% of the patients enter complete histological remission. Recently, budesonide (BUD) was reported to be a promising alternative. In this study we assessed the efficacy and safety of BUD in AIH. Eighteen patients (12 women, 6 men; mean age 45.4+/-21 years)with AIH were treated with BUD (Budenofalk) 3 mg thrice daily and followed up for at least 24 wk. Seven patients also had features of primary biliary cirrhosis (n=5) or primary sclerosing cholangitis (n=2). Advanced liver fibrosis or cirrhosis was present in 6 patients. Fifteen (83%) patients had a complete clinical and biochemical remission. Ten patients, including five with acute hepatitis,were given BUD as first-line therapy, of which seven enter remission. Three patients, two with liver cirrhosis, did not improve.All patients with second-line therapy experienced long-term remission. A histological remission was also seen in three patients. Clinically relevant BUD-induced side effects were recorded only in patients with liver cirrhosis (n=4). BUD is effective in remission induction in the majority of our patients with AIH. Side effects and treatment failure was mainly observed in patients with liver cirrhosis.


High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.
The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.


A technique for improved quantitative characterization of intracranial aneurysms.
3D digital subtraction angiograms of two intracranial aneurysms were imported to a workstation for reconstruction and postprocessing into a format allowing delineation of 1) the extent to which the diameter of the parent artery is incorporated into the aneurysm ostium (percentage of parent artery involvement or neck angle) and 2) the aneurysm volume and surface area. For clear visualization, 3D surface-rendered objects of the reconstructed artery, neck angle, and aneurysm were created.


Indications and outcomes of pediatric penetrating keratoplasty: A retrospective observational study.
Pediatric corneal transplantation can be indicated in congenital and acquired conditions. Challenges include preoperative evaluation, multiple intraoperative obstacles, and postoperative problems in follow-up and management. This study was aimed at identifying the indications and clinical outcomes of pediatric penetrating keratoplasty (PKP) in Jordan. This retrospective cohort study was conducted in Amman, Jordan. Using the hospital's electronic database, all medical records of patients aged < 18 years who underwent PKP between January 2004 and October 2019 were reviewed. Preoperative evaluations included best-corrected distance visual acuity (BCDVA) and anterior and posterior segment examinations. Postoperative complications, BCDVA, and graft survival were examined 1 year postoperatively. A total of 149 cases of pediatric PKP were performed on 141 eyes of 118 patients with an age mean ± standard deviation (SD) of 11.44 ± 4.97 years at the time of surgery. Acquired non-traumatic corneal pathologies accounted for 65.8% of indications for PKP. The most frequent indication was advanced keratoconus (55.7%). Preoperative and 1-year postoperative BCDVAs significantly differed (P < 0.001), with 111 (74.5%) patients showing improved BCDVA, 12 (8.05%) patients showing worsened BCDVA, and 26 (17.45%) patients showing no change in BCDVA. The overall 1-year graft survival rate was 80.54%. This was the largest study in Jordan involving pediatric patients who underwent PKP for various indications, showing a significant improvement in BCDVA, with a high survival rate at 1 year. Future studies with longer follow-up periods could provide stronger evidence for surgical outcomes and graft survival. Further, the option of lamellar keratoplasty in the pediatric age group should be assessed.


The roles of categorical and coordinate spatial relations in recognizing buildings.
Categorical spatial information is considered more useful for recognizing objects, and coordinate spatial information for guiding actions--for example, during navigation or grasping. In contrast with this assumption, we hypothesized that buildings, unlike other categories of objects, require both categorical and coordinate spatial information in order to be recognized. This hypothesis arose from evidence that right-brain-damaged patients have deficits in both coordinate judgments and recognition of buildings and from the fact that buildings are very useful for guiding navigation in urban environments. To test this hypothesis, we assessed 210 healthy college students while they performed four different tasks that required categorical and coordinate judgments and the recognition of common objects and buildings. Our results showed that both categorical and coordinate spatial representations are necessary to recognize a building, whereas only categorical representations are necessary to recognize an object. We discuss our data in view of a recent neural framework for visuospatial processing, suggesting that recognizing buildings may specifically activate the parieto-medial-temporal pathway.


Impact of diabetic retinopathy on vision-specific function.
To assess the influence of the spectrum of diabetic retinopathy (DR) on vision-specific function in an Asian population. Population-based cross-sectional study. Persons aged 40 to 80 years of Malay ethnicity in Singapore. The Singapore Malay Eye Study was a population-based, cross-sectional study of 3280 Asian Malays (78.7% response rate). Five end points were considered: (1) any DR, (2) macular edema (ME), (3) clinically significant macular edema (CSME), (4) vision-threatening DR (VTDR), and (5) DR severity levels ranging from none to proliferative diabetic retinopathy (PDR). Vision function was assessed using the Vision-Specific Functioning Scale validated using Rasch analysis. Vision-specific functioning score. Of 357 diabetic participants in the study, 23.2% had any DR, 5.6% had ME, 5.0% had CSME, 10.6% had VTDR, and 6.2% had PDR. In linear regression models adjusting for age, gender, stroke, diabetic risk factors, and socioeconomic factors, poorer vision-specific function was associated independently with any DR (beta, -0.21; P<0.05), ME (beta, -0.48; P<0.05), CSME (beta, -0.42; P<0.05), VTDR (beta, -0.64; P<0.05), and PDR (beta, -0.92; P<0.001). When controlling further for presenting visual acuity, VTDR (beta, -0.37; P = 0.01) and PDR (beta, -0.61; P = 0.002) were the only 2 DR categories independently associated with poorer vision-specific function and PDR. Persons with VTDR and PDR were 6 to 12 times more likely to report lower participation in daily living activities than those without these DR levels. People with VTDR and PDR have substantial difficulty undertaking vision-specific daily activities. These findings reinforce the importance of preventative efforts targeted at the earliest DR stages to prevent progression to later stages of DR. Proprietary or commercial disclosure may be found after the references.


[Comparison of conventional methods for the determination of albumin, transferrin and ceruloplasmin in serum with immunological reference methods (author's transl)].
Radial immunodiffusion, which is a presently accepted reference method, was compared with the mechanized immunoprecipitation. Each of these specific methods was compared with two normal clinical-chemical methods for the determination of albumin and transferrin, and an enzymic method for the determination of ceruloplasmin. The correlation coefficients, the mean slope for regression, and the percentage variation of the average values from those of the average values of the reference methods are presented. In the determination of albumin and ceruloplasmin, radial immunodiffusion and mechanized immunoprecipitation give the same results. Surprisingly, these two specific methods give different results in the determination of transferrin. In as far as there is no doubt concerning the accuracy of the mechanized immunoprecipitation, this method is recommended, since it also has the advantage of being less demanding in cost and time.


Laparoscopic Roux-en-Y gastric bypass with 2-metre long biliopancreatic limb for morbid obesity: technique and experience with the first 150 patients.
Laparoscopic Roux-en-Y gastric bypass (RYGBP) is being performed widely as a treatment of choice for morbid obesity. We present our method and experience with the first 150 consecutive cases of laparoscopic RYGBP with a 2-m long biliopancreatic limb (BP-limb). Between November 2001 and November 2003, a prospective analysis of 150 patients was performed identifying technical success and complications. Before surgery, patients underwent a strict multidisciplinary behavioral program. At operation the stomach was transected proximally with a linear stapler (60-mm, Endo-GIA) to create a prolongation of the esophagus (gastric tube) along the lesser curvature, resulting in a 40-50 ml pouch. Two meters of the proximal jejunum were bypassed (BP-limb), creating an antecolic Roux-en-Y gastro-jejunostomy to the posterior wall of the gastric tube using a 45-mm linear Endo-GIA stapler. The entero-anastomosis was created 50 cm below the gastro-jejunostomy, also with a 45-mm linear Endo-GIA. Mean BMI was 50.0, and 78% of patients were females. With 100% follow-up, we found an EWL of 50% 6 months after surgery, gradually rising to 80% after 18 months. The mean operating time was 116 min for the first 50 cases and decreased to 82 min for the last 50 cases. Intestinal leakage occurred in 5 patients (3%) and bleeding in 5 (3%). Most of these complications occurred in the first 50 cases, and all but one were treated successfully with an early laparoscopic re-operation. Marginal ulcers were found in 16.6% of patients. No internal hernias have occurred. The operation demands advanced laparoscopic skills, but technically it is relatively simple and has an acceptable complication rate. Short-term results regarding excess weight loss are at least comparable to the RYGBP with a long alimentary limb.


The economic implications of greater global trade in livestock and livestock products.
The Uruguay Round of the General Agreement on Tariffs and Trade (GATT) established the World Trade Organization to supervise the reduction of barriers to, and liberalisation of, world trade. The application of sanitary and phytosanitary measures will be standardised to avoid use for protectionist purposes by countries or regional trade blocks. Harmonisation of animal disease control measures within regional blocks is essential if benefits to freer trade are to occur, but this harmonisation must be balanced against potential disease risks and costs associated with disease outbreaks. World trade in livestock products is concentrated among developed countries, although developing countries are responsible for approximately a third of poultry meat imports and exports. Despite liberalisation, the share of global trade by developing countries is unlikely to increase greatly in the short term. The benefits of trade and of freer trade are emphasised. Examples are given of the impacts of trade barriers on developing countries and of the harmonisation of European Union animal health standards. Economic implications for the future of greater global trade are assessed.


Time to revisit the passive overconsumption hypothesis? Humans show sensitivity to calories in energy-rich meals.
A possible driver of obesity is insensitivity (passive overconsumption) to food energy density (ED, kcal/g); however, it is unclear whether this insensitivity applies to all meals. We assessed the influence of ED on energy intake (kcal) across a broad and continuous range of EDs comprised of noncovertly manipulated, real-world meals. We also allowed for the possibility that the association between energy intake and ED is nonlinear. We completed a secondary analysis of 1519 meals which occurred in a controlled environment as part of a study conducted by Hall and colleagues to assess the effects of food ultra-processing on energy intake. To establish the generalizability of the findings, the analyses were repeated in 32,162 meals collected from free-living humans using data from the UK National Diet and Nutrition Survey (NDNS). Segmented regressions were performed to establish ED "breakpoints" at which the association between consumed meal ED and mean centered meal caloric intake (kcal) changed. Significant breakpoints were found in both the Hall et al. data set (1.41 kcal/g) and the NDNS data set (1.75 and 2.94 kcal/g). Centered meal caloric intake did not increase linearly with consumed meal ED, and this pattern was captured by a 2-component ("volume" and "calorie content" [biologically derived from the sensing of fat, carbohydrate, and protein]) model of physical meal size (g), in which volume is the dominant signal with lower energy-dense foods and calorie content is the dominant signal with higher energy-dense foods. These analyses reveal that, on some level, humans are sensitive to the energy content of meals and adjust meal size to minimize the acute aversive effects of overconsumption. Future research should consider the relative importance of volume and calorie-content signals, and how individual differences impact everyday dietary behavior and energy balance.


Cardiac outflow tract development relies on the complex function of Sox4 and Sox11 in multiple cell types.
Congenital heart defects represent the most common human birth defects and are often life-threatening. Frequently, they are caused by abnormalities of the outflow tract whose formation results from coordinated development of cells from mesodermal and neural crest origin and depends on the activity of many different transcription factors. However, place, time, and mode of action have only been analyzed for a few of them. Here we assess the contribution of the closely related high-mobility-group transcription factors Sox4 and Sox11 to outflow tract development and determine their function. Using cell-type-specific deletion in the mouse, we show that Sox11 is required for proper development in both mesodermal cells and neural crest cells. Deletion in either mesoderm or neural crest, or both, leads to outflow tract defects ranging from double outlet right ventricle to common arterial trunk. Sox4 supports Sox11 in its function, but has additional roles with relevance for outflow tract formation in other cell types. The two Sox proteins are dispensable during early phases of cardiac neural crest development including neural tube emigration, proliferation, and migration through the pharyngeal arches. They become essential after arrival of the neural crest cells in the outflow tract for their proper differentiation and interaction with each other as well as with the environment through regulation of cytoskeletal, cell adhesion, and extracellular matrix molecules. Our results demonstrate that Sox4 and Sox11 have multiple functions in several cell types during outflow tract formation and may thus help to understand the basis of congenital heart defects in humans.


Acute pericarditis during 5-fluorouracil, docetaxel and cisplatin therapy.
DCF chemotherapy regimen includes docetaxel, cisplatin, and 5-fluorouracil (5-FU). Cardiotoxicity is one of the well-known side effects of 5-FU, docetaxel, and cisplatin. In addition, the complications and side effects are more apparent when these three agents are given in combination. For the first time we describe a case of acute pericarditis associated with DCF regimen in a male patient. A 55-year-old man recently diagnosed with syncrone nasopharenx and non-small cell lung carcinoma was admitted to the oncology unit for chemotherapy. On the fourth day of infusion therapy with DCF he developed a central chest pain that was in pleuritic character and aggravated by recumbence. On electrocardiography (ECG), there was ST elevation on V2-6, D1, D2, and AVL. The patient was immediately transported to the cardiac catheterization laboratory for primary percutaneous coronary intervention. On coronary angiography, coronary arteries were normal. There was no segmentary wall motion abnormality on left ventricle in transthoracic echocardiography. The patient was diagnosed with acute pericarditis and the DCF regimen was discontinued. After 3 days, chest pain disappeared and ECG was normalized. According to the present case, the management of DCF-induced pericarditis includes stopping the drug and administering supportive treatment. The best method to prevent recurrent pericarditis induced by DCF is to use an alternate chemotherapeutic regimen.


The mismetallation of enzymes during oxidative stress.
Mononuclear iron enzymes can tightly bind non-activating metals. How do cells avoid mismetallation? The model bacterium Escherichia coli may control its metal pools so that thermodynamics favor the correct metallation of each enzyme. This system is disrupted, however, by superoxide and hydrogen peroxide. These species oxidize ferrous iron and thereby displace it from many iron-dependent mononuclear enzymes. Ultimately, zinc binds in its place, confers little activity, and imposes metabolic bottlenecks. Data suggest that E. coli compensates by using thiols to extract the zinc and by importing manganese to replace the catalytic iron atom. Manganese resists oxidants and provides substantial activity.


The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha.
The function of the hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in cellular adaptation to hypoxia, is restricted to low oxygen tension (pO(2)). As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1alpha subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1alpha possesses two transcriptional activation domains [TAD; NH(2)-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1alpha that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygen-sensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO(2).


The present and future role of general practice surgery.
In the RSA a general practitioner may perform any operation he feels competent to do. This contention is discussed, the type and frequency of operations performed by GPs is described, and the changing role of general practice surgery, its medicolegal implications, and the experience and training needed are outlined.


Outcomes of open staged corrective surgery in the setting of adult spinal deformity.
Adult spinal deformity (ASD) represents a constellation of complex malalignments affecting the spinal column. Corrective surgical procedures aimed at improving ASD can be equally challenging, and commonly require multiple index procedures and potential revisions before definitive management. There is a paucity of data comparing the outcomes of same-day(simultaneous [SIM]) and 2-day (staged [STA]) procedures for long spinal fusions for ASD. Using a large patient cohort with surgeon- and patient-reported outcomes will be particularly useful in determining the utility and effect of staging long spinal fusions for ASD. This study aimed to compare intraoperative, perioperative, and 2-year outcomes of STA and SIM procedures correcting ASD. This is a retrospective analysis of a prospective multicenter database. A total of 142 patients (71 STA, 71 SIM) were included. Primary outcome measures were intra- and perioperative (6 weeks) complication rates. Secondary outcome measures were 2-year thoracolumbar and spinopelvic radiographic parameters, 2-year health-related quality of life (HRQoL) changes (Oswestry Disability Index [ODI] and Short Form-36 [SF-36]), and 2-year complication rates. Inclusion criteria included patients with ASD ≥18 years with 6-week and 2-year follow-up. Propensity score matching identified similar patients undergoing STA or SIM long spinal fusions based on surgical invasiveness, pelvic tilt, and sagittal vertical axis (SVA). Complications, HRQoL scores (Scoliosis Research Society-22 Patient Questionnaire [SRS-22r], SF-36, ODI), and patient characteristics were compared across and within treatment groups at follow-up with analysis of variance (ANOVA) and paired t tests at three surgical stages: intraoperatively, perioperatively (6 weeks), and postoperatively (>6 weeks). A total of 142 patients were included (71 STA, 71 SIM). Matching STA and SIM groups based on degree of deformity and surgical invasiveness created two groups similar in overall correction of the surgery. Patients undergoing STA underwent more anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) procedures, whereas patients undergoing SIM had longer fusions. Charlson comorbidity index and revision status were similar between groups (p>.05). Staging procedures had significantly more complications causing reoperation (STA: 47% vs. SIM: 8%, p=.021), and had a greater number of perioperative complications requiring a return to the operating room (OR) (STA: 9.9% vs. SIM: 1.4%, p=.029). There was no difference in intraoperative complications, mortality, or perioperative infection or wound complications (p>.05) between the two procedures. At 2-year follow-up, incidence of revision surgery was higher in STA (STA: 21.1% vs. SIM: 8.5%, p=.033). Staged spinal fusions, which add ALIFs and LLIFs to the procedure, compared with similar-correction SIM procedures, result in similar intraoperative complication incidence, but significantly higher rates of peri- and postoperative complications leading to revision. Functional outcomes, radiographic parameters, and mortality were similar. This will aid surgeons in their determination of the optimal treatment for such complex procedures.


Spatially resolved spectroscopic differentiation of hydrophilic and hydrophobic domains on individual insulin amyloid fibrils.
The formation of insoluble β-sheet-rich protein structures known as amyloid fibrils is associated with numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. A detailed understanding of the molecular structure of the fibril surface is of interest as the first contact with the physiological environment in vivo and plays a decisive role in biological activity and associated toxicity. Recent studies reveal that the inherent sensitivity and specificity of tip-enhanced Raman scattering (TERS) renders this technique a compelling method for fibril surface analysis at the single-particle level. Here, the reproducibility of TERS is demonstrated, indicating its relevance for detecting molecular variations. Consequently, individual fibrils are systematically investigated at nanometer spatial resolution. Spectral parameters were obtained by band-fitting, particularly focusing on the identification of the secondary structure via the amide III band and the differentiation of hydrophobic and hydrophilic domains on the surface. In addition multivariate data analysis, specifically the N-FINDR procedure, was employed to generate structure-specific maps. The ability of TERS to localize specific structural domains on fibril surfaces shows promise to the development of new fibril dissection strategies and can be generally applied to any (bio)chemical surface when structural variations at the nanometer level are of interest.


Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma.
c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC.


Biological perspectives: pain: it's not all in your head.
Neuroanatomy correlates with the psychological changes of pain. Neuroplastic transformation appears in the reduction of gray matter volume, or shrinkage in the top-down cortical areas vital for working memory, problem solving, sequencing and discrimination of different information and cognitive modulation of pain via the descending pain modulatory tracts and control over other cortical areas involved in the emotional perception of pain. These latter areas become more active,thereby intensifying the susceptibility to negative affect associated with pain (Geha & Apkarian, 2006).An animal model of chronic neuropathic pain was associated with impairment in the firing activity of the locus coeruleus and its expression of noradrenaline in ascending and descending pathways, which plays roles in not only pain perception, but mood, anxiety,attention and concentration, the sympathetic nervous system,and the activity of the hypothalamic-pituitary-adrenal axis,which serves to mobilize an organism's survival by the expression of cortisol in an immediate survival circumstance.


Environmental quality: outline for a national index for Canada.
I have presented an approach to constructing an EQI for Canada. The index was divided into air, water, land, and miscellaneous sections. By noting individual subindices, it is possible to study how environmental conditions vary across the country. By combining the subindices, one can obtain a more crude gauge of the broad state of the environment. As indices and mathematical methods are improved, it may eventually be possible to measure this state in the same way as the economic state of the nation is measured now. The work described herein can be viewed as a simple guide to this measurement.


The pediatric patient with sarcoma.
The results of the treatment of the commonest soft tissue sarcoma in childhood have improved dramatically during the past decade. The combination of reasonable surgery, radiotherapy and multiagent chemotherapy has been demonstrated to provide effective control of both the primary tumor and distant metastases in patients with rhabdomyosarcoma. Similar progress with the less common soft tissue malignancies will be more difficult to attain. Current therapeutic trends appear to favor a similar multimodal approach with a conservative but complete surgical excision combined with varying regimens of radiation and chemotherapy. Because of the infrequent occurrence of these unusual tumors (450 cases per year in the United States) no single institution can possibly attract a significant number of new cases to enter on treatment protocols. Substantial improvement in our current therapeutic techniques will be possible in the future only if our combined multicenter studies are continuously refined, re-examined, and extended. A plea is made for early referral of these difficult patients to regional study centers.