Sex differences in cardiovascular risk factor responses to resistance and endurance training in younger subjects.
This study compared differences in cardiovascular (CV) risk factor responses between males and females following endurance (END) and resistance (RES) training. We present the frequency of responders to each training modality and the magnitude of response. Using a randomized crossover design, 68 healthy adults [age: female (F): 24.5 ± 4.6; male (M): 27.3 ± 6.6] completed 3 mo of RES and END, with 3 mo washout. Peak oxygen consumption (V̇o2peak), strength, body composition, blood pressure, glucose, insulin, and lipids were measured. V̇o2peak (L/min) significantly increased in both sexes following END, but not RES. The magnitude of change was larger in males (F: +0.20 L/min; M: +0.32 L/min), although this did not achieve statistical significance (P = 0.051). Strength significantly increased in both sexes following RES (P < 0.01), with a larger increase in males (Leg press: F: +39 kg; M: +63 kg; P < 0.05). Lean mass significantly increased in both sexes (P < 0.01) following RES and fat mass decreased in females following END (P = 0.019). The change in C-reactive protein following END was significantly different between sexes (F: -0.4 mg/L; M: +0.5 mg/L; P = 0.035). There were no differences between sexes in the proportion of individuals who responded positively to any variable following RES or END; differences between sexes were due to the magnitude of change. Males had a larger increase in V̇o2peak following END and strength following RES. There were no sex differences in other CV risk factors. This suggests differences in physiological responses to strength and V̇o2peak may not translate to changes in CV risk in healthy subjects.NEW & NOTEWORTHY This study investigated sex differences in cardiovascular risk factors in response to different exercise training modalities. Males had a larger improvement in peak oxygen consumption following endurance training and strength following resistance training compared with females. These changes in peak oxygen consumption and strength did not translate to changes in other cardiovascular risk factors. Despite the greater magnitude of change in males, there were no sex differences in the proportion of individuals who responded to training.


IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions.
We investigated T cell receptor induced IL-18 secretion, the cellular and molecular mechanisms associated with the induction of IL-18 and the role of IL-18 in IFN-gamma production in the different stages of multiple sclerosis (MS). We found that anti-CD3/CD28 induced IL-18 production by peripheral blood mononuclear cells was increased in both relapsing-remitting and secondary progressive MS. In controls and relapsing-remitting MS neutralizing anti-IL-12 and anti-IL-18 alone equally suppressed IFN-gamma production whereas in progressive MS, maximum suppression of IFN-gamma was only observed when neutralizing anti-IL-12 and anti-IL-18 were given together, suggesting that in progressive MS, IL-12 and IL-18 function in a non-linked manner to induce IFN-gamma. Elevated IL-18 production in MS was dependent on the interaction of antigen presenting cells with activated CD4(+) T cells via CD40-CD40 ligand and the levels of IL-18 correlated with disease duration in secondary progressive MS. These results demonstrated that IL-18 has an important role in augmenting Th-1 type immune responses in MS and may be involved in immune changes that occur when patients enter the progressive stage.


mTHPC-mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicenter study of 128 patients.
The aim of this multicenter study was to assess tumor response, clinical quality-of-life benefit, survival, and safety after treatment with mTHPC in patients with recurrent/refractory squamous cell carcinoma of the head and neck unsuccessfully treated or unsuitable for treatment with conventional modalities. One hundred twenty-eight patients were treated with mTHPC followed, 96 hours later, by illumination of the tumor surface with 652-nm laser light. Tumor response was assessed with WHO criteria and tumor mass reduction from baseline. Clinical quality-of-life benefit was based on the University of Washington Quality-of-Life questionnaire. By use of WHO criteria, 38% of evaluable patients achieved an overall tumor response, and 16% achieved a complete tumor response. Forty-three percent of assessable lesions achieved 100% tumor mass reduction, and 58% achieved 50% or greater tumor mass reduction. Fifty-three percent of evaluable patients experienced significant clinical quality-of-life benefit. Subset analyses revealed two subgroups in which significantly better responses were seen in patients with tumors 10 mm or less in depth and patients with fully illuminated lesions. In patients fulfilling both categories, overall tumor response was 54%, complete tumor response was 30%, and 61% demonstrated significant clinical quality-of-life benefit. Median survival was significantly better in responders. No major toxicities were detected. Patients with advanced cancer of the head and neck, who have exhausted other treatment options, can achieve significant clinical benefit and improvement in quality of life with mTHPC.


Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS).
The TaqIB polymorphism in the cholesteryl ester transfer protein (CETP) gene is associated with HDL-C, progression of coronary artery disease (CAD) and response to pravastatin treatment in men with angiographically proven CAD (REGRESS). We hypothesized that differences in CETP concentration could explain these associations and now investigated whether CETP concentration is an independent determinant of these parameters. Plasma CETP concentrations at baseline and after 2 years' treatment with pravastatin or placebo were measured (n=674), and correlations with lipid and angiographic parameters (mean segment- and obstruction-diameter; MSD and MOD), and TaqIB genotype were studied. After segregation into three groups (baseline CETP<1.58, 1.58-2.21, >2.21 mg L(-1)), subjects with the highest CETP had significantly higher baseline total cholesterol, LDL-C and triglycerides (P<0.01), while HDL-C, MSD and MOD were not different among these groups. After 2 years of placebo, the MSD decreased threefold (P<0.001) and the MOD decreased 2.4-fold (P=0.042) more in the highest compared with the lowest CETP quartile. Pravastatin treatment reduced total cholesterol LDL-C and triglycerides significantly more in the highest CETP quartile. Moreover, only in the highest CETP quartile, pravastatin significantly reduced the MSD- (P=0.003) and MOD-decrease (P=0.014) compared with placebo, and, notably, this was independent of baseline lipids and differential lipid changes in these quartiles. Strikingly, baseline associations and treatment responses according to baseline CETP were independent of TaqIB genotype. High CETP concentration is associated with faster progression of coronary atherosclerosis in men with proven CAD. Second, pravastatin yielded the highest improvement of lipid and angiographic parameters in patients with high baseline CETP independent of baseline lipids, lipid changes and TaqIB genotype, indicating that the plasma CETP level itself is an important determinant of the response to statins.


Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.
It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.


The predictive validity of a situational judgement test and multiple-mini interview for entry into postgraduate training in Australia.
Evidence for the predictive validity of situational judgement tests (SJTs) and multiple-mini interviews (MMIs) is well-established in undergraduate selection contexts, however at present there is less evidence to support the validity of their use in postgraduate settings. More research is also required to assess the extent to which SJTs and MMIs are complementary for predicting performance in practice. This study represents the first longitudinal evaluation of the complementary roles and predictive validity of an SJT and an MMI for selection for entry into postgraduate General Practice (GP) specialty training in Australia. Longitudinal data was collected from 443 GP registrars in Australia who were selected into GP training in 2010 or 2011. All 17 Regional Training Providers in Australia were asked to participate; performance data were received from 13 of these. Data was collected for participants' end-of-training assessment performance. Outcome measures include GP registrars' performance on the Royal Australian College of General Practitioners (RACGP) applied knowledge test, key feature problems and an objective structured clinical exam. Performance on the SJT, MMI and the overall selection score significantly predicted all three end-of-training assessments (r = .12 to .54), indicating that both of the selection methods, as well the overall selection score, have good predictive validity. The SJT and MMI provide incremental validity over each other for two of the three end-of-training assessments. The SJT and MMI were both significant positive predictors of all end-of-training assessments. Results provide evidence that they are complementary in predicting end-of-training assessment scores. This research adds to the limited literature at present regarding the predictive validity of postgraduate medical selection methods, and their comparable effectiveness when used in a single selection system. A future research agenda is proposed.


Modulation during sleep of the cat trigeminal neurons responding to tooth pulp stimulation.
Sleep-induced changes in the trigeminal neuron responses to electrical stimulation of the cat tooth pulp were studied. Two parameters were adopted: One was the evoked spike number at two times the threshold intensity (2 X T response magnitude), which would reveal the level shifting of the neuronal response by the sleep-regulatory system. Another was the rate of change in the response intensity when the stimulus was raised to a level of 0.7 time the arousal threshold during light slow wave sleep (sensitivity gradient), which would reflect the influences of the pain-modulatory system driven by strong noxious inputs. It was found that during sleep the two indexes tended to show a correlated change; the neurons which came to have a greater 2 X T response magnitude tended to have a smaller sensitivity gradient than during wakefulness, and vice versa. It was suggested that two contrasting populations of tooth pulp neurons might be differentiated, and that the sleep-regulatory system and the pain-modulatory system would have differential but correlated controls over these two kinds of neurons.


N-Methylenvaline in a group of subjects occupationally exposed to formaldehyde.
Aim of this pilot study was to correlate the human exposure to formaldehyde (F) with N-methylenvaline, a molecular adduct formed by addiction of F to the N-terminal valine in hemoglobin. A group of 21 subjects employed in a plywood factory and a laminate factory, and occupationally exposed to F, together with a group of 30 controls, were recruited as volunteers to test this biomarker. Each subject received a questionnaire and a passive personal F sampler. Exposure to F vapors and occurrence of N-methylenvaline in blood were measured. Integrated F concentrations always proved lower than threshold limit value as a ceiling (TLV-TWA) (0.37 mg/m(3), 0.3 ppm). N-Methylenvaline distribution in blood, as measured by GC/MS upon derivatization, showed direct positive relationship to F exposure, with r=0.465. Prevalence of the molecular adduct expressed in nmol/g of globin was significantly higher in the exposed group (p<0.04) than in the control group. However, the N-methylenvaline marker was unable to provide significant distinction between the subjects exposed to F through tobacco smoke habit and the non smokers. Despite this interference, in this pilot study the usefulness of N-methylenvaline as a biomarker for testing occupational exposure to F was demonstrated.


Shotgun metagenomics reveals a diverse mycobiome in the seawater from a High Arctic fjord (Kongsfjorden, Svalbard).
In the Arctic fjords, the marine mycobiome experiences significant changes under environmental conditions driven by climate change. However, research on the ecological roles and the adaptive mechanisms of marine mycobiome in the Arctic fjord remains insufficiently explored. The present study employed shotgun metagenomics to comprehensively characterize the mycobiome in 24 seawater samples from Kongsfjorden, a High Arctic fjord situated in Svalbard. It revealed the presence of a diverse mycobiome with eight phyla, 34 classes, 71 orders, 152 families, 214 genera, and 293 species. The taxonomic and functional composition of the mycobiome differed significantly among the three layers, i.e., upper layer (depth of 0 m), middle layer (depths of 30-100 m), and lower layer (depths of 150-200 m). Several taxonomic groups (e.g., phylum Ascomycota, class Eurotiomycetes, order Eurotiales, family Aspergillaceae, and genus Aspergillus) and KOs (e.g., K03236/EIF1A, K03306/TC.PIT, K08852/ERN1, and K03119/tauD) were significantly distinct among the three layers. Among the measured environmental parameters, depth, NO2-, and PO43- were identified as the key factors influencing the mycobiome composition. Conclusively, our findings revealed that the mycobiome was diverse in the Arctic seawater and significantly impacted by the variability of environmental conditions in the High Arctic fjord. These results will assist future studies in exploring the ecological and adaptive responses towards the changes within the Arctic ecosystems.


Aspirin use and ovarian cancer risk using extended follow-up of the PLCO Cancer Screening Trial.
Frequent use of aspirin has been associated with reduced ovarian cancer risk in observational studies, but it is unclear if only daily, low-dose aspirin confers a protective benefit. We examined associations between patterns of aspirin use and ovarian cancer risk among postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Participants were enrolled in PLCO between 1993 and 2001 and followed for cancer outcomes through 2014. Detailed data on aspirin use (e.g., dose, frequency and duration) were ascertained via the supplemental questionnaire (SQX) administered in 2006-2007. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between aspirin use (defined as use ≥once/week) and incident ovarian cancer. We conducted analyses among all women in the study sample and stratified by age at the time of the SQX. There were 41,633 women included in this analysis, of whom 223 developed incident ovarian cancer. Overall, aspirin use was not significantly associated with ovarian cancer risk (HR: 0.93, 95% CI: 0.72-1.21). Among women <70 years, there was suggestion of an inverse association for daily use of aspirin (HR: 0.65, 95% CI: 0.40-1.05), low-dose aspirin (HR: 0.79, 95% CI: 0.51-1.24) and daily use of low-dose aspirin (HR: 0.64, 95% CI: 0.38-1.09). These findings suggest a potential modest effect of daily, low-dose aspirin in reducing ovarian cancer risk. However, effect estimates were imprecise given the small number of events, and further research will be needed to confirm and extend these findings.


Development, content validity, and piloting of an instrument designed to measure managers' attitude toward workplace breastfeeding support.
Manager attitude is influential in female employees' perceptions of workplace breastfeeding support. Currently, no instrument is available to assess manager attitude toward supporting women who wish to combine breastfeeding with work. We developed and piloted an instrument to measure manager attitudes toward workplace breastfeeding support entitled the "Managers' Attitude Toward Breastfeeding Support Questionnaire," an instrument that measures four constructs using 60 items that are rated agree/disagree on a 4-point Likert rating scale. We established the content validity of the Managers' Attitude Toward Breastfeeding Support Questionnaire measures through expert content review (n=22), expert assessment of item fit (n=11), and cognitive interviews (n=8). Data were collected from a purposive sample of 185 front-line managers who had experience supervising female employees, and responses were scaled using the Multidimensional Random Coefficients Multinomial Logit Model. Dimensionality analyses supported the proposed four-construct model. Reliability ranged from 0.75 to 0.86, and correlations between the constructs were moderately strong (0.47 to 0.71). Four items in two constructs exhibited model-to-data misfit and/or a low score-measure correlation. One item was revised and the other three items were retained in the Managers' Attitude Toward Breastfeeding Support Questionnaire. Findings of this study suggest that the Managers' Attitude Toward Breastfeeding Support Questionnaire measures are reliable and valid indicators of manager attitude toward workplace breastfeeding support, and future research should be conducted to establish external validity. The Managers' Attitude Toward Breastfeeding Support Questionnaire could be used to collect data in a standardized manner within and across companies to measure and compare manager attitudes toward supporting breastfeeding. Organizations can subsequently develop targeted strategies to improve support for breastfeeding employees through efforts influencing managerial attitude.


Intraoperative dynamic pressure measurements in carpal tunnel syndrome: Correlations with clinical signs.
This study was designed to evaluate the correlations between dynamic carpal tunnel pressure and clinical signs. From December 2008 to May 2010, open carpal tunnel release (OCTR) was performed on a total of 90 hands (83 patients). All patients completed neurological and provocation tests (two-point discrimination, Tinel test, Phalen test, reverse-Phalen test and assessment of thenar muscle atrophy). Carpal tunnel pressure (CTP) was measured in two parts of carpal tunnel (proximal and distal carpal tunnel) and in three different postures (neutral, wrist flexion and wrist extension). There were 74 females and nine males aged 36 to 86 years (mean age 54). CTP values were more elevated in the wrist extension than wrist flexion in the proximal carpal tunnel but not at the distal carpal tunnel. There was no statistically significant correlation among CTP, provocation testing, and clinical signs. However, two-point discrimination (2-PD) showed a statistically significant correlation with CTP, especially in the proximal area in the wrist extension posture (P<0.01). Duration of symptoms (SD) statistically correlated with CTP in the distal carpal tunnel in the neutral posture (P<0.01). 2-PD and duration of symptoms are correlated with the CTP value in specific areas and with hand postures. This emphasizes the importance of releasing the entire carpal tunnel lesion since CTP values appear to vary within the carpal tunnel space and according to hand posture.


Rapid detection of viable Bacillus pumilus SAFR-032 encapsulated spores using novel propidium monoazide-linked fluorescence in situ hybridization.
The survival of Bacillus pumilus SAFR-032 spores to standard industrial clean room sterilization practices necessitates the development of rapid molecular diagnostic tool(s) for detection and enumeration of viable bacterial spores in industrial clean room environments. This is of importance to maintaining the sterility of clean room processing products. This paper describes the effect of propidium monoazide (PMA) on fluorescence in situ hybridization (FISH) for detecting and enumerating B. pumilus SAFR-032 viable spores having been artificially encapsulated within poly(methylmethacrylate) (Lucite, Plexiglas) and released via an organic solvent (PolyGone-500). The results of the PMA-FISH experiments discussed herein indicate that PMA was able to permeate only the compromised coat layers of non-viable spores, identifying PMA treatment of bacterial spores prior to FISH analysis as a novel method for selecting out the fraction of the spore population that is non-viable from fluorescence detection. The ability of novel PMA-FISH to selectively distinguish and enumerate only the living spores present in a sample is of potential significance for development of improved strategies to minimize spore-specific microbial burden in a given environment.


Postoperative functional and manometric evaluation of patients with Hirschsprung's disease.
Sixty-two patients with Hirschsprung's disease (operated on according to Duhamel, Swenson, or Soave) were evaluated for quality of defecation and studied manometrically. Follow-up was 30 years. Stools were normal in 30% to 50% of patients, while the rest had either constipation, loose, or increased frequency of stools per day. Continence was complete in 30% to 60%. Enterocolitis was seen in 12 patients preoperatively and in 20 patients postoperatively, regardless of type of operative procedure. This complication improved with age. To correct some of these problems, 18 had post pull-through internal sphincter myectomy with 50% improvement. Manometrically, 50% to 70% experienced a sensation of fullness and an urge to defecate following rectal balloon inflation. The resting external sphincter pressure was high in the majority of patients and further increased following rectal balloon inflation. The internal sphincter pressure showed a normal anorectal reflex in only 10% of patients postoperatively and did not seem to be related to clinical fecal continence. We concluded from the study that an appreciable number of patients in this select group with Hirschsprung's disease suffered from a variety of stooling disorders postoperatively. The majority of these complications were managed medically and/or socially but some were quite incapacitating.


Neural network based hyperspectral imaging for substrate independent bloodstain age estimation.
Being able to determine the age of a bloodstain can be a key element in a crime scene investigation. Many techniques exploit reflectance spectroscopy because it is very versatile and can be used in the field with ease. However, there are no methods for estimating bloodstain age with adequate uncertainty, and the problem of substrate influence is not yet fully resolved. We develop a hyperspectral imaging based technique for the substrate-independent age estimation of a bloodstain. Once the hyperspectral image is acquired, a neural network model recognizes the pixels belonging to the bloodstain. The reflectance spectra belonging to the bloodstain are then processed by an artificial intelligence model that removes the effect of the substrate on the bloodstain and then estimates its age. The method is trained on bloodstains deposited on 9 different substrates over a time period of 0-385 h obtaining an absolute mean error of 6.9 h over the period considered. Within two days of age, the method achieves a mean absolute error of 1.1 h. The method is finally tested on a new material (i.e., red cardboard) never used to test or validate the neural network models. Also in this case the bloodstain age is identified with the same accuracy.


Self-assembled hemin-conjugated heparin with dual-enzymatic cascade reaction activities for acute kidney injury.
Nanozymes have prominent catalytic activities with high stability as a substitute for unstable and expensive natural enzymes. However, most nanozymes are metal/inorganic nanomaterials, facing difficulty in clinical translation due to their unproven biosafety and limited biodegradability issues. Hemin, an organometallic porphyrin, was newly found to possess superoxide dismutase (SOD) mimetic activity along with previously known catalase (CAT) mimetic activity. However, hemin has poor bioavailability due to its low water solubility. Therefore, a highly biocompatible and biodegradable organic-based nanozyme system with SOD/CAT mimetic cascade reaction activity was developed by conjugating hemin to heparin (HepH) or chitosan (CS-H). Between them, Hep-H formed a smaller (<50 nm) and more stable self-assembled nanostructure and even possessed much higher and more stable SOD and CAT activities as well as the cascade reaction activity compared to CS-H and free hemin. Hep-H also showed a better cell protection effect against reactive oxygen species (ROS) compared to CS-H and hemin in vitro. Furthermore, Hep-H was selectively delivered to the injured kidney upon intravenous administration at the analysis time point (24 h) and exhibited excellent therapeutic effects on an acute kidney injury model by efficiently removing ROS, reducing inflammation, and minimizing structural and functional damage to the kidney.


Deoxyribonucleic acid replication in human diploid fibroblasts stimulated to proliferate.
The elongation of replicating DNA chains was studied in resting (G0) cultures of WI-38 cells stimulated to proliferate. An alkaline sucrose gradient sedimentation method which avoids shear effects was employed. The earliest detected intermediate is a short (4.5 S) piece of DNA which is converted to 11 S and larger (50 to 60 S) pieces within 1 min. The 50 to 60 S pieces are gradually converted to two distinct size classes, 212 S and 275 S, which are in turn converted to a chromosomal aggregate of about 400 S. The overall rate of elongation of DNA is about 1.4 X 10(6) daltons/min.


The transfer of 239+240Pu, 241Am, 137Cs and 90Sr to the tissues of horses.
Horses are important food sources in several countries however, data on their radionuclide uptake is less available than for many other farm animals. Information on the transfer of artificial radioisotopes from the environment to the food supply is necessary for internal dose assessment and assuring the safety of the population relying on this food source. This study provides data for a less studied farm animal and, in the case of 241Am and 239+240Pu, relatively poorly studied radionuclides with respect to transfer to animal products. The transfer parameters for 239+240Pu, 241Am, 137Cs and 90Sr to the organs of 1-year old fillies, 10-year old mares and through the placental barrier into foetuses were quantified after 60-days feeding with contaminated soil or diet contaminated by a leachate solution. The transfer of radionuclides from ingested soil to tissues was generally lower, by up to three orders of magnitude, than from a diet contaminated by a leachate solution. The ingestion of soil is a particularly important source of radionuclide intake to grazing animals in the Semipalatinsk Test Site. For 241Am there is a lack of available data, the two singular entries for mutton and beef in the IAEA handbook are higher than all values observed in the current study. The maximum observed transfer factor for 241Am was 72 ± 22*10-5 d kg-1 FW in the liver of the mare fed with leachate contaminated feed. For 239+240Pu the maximum transfer factor was 31.8 ± 8*10-5 d kg-1 FW observed also in the liver of the mare fed with leachate contaminated feed. The filly fed with leachate contaminated feed had the highest transfer parameter value for 137Cs, 35.3*10-3 d kg-1 FW. The highest 90Sr transfer factor was found in the ribs of the filly fed leachate contaminated feed, 720 ± 144 *10-3 d kg-1 FW. The results presented in this paper can be used to improve the current internal dose estimates from the ingestion of horse meat produced in the area, however they are based on a low sample size; future studies need to use a larger number of animals.


Muscle precursor cells in the developing limbs of two isopods (Crustacea, Peracarida): an immunohistochemical study using a novel monoclonal antibody against myosin heavy chain.
In the hot debate on arthropod relationships, Crustaceans and the morphology of their appendages play a pivotal role. To gain new insights into how arthropod appendages evolved, developmental biologists recently have begun to examine the expression and function of Drosophila appendage genes in Crustaceans. However, cellular aspects of Crustacean limb development such as myogenesis are poorly understood in Crustaceans so that the interpretative context in which to analyse gene functions is still fragmentary. The goal of the present project was to analyse muscle development in Crustacean appendages, and to that end, monoclonal antibodies against arthropod muscle proteins were generated. One of these antibodies recognises certain isoforms of myosin heavy chain and strongly binds to muscle precursor cells in malacostracan Crustacea. We used this antibody to study myogenesis in two isopods, Porcellio scaber and Idotea balthica (Crustacea, Malacostraca, Peracarida), by immunohistochemistry. In these animals, muscles in the limbs originate from single muscle precursor cells, which subsequently grow to form multinucleated muscle precursors. The pattern of primordial muscles in the thoracic limbs was mapped, and results compared to muscle development in other Crustaceans and in insects.


Acceptability and preliminary feasibility of an internet/CD-ROM-based education and decision program for early-stage prostate cancer patients: randomized pilot study.
Prostate cancer is the most common cancer affecting men in the United States. Management options for localized disease exist, yet an evidence-based criterion standard for treatment still has to emerge. Although 5-year survival rates approach 98%, all treatment options carry the possibility for significant side effects, such as erectile dysfunction and urinary incontinence. It is therefore recommended that patients be actively involved in the treatment decision process. We have developed an Internet/CD-ROM-based multimedia Prostate Interactive Educational System (PIES) to enhance patients' treatment decision making. PIES virtually mirrors a health center to provide patients with information about prostate cancer and its treatment through an intuitive interface, using videos, animations, graphics, and texts. (1) To examine the acceptability and feasibility of the PIES intervention and to report preliminary outcomes of the program in a pilot trial among patients with a new prostate cancer diagnosis, and (2) to explore the potential impact of tailoring PIES treatment information to participants' information-seeking styles on study outcomes. Participants (n = 72) were patients with newly diagnosed localized prostate cancer who had not made a treatment decision. Patients were randomly assigned to 3 experimental conditions: (1) control condition (providing information through standard National Cancer Institute brochures; 26%), and PIES (2) with tailoring (43%) and (3) without tailoring to a patient's information-seeking style (31%). Questionnaires were administrated before (t1) and immediately after the intervention (t2). Measurements include evaluation and acceptability of the PIES intervention, monitoring/blunting information-seeking style, psychological distress, and decision-related variables (eg, decisional confidence, feeling informed about prostate cancer and treatment, and treatment preference). The PIES program was well accepted by patients and did not interfere with the clinical routine. About 79% of eligible patients (72/91) completed the pre- and post-PIES intervention assessments. Patients in the PIES groups compared with those in the control condition were significantly more likely to report higher levels of confidence in their treatment choices, higher levels of helpfulness of the information they received in making a treatment decision, and that the information they received was emotionally reassuring. Patients in the PIES groups compared with those in the control condition were significantly less likely to need more information about treatment options, were less anxious about their treatment choices, and thought the information they received was clear (P < .05). Tailoring PIES information to information-seeking style was not related to decision-making variables. This pilot study confirms that the implementation of PIES within a clinical practice is feasible and acceptable to patients with a recent diagnosis of prostate cancer. PIES improved key decision-making process variables and reduced the emotional impact of a difficult medical decision.


Volumetric White Matter Hyperintensity Ranges Correspond to Fazekas Scores on Brain MRI.
White matter hyperintensity (WMH) is an abnormal T2 signal in the deep and subcortical white matter visualized on MRI associated with hypertension, cerebrovascular disease, and aging. The Fazekas (Fz) scoring system is a commonly used qualitative tool to assess the severity of WMH. While studies have compared Fazekas scores to other scoring methods, the comparison of Fazekas scores and volume of WMH using current semiautomated volumetric techniques has not been studied. We reviewed MRI studies acquired at our institution between 2015 and 2017. Relative WMH was scored by one author trained in Fazekas scoring. A board certified neuroradiologist scored them independently for confirmation. Manual segmentations of WMH were completed using 3D Slicer 4.9. A 3D model was formed to quantify WMH in milliliters (mL). ANOVA tests were performed to determine the association of Fazekas scores with corresponding WMH volumes. Among the 198 patients in our study, WMH were visualized in 163 (Fz1: n=66; Fz2: n=49; Fz3: n=48). WMH volumes significantly differed according to Fazekas score (F = 141.1, p<0.001), with increasing WMHV associated with higher Fazekas scores: Fz1, range 0.1-8.3 mL (mean 3.7, SD 2.3); Fz2, range 6.0-17.7 mL (mean 10.8, SD 3.1); Fz3, range 14.2-77.2 mL (mean 35.2, SD 17.9); and Fz3 (excluding 11 outliers above 50 mL), 14.2-47.0 mL (mean 27.1, SD 8.9). Fazekas scores correspond with distinct ranges of WMH volume with relatively little overlap, but scores based on volumes are more efficacious. A modified Fazekas from 0-4 should be considered.


Comparison of the 80-lead body surface map to physician and to 12-lead electrocardiogram in detection of acute myocardial infarction.
Diagnosis of non-ST-elevation acute myocardial infarction (AMI) by a 12-lead electrocardiogram has poor sensitivity and specificity and, therefore, relies on biochemical markers of myocardial necrosis, which can only be reliably detected within 14 to 16 hours from symptom onset. The body surface map (BSM) improves AMI detection but is limited by its interpretation by inexperienced medical staff. To facilitate interpretation, an automated BSM algorithm was developed and is evaluated in this study. One hundred three patients with ischemic-type chest pain were recruited for this study from December 2001 to April 2002. A 12-lead electrocardiogram (Marquette Mac 5K) and BSM (PRIME-ECG) were recorded at initial presentation, and cardiac troponin I and/or creatine kinase-MB levels measured at 12 hours after symptom onset. The admitting physician's 12-lead electrocardiographic (ECG) interpretation, 12-lead ECG algorithm (Marquette 12 SL V233) diagnosis, and BSM algorithm diagnosis were documented for each patient. AMI, defined by elevation of troponin I to >1 microg/L and/or creatine kinase-MB to >25U/L, occurred in 53 patients. The admitting physician diagnosed 24 patients with AMI (sensitivity 45%, specificity 94%), the 12-lead ECG algorithm diagnosed 17 patients with AMI (sensitivity 32%, specificity 98%), and the BSM algorithm diagnosed 34 patients with AMI (sensitivity 64%, specificity 94%). The BSM algorithm improved the diagnostic sensitivity by 2.0 (p <0.001) and 1.4 (p = 0.002) compared with the 12-lead ECG algorithm or the admitting physician, respectively. There was no significant difference in specificity. Thus, the BSM algorithm improves detection of AMI compared with the 12-lead ECG algorithm or physician's 12-lead ECG interpretation.


DNA transfer: review and implications for casework.
DNA-bearing cellular material can come to be present on a surface by either direct or indirect transfer. Direct transfer includes contact, but also includes activities within the vicinity of an item that may result in the transfer of DNA directly from an individual without any contact, such as speaking, coughing, and sneezing. Indirect transfer of DNA is when DNA from an individual comes to be on an item via an intermediary surface. It is important to consider indirect transfer in the evaluation of trace DNA in casework. The term 'trace DNA' in this review refers solely to DNA that cannot be attributed to an identifiable body fluid. This review presents and considers data from trace DNA experiments to establish whether the quantity of DNA recovered from a crime stain and/or the quality of a DNA profile obtained can be used to infer the likely mechanism of transfer. The data show that varied results are obtained from apparently similar trace DNA samples, presumably due to the many factors that affect the detection of trace DNA. The nature and effect of these varying factors and the application of the data to casework is considered generally and with specific reference to DNA transfer to skin, DNA beneath fingernails, 'wearer DNA', and various contamination considerations.


Single doses of acrylamide reduce retrograde transport velocity.
Single doses of acrylamide (0-1.3 mmol/kg) produced a dose-dependent decrease in the transport of 125I-tetanus toxin to the perikarya of sensory neurons in dorsal root ganglia and motor neurons in ventral spinal cord. Acrylamide was a more potent inhibitor of retrograde transport in sensory axons than in motor axons. Substantially greater doses of N,N'-methylene-bis-acrylamide, a reportedly non-neurotoxic analog of acrylamide, were required to alter the axonal transport of 125I-tetanus toxin. Velocity of retrograde transport was assessed by determining the position of the leading edge of transported 125I-tetanus toxin at times following single doses of acrylamide. Acrylamide reduced the velocity of 125I-tetanus toxin transport in a dose-dependent manner by up to 75%. No change in neuronal uptake of 125I-tetanus toxin was detected. It is concluded that single doses of acrylamide produce profound alterations in retrograde transport which precede the appearance of structural changes in affected nerve fibers.


Insect Orientation: The Travails of Going Straight.
A study of dung beetles rolling dung balls to safety reveals unexpected facets of the beetle's acquisition and use of celestial information for keeping to a straight path.


Performance is reality: how is your revenue cycle holding up?
Expanding your organization's revenue cycle performance indicators beyond receivables, cash, and A/R days can help you: Keep a record and tell a story. Benchmark against your goals and industry best practices. Identify and manage trends, not single-period results. Illustrate relationships between key performance indicators.


Intravenous lidocaine simultaneously infused with sufentanil to accelerate gastrointestinal function recovery in patients after thoracolumbar surgery: a prospective, randomized, double-blind controlled study.
Postoperative gastrointestinal dysfunction is one of the common complications of surgery, especially after surgery for a thoracolumbar spinal fracture. Intravenous lidocaine is a potential method to improve postoperative gastrointestinal function in surgical patients, reduce opioid use and shorten hospital stays. The purpose of this study is to explore the effect of intravenous lidocaine on the recovery of gastrointestinal function in patients after thoracolumbar surgery. In this study, 48 eligible patients undergoing elective thoracolumbar spine fractures resection and internal fixation surgery were enrolled to receive intravenous injections of lidocaine in different concentrations during the perioperative period. Patients were randomly divided into three groups: control group (group A), low concentration of lidocaine group (group B) and high concentration of lidocaine group (group C), 16 patients in each group. First postoperative exhaust time, numbers of bowel sound at preoperative and postoperative 3, 6, 12, 24 h, pain scores at postoperative 0, 3, 6, 12, 24, 48 h, total sufentanil use in PACU and perioperative periods, postoperative hospital stay and analgesic remedy within postoperative 48 h were recorded and compared. The primary endpoints include: the time of first flatus passage after the operation, the number of bowel sounds per minute counted with stethoscope at 30 min before anesthesia induction and at 3, 6, 12 and 24 h postoperative. The secondary endpoints included: the pain scores at PACU (after entering into PACU), 3, 6, 12, 24 and 48 h postoperative, the amount of sufentanil administrated by intravenous push during operation and the numbers of patients needed rescuing sufentanil in PACU, and the numbers of patients needed administration of gastric motility drugs or non-steroidal analgesics at ward within 48 h postoperation, length of hospital stay (from the first day after surgery to discharge from hospital) and the incidence of adverse reactions. Compared with group A, the first postoperative exhaust time in group B and C occurred much earlier (23.3 ± 11.0 h vs. 16.0 ± 6.6 h, 16.6 ± 5.1 h, P < 0.05). Compared with preoperation, the numbers of bowel sound significantly increased at 24 h postoperatively in group B, while group B at 6 h and group C at 6 and 24 h postoperatively had significantly more active bowel sounds compared to group A (P < 0.05). There were no remarkable differences in VAS scores within 12 h postoperatively among three groups, and however, significantly lower VAS scores were found at 12, 24 and 48 h postoperatively in group C when comparing to Group A (p < 0.05). There was no statistical significance in the incidence of postoperative flatulence and nausea and vomiting, the number of patients needed rescuing sufentanil in PACU, the length of postoperative hospital stay and the number of patients requiring non-steroidal analgesics at ward within 48 h postoperation. Intravenous lidocaine infusion together with patient-controlled analgesia of sufentanil expedited the early recovery of gastrointestinal function and improved analgesic quality of sefentanyl in patients undergoing thoracolumbar surgeries.


Ocular toxicity of styrene.
We completed histories and ocular examinations of 345 workers in a styrene plant in order to determine the ocular toxicity of styrene. Despite previous case reports of retrobulbar neuritis and central retinal vein occlusion (associated with a toxic hematopoietic disorder), no such conditions were found in these workers. Conjunctival irritation from styrene was found in 22% of the workers and correlated with intensity of exposure, thus confirming previous reports.


Clinical results with beta-methyl-p-(123I)iodophenylpentadecanoic acid, single-photon emission computed tomography in cardiac disease.
This study was undertaken to evaluate the relationships, between myocardial perfusion and metabolism. Simultaneous beta-methyl-p(123I)iodophenylpentadecanoic acid (123I-BMIPP) and thallium 201 myocardial single-photon emission computed tomography (SPECT) were performed in 25 patients with myocardial infarction (group A) and 16 patients with hypertrophic cardiomyopathy (group B). The severity scores of 123I-BMIPP and 201Tl myocardial SPECT images were evaluated semiquantitatively by segmental analysis. In Group A, dissociations between thallium- and 123I-BMIPP-imaged defects were frequently observed in patients with successful reperfusion compared with those with no reperfusion and those with reinfarction. In four patients with successful reperfusion, repeated 123I-BMIPP and 201Tl myocardial SPECT showed gradual improvement of the 123I-BMIPP severity score compared with the thallium severity score. In group B, dissociations between thallium- and 123I-BMIPP-imaged defects were also demonstrated in hypertrophic myocardium. In addition, nonhypertrophic myocardium also had decreased 123I-BMIPP uptake. In groups A and B, 123I-BMIPP severity scores correlated well with left ventricular function compared with thallium severity scores. These findings indicate that 123I-BMIPP is a suitable agent for the assessment of functional integrity, because left ventricular wall motion is energy dependent and 123I-BMIPP may reflect an aspect of myocardial energy production. This agent may be useful for the early detection and patient management of various heart diseases as an alternative to positron emission tomographic study.


Rhinoplasty in Latino Patients.
Rhinoplasty is the main facial plastic procedure performed in Latin America. Mestizo or Latino patients tend to have noses with thick skin, bulbous tips with poor projection, and flimsy osteocartilaginous underlying frameworks. A technique is presented in which structural grafts are used to strengthen support structures of the nose. A gradual approach is used to obtain tip definition, rotation, and projection using sutures and grafts. Simple techniques are used initially, progressing to more aggressive and less predictable ones in patients who require greater changes. The result should be noses that look more refined, with greater definition, but without looking bigger.


Geometric and physical considerations for realistic protein models.
Protein structure is generally conceptualized as the global arrangement or of smaller, local motifs of helices, sheets, and loops. These regular, recurring secondary structural elements have well understood and standardized definitions in terms of amino acid backbone geometry and the manner in which hydrogen bonding requirements are satisfied. Recently, "tube" models have been proposed to explain protein secondary structure in terms of the geometrically optimal packing of a featureless cylinder. However, atomically detailed simulations demonstrate that such packing considerations alone are insufficient for defining secondary structure; both excluded volume and hydrogen bonding must be explicitly modeled for helix formation. These results have fundamental implications for the construction and interpretation of realistic and meaningful biomacromolecular models.


A Single Administration of OC-01 (Varenicline Solution) Nasal Spray Induces Short-Term Alterations in Conjunctival Goblet Cells in Patients with Dry Eye Disease.
Dry eye disease is characterized by a persistently unstable or deficient tear film causing discomfort or visual impairment. Varenicline is a small-molecule nicotinic acetylcholine receptor agonist recently approved for use as a preservative-free nasal spray (OC-01 [varenicline solution] nasal spray [OC-01 VNS]) to treat signs and symptoms of dry eye disease, but its effect on conjunctival goblet cells has not been studied. In this phase 2, single-center, vehicle-controlled study, patients aged 18 years or more with a diagnosis of dry eye disease and Ocular Surface Disease Index© score of at least 23 were randomized 2:1 to receive a 50-µL single dose of OC-01 0.06 mg VNS or vehicle nasal spray in each nostril. Image assessments for area and perimeter were performed pre and 10 min post treatment for goblet cells by in vivo confocal microscopy and for meibomian glands by infrared meibography. Non-parametric Wilcoxon signed-rank test compared pre- and post-treatment measurements for each treatment group. Treatment-emergent adverse events (TEAEs) were assessed. The study randomized 18 patients (mean age 61 years); 6 received vehicle (3/6 [50%] female) and 12 patients received OC-01 VNS (11/12 [92%] female). OC-01 VNS treatment decreased mean goblet cell area (pre-treatment, 106.4 µm2; post-treatment, 67.6 µm2; p = 0.02) and perimeter (pre-treatment, 38.9 µm; post-treatment, 31.2 µm; p = 0.03) but not vehicle did not (p = 0.25). There were no significant changes in mean meibomian gland area with either treatment (p ≥ 0.05). All TEAEs were non-ocular, non-serious, and mild. This study demonstrated that a single administration of OC-01 0.06 mg VNS in patients with dry eye disease reduced conjunctival goblet cell area and perimeter, suggesting goblet cell degranulation and associated release of lubricating mucin. By activating the natural tear film, OC-01 VNS may provide benefits over topical medications. ClinicalTrials.gov, NCT03688802.


A novel bacteriobiont of the Arctic lichen Flavocetraria nivalis, Lichenifustis flavocetrariae gen. nov, sp. nov. demonstrating hydrolytic properties and containing a full set of the Calvin-Benson-Bassham cycle genes.
A Gram-negative, strictly aerobic, chemoorganotrophic, bacteriochlorophyll a-containing, slow-growing bacterium was isolated from the lichen Flavocetraria nivalis and designated strain BP6-180914 T. Cells of this strain were large nonmotile rods, which reproduced by binary fission. Cells grew under oxic conditions and were able to utilize sugars and several polysaccharides, including starch and pectin. Strain BP6-180914 T was psychrotolerant and moderately acidophilic growing at 4-35 °C (optimum 20-28 °C) and between pH 4.0 and 7.5 (optimum 4.5-5.5). The major fatty acids were C18:1ω7c, C19:0 cyclo, C16:0 and C18:0. The polar lipids were diphosphatidylglycerols, phosphatidylglycerols, phosphatidylethanolamines, phosphatidylcholines, unidentified aminolipids, and a number of glycolipids, the major one being an unidentified glycolipid. The quinone was Q-10. The DNA G + C content was 63.65%. Comparative 16S rRNA gene sequence analysis revealed that strain BP6-180914 T was a member of the order Hyphomicrobiales and belonged to the family Lichenihabitantaceae defined by the lichen-dwelling facultative aerobic chemo-organotroph Lichenihabitans psoromatis (92.7% sequence similarity). The results of phylogenomic and genomic relatedness analyses showed that strain BP6-180914 T could clearly be distinguished from other species in the order Hyphomicrobiales with average nucleotide identity values of < 74.05% and genome-to-genome distance values of < 21.1%. The AAI value of 65.9% between strain BP6-180914 T and L. psoromatis allowed us to assign this strain to the novel genus of the family Lichenihabitantaceae. Therefore, it is proposed that strain BP6-180914 T represents a novel species in a new genus, Lichenifustis flavocetrariae gen. nov., sp. nov.; strain BP6-180914 T (= KCTC 92872 T = VKM B-3641 T = UQM 41506 T) is the type strain.


Gratitude and coping among familial caregivers of persons with dementia.
Gratitude is widely perceived as a key factor to psychological well-being by different cultures and religions. The relationship between gratitude and coping in the context of familial dementia caregiving has yet to be investigated. This study is the first to examine the associations among gratitude, coping strategies, psychological resources and psychological distress using a structural equation modelling approach. Findings with 101 Chinese familial caregivers of persons with dementia (mean age = 57.6, range = 40-76; 82% women) showed that gratitude was related to the greater use of emotion-focused coping (positive reframing, acceptance, humour, emotional social support seeking, religious coping) and psychological resources (caregiving competence and social support). Psychological resources and emotion-focused coping in turn explained the association between gratitude and lower levels of psychological distress (caregiving burden and depressive symptoms). The present results indicate the beneficial role of gratitude on coping with caregiving distress and provide empirical foundation for incorporating gratitude in future psychological interventions for caregivers.


Avulsion of the flexor digitorum profundus: anatomic and biomechanical considerations.
Avulsion of the profundus insertion occurs most commonly in the ring finger. The exact reason for this predilection is unknown. Clinical observation of patients with this injury reveals that a common finding is that the ring fingertip is usually more prominent or "longer" than any other fingertip during grip. A laboratory investigation shows that during grip the ring fingertip becomes 5 mm more prominent than any other digit in 90% of subjects and that it absorbs more force than any other finger during pull-away testing. These factors contribute to the susceptibility of the ring finger to the profundus avulsion injury.


CSF1 gene associated with aggressive periodontitis in the Japanese population.
Aggressive periodontitis (AgP) is characterized by the early onset of the rapid and progressive destruction of the alveolar bone. We investigated the correlation of single nucleotide polymorphisms (SNPs) in candidate genes with AgP in the Japanese population in order to determine the genetic risk factors for this complex disease. Among 11 genes related to bone formation and resorption, 43 known SNPs were tested in 98 case and 88 control samples for association with AgP by using SNP genotyping techniques. Among these, three polymorphisms located in the colony stimulating factor 1 (CSF1) gene showed a positive association with AgP. This is the first case of an association between a CSF1 polymorphism and a human disease.


Methyl-aminolevulinic acid photodynamic therapy for actinic keratoses: a useful treatment or a risk factor? A retrospective study.
Photodynamic therapy (PDT) is a non-invasive treatment, used for superficial non-melanoma skin cancer (NMSC) and actinic keratoses (AKs). Although PDT is considered a safe treatment, some authors report that PDT may have carcinogenic risks. We undertook this retrospective study to determine if there is a real risk of carcinogenicity for patients treated with MAL-PDT for AK and which risk factors may increase the rate of the malignant transformation. We reviewed the records of patients treated with PDT for one or more AKs at the Sant'Orsola-Malpighi Hospital from January 2010 to December 2012. We also considered if patients had one or more risk factors for NMSC. Three hundred fifty-seven patients were treated with PDT for AKs, among them 17 patients developed a squamous cell carcinoma (SCC) in the site of a lesion previously treated with PDT. Comparing these two groups, the group which developed the SCC presented more risk factors for NMSC. PDT is certainly a good method to treat AKs, but it is important also to consider all its side effects. Among them, the carcinogenetic risk is still underestimated. We suggest that patients with multiple risk factors for NMSC treated with PDT should undergo more frequent follow-ups, in order to prevent malignant progression.


An evaluation of suture materials used in tendon surgery.
The following suture materials have been evaluated for their suitability for use in flexor tendon repairs: 4/0 gauge monofilament and multifilament stainless steel, mono-filament nylon, monofilament polypropylene, monofilament polybutestor, braided polyester, braided polyglycolic acid and a monofilament polyglyconate. These were investigated for their tensile strength (both knotted and unknotted), their extension to failure and knot-holding properties. Stainless steel and monofilament polyglyconate appeared to be the most suitable in that they had high tensile strengths, both knotted and unknotted, and had good knot-holding security. The only disadvantages are that stainless steel is difficult to use and monofilament polyglyconate is absorbable. Polypropylene and braided polyester, although having lower tensile strengths, are reasonable alternatives.


Evaluation of femoral perfusion in a rabbit model of steroid-induced osteonecrosis by dynamic contrast-enhanced MRI with a high magnetic field MRI system.
To evaluate perfusion during the early phase after steroid administration in vivo using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a high magnetic field MRI system. The main pathogenesis of steroid-induced osteonecrosis is considered to be ischemia. A single dose of methylprednisolone (MPSL) was injected into nine rabbits. DCE-MRI was performed for these rabbits before MPSL administration and 1, 5, 10, and 14 days after administration. Time-signal intensity curves were created for each femur based on the signal intensity to evaluate perfusion. Enhancement ratio (ER), initial slope (IS), and area under the curve (AUC) were calculated and the value before MPSL administration and the minimal value after administration were compared statistically. ER, IS, and AUC values after MPSL administration significantly decreased (P < 0.05, P < 0.01, and P < 0.01, respectively). All of them decreased by the 5th day in 56% of the femora and by the 14th day in 83%, and some femora even showed a decrease from the 1st day. In this study, decreased perfusion in the femora after steroid administration was proven. Additionally, we could show that it occurred from the early days after steroid administration.


MTD: a unique pipeline for host and meta-transcriptome joint and integrative analyses of RNA-seq data.
Ribonucleic acid (RNA)-seq data contain not only host transcriptomes but also nonhost information that comprises transcripts from active microbiota in the host cells. Therefore, joint and integrative analyses of both host and meta-transcriptome can reveal gene expression of the microbial community in a given sample as well as the correlative and interactive dynamics of the host response to the microbiome. However, there are no convenient tools that can systemically analyze host-microbiota interactions through simultaneously quantifying the host and meta-transcriptome in the same sample at the tissue and the single-cell level. This poses a challenge for interested researchers with limited expertise in bioinformatics. Here, we developed a software pipeline that can comprehensively and synergistically analyze and correlate the host and meta-transcriptome in a single sample using bulk and single-cell RNA-seq data. This pipeline, named meta-transcriptome detector (MTD), can extensively identify and quantify microbiome, including viruses, bacteria, protozoa, fungi, plasmids and vectors, in the host cells and correlate the microbiome with the host transcriptome. MTD is easy to install and run, involving only a few lines of simple commands. It offers researchers with unique genomics insights into host responses to microorganisms.


Associations between prenatal phthalate exposure and childhood epigenetic age acceleration.
Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement. Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood. We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant. Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships.


Is it time to switch to doxycycline from azithromycin for treating genital chlamydial infections in women? Modelling the impact of autoinoculation from the gastrointestinal tract to the genital tract.
Single-dose azithromycin is recommended over multi-dose doxycycline as treatment for chlamydial infection. However, even with imperfect adherence, doxycycline is more effective in treating genital and rectal infection. Recently, it has been suggested that autoinoculation from the rectum to the genitals may be a source of persistent chlamydial infection in women. We estimated the impact autoinoculation may have on azithromycin and doxycycline effectiveness. We estimate treatment effectiveness using a simple mathematical model, incorporating data on azithromycin and doxycycline efficacy from recent meta-analyses, and data on prevalence of rectal infection in women with genital chlamydial infection. When the possibility of autoinoculation is taken into account, we calculate that doxycycline effectiveness may be 97% compared to just 82% for azithromycin. Consideration should be given to re-evaluating azithromycin as the standard treatment for genital chlamydia in women.


A General and Extremely Simple Remote Approach toward Graphene Bulks with In Situ Multifunctionalization.
Functional graphene bulks are developed by a general and simple approach for largescale preparation. This method shows promise for energy-related applications.


Ischaemic heart disease in pregnancy.
Ischaemic heart disease (IHD) in pregnancy, particularly myocardial infarction (MI), is a rare yet potentially fatal condition for the mother and the foetus. With delays in the age of conception, the changes in some social habits among females including cigarette and shisha smoking in addition to an increased prevalence of diabetes mellitus, IHD may represent a real hazard among pregnant women in the near future. The difficulty in the diagnosis emerges from the similarity of the signs and symptoms of ischaemia and infarct to some of the physiological adaptations that occur in a normal pregnancy. The physiological changes that are normal in pregnancy may aggravate pre-existing disease and may unmask some underlying unrecognized coronary vascular changes; therefore, the diagnosis requires a high index of suspicion and careful assessment of the underlying risk factors. The management of IHD always requires a multidisciplinary team approach. The management of each patient should be individualized according to the clinical condition, the risk factors, and the availability of the necessary support. Pregnancy after MI may be an acceptable and reasonably safe option provided the cited criteria are met. A systematic PubMed search was performed to identify all published data including cases reports, small series and systematic reviews in the existing literature. These publications were comprised of both retrospective and cross sectional population studies to maximize the number of cases considered in order to reach conclusions and make recommendations based on the best available evidence considering the rare occurrence of this event. The epidemiology, diagnosis, medical and surgical treatment, and prognosis of IHD in pregnancy are the subjects of the present review.


Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific human A3s for proteasomal degradation. Vif recruits cellular transcription cofactor CBF-β and Cullin-5 (CUL5) RING E3 ubiquitin ligase to bind different A3s distinctively, but how this is accomplished remains unclear in the absence of the atomic structure of the complex. Here, we present the cryo-EM structures of HIV-1 Vif in complex with human A3H, CBF-β and components of CUL5 ubiquitin ligase (CUL5, ELOB, and ELOC). Vif nucleates the entire complex by directly binding four human proteins, A3H, CBF-β, CUL5, and ELOC. The structures reveal a large interface area between A3H and Vif, primarily mediated by an α-helical side of A3H and a five-stranded β-sheet of Vif. This A3H-Vif interface unveils the basis for sensitivity-modulating polymorphism of both proteins, including a previously reported gain-of-function mutation in Vif isolated from HIV/AIDS patients. Our structural and functional results provide insights into the remarkable interplay between HIV and humans and would inform development efforts for anti-HIV therapeutics.


Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.
Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma. This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated. Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group. Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma. Taiho Pharmaceutical.


Characterization of electrograms associated with termination of chronic atrial fibrillation by catheter ablation.
This study sought to determine the characteristics of atrial electrograms predictive of slowing or termination of atrial fibrillation (AF) during ablation of chronic AF. There is growing recognition of a role for electrogram-based ablation. Forty consecutive patients (34 male, 59 +/- 10 years) undergoing ablation for chronic AF persisting for a median of 12 months (range 1 to 84 months) were included. After pulmonary vein isolation and roof line ablation, electrogram-based ablation was performed in the left atrium and coronary sinus. Targeted electrograms were acquired in a 4-s window and characterized by: 1) percentage of continuous electrical activity; 2) bipolar voltage; 3) dominant frequency; 4) fractionation index; 5) mean absolute value of derivatives of electrograms; 6) local cycle length; and 7) presence of a temporal gradient of activation. Electrogram characteristics at favorable ablation regions, defined as those associated with slowing (a >or=6-ms increase in AF cycle length) or termination of AF were compared with those at unfavorable regions. The AF was terminated by electrogram-based ablation in 29 patients (73%) after targeting a total of 171 regions. Ablation at 37 (22%) of these regions was followed by AF slowing, and at 29 (17%) by AF termination. The percentage of continuous electrical activity and the presence of a temporal gradient of activation were independent predictors of favorable ablation regions (p = 0.016 and p = 0.038, respectively). Other electrogram characteristics at favorable ablation regions were not significantly different from those at unfavorable ablation regions. Catheter ablation at sites displaying a greater percentage of continuous activity or a temporal activation gradient is associated with slowing or termination of chronic AF.


Usability of administration devices for oral and respiratory medicines: Views from a UK primary school.
The correct use of medicine administration devices is pivotal for optimal drug therapy in children. Little is known about end users' perspectives on administration device use. Thus, the aim of this study was to conduct a survey to gain information and opinions from caregivers and children regarding the usability of paediatric medicine administration devices. A survey was conducted at a primary school in the United Kingdom in children aged 10-12 years and their caregivers. It focused on oral and respiratory devices and comprised two identical parts: 1) for the caregivers, 2) for the children with parental consent. Ethics approval (REC4612-016) was obtained. A total of 57 caregiver-child pairs accessed the survey and it was completed by parents only (n = 4), children only (n = 31) or jointly (n = 22). Most participants (65 %) had taken liquid dosage forms (e.g., syrups/suspensions) compared to solid dosage forms (34 %). Oral devices most frequently used were oral syringes (42 %), measuring spoons (22 %), and household spoons (18 %), with parents most frequently demonstrating device use to their children. Respiratory devices were used less frequently, and pressurised metered-dose inhalers with/without spacer (pMDIs) were the most commonly used devices (11/13). Instructions on use were provided by healthcare professionals to both caregivers and children. Generally, oral and respiratory devices were considered easy to use and instructions were clear. However, for both oral and respiratory devices, some suggestions for device improvement were provided by participants. Education/training by healthcare professionals and clear supplier instructions (e.g., pictograms) may be especially effective in ensuring that caregivers and children are able to use administration devices appropriately and receive sufficient information on their correct use.


Molecular diversity of 16S rRNA and gyrB genes in copper mines.
The molecular diversities of the microbial communities from four sites impacted by acid mine drainage (AMD) at Dexing Copper Mine in Jiangxi province of China were studied using 16S rRNA sequences and gyrB sequences. Of the four sampled sites, each habitat exhibited distinct geochemical characteristics and the sites were linked geographically allowing us to correlate microbial community structure to geochemical characteristics. In the present study, we examined the molecular diversity of 16S rRNA and gyrB genes from water at these sites using a PCR-based cloning approach. We found that the microbial community appears to be composed primarily of Proteobacteria, Acidobacteria, Actinobacteria, Nitrospira, Firmicutes, Chlorella and unknown phylotypes. Of clones affiliated with Nitrospira, Leptospirillum ferrooxidans, Leptospirillum ferriphilum and Leptospirillum group III were all detected. Principal-component analysis (PCA) revealed that the distribution of the microbial communities was influenced greatly by geochemical characteristics. The overall PCA profiles showed that the sites with similar geochemical characteristics had more similar microbial community structures. Moreover, our results also indicated that gyrB sequence analysis may be very useful for differentiating very closely related species in the study of microbial communities.


Pregnancy-associated plasma protein A in the prediction of early pregnancy failure.
Maternal circulating pregnancy-associated plasma protein A (PAPP-A) was measured in 51 patients with vaginal bleeding in the first half of pregnancy. Concentrations of PAPP-A were consistently lower in pregnancies which failed. In the prediction of early pregnancy failure, the predictive value of depressed maternal PAPP-A levels was 58%, the sensitivity was 91.9%, and specificity was 95.1%. These results compared favorably with other biochemical tests of placental function. However, if fetal life was demonstrated ultrasonically, depressed levels of PAPP-A substantially differentiated between those pregnancies which continued normally and those which did not, suggesting that PAPP-A estimations would be of clinical value in cases previously beyond the reach of any diagnostic measure.


Contractile response of guinea pig ileum by repetitive application of morphine.
1. The repetitive application of morphine gradually induced a contracture in the isolated guinea pig ileum. 2. The optimum conditions for induction of the contracture were as follows: the concentration, incubation time and washout time of morphine were 1 or 10 microM, 2 and 3 min, respectively. 3. Preincubation with naloxone or TTX blocked this morphine-induced contracture. 4. Among twitch-inhibiting drugs, only clonidine induced a contracture similar to that induced by morphine, while tetrodotoxin (TTX) and adenosine did not. 5. The contracture was also observed in the longitudinal muscle-myenteric plexus preparations. 6. These findings indicate that morphine has a dual inhibitory and excitatory action on the guinea pig ileum and that its repetitive application preferentially diminish the inhibitory one.


Pediatric reference value distributions for vitamins A and E in the CALIPER cohort and establishment of age-stratified reference intervals.
Vitamin A (retinol) and vitamin E (α-tocopherol) are fat soluble micronutrients most commonly measured in the pediatric population to monitor deficiencies due to malabsorption secondary to gastrointestinal (GI) disorders. One of the major challenges of vitamin A and E testing is the lack of reliable pediatric reference intervals which limits accurate interpretation of results. Here we report new pediatric reference intervals (RI) for both vitamins as part of the Canadian Laboratory Initiative for Pediatric Reference Intervals (CALIPER). A total of 342 blood samples were collected from healthy children 1 day to 19 years of age recruited from the community. Retinol and α-tocopherol were extracted from serum using hexane before concentrations were measured with high-performance liquid chromatography (HPLC). Age and sex-specific RI were calculated with guidance from CLSI C28-A2. Non-parametric and robust methods were used to calculate the 95th percentile ranges of the reference intervals along with the 90% confidence intervals. Vitamin A demonstrated increasing levels with age necessitating four distinct age stratifications. Vitamin E levels peaked within the first year of life requiring only 2 age partitions. Ratios of vitamin E to cholesterol and triglyceride were also calculated, and correlated well to vitamin E levels. Sex-specific differences were not observed. This study establishes pediatric RI for vitamins A and E in a healthy population of children from neonates to early adulthood. These values will be beneficial in assessing accurate vitamin status when monitoring children with GI disorders or malnutrition.


The effects of 2-thiophenecarboxylic acid on serum ionic calcium and magnesium levels in rats.
1. Administration of 2-thiophenecarboxylic acid to rats maintained on a low calcium diet resulted in a significant depression in the serum levels of total and ionized calcium and inorganic phosphate. 2. The serum magnesium levels were not altered by the drug.


Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP.
The network of proteins that orchestrate the distribution of cholesterol among cellular organelles is not fully characterized. We previously proposed that oxysterol-binding protein (OSBP) drives cholesterol/PI4P exchange at contact sites between the endoplasmic reticulum (ER) and the trans-Golgi network (TGN). Using the inhibitor OSW-1, we report here that the sole activity of endogenous OSBP makes a major contribution to cholesterol distribution, lipid order, and PI4P turnover in living cells. Blocking OSBP causes accumulation of sterols at ER/lipid droplets at the expense of TGN, thereby reducing the gradient of lipid order along the secretory pathway. OSBP consumes about half of the total cellular pool of PI4P, a consumption that depends on the amount of cholesterol to be transported. Inhibiting the spatially restricted PI4-kinase PI4KIIIβ triggers large periodic traveling waves of PI4P across the TGN These waves are cadenced by long-range PI4P production by PI4KIIα and PI4P consumption by OSBP Collectively, these data indicate a massive spatiotemporal coupling between cholesterol transport and PI4P turnover via OSBP and PI4-kinases to control the lipid composition of subcellular membranes.


Evaluating the efficacy of rapid diagnostic tests for imported malaria in high income countries: A systematic review.
Malaria is a life-threatening disease. Prior to the pandemic, over a million people annually from non-endemic, high income countries such as Europe and North America visited countries with a risk of malaria transmission. Emergency care nurses in non-endemic countries frequently encounter returning travellers, presenting with symptoms suggestive of malaria. While rapid diagnostic tests are used in countries with endemic malaria, in countries such as the United Kingdom diagnosis is undertaken by microscopy and three negative tests are required to exclude. Are rapid diagnostic tests effective for diagnosing imported malaria in non-endemic, high income countries? A systematic review of published research (January 2009 - November 2020) comparing rapid diagnostic tests with microscopy. Fourteen studies were included, conducted in five countries with 14 different RDTs evaluated. Mean sensitivity and specificity for Plasmodium Falciparum was 91.8% and 97.7% and Plasmodium Vivax 81.6% and 99.2%. Higher sensitivities were related to higher parasite densities. International travel will return post-pandemic and rapid, accurate and cost-efficient tests will be required. The rapid diagnostic tests in these studies showed significant variation and were not as accurate as microscopy. Consequently, it cannot be recommended that rapid diagnostic tests replace the gold standard of microscopy. Further research is required.


Mass Sperm Motility Is Correlated to Sperm Motility as Measured by Computer-Aided Sperm Analysis (CASA) Technology in Farmed Ostriches.
Semen analyses have gained momentum in various livestock industries. However, in farmed ostriches, semen analysis is still in its experimental stage, and males are not screened for sperm quality before breeding. This study investigated the correlations between computer-aided sperm analysis (CASA) technology and the traditional, yet affordable, mass sperm motility score. Semen was collected from nine South African Black ostrich males (mean age ± SD: 5.25 ± 1.21 years), using the dummy female method for 5 consecutive days monthly, for 8 months. Mass sperm motility scores were recorded on a scale of 1−5 (1: little to no sperm movement; 5: rapid sperm movement). The CASA traits recorded were: total motility (MOT), progressive motility (PMOT), curve−linear velocity (VCL), straight-line velocity (VSL), average path velocity (VAP), amplitude of lateral head displacement (ALH), linearity (LIN), straightness (STR), wobble (WOB), and beat-cross frequency (BCF). The results revealed positive correlations between mass sperm motility and PMOT, MOT, VCL, and VAP ranging from 0.34 to 0.59 (p < 0.0001). In contrast, negative correlations were recorded between mass sperm motility and LIN, STR, and BCF, with correlations ranging from −0.20 to −0.39 (p < 0.0001). VSL, ALH, and WOB were not correlated to mass sperm motility (p > 0.05). Ostrich farmers may thus be able to evaluate sperm motility reliably and potentially select breeding males by using the affordable mass sperm motility scoring method. Determining the correlation between these methods and fertility after artificial insemination or natural mating is however needed.


Fracture resistance and primary failure mode of endodontically treated teeth restored with a carbon fiber-reinforced resin post system in vitro.
This study was undertaken to characterize the fracture resistance and mode of fracture of endodontically treated incisors restored with cast post-and-core, prefabricated stainless steel post, or carbon fiber-reinforced composite post systems. Ten endodontically treated teeth restored with each technique were subjected to a compressive load delivered at a 130-degree angle to the long axis until the first sign of failure was noted. The fracture load and the mode of fracture were recorded. The failure loads registered in the three groups were not significantly different. Between 70%, and 80% of teeth from any of the three groups displayed fractures that were located above the simulated bone level. The use of carbon fiber-reinforced composite posts did not change the fracture resistance or the failure mode of endodontically treated central incisors compared to the use of metallic posts.


Non-GMP plasmid production for transient transfection in bioreactors.
We describe a generic plasmid purification process for producing DNA for larger-scale transient transfection. Data on plasmid quality with regard to residual protein, endotoxin content and presence of different plasmid forms is given. The effects of contaminants and plasmid forms on expression levels of TNFRp55 and SEAP are discussed. Transient transfection of serum-free suspension grown mammalian cells represents a suitable approach to provide research quantities of proteins (50-100 mg) within1-2 weeks.


Basilar multiplane cephalometric analysis.
This article presents a method of cephalometric tracing and analysis using the basilar view cephalogram and discusses its role in diagnosis and treatment planning. Landmarks and structures found in each of three separate basilar planes are defined and instructions for tracings are presented. The analysis is applied to the study of orbital hypertelorism, craniofacial synostosis, and hemicraniofacial microsomia. The multiplane tracing technique is demonstrated to provide a three-dimensional concept of deformities in the craniofacial skeleton. A method to determine an anteroposterior midline construct from structures in the cranial base is described. As is practiced with the lateral cephalogram, presurgical tracings of the basilar film may be manipulated to simulate the skeletal changes anticipated in surgery.


Invasive pleural malignant mesothelioma with rib destruction and concurrent osteosarcoma in a dog.
A 7-year-old Dachshund was clinically examined because of a 10-day history of lameness in the left hind limb. On the basis of radiological and cytological findings, an osteosarcoma of the left acetabular region was suspected. The dog underwent a hemipelvectomy and osteosarcoma was diagnosed by subsequent histopathological examination. An immovable subcutaneous mass was noted on the left chest wall during the physical examination and non-septic neutrophilic inflammation was diagnosed by cytology. Forty days later, the dog showed signs of respiratory distress with an in-diameter increase of the subcutaneous mass up to 4 cm. Thoracic radiography and ultrasonography revealed pleural effusion and a lytic process in the fourth left rib. Furthermore, ultrasound examination revealed a mixed echogenic mobile structure with a diameter of around 2 cm floating within the pleural fluid of the left hemithorax close to the pericardium. The dog underwent surgery for an en bloc resection of the subcutaneous mass together with the fourth rib and the parietal pleura. Moreover, the left altered lung lobe, corresponding to the mobile structure detected by ultrasound, was removed. Based on cytological, histopathological, and immunohistochemical examinations, an invasive epithelioid pleural malignant mesothelioma was diagnosed.


Detection of gonadotrophic hormones on isolated thecal interstitial cells of the domestic hen, Gallus domesticus, by an immunohistochemical method.
An immunohistochemical method was used to demonstrate the presence of gonadotrophins in isolated ovarian interstitial cells. The cells were obtained by collagenase digestion of large ovarian follicles after removal of the yolk and the granulosa layer. Using a peroxidase-labelled anti-rabbit serum with anti-chicken follicle stimulating hormone (FSH) serum raised in rabbits, a strong positive reaction was obtained. Anti-human FSH serum also produced a positive result but the reaction was weaker. There was no apparent difference in the staining reaction of cells which had been preincubated with ovine FSH serum. Treatment with anti-ovine luteinizing hormone (LH) resulted in a faintly positive reaction. The viability of the cells was tested by the Trypan Blue method and they were identified as steroid-producing cells by the histochemical demonstration of their 3 beta-hydroxysteroid dehydrogenase activity.


Increased aortic stiffness and elevated blood pressure in response to exercise in adult survivors of prematurity.
Adults born prematurely have an increased risk of early heart failure. The impact of prematurity on left and right ventricular function has been well documented, but little is known about the impact on the systemic vasculature. The goals of this study were to measure aortic stiffness and the blood pressure response to physiological stressors; in particular, normoxic and hypoxic exercise. Preterm participants (n = 10) were recruited from the Newborn Lung Project Cohort and matched with term-born, age-matched subjects (n = 12). Aortic pulse wave velocity was derived from the brachial arterial waveform and the heart rate and blood pressure responses to incremental exercise in normoxia (21% O2 ) or hypoxia (12% O2 ) were evaluated. Aortic pulse wave velocity was higher in the preterm groups. Additionally, heart rate, systolic blood pressure, and pulse pressure were higher throughout the normoxic exercise bout, consistent with higher conduit artery stiffness. Hypoxic exercise caused a decline in diastolic pressure in this group, but not in term-born controls. In this first report of the blood pressure response to exercise in adults born prematurely, we found exercise-induced hypertension relative to a term-born control group that is associated with increased large artery stiffness. These experiments performed in hypoxia reveal abnormalities in vascular function in adult survivors of prematurity that may further deteriorate as this population ages.


Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population.
X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. STS activity was measured in the leukocytes using 7-[(3)H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5' STS, 3' STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5' STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3' STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3' STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients.


Preconception thyroid-stimulating hormone levels and adverse pregnancy outcomes.
Evidence for the association between subclinical thyroid dysfunction before conception and its pregnancy outcomes is inconsistent. Thus, we evaluated the relationship between preconception thyroid-stimulating hormone (TSH) levels and adverse pregnancy outcomes. Retrospective cohort study. A total of 50,217 women without prior thyroid disease who became pregnant within 1 year after undertaking a routine TSH test in the Chongqing Municipality of China (2010-2016) were studied. Restricted cubic spline regression and logistic regression were used to estimate the association between preconception TSH levels and pregnancy outcomes. The main outcomes were individual and composite adverse pregnancy outcomes (CAPOs) comprising pregnancy loss, small for gestational age, large for gestational age, and preterm birth. Incidence of CAPO was 24.19%. Increased preconception TSH level was positively associated with CAPO (odds ratio [OR]/SD: 1.04, 95% confidence interval [CI]: 1.01-1.07) when TSH was ≥2.1 mIU/L, positively associated with pregnancy loss (OR/SD: 1.06, 95% CI: 1.01-1.12) when TSH was <2.1 mIU/L, negatively and positively associated with preterm delivery when TSH levels were <1.3 mIU/L (OR/SD: 0.90, 95% CI: 0.83-0.97) and >3.0 mIU/L (OR/SD: 1.08, 95% CI: 1.00-1.17), respectively. Women with subclinical hypothyroidism before conception were at a higher risk for CAPO (adjusted odds ratio [aOR]: 1.12, 95% CI: 1.04-1.22), while those with subclinical hyperthyroidism had a higher risk of preterm delivery (aOR: 1.31, 95% CI: 1.01-1.70). Nonlinear associations were indicated between preconception TSH levels and pregnancy outcomes. Subclinical thyroid dysfunction before conception was associated with an increased risk of adverse pregnancy outcomes.


Graves' Autoantibodies Exhibit Different Stimulating Activities in Cultures of Thyrocytes and Orbital Fibroblasts Not Reflected by Clinical Assays.
Background: The pathogenesis of Graves' hyperthyroidism (GH) and associated Graves' orbitopathy (GO) appears to involve stimulatory autoantibodies (thyrotropin receptor [TSHR]-stimulating antibodies [TSAbs]) that bind to and activate TSHRs on thyrocytes and orbital fibroblasts. In general, measurement of circulating TSHR antibodies by clinical assays correlates with the status of GH and GO. However, most clinical measurements of TSHR antibodies use competitive binding assays that do not distinguish between TSAbs and antibodies that bind to but do not activate TSHRs. Moreover, clinical assays for TSAbs measure stimulation of only one signaling pathway, the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, in engineered cells that are not thyrocytes or orbital fibroblasts. We determined whether measuring TSAbs by a cAMP-PKA readout in engineered cells accurately reveals the efficacies of stimulation by these antibodies on thyrocytes and orbital fibroblasts. Methods: We measured TSAb stimulation of normal human thyrocytes and orbital fibroblasts from patients with GO in primary cultures in vitro. In thyrocytes, we measured secretion of thyroglobulin (TG) and in orbital fibroblasts secretion of hyaluronan (hyaluronic acid [HA]). We also measured stimulation of cAMP production in engineered TSHR-expressing cells in an assay similar to clinical assays. Furthermore, we determined whether there were differences in stimulation of thyrocytes and orbital fibroblasts by TSAbs from patients with GH alone versus from patients with GO understanding that patients with GO have accompanying GH. Results: We found a positive correlation between TSAb stimulation of cAMP production in engineered cells and TG secretion by thyrocytes as well as HA secretion by orbital fibroblasts. However, TSAbs from GH patients stimulated thyrocytes more effectively than TSAbs from GO patients, whereas TSAbs from GO patients were more effective in activating orbital fibroblasts than TSAbs from GH patients. Conclusions: Clinical assays of stimulation by TSAbs measuring activation of the cAMP-PKA pathway do correlate with stimulation of thyrocytes and orbital fibroblasts; however, they do not distinguish between TSAbs from GH and GO patients. In vitro, TSAbs exhibit selectivity in activating TSHRs since TSAbs from GO patients were more effective in stimulating orbital fibroblasts and TSAbs from GH patients were more effective in stimulating thyrocytes.


Advanced head and neck cancer and clinical experience of an effective new agent: docetaxel.
Docetaxel is a taxoid cytotoxic agent known to have considerable clinical activity in a broad range of malignancies. A series of phase I/II studies have been performed to elucidate its toxicity and antitumor activity in advanced squamous cell carcinoma of the head and neck. DOCETAXEL AS FIRST-LINE MONOTHERAPY: Docetaxel administered at 100 mg/m2 as a 1-hour infusion every 3-4 weeks initiated an overall response of 27-42% for a duration of 5-6.5 months in patients with recurrent locoregional or metastatic disease. These results compare favourably with other single-agents in this setting. Preliminary analysis of combined docetaxel/cisplatin with or without 5-fluorouracil in locally advanced, unresectable or metastatic disease resulted in complete responses of 11-25%, partial responses of 50-67%, and overall responses of 75% or over. A docetaxel-based induction regimen in chemonative patients gave a universal complete response for primary disease and a 57% complete response for nodal involvement. Short lasting neutropenia rarely complicated by fever or infection is the main dose limiting toxicity of docetaxel. Acute hypersensitivity reactions and fluid retention are commonly associated with this agent but are markedly reduced by prophylactic corticosteroids. Docetaxel appears to have substantial antitumour activity in advanced head and neck cancer and further studies are justified to determine its full role in the management of this disease.


Multifaceted Roles of Plant Autophagy in Lipid and Energy Metabolism.
Together with sugars and proteins, lipids constitute the main carbon reserves in plants. Lipids are selectively recycled and catabolized for energy production during development and in response to environmental stresses. Autophagy is a major catabolic pathway, operating in the recycling of cellular components in eukaryotes. Although the autophagic degradation of lipids has been mainly characterized in mammals and yeast, growing evidence has highlighted the role of autophagy in several aspects of lipid metabolism in plants. Here, we summarize recent findings focusing on autophagy functions in lipid droplet (LD) metabolism. We further provide novel insights regarding the relevance of autophagy in the maintenance and clearance of mitochondria and peroxisomes and its consequences for proper lipid usage and energy homeostasis in plants.