Use of image-guided systems in the reconstruction of the periorbital region.
The conflict in the Middle East has led to an increase in the incidence and severity of facial trauma evaluated at tertiary military medical facilities. The Naval Medical Center San Diego, San Diego, Calif, has treated 5 patients with penetrating injuries to the orbit with associated comminuted fractures. We have used the technology of image-guided surgery to assist in reconstructing these injuries. Image-guided surgery has many applications in the head and neck. This review consists of a series of traumatic applications of the image-guided system with a focus on orbital and midfacial trauma. We will discuss the benefits and drawbacks of this technique compared with previously described techniques.


Statistical analysis of genealogical trees for polygamic species.
Repetitions within a given genealogical tree provide some information about the degree of consanguinity of a population. They can be analyzed with techniques usually employed in statistical physics when dealing with fixed point transformations. In particular, we show that the tree features strongly depend on the fractions of males and females in the population, and also on the offspring probability distribution. We check different possibilities, some of them relevant to human groups, and compare them with simulations.


Observation of a short, strong hydrogen bond in the active site of hydroxynitrile lyase from Hevea brasiliensis explains a large pKa shift of the catalytic base induced by the reaction intermediate.
The hydroxynitrile lyase from Hevea brasiliensis (HbHNL) uses a catalytic triad consisting of Ser(80)-His(235)-Asp(207) to enhance the basicity of Ser(80)-O gamma for abstracting a proton from the OH group of the substrate cyanohydrin. Following the observation of a relatively short distance between a carboxyl oxygen of Asp(207) and the N delta(1)(His(235)) in a 1.1 A crystal structure of HbHNL, we here show by (1)H and (15)N-NMR spectroscopy that a short, strong hydrogen bond (SSHB) is formed between the two residues upon binding of the competitive inhibitor thiocyanate to HbHNL: the proton resonance of H-N delta 1(His(235)) moves from 15.41 ppm in the free enzyme to 19.35 ppm in the complex, the largest downfield shift observed so far upon inhibitor binding. Simultaneously, the D/H fractionation factor decreases from 0.98 to 0.35. In the observable pH range, i.e. between pH 4 and 10, no significant changes in chemical shifts (and therefore hydrogen bond strength) were observed for free HbHNL. For the complex with thiocyanate, the 19.35 ppm signal returned to 15.41 ppm at approximately pH 8, which indicates a pK(a) near this value for the H-N epsilon(2)(His(235)). These NMR results were analyzed on the basis of finite difference Poisson-Boltzmann calculations, which yielded the relative free energies of four protonation states of the His(235)-Asp(207) pair in solution as well as in the protein environment with and without bound inhibitor. The calculations explain all the NMR features, i.e. they suggest why a short, strong hydrogen bond is formed upon inhibitor binding and why this short, strong hydrogen bond reverts back to a normal one at approximately pH 8. Importantly, the computations also yield a shift of the free energy of the anionic state relative to the zwitterionic reference state by about 10.6 kcal/mol, equivalent to a shift in the apparent pK(a) of His(235) from 2.5 to 10. This huge inhibitor-induced increase in basicity is a prerequisite for His(235) to act as general base in the HbHNL-catalyzed cyanohydrin reaction.


Stable isotopes as valid components for identification of drugs in biological specimens.
Selected ion monitoring in mass spectrometric methods (SIM-MS) is generally used to confirm the presence of a drug in biological samples. Criteria for identification of a compound by MS are based on some specific guidelines. However, some disparities exist between the guidelines as to how many and what type of ions to monitor. Although European guidelines allow the monitoring of isotopic ions, such monitoring is not valid by SOFT/AAFS guidelines. The feasibility of monitoring a stable isotopic ion as an alternate to the fragment ion was examined in our study. Area ratios of stable isotopic ion m/z 275 and its parent ion m/z 274 of optical isomers of methamphetamine as (R)-(-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl derivative were found to be within +/- 4% of theoretical value (14.969) calculated from fragment formula C(13)H(15)F(3)NO(2) and isotopic abundances (C(13) = 1.1%, H(2) = 0.015%, F = 0%, N(15) = 0.37%, and O(17) = 0.037%). In another example, the area ratios of a stable isotopic ion m/z 283 and the parent ion m/z 282 of 6-pentafluoropropionyl codeine was also within +/- 4% of theoretical value (20.542) calculated from fragment formula C(18)H(20)NO(2). This relationship between the isotopic abundance and fragment composition was also useful in assigning structures to many fragment ions of methamphetamine, LSD, morphine, and 6-acetylmorphine derivatives, whereas structural assignment to the ions based on mass alone was difficult. The predictability of the relative abundance of the examined isotopic ions has proven reliable in our studies. The use of an isotope was found to be an important additional tool for compound identification by MS.


Exposure to COVID-19 among unvaccinated healthcare personnel and risk for infection: a single-center retrospective study.
Characteristics of exposure and infection risk, are important in strategy development for infection control among healthcare workers (HCWs). Our objective was to investigate the characteristics of exposure of HCWs to SARS-CoV-2 and determine the risk of COVID-19 development. This is a retrospective single-center cohort study, conducted between March and December 2020. Unvaccinated and exposed HCWs were asked to complete a standard form, including demographic data and characteristics of exposure(s). Exposures were stratified according to national guidelines. STROBE checklist was used. Among a total of 4,385 healthcare workers, 1,483 HCWs (33.8%) with a total of 1,903 exposures to SARS-CoV-2 were identified. Median age was 31 (IQR: 26-40) years and 45.4% were male (N = 673). Following exposure, 78 HCWs became SARS-CoV-2-positive (attack rate: 3.9%) and secondary attack rate was 4/16. In terms of infection, exposure to SARS-CoV-2-positive HCWs posed a greater risk compared to contact with patients (8.9%, [n = 66] vs. 3.8% [n = 12], respectively, p = 0.003). PCR positivity rates were 11.5%, 6.3%, and 8.4% for low, medium, and high-risk contacts (p = 0.152). Median time to infection post-exposure was 7 (IQR: 4-13) days. Given the attack rates, there was no correlation between risk levels and PCR test positivity rates. There was no difference between HCWs with or without work restrictions, in terms of PCR positivity. Due to feasibility issues, prioritizing universally applied symptom screening and resource control strategies and suspending contact tracing and work restrictions, appear to be safe during high prevalence period.


Tuberculosis in medical doctors - a study of personal experiences and attitudes.
The concurrent TB and HIV epidemics in sub-Saharan Africa place all health care workers (HCWs) at increased risk of exposure to Mycobacterium tuberculosis. This study explores personal experiences, attitudes and perceptions of medical doctors following treatment for TB within the healthcare system. Sixty-two medical doctors who were diagnosed and treated for TB during 2007 - 2009 agreed to participate and complete a semi-structured questionnaire. The response rate was 64.5% (N=40). Mean age ±SD of participants was 33.7±10.6 years. A correct diagnosis of TB was made within 7 days of clinical presentation in 20% of participants, and was delayed beyond 3 weeks in 52.5%. Non-routine special investigations and procedures were performed in 26 participants. Complications following invasive procedures were reported by 8 participants. Multi-drug resistant TB (MDR-TB) was diagnosed in 4 participants. Nineteen considered defaulting on their treatment because of drug side-effects. The majority (n=36) expressed concerns regarding lack of infection control at the workplace, delays in TB diagnosis and negative attitudes of senior medical colleagues and administrators. Ninety per cent of participants indicated that their personal illness experiences had positively changed their professional approach to patients in their current practice. The inappropriate delays in diagnosis in a large number of participants, coupled with a number of negative personal perceptions towards their treatment, are cause for concern. The results further amplify the need for improved educational and awareness programmes among all healthcare personnel (including hospital administrators), adherence to national health guidelines, effective infection control measures, pre- and post-employment screening in all HCWs, and changes in attitudes on the part of senior medical colleagues and administrators.


A single mediaprocessor-based programmable ultrasound system.
We have developed a programmable ultrasound imaging system using a single commercially available mediaprocessor. We have efficiently mapped all of the necessary B-mode processing algorithms on the underlying processor architecture, including envelope detection, dynamic range compression, lateral and axial filtering, persistence processing, and scan conversion. Our system can handle varying specifications ranging from 128 vectors and 512 samples per vector to more than 256 vectors and 1024 samples per vector. For an image size of 330 vectors and 512 samples per vector, it can process 30 frames per second using a 300-MHz MAP-CA mediaprocessor from Hitachi/Equator Technologies. This programmable ultrasound machine will not only offer significant advantages in terms of low cost, portability, scalability, and reduced development time, but also provide a flexible platform for developing and deploying new clinical applications to aid the clinicians and improve the quality of healthcare to patients.


Heart rate and blood pressure changes with endurance training: the HERITAGE Family Study.
The purpose of this study was to determine the magnitude of change in resting and exercise heart rate (HR) and blood pressure (BP), by race, sex, and age, after a 20-wk endurance training program in 507 healthy and previously sedentary subjects from the HERITAGE Family Study. After baseline measurements, subjects exercised on cycle ergometers 3 d x wk(-1) for a total of 60 exercise sessions starting at 55% of VO2max for 30 min x session(-1) and building to 75% of VO2max for 50 min x session(-1) for the last 6 wk. HR and BP at rest and during exercise (50 W, 60% of VO2max maximal exercise) were each determined in duplicate on two different days both before and after training (resting values at 24-h and 72-h posttraining). After the period of training, there was a small decrease in resting HR (-2.7 to -4.6 beats x min(-1) across groups at 72-h posttraining), and small changes (i.e., < 3 mm Hg) in resting systolic (SBP), diastolic (DBP), and calculated mean BP (MBP), which varied by race, sex, and age. During exercise at the same absolute work rate (50 W), HR, SBP, DBP, and MBP were all significantly reduced, with greater reductions in HR in women compared with men, and greater reductions in BP in blacks and older subjects compared with whites and younger subjects, respectively. At the same relative work rate (60% VO2max), HR, DBP, and MBP were reduced, but SBP remained unchanged. Blacks had a greater reduction in DBP, but whites had a greater reduction in HR. Finally, at maximal exercise, there was a small decrease in HR, with men and whites decreasing more than women and blacks; an 8 mm Hg increase in SBP, with men increasing more than women; a 4 mm Hg decrease in DBP, with blacks decreasing more than whites; and no change in MBP. In conclusion, the reductions in resting HR and BP with training were generally small, but the reductions during exercise were substantial and clinically important, with the older and the black populations experiencing greater reductions.


[Estimation of antibacterial activity of various antibiotics against Pseudomonas aeruginosa by score method].
Antibacterial activity of various antibiotics against Pseudomonas aeruginosa isolated from each hospitals depends on the variety or amount of antibiotics used in each hospital. The antibiotic, which is effective to P. aeruginosa in a certain hospital is not always effective to that in other hospital. The excellent antibiotics in antibacterial activity have low MIC and hard to progress in resistance, and such antibiotics may be effective against P. aeruginosa isolated from any hospitals. Therefore we thought that the antibiotic, which was progress to resistance, would show a great difference in MIC among hospitals, and we investigated MIC and difference of MIC of various antibiotics against P. aeruginosa isolated from six hospitals. Furthermore, we converted the data of MICs and difference of MIC among six hospitals into the score, and tried to estimate antibacterial activity of various antibiotics by using those scores. From the results of analysis in this report, we think the antibiotics actually surpass in antibacterial activity may be imipenem, cefozopran, cefsulodin and amikacin. New analytical method proposed in this report will become one of potential methods to estimate antibacterial activity of antibiotics against bacteria isolated from inpatient with bacterial infections.


Particulate matter exposure, dietary inflammatory index and preterm birth in Mexico city, Mexico.
Particulate matter ≤10 μm in aerodynamic diameter (PM10) and diet quality are risk factors for systemic inflammation, which is associated with preterm birth (PTB). PM10 and a pro-inflammatory diet (assessed by the Dietary Inflammatory Index [DII®]) have been individually evaluated as causes of PTB and differences by offspring sex have been reported for the DII. However, additional studies are needed to evaluate joint effects of these associations to inform intervention efforts. To evaluate the independent and joint effects of PM10 and energy-adjusted DII (E-DII) on PTB risks. PM10 estimates were generated from daily citywide averages for 1216 pregnant women from three subcohorts of the Early Life Exposures in Mexico to Environmental Toxicants study using data from the Mexico City Outdoor Air Monitoring Network. Among a subset of participants (N = 620), E-DII scores were calculated using a validated food frequency questionnaire. Cox Proportional Hazards models were run for select periods during pregnancy and entire pregnancy averages for E-DII and PM10. We assessed for potential non-linear associations using natural splines. In adjusted models, PM10 exposure was associated with increased risks of PTB for a range of values (58-72 μg/m3) during the second trimester, while negative associations were seen during the second (≥74 μg/m3) and third trimesters (55-65 μg/m3). Analyses conducted using distributed lag models for periods closer to delivery (max lag = 90) did not show negative associations between PM10 exposure and preterm birth, and indeed positive significant associations were observed (estimates and figures). E-DII was not associated with PTB and there was no evidence of effect modification by infant sex. There was no evidence of interaction between PM10 and E-DII and the risk of preterm birth. Associations between PM10 and PTB in Mexico City varied over time and across levels of PM10. Our findings of negative associations in the second and third trimesters, which are contrary to the hypothesized relationship between PM10 and PTB, may be due to a number of factors, including live birth bias and the exposure period evaluated. Differences in results for the periods evaluated suggest that PM10 from shorter exposure windows may play a more proximal role in initiating preterm labor.


Integrating intensified case finding of tuberculosis into HIV care: an evaluation from rural Swaziland.
Swaziland has the highest HIV prevalence in the world and the highest estimated tuberculosis incidence rate in the world. An estimated 80% of TB patients are also infected with HIV. TB detection through intensified case finding (ICF) has yet to become a routine aspect of integrated tuberculosis and HIV care. The purpose of this study was to evaluate implementation of ICF for TB into routine integrated tuberculosis and HIV care at 16 community clinics and one district hospital in Swaziland. Nurses and lay counsellors conducted ICF using a TB screening tool and patient pathway at all HIV service entry points in clinics and the hospital. The patient pathway had three-stages; screening, sputum smear diagnosis and TB treatment initiation. Outcomes and losses to follow up were monitored at each stage. Patient demographics, access, and service feasibility and effectiveness were compared at hospital and clinic sites. 1467 HIV patients at clinics and the hospital were screened over a 3 month period. Large losses to follow up occurred prior to the sputum diagnosis stage; only 47% (n = 172) of TB suspects provided a specimen. 28 cases of smear positive TB were diagnosed and 24 commenced treatment. People screened at clinics were significantly more likely to be female, older, and from rural or geographically remote areas (p < 0.001). There was no significant difference between the hospital and clinics sites in the proportion of all participants screened who were smear positive (x2 = 1.909; p = 0.16). The number needed to screen to detect one sputum positive TB case was 34 at clinics and 63 at the district hospital. ICF was operationally feasible and became established as a routine aspect of tuberculosis and HIV integrated care. ICF in community clinics was potentially more accessible to an underserved, rural population and was as effective as the hospital service in detecting smear positive TB.


Polar metals by geometric design.
Gauss's law dictates that the net electric field inside a conductor in electrostatic equilibrium is zero by effective charge screening; free carriers within a metal eliminate internal dipoles that may arise owing to asymmetric charge distributions. Quantum physics supports this view, demonstrating that delocalized electrons make a static macroscopic polarization, an ill-defined quantity in metals--it is exceedingly unusual to find a polar metal that exhibits long-range ordered dipoles owing to cooperative atomic displacements aligned from dipolar interactions as in insulating phases. Here we describe the quantum mechanical design and experimental realization of room-temperature polar metals in thin-film ANiO3 perovskite nickelates using a strategy based on atomic-scale control of inversion-preserving (centric) displacements. We predict with ab initio calculations that cooperative polar A cation displacements are geometrically stabilized with a non-equilibrium amplitude and tilt pattern of the corner-connected NiO6 octahedral--the structural signatures of perovskites--owing to geometric constraints imposed by the underlying substrate. Heteroepitaxial thin-films grown on LaAlO3 (111) substrates fulfil the design principles. We achieve both a conducting polar monoclinic oxide that is inaccessible in compositionally identical films grown on (001) substrates, and observe a hidden, previously unreported, non-equilibrium structure in thin-film geometries. We expect that the geometric stabilization approach will provide novel avenues for realizing new multifunctional materials with unusual coexisting properties.


Evaluation of physical, chemical and microbiological properties of lake Uluabat, Turkey.
Lake Uluabat, known for its scenic beauty and richness of aquatic life, is situated in Marmara Region, Bursa (Turkey). On account of its importance, lake Uluabat was designated by the Ministry of Environment as a Ramsar site in 1998. Physical, chemical and microbiological parameters of the aquatic ecosystem in lake Uluabat were measured monthly at five stations from February 2003 to January 2004. The results showed that lake Uluabat can be classified as Class I with respect to temperature (16.36 +/- 7.47 degrees C), nitrate nitrogen (0.63 +/- 0.50 mgl(-1)), sodium (9.64 +/- 2.78 mgl(-1)), chloride (20.45 +/- 4.59 mgl(-1)), sulphate (54.80 +/- 29.97 mgl(-1)); as Class II with respect to dissolved oxygen (7.62 +/- 1.99 mgl(-1)), ammonium nitrogen (0.52 +/- 0.49 mgl(-1)), chemical oxygen demand (35.74 +/- 10.66 mgl(-1)), total coliform (2027 MPN100 ml(-1) (average value)); as Class III with respect to pH (8.69 +/- 0.16) and as Class IV with respect to total nitrogen (84.94 +/- 66.13 mgl(-1)), total phosphorus (1.11 +/- 3.01 mgl(-1)), biochemical oxygen demand (21.21 +/- 6.60 mgl(-1)) according to TWPCR (Turkey Water Pollution Control Regulation). The nutrient content of lake waterapparently indicated that lake had an eutrophic characteristic. Phosphorus was determined as a limiting factor in lake. The measured hardness values (140.94 +/- 14.61 CaCO3 mgl(-1)) indicated that lake water was classified as soft/hard during the study period. Eutrophic characteristic of the lake and contaminant accumulation in water will probably affect the future use of the lake. Therefore, pollution parameters must be regularly monitored and evaluated according to aquatic living and local regulations.


New dimensions in the laboratory diagnosis of pancreatic disease.
The laboratory diagnosis of pancreatic disease has been made more precise by certain modifications in older methods and by the introduction of a variety of new technical procedures. The principal human isoamylases may now be distinguished and their activities in serum and urine measured. A test has been devised which helps indicate the presence of acute pancreatitis by showing relatively increased excretion of amylase in the urine as compared with creatinine. The ratio of amylase to creatinine in the urine appears to be a good index of relative hyperamylasuria. A screening test for pancreatic-type hyperamylasuria has been formulated that allows increased urinary excretion of this isoamylase to be identified. These additions and developments have sharpened the interpretation of hyperamylasemia and hyperamylasuria and have added new dimensions to the laboratory diagnosis of pancreatic disease.


A comparison of two DNA base excision repair glycosylases from Arabidopsis thaliana.
Plants contain the genes for both formamidopyrimidine-DNA glycosylase (FPG) and oxoguanine glycosylase (OGG). These enzymes play analogous roles in the base excision repair pathways of bacteria (FPG) and archaea, yeast, and mammals (OGG). Why have plants retained both genes? We tested one hypothesis by comparing the specificities of Arabidopsis FPG and OGG purified from Escherichia coli expression clones. Using depurinated DNA as substrate, the specific activity of Arabidopsis FPG was higher than that of Arabidopsis OGG. Using DNA oxidized by treatment with light in the presence of methylene blue, the specific activities of Arabidopsis FPG and OGG were equal. Using an oligonucleotide containing one oxoguanine (paired with C) and labeled with fluorescein, the specific activity of Arabidopsis OGG was greater than that of either FPG. The results support the hypothesis that genes for the two enzymes have been retained during evolution of plants for their specialized enzyme activities.


Natural products from thioester reductase containing biosynthetic pathways.
Covering: up to 2018 Thioester reductase domains catalyze two- and four-electron reductions to release natural products following assembly on nonribosomal peptide synthetases, polyketide synthases, and their hybrid biosynthetic complexes. This reductive off-loading of a natural product yields an aldehyde or alcohol, can initiate the formation of a macrocyclic imine, and contributes to important intermediates in a variety of biosyntheses, including those for polyketide alkaloids and pyrrolobenzodiazepines. Compounds that arise from reductase-terminated biosynthetic gene clusters are often reactive and exhibit biological activity. Biomedically important examples include the cancer therapeutic Yondelis (ecteinascidin 743), peptide aldehydes that inspired the first therapeutic proteasome inhibitor bortezomib, and numerous synthetic derivatives and antibody drug conjugates of the pyrrolobenzodiazepines. Recent advances in microbial genomics, metabolomics, bioinformatics, and reactivity-based labeling have facilitated the detection of these compounds for targeted isolation. Herein, we summarize known natural products arising from this important category, highlighting their occurrence in Nature, biosyntheses, biological activities, and the technologies used for their detection and identification. Additionally, we review publicly available genomic data to highlight the remaining potential for novel reductively tailored compounds and drug leads from microorganisms. This thorough retrospective highlights various molecular families with especially privileged bioactivity while illuminating challenges and prospects toward accelerating the discovery of new, high value natural products.


Smoking cessation care among patients with head and neck cancer: a systematic review.
To examine the effectiveness of smoking cessation interventions in improving cessation rates and smoking related behaviour in patients with head and neck cancer (HNC). A systematic review of randomised and non-randomised controlled trials. We searched the following data sources: CENTRAL in the Cochrane Library, MEDLINE, EMBASE, PsycINFO and CINAHL up to February 2016. A search of reference lists of included studies and Google Scholar (first 200 citations published online between 2000 and February 2016) was also undertaken. The methodological quality of included studies was assessed using the Effective Public Health Practice Project Quality Assessment Tool (EPHPP). 2 study authors independently screened and extracted data with disagreements resolved via consensus. Of the 5167 studies identified, 3 were eligible and included in the review. Trial designs of included studies were 2 randomised controlled trials and 1 non-randomised controlled trial. 2 studies received a weak methodological rating and 1 received a moderate methodological rating. The trials examine the impact of the following interventions: (1) nurse delivered cognitive-behaviour therapy (CBT) via telephone and accompanied by a workbook, combined with pharmacotherapy; (2) nurse and physician brief advice to quit and information booklets combined with pharmacotherapy; and (3) surgeon delivered enhanced advice to quit smoking augmented by booster sessions. Only the trial of the nurse delivered CBT and pharmacotherapy reported significant increases in smoking cessation rates. 1 study measured quit attempts and the other assessed consumption of cigarettes per day and readiness to change. There was no significant improvement in quit attempts or cigarettes smoked per day among patients in the intervention groups, relative to control. There are very few studies evaluating the effectiveness of smoking cessation interventions that report results specific to the HNC population. The 3 trials identified reported equivocal findings. Extended CBT counselling coupled with pharmacotherapy may be effective. CRD42016016421.


Haptic face processing.
We present an overview of a new multidisciplinary research program that focuses on haptic processing of human facial identity and facial expressions of emotion. A series of perceptual and neuroscience experiments with live faces and/or rigid three-dimensional facemasks is outlined. To date, several converging methodologies have been adopted: behavioural experimental studies with neurologically intact participants, neuropsychological behavioural research with prosopagnosic individuals, and neuroimaging studies using fMRI techniques. In each case, we have asked what would happen if the hands were substituted for the eyes. We confirm that humans can haptically determine both identity and facial expressions of emotion in facial displays at levels well above chance. Clearly, face processing is a bimodal phenomenon. The processes and representations that underlie such patterns of behaviour are also considered.


Comparison of Oculab Tono-Pen readings obtained from various corneal and scleral locations.
When estimating intraocular pressure in patients who are uncooperative or who have central corneal disturbances, the physician may find it either impractical or undesirable to place the small tip of a portable electronic applanation tonometer (Tono-Pen) over the central cornea. To gauge better the usefulness of Tono-Pen readings obtained from various locations, we compared such readings measured through the central cornea, midperipheral cornea, limbal cornea, and sclera of 15 cannulated eye bank eyes. Mean Tono-Pen readings from the midperipheral and clear limbal cornea did not differ significantly from central corneal readings over a 10- to 35-mm Hg range of intraocular pressures and were within +/- 2.4 mm Hg of mean central corneal readings. Mean readings taken from the sclera, however, were 8.8 to 17.0 mm Hg higher than mean central corneal readings over the 10- to 40-mm Hg range. We concluded that multiple noncentral corneal readings with the Tono-Pen provided a useful approximation of intraocular pressure, whereas scleral readings did not.


Carbon source dependence of transposable element-associated gene activation in Saccharomyces cerevisiae.
Seven cis-dominant mutations leading to the overproduction of the glucose-repressible alcohol dehydrogenase isozyme ADHII (structural gene, ADH2) in Saccharomyces cerevisiae have previously been shown to be due to insertion of a transposable element, Ty, in the 5' regulatory region of the ADH2 gene. We showed that although mating-competent cells (a, alpha, a/a, or alpha/alpha cells) overproduced both ADHII enzyme and ADH2 mRNA, mating-incompetent cells (a/alpha or ste-cells) produced much less ADHII enzyme and ADH2 mRNA. This mating type effect on ADH2 expression was greatest in the presence of a normally derepressing carbon source, glycerol, and much less apparent in the presence of a repressing carbon source, glucose. In addition, Ty insertion led to an aberrant carbon source response in mating-incompetent cells--the normally glucose-repressible ADHII becomes glycerol repressible. The mating type effect and aberrant carbon source response in mating-incompetent cells was specific for Ty-associated mutations in the 5' flanking region of the ADH2 gene in that a non-Ty mutation in the same region did not show these effects. Finally, Ty1 RNA levels also showed a/alpha, suppression, which was apparent only during growth on a nonfermentable carbon source such as glycerol. This suggests that Ty-mediated gene expression is subject to regulation by both mating competence and carbon catabolites.


Combined endo-laparoscopic treatment of large gastrointestinal stromal tumor of the stomach: Report of a case and literature review.
Gastrointestinal stromal tumours (GISTs) are the most common malignant subepithelial lesions of gastrointestinal tract, originating from Cajal's cells and characterized by the over expression of tyrosine kinase receptor C-KIT. The prognosis of this disease is associated with tumour size and mitotic index. Standard treatment of a GIST with no metastasis is surgical resection. We report a case of a 75-year-old Caucasian man with unknown voluminous gastric GIST, who came to our attention complaining black stool. We decided to perform a laparoscopic-endoscopic combined surgical approach. Intraoperative gastroscopy identified the gastric GIST and confirmed the submucosal origin and the integrity of the tumor capsule. A 10 cm laparoscopic gastrotomy was carried out along the gastric fundus in order to realize a laparo-endoscopic rendez-vous procedure. Laparoscopic approach is feasible and safe for Gastric GIST both in elective and urgent settings. Even for lesions greater than 5 cm, laparoscopy shows a recurrence rate similar to open surgery when radical resection are performed. An important point to take in consideration is surgical team experience, which seems to be one of the most important factors reducing the incidence of operative complications with better long-term outcomes, both postoperative and oncological. Mini-invasive approaches for gastric GIST are safe and feasible. The combined approach both laparoscopic and endoscopic has shown to be an effective technique and it may allow a better exposure of the tumour which ensure a radical resection.


Transcriptional reprogramming and ultrastructure during atrophy and recovery of mouse soleus muscle.
This study investigated the use of the hindlimb suspension (HS) and reloading model of mice for the mapping of ultrastructural and gene expressional alterations underlying load-dependent muscular adaptations. Mice were hindlimb suspended for 7 days or kept as controls (n = 12). Soleus muscles were harvested after HS (HS7, n = 23) or after resuming ambulatory cage activity (reloading) for either 1 day (R1, n = 13) or 7 days (R7, n = 9). Using electron microscopy, a reduction in mean fiber area (-37%) and in capillary-to-fiber ratio (from 1.83 to 1.42) was found for HS7. Subsequent reloading caused an increase in interstitial cells (+96%) and in total capillary length (+57%), whereas mean fiber area and capillary-to-fiber ratio did not significantly change compared with HS. Total RNA in the soleus muscle was altered with both HS (-63%) and reloading (+108% in R7 compared with control). This is seen as an important adaptive mechanism. Gene expression alterations were assessed by a muscle-specific low-density cDNA microarray. The transcriptional adjustments indicate an early increase of myogenic factors during reloading together with an overshoot of contractile (MyHC I and IIa) and metabolic (glycolytic and oxidative) mRNA amounts and suggest mechano-sensitivity of factors keeping the sarcomeres in register (desmin, titin, integrin-beta1). Important differences to published data from former rat studies were found with the mouse HS model for contractile and glycolytic enzyme expression. These species-specific differences need to be considered when transgenic mice are used for the elucidation of monogenetic factors in mechano-dependent muscle plasticity.


Dual-specificity phosphatase 6 plays a critical role in the maintenance of a cancer stem-like cell phenotype in human endometrial cancer.
The prognosis of patients with high-grade or advanced-stage endometrial cancer remains poor. As cancer stem-like cells (CSCs) are thought to be associated with endometrial cancers, it is essential to investigate the molecular mechanisms that regulate endometrial CSCs. Dual-specificity phosphatase 6 (DUSP6) functions as a negative-feedback regulator of MAPK-ERK1/2 signaling, but its role in endometrial cancer remains unknown. We investigated whether DUSP6 is involved in cancer cell stemness using endometrial cancer cell lines and specimens from endometrial cancer patients. DUSP6 induced the expression of CSC-related genes including ALDH1, Nanog, SOX2 and Oct4A, increased the population of cells in the G0/G1 phase, and promoted sphere formation ability. DUSP6 knockdown resulted in reduced cell invasion and metastasis, whereas DUSP6 overexpression inhibited apoptosis under serum-free conditions. Moreover, DUSP6 decreased phosphorylated ERK1/2 and increased phosphorylated Akt levels, which potentially induces CSC features. In patients with endometrial cancers, DUSP6 expression was determined using immunohistochemistry, and based on the results, the patients were dichotomized into high- and low-DUSP6-expression groups. Progression-free survival and overall survival were significantly shorter in the high-DUSP6-expression group. These results suggest that DUSP6 has potential value as a biomarker of CSCs and as a target of therapies designed to eliminate CSCs in endometrial cancer.


[Reoperation for primary hyperparathyroidism].
Twenty-one patients in a series of 283 treated surgically for primary hyperparathyroidism between 1960 and 1982, underwent reoperation. Eleven had been previously treated elsewhere. The initial cervicotomy was negative in fourteen cases, but had led to the ablation of one or more adenomas in seven. The reason for reoperation was recurrence or persistence of hyperparathyroidism (HPT). It was commenced by cervicotomy in the eleven patients initially treated elsewhere, and by cervicotomy and/or sternotomy for the others. Reoperation involved ablation of adenomas in thirteen cases, but was negative in the remaining eight. Three of the eight underwent a second reoperation, with success in two cases. Overall, reoperations led to ablation of sixteen adenomas in fifteen patients. Ten adenomas were ectopic, including eight located mediastinally . Ten sternotomies were performed, leading to ablation of four mediastinal adenomas. Postoperative complications included five recurrent paralyses and two severe cases of hypocalcemia. One patient with parathyroidal carcinoma died of malignant hypercalcemia. Fifteen of the twenty one patients (71%) were cured of their HPT. Basing themselves on these cases, and a review of the literature, the authors describe the indications and practical management of reoperative surgery for primary HPT.


Spin-correlations and magnetic structure in an Fe monolayer on 5d transition metal surfaces.
We present a detailed first principles study on the magnetic structure of an Fe monolayer on different surfaces of 5d transition metals. We use the spin-cluster expansion technique to obtain parameters of a spin model, and predict the possible magnetic ground state of the studied systems by employing the mean field approach and, in certain cases, by spin dynamics calculations. We point out that the number of shells considered for the isotropic exchange interactions plays a crucial role in the determination of the magnetic ground state. In the case of Ta substrate we demonstrate that the out-of-plane relaxation of the Fe monolayer causes a transition from ferromagnetic to antiferromagnetic ground state. We examine the relative magnitude of nearest neighbour Dzyaloshinskii-Moriya (D) and isotropic (J) exchange interactions in order to get insight into the nature of magnetic pattern formations. For the Fe/Os(0 0 0 1) system we calculate a very large D/J ratio, correspondingly, a spin spiral ground state. We find that, mainly through the leading isotropic exchange and Dzyaloshinskii-Moriya interactions, the inward layer relaxation substantially influences the magnetic ordering of the Fe monolayer. For the Fe/Re(0 0 0 1) system characterized by large antiferromagnetic interactions we also determine the chirality of the 120° Néel-type ground state.


Static T2w MRU in noncalcular urinary obstruction: comparison of its two techniques.
The purpose of this study was to compare the diagnostic accuracy of T2-weighted (T2w) MR urography (MRU) techniques - the standard MRU using fast spin echo (FSE) and postprocessing maximum intensity projection (MIP) and the single-shot MRU - in the diagnosis of ureteric obstruction in patients with noncalcular urinary obstruction. The study included 150 patients admitted to our center between January 2005 and December 2006. There were 203 renal units with noncalcular obstruction; 53 patients had bilateral obstruction. Patients with calcular obstruction were excluded. There were 85 males and 65 females with a mean age of 50 (range: 5-83) years. All patients were examined with static MRU using both single-shot (thick slab) and multisection MRU. Using single-shot MRU, we obtained images at the direct coronal and oblique coronal, as well as sagittal, planes for each renal unit. Postprocessing MIP for the standard coronal heavy T2 source images to obtain coronal and oblique images was done. Among the obstructed 203 units, the intrinsic causes were present in 157 units (151 were stricture and six were ureteric tumors), while the extrinsic causes were present in 46 units (35 bladder tumor, four ureterocele, five retroperitoneal fibrosis, one prostatic tumor, and one local pelvic recurrence after radical cystectomy for bladder cancer). The overall accuracy of single-shot MRU was 89% and was 93% for the multisection MRU in cases of intrinsic ureteric obstruction, while in cases of extrinsic obstruction, it was 20% for single-shot MRU and 96% for multisection MRU. T2w static MRU is a very useful technique in diagnosing noncalcular ureteric obstruction. Multisection MRU has a high diagnostic accuracy and reliability over that of the single-shot technique. The single-section technique is very rapid and useful in diagnosing ureteric stricture so it could be used as a localizer, while multisection images with postprocessing MIP is mandatory, especially in cases of suspected ureteric tumors or extraureteric causes.


The role of IBV PL1pro in virus replication and suppression of host innate immune responses.
Coronavirus papain-like proteases (PLpros) play a crucial role in virus replication and the evasion of the host immune response. Infectious bronchitis virus (IBV) encodes a proteolytically defective remnant of PL1pro and an active PL2pro. However, the function of PL1pro in IBV remains largely unknown. This study aims to explore the effect of PL1pro on virus replication and underlying mechanisms. The recombinant viruses rIBV-ΔPL1pro and rIBV-ΔPL1pro-N were obtained using reverse genetic techniques through the deletion of the IBV PL1pro domain and the N-terminal conserved sequence of PL1pro (PL1pro-N). We observed significantly lower replication of rIBV-ΔPL1pro and rIBV-ΔPL1pro-N than wild-type IBV. Further investigation revealed that the lack of PL1pro-N in IBV decreased virus resistance to interferon (IFN) while also inducing host immune response by enhancing the production of IFN-β and activating the downstream STAT1 signaling pathway of IFNs. In addition, the overexpression of PL1pro-N significantly suppressed type I IFN response by down-regulating the expressions of genes in the IFN pathway. Our data demonstrated that IBV PL1pro plays a crucial role in IBV replication and the suppression of host innate immune responses, suggesting that IBV PL1pro could serve as a promising molecular target for antiviral therapy.


Novel rheumatoid arthritis susceptibility locus at 22q12 identified in an extended UK genome-wide association study.
The number of confirmed rheumatoid arthritis (RA) loci currently stands at 32, but many lines of evidence indicate that expansion of existing genome-wide association studies (GWAS) enhances the power to detect additional loci. This study was undertaken to extend our previous RA GWAS in a UK cohort, adding more independent RA cases and healthy controls, with the aim of detecting novel association signals for susceptibility to RA in a homogeneous UK cohort. A total of 3,223 UK RA cases and 5,272 UK controls were available for association analyses, with the extension adding 1,361 cases and 2,334 controls to the original GWAS data set. The genotype data for all RA cases were imputed using the Impute program version 2. After stringent quality control thresholds were applied, 3,034 cases and 5,271 controls (1,831,729 single-nucleotide polymorphisms [SNPs]) were available for analysis. Association testing was performed using Plink software. The analyses indicated a suggestive association with susceptibility to RA (P < 0.0001) for 6 novel RA loci that have been previously found to be associated with other autoimmune diseases; these 6 SNPs were genotyped in independent samples. Two of the associated loci were validated, one of which was associated with RA at genome-wide levels of significance in the combined analysis, identifying a novel RA locus at 22q12 (P = 6.9 × 10(-9) ). In addition, most of the previously known RA susceptibility loci were confirmed to be associated with RA, and for 16 of the loci, the strength of the association was increased. This study identified a new RA locus mapping to 22q12. These results support the notion that increasing the power of GWAS enhances novel gene discovery.


Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques.
Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history-in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.


Cleavage of Hg-C Bonds of Organomercurials Induced by ImOHSe via Two Distinct Pathways.
We show that the N-methylimidazole-based selone ImOHSe having an N-CH2CH2OH substituent has the remarkable ability to degrade methylmercury by two distinct pathways. Under basic conditions, ImOHSe converts MeHgCl into biologically inert HgSe nanoparticles and Me2Hg via the formation of an unstable intermediate (MeHg)2Se (pathway I). However, under neutral conditions, in the absence of any base, ImOHSe facilitates the cleavage of the Hg-C bond of MeHgCl at room temperature (23 °C), leading to the formation of a stable cleaved product, the tetracoordinated mononuclear mercury compound (ImOHSe)2HgCl2 and Me2Hg (pathway II). The initial rate of Hg-C bond cleavage of MeHgCl induced by ImOHSe is almost 2-fold higher than the initial rate observed by ImMeSe. Moreover, we show that ImYSe (Y = OH, Me) has an excellent ability to dealkylate Me2Hg at room temperature. Under acidic conditions, in the presence of excess ImYSe, the volatile and toxic Me2Hg further decomposes to the tetracoordinated mononuclear mercury compound [(ImYSe)4Hg]2+. In addition, the treatment of ImOHSe with MeHgCys or MeHgSG in phosphate buffer (pH 8.5) afforded water-soluble Hg(SeS) nanoparticles via unusual ligand exchange reactions, whereas its derivative ImOMeSe or ImMeSe, lacking the N-CH2CH2OH substituent, failed to produce Hg(SeS) nanoparticles under identical reaction conditions.


The impact of insecticides and plant extracts on the suppression of insect vector (Bemisia tabaci) of Mungbean yellow mosaic virus (MYMV).
Mungbean yellow mosaic virus (MYMV) is an important constraint in successful production of mungbean (Vigna radiata L.) in many countries, including Pakistan. The MYMV spreads by insect vector whitefly (Bemisia tabaci Gennadius). The use of resistant cultivars is the most effective management tactics for MYMV. Twenty mungbean varieties/lines were screened against insect vector of MYMV under field condition in the current study. Resistance levels for varieties/lines were assessed through visual scoring of typical disease symptoms. Furthermore, the impacts of two insecticides 'Imidacloprid' and 'Thiamethoxam' and two plant extracts, i.e., neem (Azadirachta indica), and Eucalyptus (Eucalyptus camaldulensis) were tested on the suppression of whitefly. Field screening indicated that none of the tested varieties/lines proved immune/highly resistant, while significant variations were recorded among varieties/lines for resistance level. All varieties/lines were systemically infected with MYMV. The varieties 'AARI-2006' and 'Mung-14043' were considered as resistant to MYMV based on visual symptoms and the lowest vector population. These varieties were followed by 'NM-2006' and 'NL-31', which proved as moderately resistant to MYMV. All remaining varieties/lines were grouped as moderately to highly susceptible to MYMV based on visual symptoms' scoring. These results revealed that existing mungbean germplasm do not possess high resistance level MYMV. However, the lines showing higher resistance in the current study must be exploited in breeding programs for the development of resistant mungbean varieties/lines against MYMV. Imidacloprid proved as the most effective insecticide at all concentrations to manage whitefly population. Therefore, use of the varieties with higher resistance level and spraying Imidacloprid could lower the incidence of MYMV.


The phosphoenolpyruvate phosphotransferase system regulates Vibrio cholerae biofilm formation through multiple independent pathways.
The bacterial phosphoenolpyruvate phosphotransferase system (PTS) is a highly conserved phosphotransfer cascade that participates in the transport and phosphorylation of selected carbohydrates and modulates many cellular functions in response to carbohydrate availability. It plays a role in the virulence of many bacterial pathogens. Components of the carbohydrate-specific PTS include the general cytoplasmic components enzyme I (EI) and histidine protein (HPr), the sugar-specific cytoplasmic components enzymes IIA (EIIA) and IIB (EIIB), and the sugar-specific membrane-associated multisubunit components enzymes IIC (EIIC) and IID (EIID). Many bacterial genomes also encode a parallel PTS pathway that includes the EI homolog EI(Ntr), the HPr homolog NPr, and the EIIA homolog EIIA(Ntr). This pathway is thought to be nitrogen specific because of the proximity of the genes encoding this pathway to the genes encoding the nitrogen-specific sigma factor sigma(54). We previously reported that phosphorylation of HPr and FPr by EI represses Vibrio cholerae biofilm formation in minimal medium supplemented with glucose or pyruvate. Here we report two additional PTS-based biofilm regulatory pathways that are active in LB broth but not in minimal medium. These pathways involve the glucose-specific enzyme EIIA (EIIA(Glc)) and two nitrogen-specific EIIA homologs, EIIA(Ntr1) and EIIA(Ntr2). The presence of multiple, independent biofilm regulatory circuits in the PTS supports the hypothesis that the PTS and PTS-dependent substrates have a central role in sensing environments suitable for a surface-associated existence.


Participation of DNA-PKcs in DSB repair after exposure to high- and low-LET radiation.
Cellular lesions (e.g. DSBs) are induced into DNA upon exposure to radiation, with DSB complexity increasing with radiation ionization density. Using M059K and M059J human glioblastoma cells (proficient and deficient in DNA-PKcs activity, respectively), we investigated the repair of DNA damage, including DSBs, induced by high- and low-LET radiation [gamma rays, alpha particles and high-charge and energy (HZE) ions]. In the absence of DNA-PKcs activity, less DSB repair and increased recruitment of RAD51 was seen at 24 h. After exposure to (56)Fe heavy ions, the number of cells with RAD51 tracks was less than the number of cells with gamma-H2AX at 24 h with both cell lines. Using alpha particles, comparable numbers of cells with visible gamma-H2AX and RAD51 were seen at 24 h in both cell lines. M059J cells irradiated with alpha particles accumulated in S phase, with a greater number of cyclin A and RAD51 co-stained cells seen at 24 h compared with M059K cells, where an S-phase block is absent. It is proposed that DNA-PKcs plays a role in the repair of some frank DSBs, which are longer-lived in NHEJ-deficient cells, and some non-DSB clustered damage sites that are converted into DSBs at replication as the cell cycles through to S phase.


Health system influences on the implementation of tuberculosis infection prevention and control at health facilities in low-income and middle-income countries: a scoping review.
Tuberculosis infection prevention and control (TB-IPC) measures are consistently reported to be poorly implemented globally. TB-IPC guidelines provide limited recognition of the complexities of implementing TB-IPC within routine health systems, particularly those facing substantive resource constraints. This scoping review maps documented system influences on TB-IPC implementation in health facilities of low/middle-income countries (LMICs). We conducted a systematic search of empirical research published before July 2018 and included studies reporting TB-IPC implementation at health facility level in LMICs. Bibliometric data and narratives describing health system influences on TB-IPC implementation were extracted following established methodological frameworks for conducting scoping reviews. A best-fit framework synthesis was applied in which extracted data were deductively coded against an existing health policy and systems research framework, distinguishing between social and political context, policy decisions, and system hardware (eg, information systems, human resources, service infrastructure) and software (ideas and interests, relationships and power, values and norms). Of 1156 unique search results, we retained 77 studies; two-thirds were conducted in sub-Saharan Africa, with more than half located in South Africa. Notable sociopolitical and policy influences impacting on TB-IPC implementation include stigma against TB and the availability of facility-specific TB-IPC policies, respectively. Hardware influences on TB-IPC implementation referred to availability, knowledge and educational development of staff, timeliness of service delivery, availability of equipment, such as respirators and masks, space for patient separation, funding, and TB-IPC information, education and communication materials and tools. Commonly reported health system software influences were workplace values and established practices, staff agency, TB risk perceptions and fears as well as staff attitudes towards TB-IPC. TB-IPC is critically dependent on health system factors. This review identified the health system factors and health system research gaps that can be considered in a whole system approach to strengthen TB-IPC practices at facility levels in LMICs.


Effects of luminance quantization error on color image processing.
A common approach to color image processing is to apply monochrome techniques to the quantized intensity component. However, the quantization error in the intermediate intensity image propagates to the final processed image. This can lead to significant distortion, depending on the input RGB values and on the particular image processing function being applied. A theoretical analysis of the worst-case quantization error is presented. Experimental results with histogram equalization demonstrate how the histogram resolution affects the performance.


Benign Paroxysmal Positional Vertigo in Children: A Narrative Review.
Benign paroxysmal positional vertigo is a rare vestibular disorder in the pediatric population. It is a vestibulopathy characterized by brief attacks of vertigo, which occur after specific movements. This review aims to provide the current evidence regarding benign paroxysmal positional vertigo in children. This is a narrative review of the available literature on benign paroxysmal positional vertigo in children. The studies were retrieved from systematic searches on PubMed and by cross referencing. Few studies have focused on pediatric benign paroxysmal positional vertigo, and most are retrospective non-controlled studies that include a small number of children. The vast majority of cases of benign paroxysmal positional vertigo in children have been reported to be secondary. The most frequent forms involve the posterior canal and the horizontal canal. The diagnosis is based on positional maneuvers, respectively the Dix-Hallpike maneuver, which reveals a torsional upbeating nystagmus; and the supine roll test, which reveals a geotropic, horizontal nystagmus. The treatment consists of physical repositioning maneuvers: the Semont or the modified Epley maneuver for benign paroxysmal positional vertigo involving the posterior canal and the Gufoni or the Barbecue maneuver in case of the horizontal canal. Benign paroxysmal positional vertigo in children can be resistant to treatment and repetitive positional maneuvers may be necessary, particularly for children with vestibular migraine or benign paroxysmal vertigo of childhood, who have a statistically significant major risk of having recurrences compared to patients who do not. Benign paroxysmal positional vertigo in children is a rare but well-recognized clinical entity. It is diagnosed by positional testing and treated by repositioning maneuvers. Wide awareness and education among pediatric providers and otolaryngologists are needed in order to avoid a delay in identification and treatment.


Characterization of RanBPM molecular determinants that control its subcellular localization.
RanBPM/RanBP9 is a ubiquitous, nucleocytoplasmic protein that is part of an evolutionary conserved E3 ubiquitin ligase complex whose function and targets in mammals are still unknown. RanBPM itself has been implicated in various cellular processes that involve both nuclear and cytoplasmic functions. However, to date, little is known about how RanBPM subcellular localization is regulated. We have conducted a systematic analysis of RanBPM regions that control its subcellular localization using RanBPM shRNA cells to examine ectopic RanBPM mutant subcellular localization without interference from the endogenously expressed protein. We show that several domains and motifs regulate RanBPM nuclear and cytoplasmic localization. In particular, RanBPM comprises two motifs that can confer nuclear localization, one proline/glutamine-rich motif in the extreme N-terminus which has a dominant effect on RanBPM localization, and a second motif in the C-terminus which minimally contributes to RanBPM nuclear targeting. We also identified a nuclear export signal (NES) which mutation prevented RanBPM accumulation in the cytoplasm. Likewise, deletion of the central RanBPM conserved domains (SPRY and LisH/CTLH) resulted in the relocalization of RanBPM to the nucleus, suggesting that RanBPM cytoplasmic localization is also conferred by protein-protein interactions that promote its cytoplasmic retention. Indeed we found that in the cytoplasm, RanBPM partially colocalizes with microtubules and associates with α-tubulin. Finally, in the nucleus, a significant fraction of RanBPM is associated with chromatin. Altogether, these analyses reveal that RanBPM subcellular localization results from the combined effects of several elements that either confer direct transport through the nucleocytoplasmic transport machinery or regulate it indirectly, likely through interactions with other proteins and by intramolecular folding.


[The duration of disability pensions in Iceland].
To analyze the long-term outcome for recipients of disability pension in Iceland. The study includes all those receiving disability pension for the first time in 1992 in Iceland. Their status in the disability register at the State Social Security Institute of Iceland November 30th 2004 was examined as to whether they were still receiving disability pension, had died, had reached the age of retirement or were not receiving disability pension any more for some other reasons. In 1992 there were 725 new recipients of disability pension in Iceland, 428 females and 297 males. Twelve years later 434 from this group were no longer receiving disability pension, 240 females and 194 males. In most cases this was because they had reached the age of retirement or died (on average 88% of the females and 91% of the males each year). Only 12% of the females and 9% of the males ceased to receive disability pension (and probably went back to work). In Iceland few people return to work once they have started receiving disability pension.


Cell cycle-dependent nuclear localization of yeast RNase III is required for efficient cell division.
Members of the double-stranded RNA-specific ribonuclease III (RNase III) family were shown to affect cell division and chromosome segregation, presumably through an RNA interference-dependent mechanism. Here, we show that in Saccharomyces cerevisiae, where the RNA interference machinery is not conserved, an orthologue of RNase III (Rnt1p) is required for progression of the cell cycle and nuclear division. The deletion of Rnt1p delayed cells in both G1 and G2/M phases of the cell cycle. Nuclear division and positioning at the bud neck were also impaired in Deltarnt1 cells. The cell cycle defects were restored by the expression of catalytically inactive Rnt1p, indicating that RNA cleavage is not essential for cell cycle progression. Rnt1p was found to exit from the nucleolus to the nucleoplasm in the G2/M phase, and perturbation of its localization pattern delayed the progression of cell division. A single mutation in the Rnt1p N-terminal domain prevented its accumulation in the nucleoplasm and slowed exit from mitosis without any detectable effects on RNA processing. Together, the data reveal a new role for a class II RNase III in the cell cycle and suggest that at least some members of the RNase III family possess catalysis-independent functions.


DVT and pulmonary embolism: Part II. Treatment and prevention.
Treatment goals for deep venous thrombosis include stopping clot propagation and preventing the recurrence of thrombus, the occurrence of pulmonary embolism, and the development of pulmonary hypertension, which can be a complication of multiple recurrent pulmonary emboli. About 30 percent of patients with deep venous thrombosis or pulmonary embolism have a thrombophilia. An extensive evaluation is suggested in patients younger than 50 years with an idiopathic episode of deep venous thrombosis, patients with recurrent thrombosis, and patients with a family history of thromboembolism. Infusion of unfractionated heparin followed by oral administration of warfarin remains the mainstay of treatment for deep venous thrombosis. Subcutaneously administered low-molecular-weight (LMW) heparin is at least as effective as unfractionated heparin given in a continuous infusion. LMW heparin is the agent of choice for treating deep venous thrombosis in pregnant women and patients with cancer. Based on validated protocols, warfarin can be started at a dosage of 5 or 10 mg per day. The intensity and duration of warfarin therapy depends on the individual patient, but treatment of at least three months usually is required. Some patients with thrombophilias require lifetime anticoagulation. Treatment for pulmonary embolism is similar to that for deep venous thrombosis. Because of the risk of hypoxemia and hemodynamic instability, in-hospital management is advised. Unfractionated heparin commonly is used, although LMW heparin is safe and effective. Thrombolysis is used in patients with massive pulmonary embolism. Subcutaneous heparin, LMW heparin, and warfarin have been approved for use in surgical prophylaxis. Elastic compression stockings are useful in patients at lowest risk for thromboembolism. Intermittent pneumatic leg compression is a useful adjunct to anticoagulation and an alternative when anticoagulation is contraindicated.


Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis.
To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.


The validity of the family history screen for assessing family history of mental disorders.
There is a need to collect psychiatric family history information quickly and economically (e.g., for genome-wide studies and primary care practice). We sought to evaluate the validity of family history reports using a brief screening instrument, the Family History Screen (FHS). We assessed the validity of parents' reports of seven psychiatric disorders in their adult children probands from the Dunedin Study (n = 959, 52% male), using the proband's diagnosis as the criterion outcome. We also investigated whether there were informant characteristics that enhanced accuracy of reporting or were associated with reporting biases. Using reports from multiple informants, we obtained sensitivities ranging from 31.7% (alcohol dependence) to 60.0% (conduct disorder) and specificities ranging from 76.0% (major depressive episode) to 97.1% (suicide attempt). There was little evidence that any informant characteristics enhanced accuracy of reporting. However, three reporting biases were found: the probability of reporting disorder in the proband was greater for informants with versus without a disorder, for female versus male informants, and for younger versus older informants. We conclude that the FHS is as valid as other family history instruments (e.g., the FH-RDC, FISC), and its brief administration time makes it a cost-effective method for collecting family history data. To avoid biasing results, researchers who aim to compare groups in terms of their family history should ensure that the informants reporting on these groups do not differ in terms of age, sex or personal history of disorder.


STK35 Gene Therapy Attenuates Endothelial Dysfunction and Improves Cardiac Function in Diabetes.
Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis that leads to progressive heart failure. The mechanisms underlying DCM pathogenesis remain obscure, and no effective treatments for the disease have been available. In the present study, we observed that STK35, a novel kinase, is decreased in the diabetic human heart. High glucose treatment, mimicking hyperglycemia in diabetes, downregulated STK35 expression in mouse cardiac endothelial cells (MCEC). Knockdown of STK35 attenuated MCEC proliferation, migration, and tube formation, whereas STK35 overexpression restored the high glucose-suppressed MCEC migration and tube formation. Angiogenesis gene PCR array analysis revealed that HG downregulated the expression of several angiogenic genes, and this suppression was fully restored by STK35 overexpression. Intravenous injection of AAV9-STK35 viral particles successfully overexpressed STK35 in diabetic mouse hearts, leading to increased vascular density, suppression of fibrosis in the heart, and amelioration of left ventricular function. Altogether, our results suggest that hyperglycemia downregulates endothelial STK35 expression, leading to microvascular dysfunction in diabetic hearts, representing a novel mechanism underlying DCM pathogenesis. Our study also emerges STK35 is a novel gene therapeutic target for preventing and treating DCM.


Short-term outcomes after combined colon and liver resection for synchronous colon cancer liver metastases: a population study.
The timing of surgical resection for stage IV colon cancer with liver metastasis and the safety of simultaneous colon and liver resection remains controversial. The purpose of our study was to evaluate short-term outcomes after combined colon and liver resection (CCLR) versus colon resection (CR) or liver resection alone (LR) using a population database. The National Inpatient Sample was used to select patients who had surgery for colon cancer from 2002 to 2006. We evaluated for in-hospital morbidity, mortality, and prolonged length of stay (PLOS). Our analysis was done using design-weighted unadjusted analysis and logistic regression. We identified 361,096 patients during our study period (CCLR 3,625; CR 322,286; LR 35,185). CCLR was not associated with an increased risk of complications (odds ratio (OR) 1.12; 95% confidence interval (CI) 0.94-1.33; P=0.21) or PLOS (OR 1.19; 95% CI 0.99-1.4; P=0.06) compared with CR. In-hospital mortality occurred in 3.5% of patients who underwent CCLR and was not significantly associated with mortality compared with CR alone (OR 1.17; 95% CI 0.79-1.74; P=0.43). Liver lobectomy with CR was associated with a PLOS and a trend toward increased morbidity and mortality. Significant predictors of complications, mortality, and PLOS included: age>70 years, male gender, nonprivate health insurance, and Elixhauser score>1. CCLR with limited liver resection can be performed with similar morbidity and mortality to colectomy alone. For patients who require hepatic lobectomy, however, strong consideration should be given to a staged approach.


Hierarchical parameter estimation of GRN based on topological analysis.
Reverse engineering of gene regulatory network (GRN) is an important and challenging task in systems biology. Existing parameter estimation approaches that compute model parameters with the same importance are usually computationally expensive or infeasible, especially in dealing with complex biological networks.In order to improve the efficiency of computational modeling, the paper applies a hierarchical estimation methodology in computational modeling of GRN based on topological analysis. This paper divides nodes in a network into various priority levels using the graph-based measure and genetic algorithm. The nodes in the first level, that correspond to root strongly connected components(SCC) in the digraph of GRN, are given top priority in parameter estimation. The estimated parameters of vertices in the previous priority level ARE used to infer the parameters for nodes in the next priority level. The proposed hierarchical estimation methodology obtains lower error indexes while consuming less computational resources compared with single estimation methodology. Experimental outcomes with insilico networks and a realistic network show that gene networks are decomposed into no more than four levels, which is consistent with the properties of inherent modularity for GRN. In addition, the proposed hierarchical parameter estimation achieves a balance between computational efficiency and accuracy.


Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates.
AnkyrinG 480/270 kDa and three ankyrin-binding integral membrane proteins (neurofascin, NrCAM, and the voltage-dependent sodium channel) colocalize within a specialized domain of the spectrin-actin network found at axonal segments of nodes of Ranvier in myelinated axons. Before myelination in embryonic nerves, ankyrinG 480/270 kDa and the related ankyrin isoform ankyrinB 440 kDa are co-expressed along with NrCAM in an abundant, continuous distribution along the length of axons. This study has resolved intermediate stages in the developmental transition from a continuous distribution of ankyrinG 480/270 kDa in all axons to a highly polarized localization at the node of Ranvier in the developing rat sciatic nerve. The first detected event is formation of clusters containing the cell adhesion molecules neurofascin and NrCAM at sites independent of myelin-associated glycoprotein (MAG)-staining Schwann cell processes. Subsequent steps involve recruitment of ankyrinG 480/270 kDa and the voltage-dependent sodium channel to cluster sites containing cell adhesion molecules, and elaboration of MAG-staining Schwann cell processes adjacent to these cluster sites. Formation of the mature node of Ranvier results from the fusion of asynchronously formed pairs of clusters associated with MAG-positive Schwann cells flanking the site of presumed node formation. Studies with the hypomyelinating mutant mouse trembler demonstrate that the elaboration of compact myelin is not required for the formation of these clustered nodal intermediates. Clustering of neurofascin and NrCAM precedes redistribution of ankyrinG 480/270 kDa and the voltage-dependent sodium channel, suggesting that the adhesion molecules define the initial site for subsequent assembly of ankyrin and the voltage-dependent sodium channel.


Isolated papillary endothelial hyperplasia in the left atrial appendage.
Papillary endothelial hyperplasia (PEH) of the heart is extremely rare. This report describes a case of left atrial appendage PEH discovered by intraoperative palpation during mitral valve repair in a 69-year-old woman. The lesion was treated successfully by surgical excision of the left atrial appendage. Immunohistochemistry analysis confirmed the diagnosis and the patient was discharged without any complications.


Characterization of eight new phlebotomus fever serogroup arboviruses (Bunyaviridae: Phlebovirus) from the Amazon region of Brazil.
Eight new members of the phlebotomus fever arbovirus serogroup (family Bunyaviridae; genus Phlebovirus) from the Amazon region of Brazil are described. One serotype was recovered from a febrile patient, three from small wild animals and four from sand flies. A small serum survey carried out with the human isolate, Alenquer virus, suggests that it rarely infects man. Complement-fixation and plaque reduction neutralization tests were done, comparing the eight new viruses with other members of the phlebotomus fever serogroup. A close antigenic relationship was demonstrated between one of the new agents (Belterra) and Rift Valley fever virus. This finding is of considerable interest and deserves further investigation. Addition of these eight new viruses to the genus Phlebovirus brings to 14 the number of serotypes known to occur in the Amazon region and to 36 the total number reported worldwide. More detailed clinical and epidemiological studies should be conducted in Amazonia in order to define the public health impact caused by phleboviruses.


Algorithms for imputing partially observed recurrent events with applications to multiple imputation in pattern mixture models.
Five algorithms are described for imputing partially observed recurrent events modeled by a negative binomial process, or more generally by a mixed Poisson process when the mean function for the recurrent events is continuous over time. We also discuss how to perform the imputation when the mean function of the event process has jump discontinuities. The validity of these algorithms is assessed by simulations. These imputation algorithms are potentially very useful in the implementation of pattern mixture models, which have been popularly used as sensitivity analysis under the non-ignorability assumption in clinical trials. A chronic granulomatous disease trial is analyzed for illustrative purposes.


Effect of a single methyl substituent on the electronic structure of cobaltocene studied by computationally assisted MATI spectroscopy.
Metallocenes represent archetypical organometallic compounds playing key roles in various fields of fundamental and applied chemistry. Many of their unique properties arise from low ionization energies (IE) which can be tuned by introducing substituents into the rings. Here we report the first mass-analyzed threshold ionization (MATI) spectrum of a methylmetallocene, (Cp')(Cp)Co (Cp' = η5-C5H4Me, Cp = η5-C5H5). The presence of a single Me group allows us to study the "pure" effect of methylation without the mutual influence of substituents. The MATI technique provides an extremely high accuracy in determining the adiabatic IE of (Cp')(Cp)Co which equals 5.2097(6) eV. The effect of a Me group on the IE of cobaltocene appears to be 36% stronger than that in bis(η6-benzene)chromium. The MATI spectrum of (Cp')(Cp)Co shows a rich vibronic structure from which vibrational frequencies of the free ion are determined. This information provides a solid basis for testing the quality of quantum chemical calculations. Various levels of the DFT and coupled cluster computations are used to describe the structural and electronic transformations accompanying the detachment of an elctron from (Cp')(Cp)Co. New aspects of the methyl substituent influence on the potential energy surfaces, as well as on the inhomogeneous changes in charge density and electrostatic potential caused by ionization, are discussed.


[Diagnostic problems in neurosyphilis].
In two patients admitted to hospital-one with signs of cerebral infarction, the other with headaches, vertigo and paraesthesias-the TPHA test was "reactive", while the 19S(IgM)-FTA-ABS test was not. There was no cerebrospinal fluid (CSF) pleocytosis. Further CSF analyses and serological tests for syphilis (including CSF protein profile, demonstration of oligoclonal IgG, quantitative determination of Treponema-specific antibodies in serum and CSF) confirmed the diagnosis of neurosyphilis requiring treatment. In both patients the biologically false-negative 19S(IgM)-FTA-ABS test at first became transiently reactive after treatment. This unusual finding was probably due to antigen, liberated by treatment, again stimulating previously blocked IgM antibody synthesis. The listed additional tests should be performed in all patients with a reactive TPHA test and neurological or psychiatric signs and symptoms.


[Use of nopal dietary fiber in a powder dessert formulation].
The development of diverse types of foods of low caloric value and with high content in dietary fiber have occupied a preponderant place in the food industry in the last years, due to the growing interest of the consumers for a healthy and nutritious diet. Pre-cooked or quick to prepare foods are attractive for the time they save; if to this you add their nutritious value, the attractiveness is even greater. For this reason, this study analyzes different formulations of a powder to prepare a dessert (flan), with different percentages of incorporation of nopal flour, as a source of dietary fiber (16%, 18%, 20%). Two flavors (melon and banana) were tried. It was observed that the flan flavored with banana and with 16% of nopal flour, reached better sensorial characteristics. Greater percentages of nopal flour negatively affected the sensorial characteristics, mainly flavor, color and texture. The analysis showed that the powder presented 5.7% of moisture, low water activity (0.48) and therefore a low total recount of microorganisms. The content of protein was high (27.2%), the ether extract low (2.0%) similar to the caloric contribution (40 Kcal/portion). The flan showed a 9.8% of total dietary fiber, being greater the contribution of soluble fiber (6.1%) than that of insoluble fiber (3.7%). Due to these characteristics this formulation could be considered as a food that provides benefits for the human health.


Structure determination of the glutamate dehydrogenase from the hyperthermophile Thermococcus litoralis and its comparison with that from Pyrococcus furiosus.
Glutamate dehydrogenase catalyses the oxidative deamination of glutamate to 2-oxoglutarate with concomitant reduction of NAD(P)(+), and has been shown to be widely distributed in nature across species ranging from psychrophiles to hyperthermophiles. Extensive characterisation of this enzyme isolated from hyperthermophilic organisms has led to its adoption as a model system for analysing the determinants of thermal stability. The crystal structure of the extremely thermostable glutamate dehydrogenase from Thermococcus litoralis has been determined at 2.5 A resolution, and has been compared to that from the hyperthermophile Pyrococcus furiosus. The two enzymes are 87 % identical in sequence, yet differ 16-fold in their half-lives at 104 degrees C. This is the first reported comparative analysis of the structures of a multisubunit enzyme from two closely related yet distinct hyperthermophilies. The less stable T. litoralis enzyme has a decreased number of ion pair interactions; modified patterns of hydrogen bonding resulting from isosteric sequence changes; substitutions that decrease packing efficiency; and substitutions which give rise to subtle but distinct shifts in both main-chain and side-chain elements of the structure. This analysis provides a rational basis to test ideas on the factors that confer thermal stability in proteins through a combination of mutagenesis, calorimetry, and structural studies.


In vitro Comparison of Pancreatic Enzyme Preparations Available in the Indian Market.
Pancreatic enzyme replacement therapy (PERT) involves exogenous enzyme supplementation and is used in the treatment of pancreatic exocrine insufficiency. Clinical efficacy of PERT preparations is a function of physical properties and release kinetics that vary between commercially available products. In this study, we evaluated the physical properties, in vitro dissolution, and release kinetics of commercially available pancreatic enzyme preparations available in the Indian market. Physical properties such as particle size distribution and water content of the capsules were measured by dynamic light scattering and Karl-Fischer titration method, respectively. An analytical procedure based on the European pharmacopoeia (EP) method was used to determine lipase activity, and a modified United States pharmacopoeia (USP)-based method was used for dissolution studies. Enzyme release was ascertained under gastroduodenal conditions in buffered media. Considerable variations in physical properties such as particle size and water content were observed between pancreatic enzyme preparations. Some preparations failed to meet the labeled lipase content as per USP standards (>90% label claim) and showed inconsistent release behavior (>5% relative standard deviation). Differences exist between pancreatic enzyme preparations in terms of physical properties, dissolution, and release behavior that can affect their clinical efficacy. The present study suggests, therefore, that these preparations should not be used interchangeably.


[Morphologic changes in the lymph microcirculation of serous membranes in rheumatism and systemic lupus erythematosus].
Microcirculation consists of two elements--hemomicrocirculation and lymphomicrocirculation, the both being closely interrelated with each other. Lymphomicrocirculation was studied on the serous membranes taken from dead people who had died of rheumatism and systemic lupus erythematosus (SLE). The microcirculatory bed in the serous membranes was identified by V. V. Kupriyanov's method. The results of the studies showed that in serous membranes in rheumatism there occurred gradual emptying of lymphomicrocirculation and at the same time--compensatory-adaptive and regeneratory processes, the latter being manifested in formation of blind projections of capillaries, in broadening of the lumen. In SLE the lymphatic link actively participated in elimination of metabolism products and underwent a continuous rearrangement with formation of closed and communicant cysterns. Moreover, there was noted a new formation of lymphatic capillaries, which should be considered as a compensatory-adaptive process. Hemo- and lymphomicrocirculation elements are intimately connected due to close contacts between capillaries of the two elements of microcirculation, however, without formation of connecting fistulas. Hemo- and lymphomicrocirculation is an integrate, and under conditions of pathology there developed therein compensatory-adaptive and regenerative processes aimed at the maintenance of tissue metabolic and hemodynamic homeostasis.


COMPARISON OF IMMUNOCHEMICAL METHODS WITH THE RAT OVARIAN HYPEREMIA TEST IN ROUTINE ASSAYS OF HUMAN URINARY CHORIONIC GONADOTROPIN.
Positive rat ovarian hyperemia tests (AZ) in most cases of normal pregnancy agreed well with the positive results of commercial immunochemical in vitro assay methods. Immunochemically reactive and biologically undetectable urinary chorionic gonadotropin (HCG) was observed in one case of normal pregnancy, in one case of presumably normal pregnancy and in several cases of abortion. HCG excreted by a patient with choriocarcinoma was biologically active and immunochemically reactive; it became undetectable after methotrexate therapy. The in vitro tests have been successfully applied in quantitative gonadotropin assays. Negative bioassays and weakly positive immunochemical tests were observed in the urine of several patients in whom an increased pituitary gonadotropin output was suspected.


Management of acute uncomplicated urinary tract infections in general practice in the south of The Netherlands.
There is debate about the ideal diagnostic procedure for urinary tract infections (UTIs) in general practice. The aim of this study was to evaluate nitrite and leucocyte esterase strip test procedures in general practice patients, and to relate the results to the decision of the general practitioner to prescribe antibiotic therapy. A total of 292 female patients from eight general practices in the Maastricht area, who were aged 12 years or over with complaints suggesting UTI, were included in the study. All eight practices tested fresh urine samples using the nitrite strip test, and seven also used the leucocyte esterase strip test. The positive predictive value of the nitrite test was greater than the leucocyte test. Antibiotic therapy was nearly always prescribed when either or both of these tests were positive. Bacterial culture was positive in 159 (59%) cases, although treatment was started in 70 (27%) cases where there was an absence of significant bacteruria. It was found that the choice of agent used to treat the patient was related to the antibiotic susceptibility of the uropathogens that were isolated.


Implantable loop recorders in the real world: a study of two Canadian centers.
Implantable loop recorders (ILRs) are increasingly being used for ambulatory electrocardiography. We sought to evaluate ILR indications, diagnostic yield, ILR-guided interventions, and complications in two Canadian centers. This was a retrospective study using electronic medical records to identify ILR implants at Queen's University and the University of Manitoba. Information was collected on patient characteristics, medications, indication for implant, results of prior investigations, diagnostic outcome, and subsequent management. A total of 540 patients were identified; 386 had completed monitoring at time of analysis. Forty patients were lost to follow-up. Indications were unexplained syncope 84.8%, palpitations 12.8%, and suspected atrial fibrillation 11.7%. For syncope, ILRs documented arrhythmia or conduction disorder in 46%. Most common conditions were asystole/sinus pause (22%), complete heart block (10.4%), and atrial fibrillation (AF) (6.9%). After ILR diagnosis, 39.9% of implanted patients received pacemaker/ICD and 2.7% underwent catheter ablation. For palpitations, ILRs documented arrhythmia or conduction disorder in 60.4%. Most common conditions were AVNRT, AF, complete heart block, and ventricular tachycardia. After diagnosis, 25% underwent catheter ablation and 22.9% received pacemaker/ICD. For suspected AF, AF was diagnosed in 40%. Complications were observed in 3.3% of implanted patients: implant site infection 1.5%, non-infectious implant site pain requiring device removal or pocket revision 1.5%, 0.2% hypertrophic scar, and 0.2% device malfunction. An ILR has excellent diagnostic yield for syncope, palpitations, and suspected AF, and a considerable proportion of patients undergo ILR-directed interventions following monitoring. ILR implantation is a low-risk procedure.


Recipients of hyperbaric oxygen treatment for carbon monoxide poisoning and exposure circumstances.
Unintentional carbon monoxide poisoning is preventable. Severe cases are often referred for hyperbaric oxygen treatment. To guide prevention efforts and treatment practices, this study provides some of the most detailed current information about patients with carbon monoxide poisoning who have been treated at hyperbaric facilities across the United States and the circumstances surrounding their exposures. This study can help improve efforts to prevent carbon monoxide poisoning and enhance treatment practices. From August 2008 to January 2010, nonidentifiable, patient-level data were reported by 87 hyperbaric facilities in 39 states via an online reporting system. This reporting system was developed collaboratively by the Undersea and Hyperbaric Medical Society and the Centers for Disease Control and Prevention. Among the 864 patients reported to receive hyperbaric oxygen treatment for unintentional, non-fire-related, carbon monoxide poisoning, most of the patients were white men aged between 18 and 44 years. Only 10% of patients reported the presence of a carbon monoxide alarm at their exposure location, and 75% reported being part of a group exposure. Nineteen patients (2%) reported a prior carbon monoxide exposure. About half (55%) of the patients treated were discharged after treatment; 41% were hospitalized. The findings in this report expand the knowledge about patients with carbon monoxide poisoning. These results suggest that prevention efforts, such as educating the public about using carbon monoxide alarms and targeting the most at-risk populations, may help reduce the number of exposures, the number of persons with chronic cognitive sequelae, and the resulting burden on the health care system.


News from the protein mutability landscape.
Some mutations of protein residues matter more than others, and these are often conserved evolutionarily. The explosion of deep sequencing and genotyping increasingly requires the distinction between effect and neutral variants. The simplest approach predicts all mutations of conserved residues to have an effect; however, this works poorly, at best. Many computational tools that are optimized to predict the impact of point mutations provide more detail. Here, we expand the perspective from the view of single variants to the level of sketching the entire mutability landscape. This landscape is defined by the impact of substituting every residue at each position in a protein by each of the 19 non-native amino acids. We review some of the powerful conclusions about protein function, stability and their robustness to mutation that can be drawn from such an analysis. Large-scale experimental and computational mutagenesis experiments are increasingly furthering our understanding of protein function and of the genotype-phenotype associations. We also discuss how these can be used to improve predictions of protein function and pathogenicity of missense variants.


Protective association of milk intake on the risk of hip fracture: results from the Framingham Original Cohort.
Dairy foods are rich in bone-beneficial nutrients, yet the role of dairy foods in hip fracture prevention remains controversial. Our objective was to evaluate the association of milk, yogurt, cheese, cream, and milk + yogurt intakes with incident hip fracture in the Framingham Original Cohort. A total of 830 men and women from the Framingham Original Cohort, a prospective cohort study, completed a food-frequency questionnaire (1988 to 1989) and were followed for hip fracture until 2008. In this population-based study, Cox-proportional hazards regression was used to estimate hazard ratios (HR) by categories of energy-adjusted dairy intake (servings/wk), adjusting for standard confounders and covariates. The exposure was energy-adjusted intakes of milk, yogurt, cheese, cream, and milk + yogurt (servings/wk). Risk of hip fracture over the follow-up was the primary outcome; the hypothesis being tested was formulated after data collection. The mean age at baseline was 77 years (SD 4.9, range 68 to 96). Ninety-seven hip fractures occurred over the mean follow-up time of 11.6 years (range 0.04 to 21.9 years). The mean ± SD (servings/wk) of dairy intakes at baseline were: milk = 6.0 ± 6.4; yogurt = 0.4 ± 1.3; cheese = 2.6 ± 3.1; and cream = 3.4 ± 5.5. Participants with medium (>1 and <7 servings/wk) or higher (≥7 servings/wk) milk intake tended to have lower hip fracture risk than those with low (≤1 serving/wk) intake (high versus low intake HR 0.58, 95% confidence interval [CI] 0.31-1.06, p = 0.078; medium versus low intake HR 0.61, 95% CI 0.36-1.08, p = 0.071; p trend = 0.178]. There appeared to be a threshold for milk, with 40% lower risk of hip fracture among those with medium/high milk intake compared with those with low intake (p = 0.061). A similar threshold was observed for milk + yogurt intake (p = 0.104). These associations were further attenuated after adjustment for femoral neck bone mineral density. No significant associations were seen for other dairy foods (p range = 0.117 to 0.746). These results suggest that greater intakes of milk and milk + yogurt may lower risk for hip fracture in older adults through mechanisms that are partially, but not entirely, attributable to effects on bone mineral density.


Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options.
There are an estimated 500,000 ST-segment elevation myocardial infarction (STEMI) events in the U.S. annually. Despite improvements in care, up to one-third of patients presenting with STEMI within 12 h of symptom onset still receive no reperfusion therapy acutely. Clinical studies indicate that speed of reperfusion after infarct onset may be more important than whether pharmacologic or mechanical intervention is used. Primary percutaneous coronary intervention (PCI), when performed rapidly at high-volume centers, generally has superior efficacy to fibrinolysis, although fibrinolysis may be more suitable for many patients as an initial reperfusion strategy. Because up to 70% of STEMI patients present to hospitals without on-site PCI facilities, and prolonged door-to-balloon times due to inevitable transport delays commonly limit the benefit of PCI, the continued role and importance of the prompt, early use of fibrinolytic therapy may be underappreciated. Logistical complexities such as triage or transportation delays must be considered when a reperfusion strategy is selected, because prompt fibrinolysis may achieve greater benefit, especially if the fibrinolytic-to-PCI time delay associated with transfer exceeds approximately 1 h. Selection of a fibrinolytic requires consideration of several factors, including ease of dosing and combination with adjunctive therapies. Careful attention to these variables is critical to ensuring safe and rapid reperfusion, particularly in the prehospital setting. The emerging modality of pharmacoinvasive therapy, although controversial, seeks to combine the benefits of mechanical and pharmacologic reperfusion. Results from ongoing clinical trials will provide guidance regarding the utility of this strategy.


Urokinase-type plasminogen activator (uPA) and its receptor (uPAR): development of antagonists of uPA/uPAR interaction and their effects in vitro and in vivo.
In cancer, increased levels of the tumor-associated serine protease uPA (urokinase-type plasminogen activator) and its receptor uPAR (CD87) are linked to tumor progression, metastasis, and shortened survival in patients afflicted with this disease. Strong clinical and experimental evidence has accumulated that the cell surface interaction of uPA with uPAR facilitates extravasation and intravasation of cancer cells by regulating local proteolysis and attachment of the cells to components of the extracellular matrix. Moreover, the uPA/uPAR system is also implicated in proliferation of some tumor cells and migration of tumor and endothelial cells. Thus, metastasis formation is facilitated via tumor cell spread through the blood circulation system and neovascularization at the metastatic site. This multifunctional potential has rendered the uPA/uPAR system an attractive novel target for anti-metastatic therapy. Consequently, inhibitors of the uPA/uPAR interaction have been and are currently developed for suppression of tumor growth and angiogenesis. In addition to antibodies and recombinant uPA- or uPAR-derived proteins, various linear and cyclic peptides as well as small molecules have been designed and synthesized which potently interfere with the uPA/uPAR interaction, leading to reduced tumor progression in experimental animals. Such compounds affecting the uPA/uPAR system represent novel tumor biology-based therapeutic agents, thereby opening new ways for patient optimized and individualized cancer therapy.