Effects of macrophage- and granulocyte-colony stimulating factors on thymidylate synthase and thymidine kinase activity in rat hematopoietic cells.
The effects of macrophage (M) and granulocyte (G) colony-stimulating factors (CSFs) on the activity of thymidylate synthase and thymidine kinase, which are involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, were investigated in the hematopoietic cells of rats treated with cyclophasphamide. Thymidine kinase activity, but not that of thymidylate synthase, was markedly enhanced in these cells by M- and G-CSF treatment (p < 0.05 and p < 0.01). G-CSF directly, and M-CSF indirectly stimulate myeloid cells and lead to S-phase predominantly via the salvage pathway for pyrimidine nucleotide synthesis. The present study indicates that these CSFs can be effective inducers of complete remission in acute leukemias when employed together with chemotherapy.


Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial.
Our aim was to assess the effects of metformin on menstrual frequency, fasting plasma glucose (FPG), insulin resistance assessed as HOMA-index, weight, waist/hip ratio, blood pressure (BP), serum lipids, and testosterone levels in women with polycystic ovary syndrome (PCOS) METHODS: In a randomized, controlled, double-blinded setup, 56 women aged 18-45 with PCOS were treated with either metformin 850 mg or placebo twice daily for 6 months. After a wash-out period of 3 months participants received the alternate treatment for 6 months. The changes in the measured parameters were analysed by intention-to-treat and per protocol. There were no changes in menstrual frequency. In the intention-to-treat analysis, weight and systolic BP were reduced on metformin treatment (p=0.009 and 0.047, respectively), while high-density lipoprotein (HDL) increased (p=0.001). On placebo, weight and FPG increased (p<0.05). Post-hoc subgrouping according to BMI revealed reductions in testosterone (p=0.013), FPG (p=0.018), insulin (p=0.045) and HOMA-index (p=0.022) in obese women. Per protocol analysis showed the following differences between the changes on placebo and metformin (mean (5 - 95 % percentiles): weight (-4.2 (-7.0, -1.9) kg, p<0.001), FPG (-0.23 (-0.44, -0.01) mmol/l, p=0.041), insulin (-4.17 (-8.10, -0.23) mIU/l, p=0.039) and HOMA index (-1.50 (-2.53, -0.47) mIU/l*mmol/l, p=0.006). Weight, FPG and HOMA index were lower after metformin than after placebo. Metformin treatment lowered weight and systolic blood pressure and increased HDL in women with PCOS. In post-hoc analysis it increased insulin sensitivity and lowered testosterone in obese women. Non-obese women did not benefit from metformin.


Fast, short-column separation and fluorometric determination of monosodium glutamate in foods.
In a simple and fast procedure, monosodium glutamate in food products is first separated by a short ion exchange column and subsequently determined fluorometrically with fluorescamine. An average recovery of 90.8% with a standard deviation of plus or minus 6.67% was obtained for added monosodium glutamate in a series of 8 products. As little as 0.05% monosodium glutamate can be determined. The method is faster than the official method and saves 5 hr/determination.


[Primary hypertension of the lesser circulation].
The article presents a survey of the literature data and findings of the author's own investigations concerning various aspects of primary pulmonary hypertension (PPH). PPH -- is a polyentiological suffering. As a nosological form it was described in the fifities. There are two forms of PPH: congenital and acquired. In its turn, the congenital form comprises two variants of anomalies of the pulmonary vessels: the retnetion of the fetal structure of the pulmonary arteries and an anomaly at the level of intraorgan vascular anastomoses. Constant morphological characteristics of the two forms of PPH are as follows: endosclerosis of major branches of the pulmonary artery and focal sclerosis of their tunica media; a considerable degree of hypertrophy of the right ventricle usually not observed in other diseases. The acquired PPH may develop as a result of exposure to drugs, in thromboembolism, under high mountain conditions, etc. A question arises, whether it is justifiable to call as "primary" the acquired forms of pulmonary hypertension, since in the majority of cases their secondary nature is evident. Thus, the term "primary pullomonary hypertension" should be applied only to congenital forms of the disease. Possible in order to single out this group of desorders it would be reasonable to devise a more suitable name, for instance, "isolated pulmonary hypertension" which will render a broader sense to this polyetiological suffering.


Lysis of gram-positive and gram-negative bacteria by antibacterial porous polymeric monolith formed in microfluidic biochips for sample preparation.
Bacterial cell lysis is demonstrated using polymeric microfluidic biochips operating via a hybrid mechanical shearing/contact killing mechanism. These biochips are fabricated from a cross-linked poly(methyl methacrylate) (X-PMMA) substrate by well-controlled, high-throughput laser micromachining. The unreacted double bonds at the surface of X-PMMA provide covalent bonding for the formation of a porous polymeric monolith (PPM), thus contributing to the mechanical stability of the biochip and eliminating the need for surface treatment. The lysis efficiency of these biochips was tested for gram-positive (Enterococcus saccharolyticus and Bacillus subtilis) and gram-negative bacteria (Escherichia coli and Pseudomonas fluorescens) and confirmed by off-chip PCR without further purification. The influence of the flow rate when pumping the bacterial suspension through the PPM, and of the hydrophobic-hydrophilic balance on the cell lysis efficiency was investigated at a cell concentration of 10(5) CFU/mL. It was shown that the contribution of contact killing to cell lysis was more important than that of mechanical shearing in the PPM. The biochip showed better lysis efficiency than the off-chip chemical, mechanical, and thermal lysis techniques used in this work. The biochip also acts as a filter that isolates cell debris and allows PCR-amplifiable DNA to pass through. The system performs more efficient lysis for gram-negative than for gram-positive bacteria. The biochip does not require chemical/enzymatic reagents, power consumption, or complicated design and fabrication processes, which makes it an attractive on-chip lysis device that can be used in sample preparation for genetics and point-of-care diagnostics. The biochips were reused for 20 lysis cycles without any evidence of physical damage to the PPM, significant performance degradation, or DNA carryover when they were back-flushed between cycles. The biochips efficiently lysed both gram-positive and gram-negative bacteria in about 35 min per lysis and PPM regeneration cycle.


Flow-cytometric studies with eleutherococcus senticosus extract as an immunomodulatory agent.
A placebo-controlled study of the effect of an Eleutherococcus senticosus extract (Eleukokk) on the immune system was performed with 36 healthy volunteers utilising quantitative multi-parameter flow cytometry with monoclonal antibodies directed against specific surface markers of human lymphocyte subsets. Volunteers in the verum group received 10 ml of an ethanolic (vincamine free) eleutherococcus senticosus preparation, 3 times daily for 4 weeks. In the placebo, the eleutherococcus extract was substituted by additional wine, resulting in identical final concentrations of ethanol in both preparations. The purpose of the double-blind study was the demonstration of possible effects on the cellular immune status, as determined by quantitative flow cytometry. The most salient feature in the verum group was a drastic increase in the absolute number of immunocompetent cells, with an especially pronounced effect on T lymphocytes, predominantly of the helper/inducer type, but also on cytotoxic and natural killer cells. In addition, a general enhancement of the activation state of T lymphocytes was observed. No side effects were observed during the trial or afterwards (observation period 6 months).


Post-translational Claisen Condensation and Decarboxylation en Route to the Bicyclic Core of Pantocin A.
Pantocin A (PA) is a member of the growing family of ribosomally encoded and post-translationally modified peptide natural products (RiPPs). PA is much smaller than most known RiPPs, a tripeptide with a tight bicyclic core that appears to be cleaved from the middle of a larger 30-residue precursor peptide. We show here that the enzyme PaaA catalyzes the double dehydration and decarboxylation of two glutamic acid residues in the 30-residue precursor PaaP. Further truncates of PaaP leader and follower peptide sequences demonstrate the different impacts of these two regions on PaaA-mediated tailoring and delineate an essential role for the follower sequence in the decarboxylation step. The crystal structure of apo PaaA is reported, allowing identification of structural features that set PaaA apart from other homologous enzymes that typically do not catalyze such extended post-translational chemistry. Together, these data reveal how additional chemistry can be extracted from a ubiquitous enzyme family toward ribosomally derived peptide natural product biosynthesis and suggest that more examples of such enzymes likely exist in untapped genomic space.


Borna disease virus nucleoprotein requires both nuclear localization and export activities for viral nucleocytoplasmic shuttling.
Nuclear transport of viral nucleic acids is crucial to the life cycle of many viruses. Borna disease virus (BDV) belongs to the order Mononegavirales and replicates its RNA genome in the nucleus. Previous studies have suggested that BDV nucleoprotein (N) and phosphoprotein (P) have important functions in the nuclear import of the viral ribonucleoprotein (RNP) complexes via their nuclear targeting activity. Here, we showed that BDV N has cytoplasmic localization activity, which is mediated by a nuclear export signal (NES) within the sequence. Our analysis using deletion and substitution mutants of N revealed that NES of BDV N consists of a canonical leucine-rich motif and that the nuclear export activity of the protein is mediated through the chromosome region maintenance protein-dependent pathway. Interspecies heterokaryon assay indicated that BDV N shuttles between the nucleus and cytoplasm as a nucleocytoplasmic shuttling protein. Furthermore, interestingly, the NES region overlaps a binding site to the BDV P protein, and nuclear export of a 38-kDa form of BDV N is prevented by coexpression of P. These results suggested that BDV N has two contrary activities, nuclear localization and export activity, and plays a critical role in the nucleocytoplasmic transport of BDV RNP by interaction with other viral proteins.


Polymorphisms of the DNA repair genes XRCC1, XRCC3, XPD, interaction with environmental exposures, and bladder cancer risk in a case-control study in northern Italy.
Tobacco smoking and occupational exposures are the main known risk factors for bladder cancer, causing direct and indirect damage to DNA. Repair of DNA damage is under genetic control, and DNA repair genes may play a key role in maintaining genome integrity and preventing cancer development. Polymorphisms in DNA repair genes resulting in variation of DNA repair efficiency may therefore be associated with bladder cancer risk. A hospital-based case-control study was conducted in Brescia, Italy, to assess the relationship between polymorphisms in DNA repair genes XRCC1 (Arg(399)Gln), XRCC3 (Thr(241)Met), and XPD (Lys(751)Gln) and bladder cancer risk. A total of 201 male incident bladder cancer cases and 214 male controls with urological nonneoplastic diseases were recruited and frequency-matched on age, period, and hospital of recruitment. Detailed information was collected using a semistructured questionnaire on demographic, dietary, environmental, and occupational factors. Genotypes were determined by PCR-RFLP analysis. The XRCC3 codon 241 variant genotype exhibited a protective effect against bladder cancer [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.42-0.93], which was prominent among heavy smokers (OR, 0.49; 95% CI, 0.28-0.88) but not among never and light smokers. No overall impact of the XRCC1 codon 399 polymorphism was found (OR, 0.86; 95% CI, 0.59-1.28), but a protective influence of the homozygous variant was suggested among heavy smokers (OR, 0.38; 95% CI, 0.14-1.02). XPD polymorphisms did not show an association with bladder cancer (OR, 0.92; 95% CI, 0.62-1.37). There was no statistical evidence of an interaction between these three genetic polymorphisms and either tobacco smoking or occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines. The XRCC3 codon 241 polymorphism had an overall protective effect against bladder cancer that was most apparent among heavy smokers. Similarly, the XRCC1 codon 399 polymorphism also had a protective effect on bladder cancer among heavy smokers. The XPD polymorphism was not, however, associated with bladder cancer risk.


Vascular capacitance responses to severe systemic hypercapnia and hypoxia in dogs.
The magnitude of vascular capacitance change induced by hypercapnia, hypoxia, or hypoxic hypercapnia was estimated during the administration of experimental gas mixtures to anesthetized dogs for 25 min. Mean circulatory filling pressure (Pcf) was determined by fibrillating the heart and equilibrating arterial and venous pressures with a pump. We assumed that the total blood volume remained constant and that the magnitude of change in peripheral venous volume equaled the sum of the changes in blood volume in the cardiopulmonary and arterial beds. We further assumed that active (reflex) peripheral venoconstriction occurred if the cardiopulmonary and arterial bed blood volumes, as well as the Pcf, increased. Within 3 min, severe hypercapnia and hypoxic hypercapnia induced a 5.2 and 7.3 ml/kg reduction in systemic vascular capacity, and, by 19 min of experimental gas presentation, increased Pcf by 5.5 and 7.0 mmHg, respectively. Severe hypoxia had less effect (0.7 ml/ kg and 2.5 mmHg, respectively) at 19 min. Severe hypercapnia also increased the central venous, systemic arterial, and pulmonary arterial pressures and decreased heart rate. Hypoxic hypercapnia additionally increased cardiac output. We conclude that severe systemic hypercapnia, whether alone or in combination with hypoxia, causes a significant active reduction in vascular capacitance, but severe hypoxia is less effective.


[Eosinophilic ulcer of the tongue. Pathogenic role of eosinophils].
A male patient with an ulcerative lesion on the edge of his tongue is present. The histopathologic findings were typical for "Eosinophilic Ulcer of the Tongue". This was contiguous with a carious molar, the remotion of which was followed by total remission of the ulcer. Its possible aetiology and pathogenesis are discussed. Based on the injurious effects of eosinophils mentioned in anothers affections the authors postulate that eosinophils may have an important rol in production or maintainance of this ulcer.


[The evaluation of the severity of mitral regurgitation using color Doppler echocardiographic methods].
This study was planned to assess the vena contracta (VC), flow convergence area (PISA) and jet area (JA) methods in evaluating the severity of mitral regurgitation (MR) and to test the accuracy of a proposed algorithm using these methods. Eighty-seven patients with chronic MR were enrolled in the study. VC of < 0.3 cm, maximal MR flow rate calculated by PISA (Qmax) of < 72 cm3/sn and JA of < 4 cm2 were classified as mild MR. VC of > 0.5 cm, Qmax of > 240 cm3/sn and JA of > 8 cm2 were classified as severe MR. Whereas the values between these ranges were called to be moderate MR. The algorithm was planned as follows: In the first step, VC width was measured. If a patient has VC = 0.3-0.5 cm, it was used Qmax in the eccentric jets and JA in the central jets in the second step. The severity of MR were considered as severe, moderate and mild for > 50%, 21-49% and 20% of the regurgitant fraction calculated by the reference method (the quantitative Doppler method depending on aortic and mitral stroke volumes), respectively. The sensitivity of VC was low in differentiating between moderate and severe MR (63%). In eccentric jets, the regurgitant volume calculated by PISA was higher than that of reference method (70 +/- 49 vs. 59 +/- 29 cm3) and the JA was found to be less than that of central jets despite similar regurgitant fraction (6.8 +/- 3.2 vs. 8.5 +/- 3.3 cm2). The algorithm agreed well with the reference method and it was better than those of each tree methods (Cappa coefficients 0.89 vs. 0.65, 0.63 and 0.45 for VC, Qmax and JA; respectively). The accuracies of the algorithm in discriminating between mild and moderate MR or severe and non-severe MR were high (98% and 95%, respectively). The severity of MR can be determined accurately and simply by using VC, PISA and JA methods together.


Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators.
Several treatments have been proven to be effective for variceal bleeding in patients with cirrhosis. The aim of this multicenter, prospective, cohort study was to assess how these treatments are used in clinical practice and what are the posttherapeutic prognosis and prognostic indicators of upper digestive bleeding in patients with cirrhosis. A training set of 291 and a test set of 174 bleeding cirrhotic patients were included. Treatment was according to the preferences of each center and the follow-up period was 6 weeks. Predictive rules for 5-day failure (uncontrolled bleeding, rebleeding, or death) and 6-week mortality were developed by the logistic model in the training set and validated in the test set. Initial treatment controlled bleeding in 90% of patients, including vasoactive drugs in 27%, endoscopic therapy in 10%, combined (endoscopic and vasoactive) in 45%, balloon tamponade alone in 1%, and none in 17%. The 5-day failure rate was 13%, 6-week rebleeding was 17%, and mortality was 20%. Corresponding findings for variceal versus nonvariceal bleeding were 15% versus 7% (P =.034), 19% versus 10% (P =.019), and 20% versus 15% (P =.22). Active bleeding on endoscopy, hematocrit levels, aminotransferase levels, Child-Pugh class, and portal vein thrombosis were significant predictors of 5-day failure; alcohol-induced etiology, bilirubin, albumin, encephalopathy, and hepatocarcinoma were predictors of 6-week mortality. Prognostic reassessment including blood transfusions improved the predictive accuracy. All the developed prognostic models were superior to the Child-Pugh score. In conclusion, prognosis of digestive bleeding in cirrhosis has much improved over the past 2 decades. Initial treatment stops bleeding in 90% of patients. Accurate predictive rules are provided for early recognition of high-risk patients.


Mobile robot localization using sonar.
This correspondence describes a method by which range data from a sonar rangefinder can be used to determine the two-dimensional position and orientation of a mobile robot inside a room. The plan of the room is modeled as a list of segments indicating the positions of walls. The algorithm works by correlating straight segments in the range data against the room model, then eliminating implausible configurations using the sonar barrier test, which exploits physical constraints on sonar data. The approach is extremely tolerant of noise and clutter. Transient objects such as furniture and people need not be included in the room model, and very noisy, low-resolution sensors can be used. The algorithm's performance is demonstrated using a Polaroid Ultrasonic Rangefinder.


Visualization of Atrioventricular Nodal Reentry Tachycardia Slow Pathways Using Voltage Mapping for Pediatric Catheter Ablation.
Catheter ablation of the slow atrioventricular (AV) pathway has been shown to be safe and effective in pediatric patients with atrioventricular nodal reentrant tachycardia (AVNRT). Despite that, acute success is not guaranteed, and safety of ablating near the AV node remains a concern. A retrospective analysis was performed of all AVNRT ablations using the Ensite NavX voltage mapping technique at our institution. Each map was reviewed with patient and NavX computer data recorded. To account for a learning curve, each map was idealized and compared with the original map. Procedure and fluoroscopy time were compared with a control group. Twenty-eight patients underwent catheter ablation for AVNRT from September 2011 until December 2012 using the voltage mapping technique. The historical control group comprised 24 patients who underwent catheter ablation using the electroanatomic approach. There was 96% acute success with one recurrence in the voltage mapping group, at a mean follow-up of 24 months. The slow pathway was visualized in 86% of patients at the time of ablation, while three of four without could be found on idealization of the voltage map. Mean high- and low-voltage parameters increased with idealization, but showed no correlation with age, gender, or weight. Estimated pathway size had significant inter-patient variability. Procedure and fluoroscopy times did not vary significantly compared with controls. Visualization of the AV nodal slow pathway in a pediatric population is possible using voltage mapping technique with the potential to increase safety and efficacy. Variability exists in the voltage parameters needed to visualize individual slow pathways, which leads to a distinct learning curve.


The impact of dietary magnesium restriction on magnesiotropic and calciotropic genes.
Magnesium (Mg(2+)) is an essential electrolyte with important physiological functions. Consequently, hypomagnesaemia, an electrolyte disorder frequently diagnosed in critically ill patients, can have life-threatening consequences. The kidney plays a central role in the regulation of the Mg(2+) balance. The present study investigated the molecular consequences of dietary Mg(2+) restriction on renal Mg(2+) transporters. Two groups of 10 mice were fed a Mg(2+)-deficient diet or a Mg(2+)-enriched diet for 2 weeks. Serum and urine electrolyte concentrations were assayed. Next, renal mRNA expression levels of Mg(2+)-related genes were measured to determine their sensitivity to the dietary Mg(2+) content. Subsequently, parvalbumin (PV) and the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), both co-expressed in the distal convoluted tubule (DCT) with TRPM6, were further analysed at the protein level using immunoblotting and immunohistochemistry. Serum and urine electrolyte measurements revealed that dietary Mg(2+) restriction resulted in significant reduction of serum Mg(2+) and Ca(2+) levels, and that the urinary excretion of these ions was also markedly reduced, while phosphate (Pi) excretion was significantly increased. In addition, the serum FGF23 level was markedly increased, whereas Pi was not significantly changed in the Mg(2+)-restricted mouse group. The renal abundance of hepatocyte nuclear factor 1 homeobox B (HNF1B) and the epithelial Mg(2+) channel TRPM6 were increased in response to dietary Mg(2+) restriction, whereas other magnesiotropic transporters were not affected. PV abundance was upregulated, while NCC was significantly downregulated. Furthermore, the expression levels of the epithelial Ca(2+) channel TRPV5 and calbindin-D28K were markedly reduced in the low Mg(2+) group. Our data indicate an essential adaptive role for DCT during hypomagnesaemia since TRPM6, HNF1B, PV and NCC expression levels were adjusted. Moreover, hypomagnesaemia resulted in severe changes in Ca(2+) and Pi reabsorption and expression levels of calciotropic proteins.


Rapid induction of selective transcription by auxins.
Nuclei isolated from excised soybean plumules that were treated with 2,4-dichlorophenoxyacetic acid (2,4-D) were active in transcription of four auxin-regulated genes or DNA sequences, which have been described previously (G. Hagen, A. Kleinschmidt, and T. Guilfoyle, Planta 162:147-153, 1984). The rates of transcription of the auxin-responsive sequences were 10- to 100-fold greater with nuclei isolated from auxin-treated plumules than with those from untreated plumules. The transcriptional response was also observed with hypocotyls of intact soybean seedlings and hypocotyl sections, as well as with green bean and mung bean plumules that were treated with 2,4-D. Other auxins, including 2,4,5-trichlorophenoxyacetic acid, alpha-naphthaleneacetic acid, and indole-3-acetic acid, also induced the transcriptional response. Increased transcription rates were observed within 5 min after application of auxins to excised plumules, and half-maximal to maximal transcription rates were achieved by 15 min after application of auxins. As little as 10(-7) to 10(-8) M 2,4-D induced a transcriptional response, but maximal transcription rates were achieved at 10(-3) M 2,4-D. Brief treatment with the protein synthesis inhibitor cycloheximide did not inhibit the induction of transcription by auxins. These results clearly demonstrated that auxin-regulated gene expression is under rapid transcriptional control.


Assessment of four methodologies (microparticle enzyme immunoassay, chemiluminescent enzyme immunoassay, affinity column-mediated immunoassay, and flow injection assay-tandem mass spectrometry) for measuring tacrolimus blood concentration in Japanese liver transplant recipients.
Therapeutic drug monitoring (TDM) and subsequent dosage adjustment for individual patients in the treatment with tacrolimus are required after liver transplantation to prevent rejection and over-immunosuppression, which leads to severe infection and adverse reactions including nephrotoxicity. The purpose of this study was to evaluate the analytical performance among commercially available immunoassay methods, which were microparticle enzyme immunoassay (MEIA), chemiluminescent enzyme immunoassay (CLIA), and affinity column-mediated immunoassay (ACMIA), compared with an assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the flow injection assay (FIA-MS/MS) was also evaluated to determine whether it could be available as a new method of analysis in tacrolimus therapy. The blood tacrolimus concentrations in samples from liver transplant recipients (n = 102) were measured using MEIA, CLIA, ACMIA, and LC-MS/MS. Additional blood samples from liver transplant recipients (n = 54) were analyzed using both FIA-MS/MS and LC-MS/MS. Because the assay performance and characteristics of MEIA, CLIA, ACMIA, and FIA-MS/MS are relatively different, the measured data should be carefully considered depending on the methodology.


The functional relationship between artificial food colors and hyperactivity.
The presence of a functional relationship between the ingestion of artificial food colors and an increase in the frequency and/or duration of selected behaviors that are representative of the hyperactive behavior syndrome was experimentally investigated. Two eight-year-old females, who had been on the Feingold K-P diet for a minimum of 11 months, were the subjects studied. The experimental design was a variation of the BAB design, with double-blind conditions. This design allowed an experimental analysis of the placebo phases as well as challenge phases. Data were obtained by trained observers on Out of Seat, On Task, and Physically Aggressive behaviors, as they occurred in the subjects' regular class setting. Results indicated (a) the existence of a functional relationship between the ingestion of artificial food colors and an increase in both the duration and frequency of hyperactive behaviors, (b) the absence of a placebo effect, and (c) differential sensitivity of the dependent variables to the challenge effects.


The recursive effects of quality of life and functional limitation among older adult cancer patients: evidence from the Survey of Health, Ageing and Retirement in Europe.
Older cancer patients need to cope with two major stressful situations simultaneously - age-related stress and illness-related stress. The current study aimed to explore whether patients' quality of life (QoL) and functional limitations have a reciprocal effect over time, and further aimed to assess whether these effects differ by age group. Data were drawn from the two first waves of the Survey of Health, Ageing and Retirement in Europe. Five hundred ninety-eight participants reported that they were diagnosed with cancer or malignant tumours. All participants completed self-report questionnaires tapping personal and medical data, QoL and functional limitations. By using a two-wave cross-lagged design, findings showed a reciprocal relationship between QoL and functional limitations among older cancer patients. This reciprocal relationship was stronger in the direction from QoL to functional limitations, especially among those 75 and older in comparison with younger patients (50-74). This suggests that assessment of QoL may be beneficial to clinicians in predicting deterioration in functional limitations among older patients receiving cancer treatment.


Illegal product purchasing in the experimental tobacco marketplace: Effects of menthol cigarette and cigarette ventilation ban.
Tobacco regulations may increase demand for illegal cigarettes. We use the Experimental Tobacco Marketplace to estimate the impact of banning menthol cigarettes (Experiment 1) and decreasing allowable cigarette filter ventilation levels (Experiment 2). Crowdsourced participants were randomized into one of four groups (2×2 factorial design). Experiment 1 included menthol availability (yes/no) by purchasing option (legal only vs illegal available). Experiment 2 included filter-vented cigarettes availability (yes/no) by purchasing option (legal only vs illegal available). Participants were given an individualized budget to purchase tobacco. Percent budget spent was the outcome measure. Experiment 1, with a legal marketplace only, non-menthol cigarette purchasing was lower (p=0.010) and electronic-cigarette purchasing was higher (p=0.016), when cigarettes were banned compared to when they were available. With an illegal marketplace, switching to legal non-menthol cigarettes was less likely (p<0.001) and purchasing illegal menthol cigarettes was higher (p<0.001), when cigarettes were banned compared to when they were available. Experiment 2, with a legal marketplace only, cigarette purchasing was lower (p=0.010), when the participant's filtered vented cigarettes were banned compared to when they were available. With an illegal marketplace, purchasing the legal low-ventilated cigarette option was lower (p<0.001) and significant differences in illegal filter-vented cigarette purchasing were not observed, when their filter-vented cigarettes were banned compared to when they were available legally. Without an illegal option, both restrictions decreased cigarette purchasing, but the menthol ban increased e-cigarette purchasing. With an illegal option, a menthol ban increased illegal cigarette purchasing, but decreasing filter ventilation did not.


Probing the Conformationally Excited States of Membrane Proteins via 1H-Detected MAS Solid-State NMR Spectroscopy.
Proteins exist in ensembles of conformational states that interconvert on various motional time scales. High-energy states of proteins, often referred to as conformationally excited states, are sparsely populated and have been found to play an essential role in many biological functions. However, detecting these states is quite difficult for conventional structural techniques. Recent progress in solution NMR spectroscopy made it possible to detect conformationally excited states in soluble proteins and characterize them at high resolution. As for soluble proteins, integral or membrane-associated proteins populate different structural states often modulated by their lipid environment. Solid-state NMR spectroscopy is the method of choice to study membrane proteins, as it can detect both ground and excited states in their natural lipid environments. In this work, we apply newly developed 1H-detected 15N-HSQC type experiments under moderate magic angle spinning speeds to detect the conformationally excited states of phospholamban (PLN), a single-pass cardiac membrane protein that regulates Ca2+ transport across sarcoplasmic reticulum membrane. In its unbound state, the cytoplasmic domain of PLN exists in equilibrium between a T state, which is membrane bound and helical, and an R state, which is membrane detached and unfolded. The R state is important for regulation of the sarcoplasmic reticulum Ca2+-ATPase, but also for binding to protein kinase A. By hybridizing 1H detected solution and solid-state NMR techniques, it is possible to detect and resolve the amide resonances of the R state of PLN in liquid crystalline lipid bilayers. These new methods can be used to study the conformationally excited states of membrane proteins in native-like lipid bilayers.


A critical role of gastric mucosal ascorbic acid in the progression of acute gastric mucosal lesions induced by compound 48/80 in rats.
To study the role of gastric mucosal ascorbic acid (AA) in the progression of acute gastric mucosal lesions induced by compound 48/80 (C48/80), a mast cell degranulator, in rats. C48/80 (0.75 mg/kg) was intraperitoneally injected to fasted Wistar rats. Oral administration of AA (10, 50 or 100 mg/kg) was performed 0.5 h after C48/80 treatment. Determinations for gastric mucosal lesion severity and blood flow, and assays for gastric mucosal total AA, reduced AA, oxidized AA, vitamin E, thiobarbituric acid reactive substances (TBARS), adherent mucus, nitrite/nitrate (NOx), non-protein SH (NPSH), and myeloperoxidase (MPO), and serum total AA, reduced AA, oxidized AA, and NOx were conducted 0.5 and 3 h after C48/80 treatment. Gastric mucosal lesions occurred 0.5 h after C48/80 treatment and progressed at 3 h. Gastric mucosal blood flow decreased 0.5 h after C48/80 treatment but the decrease was recovered at 3 h. Gastric mucosal total AA, reduced AA, vitamin E, and adherent mucus concentrations decreased 3 h after C48/80 treatment. Gastric mucosal oxidized AA concentration remained unchanged after C48/80 treatment. Gastric mucosal NPSH concentration decreased 0.5 h after C48/80 treatment, but the decrease was recovered at 3 h. Gastric mucosal TBARS concentration and MPO activity increased 0.5 h after C48/80 treatment and further increased at 3 h. Serum total AA and reduced AA concentrations increased 0.5 h after C48/80 treatment and further increased at 3 h, while serum oxidized AA concentration increased at 0.5 h. Serum and gastric mucosal NOx concentrations increased 3 h after C48/80 treatment. AA administration to C48/80-treated rats at 0.5 h after the treatment prevented the gastric mucosal lesion progression and the changes in gastric mucosal total AA, reduced AA, vitamin E, adherent mucus, NOx, and TBARS concentrations and MPO activity and serum NOx concentration found at 3 h after the treatment dose-dependently. The AA administration to C48/80-treated rats caused further increases in serum total AA and reduced AA concentrations at 3 h after the treatment dose-dependently. Gastric mucosal AA plays a critical role in the progression of C48/80-induced acute gastric mucosal lesions in rats.


Influence of operating parameters on lead removal from wastewater by phosphogypsum.
The aim of this study was to investigate the influence of operating parameters on lead removal from wastewater by phosphogypsum. Batch adsorption studies were carried out to examine the effect of these parameters on lead removal from wastewater. The operating parameters investigated were adsorbent dosage, contact time, pH and initial lead concentration. Adsorption isotherms were modelled with the help of both Langmuir and Freundlich formulae. The kinetics of the adsorption process which is important in the design of waste treatment systems, was also studied.


Partitioning of the Golgi apparatus during mitosis in living HeLa cells.
The Golgi apparatus of HeLa cells was fluorescently tagged with a green fluorescent protein (GFP), localized by attachment to the NH2-terminal retention signal of N-acetylglucosaminyltransferase I (NAGT I). The location was confirmed by immunogold and immunofluorescence microscopy using a variety of Golgi markers. The behavior of the fluorescent Golgi marker was observed in fixed and living mitotic cells using confocal microscopy. By metaphase, cells contained a constant number of Golgi fragments dispersed throughout the cytoplasm. Conventional and cryoimmunoelectron microscopy showed that the NAGT I-GFP chimera (NAGFP)-positive fragments were tubulo-vesicular mitotic Golgi clusters. Mitotic conversion of Golgi stacks into mitotic clusters had surprisingly little effect on the polarity of Golgi membrane markers at the level of fluorescence microscopy. In living cells, there was little self-directed movement of the clusters in the period from metaphase to early telophase. In late telophase, the Golgi ribbon began to be reformed by a dynamic process of congregation and tubulation of the newly inherited Golgi fragments. The accuracy of partitioning the NAGFP-tagged Golgi was found to exceed that expected for a stochastic partitioning process. The results provide direct evidence for mitotic clusters as the unit of partitioning and suggest that precise regulation of the number, position, and compartmentation of mitotic membranes is a critical feature for the ordered inheritance of the Golgi apparatus.


Fractures of the proximal phalanx and metacarpals in the hand: preferred methods of stabilization.
Treatment of fractures of the proximal phalanx and metacarpals is based on the presentation of the fracture, degree of displacement, and difficulty in maintaining fracture reduction. A wide array of treatment options exists for the variation in fracture patterns observed. Inherently stable fractures do not require surgical treatment; all other fractures should be considered for additional stabilization. In general, of the many combinations of internal fixation possible, Kirschner wires and screw-and-plate fixation predominate. Early closed reduction typically is successful for unicondylar fractures of the head of the proximal phalanx. Bicondylar proximal phalanx fractures usually are treated with plate fixation. Transverse and short oblique proximal phalanx fractures generally are treated with Kirschner wires, although a stable short oblique transverse shaft fracture can be managed with an intrinsic plus splint. Plate fixation is used in comminuted proximal phalanx as well as comminuted metacarpal fractures, and lag screws in spiral long oblique phalanx shaft fractures and metacarpal head fractures. Kirschner wire fixation is successful in metacarpal neck fractures as well as both short and long transverse oblique shaft fractures.


Oligomeric forms of the 148 kDa cartilage matrix protein.
The 148 kDa cartilage matrix protein (CMP), composed of three disulphide-bonded subunits, is a cartilage-specific glycoprotein found in association with fibrils of type II collagen and possibly with aggrecan. It is probable that CMP serves a structural role. As cartilage ages, an increasing proportion of the CMP becomes insoluble and resistant to extraction. In the present study, the isolation of CMP has been improved by inclusion of a hydrophobic chromatography step, thereby removing the remaining traces of collagen and proteoglycan. Evidence of self-association of CMP is presented. Higher-molecular-mass forms of CMP, ranging in apparent molecular mass from 270 to 510 kDa and separated by SDS/PAGE, were located using a specific anti-CMP monoclonal antibody. Both CMP and its oligomeric forms are reducible to 52 kDa subunits, and only trace amounts of other proteins. The formation of oligomers, which may constitute 23% of the total cartilage matrix protein, could occur as a byproduct of the normal biosynthetic trimerization of subunits. Alternatively, the oligomers may represent a step toward the age-related cross-linking and insolubilization of CMP.


Influence of Mg++ on the effect of diltiazem to increase dihydropyridine binding to receptors on Ca++-channels in chick cardiac and skeletal muscle membranes.
The influence of Mg++ on the effect of diltiazem to increase ligand binding to a high-affinity state of dihydropyridine receptors on voltage-dependent Ca-channels has been studied in chick cardiac and skeletal muscle membranes at 25 degrees C. The high-affinity binding of the Ca-channel inhibitors (+)-[3H]PN 200-110 and [3H]nitrendipine to cardiac membranes was depressed markedly by EDTA and restored fully by the addition of free Mg++ (Ptasienski et al., Biochem. Biophys. Res. Commun. 129: 910-917, 1985). Similar results have now been obtained with skeletal muscle membranes. In the presence of EDTA alone, diltiazem, which binds to another receptor on the Ca-channel, increased the high-affinity binding of both ligands to cardiac and skeletal muscle membranes. However, in the presence of added Mg++, diltiazem had smaller or no effects on the binding of these dihydropyridines. Analyses of the data indicated that both Mg++ and diltiazem could increase the maximum binding (Bmax) for these ligands, but the effect of diltiazem was smaller than, and not additive to, that of Mg++. Specific binding of the Ca-channel activator [3H]Bay k 8644 was only observed in assays containing Mg++ in excess of EDTA. The Bmax for [3H]Bay k 8644 in skeletal muscle membranes was less than that for [3H]PN 200-110 and [3H]nitrendipine, whereas with cardiac membranes equal Bmax values were obtained for all ligands. Diltiazem increased the Bmax for [3H]Bay k 8644 in skeletal muscle, but not in cardiac membranes.(ABSTRACT TRUNCATED AT 250 WORDS)


The structure of night sleep and cardiac rhythm in patients suffering for many years from hypo- and akinesia.
The polygram of night sleep was studied in 3 patients, who due to a lesion to the CNS and peripheral nervous system were in a state of long-term akinesia and artificial lung ventilation. The cyclic organization of sleep and its transition from stage to stage, as a whole corresponded with those in healthy subjects. However, there was a general tendency in all patients to a reduction of sleep spindles. There was also a tendency to the stability of heart rate during night sleep. The relationship between delta-sleep and sleep spindles and motor activity is discussed.


Biodiversity conservation in metacommunity networks: linking pattern and persistence.
A central goal of conservation science is to identify the most important habitat patches for maintaining biodiversity on a landscape. Spatial biodiversity patterns are often used for such assessments, and patches that harbor unique diversity are generally prioritized over those with high community similarity to other areas. This places an emphasis on biodiversity representation, but removing a patch can have cascading effects on biodiversity persistence in the remaining ecological communities. Metacommunity theory provides a mechanistic route to the linking of biodiversity patterns on a landscape with the subsequent dynamics of diversity loss after habitat is degraded. Using spatially explicit neutral theory, I focus on the situation where spatial patterns of diversity and similarity are generated by the structure of dispersal networks and not environmental gradients. I find that gains in biodiversity representation are nullified by losses in persistence, and as a result the effects of removing a patch on metacommunity diversity are essentially independent of complementarity or other biodiversity patterns. In this scenario, maximizing protected area and not biodiversity representation is the key to maintaining diversity in the long term. These results highlight the need for a broader understanding of how conservation paradigms perform under different models of metacommunity dynamics.


Bispecific antibody targeted T cell therapy of ovarian cancer: clinical results and future directions.
The high frequency of relapse after induction chemotherapy in advanced ovarian carcinoma patients calls for new therapeutic modalities. Retargeted T cell-mediated lysis can be achieved using the bispecific antibody (BsmAb) OCTR, directed to CD3 on T cells and to the folate receptor on ovarian carcinoma cells. Twenty-eight patients with limited intraperitoneal disease after first-line therapy entered a phase II study. They received two i.p. 5 day cycles of activated PBMC retargeted with OCTR. Despite unfavorable tumor characteristics, 7 of 26 patients (27%) showed complete or partial intraperitoneal responses with strict surgicopathologic evaluation. In most cases, the disease relapsed outside the peritoneal cavity, and in 1 case complete intraperitoneal response was accompanied by progression in retroperitoneal lymph nodes. The morbidity was mild to moderate and transient. Combination of i.v. and i.p. administration of OCTR-retargeted lymphocytes will possibly lead to extraperitoneal cure. Ongoing clinical studies indicate that the i.v. infusion of up to 8 x 10(8) OCTR-retargeted T lymphocytes does not induce a higher toxicity than the i.p. treatment. To avoid PBMC preactivation, new approaches for delivering accessory signals are under investigation. Preliminary results indicate that nonactivated PBMC retargeted by OCTR in the presence of an anti-CD28 monoclonal antibody (mAb) are able to significantly inhibit tumor growth.


Effects of vitamin D supplementation on circulatory YKL-40 and MCP-1 biomarkers associated with vascular diabetic complications: A randomized, placebo-controlled, double-blind clinical trial.
Diabetic patients predispose to vascular diseases such as nephropathy, and retinopathy. Poor adherence to medical treatment and dietary recommendations in uncontrolled diabetes leads to vascular damages. Vitamin D has been extensively studied and found to be protective against diabetes mellitus. YKL-40 and Monocyte chemoattractant protein-1 (MCP-1) are considered to exert crucial role in diabetes and its complications. Therefore, this study was designed to investigate effects of vitamin D supplementation on serum levels of YKL-40 and MCP-1 involved in the development of diabetic complications. For 12 weeks, 48 type 2 diabetic patients enrolled in the trial and randomly were divided into two groups (n = 24 per group), receiving one of the following: 100 μg (4000 IU) vitamin D or placebo. Before and after intervention, serumYKL-40, MCP-1, insulin, IL-6, TNF-α, 25- (OH) vitamin D and HbA1c were measured. Our results revealed that serum levels of 25 (OH) vitamin D significantly increased in vitamin D group (p < 0.001). Vitamin D supplementation also significantly reduced serum YKL-40 levels (-22.7 vs. -2.4 ng/ml; (p-value = 0.003)). There was a significant decline in MCP-1 concentration in intervention group at the end of the study (-45.7 vs. -0.9 pg/ml; (p = 0.001)). Furthermore, there was a significant decrease in IL-6, fasting insulin and HOMA-IR in intervention group after 3 months supplementation. Daily vitamin D supplementation effectively reduced circulatory YKL-40 and MCP-1 levels in patients with type-2 diabetes and vitamin D deficiency. Vitamin D might contribute in reducing diabetic complications via modulating YKL-40 and MCP-1 signaling pathways.


Use of a registry-generated audit, feedback, and patient reminder intervention in an internal medicine resident clinic--a randomized trial.
Disease registries, audit and feedback, and clinical reminders have been reported to improve care processes. To assess the effects of a registry-generated audit, feedback, and patient reminder intervention on diabetes care. Randomized controlled trial conducted in a resident continuity clinic during the 2003-2004 academic year. Seventy-eight categorical Internal Medicine residents caring for 483 diabetic patients participated. Residents randomized to the intervention (n = 39) received instruction on diabetes registry use; quarterly performance audit, feedback, and written reports identifying patients needing care; and had letters sent quarterly to patients needing hemoglobin A1c or cholesterol testing. Residents randomized to the control group (n = 39) received usual clinic education. Hemoglobin A1c and lipid monitoring, and the achievement of intermediate clinical outcomes (hemoglobin A1c <7.0%, LDL cholesterol <100 mg/dL, and blood pressure <130/85 mmHg) were assessed. Patients cared for by residents in the intervention group had higher adherence to guideline recommendations for hemoglobin A1c testing (61.5% vs 48.1%, p = .01) and LDL testing (75.8% vs 64.1%, p = .02). Intermediate clinical outcomes were not different between groups. Use of a registry-generated audit, feedback, and patient reminder intervention in a resident continuity clinic modestly improved diabetes care processes, but did not influence intermediate clinical outcomes.


Comparison of porcine parvovirus to other parvoviruses by restriction site mapping and hybridization analysis of Southern Blots.
The genomic relationship between porcine parvovirus (PPV) and several other autonomous parvoviruses was examined by restriction site and hybridization analysis. Restriction site maps of the PPV genome were prepared by digesting the double-stranded replicative form of the viral DNA with each of eight restriction enzymes. Subsequent comparison of such maps with those previously reported for PPV, canine parvovirus (CPV), feline panleukopenia virus (FPV), minute virus of mice (MVM), H-1 virus (H-1) and bovine parvovirus (BPV) revealed that while the maps of CPV, FPV, MVM and H-1 had a number of features in common, those of PPV and BPV were substantially different. For hybridization analysis radioactive probes prepared by nick translation of PPV, CPV and BPV genomes were tested under conditions of both low and high stringency for homologous hybridization and for heterologous hybridization with each of the other two viruses and with FPV. The results of these tests indicated homology among the genomes of PPV, CPV and FPV, but little or no homology between the genome of BPV and those of any of the other viruses tested. Additional tests with restriction fragments of PPV and a CPV probe indicated that heterologous hybridization was confined primarily to a segment of the genome between 1.85 and 2.7 kb from the 3' end. Based on transcriptional maps previously determined for several of the rodent parvoviruses, this interval is likely to include part of the coding sequences for both non-structural and structural proteins and may be the genetic basis for the replicative as well as the antigenic similarities between PPV and both CPV and FPV.


What a difference a methylene makes: replacing Glu with Asp or Aad in the Lys-urea-Glu pharmacophore of PSMA-targeting radioligands to reduce kidney and salivary gland uptake.
The aim of this study was to investigate the effect of replacing Glu in the Lys-urea-Glu PSMA-targeting pharmacophore of [68Ga]Ga-HTK03041 with a close analog on the uptake of kidneys, salivary glands and PSMA-expressing tumor xenografts. Methods: HTK03161, HTK03149 and HTK03189A/B were obtained by replacing Glu in HTK03041 with Asp, Aad (L-2-aminoadipic acid) and Api (2-aminopimelic acid), respectively. PSMA binding affinities were measured by competition binding assays. PET imaging and biodistribution studies of 68Ga-labeled ligands were performed in LNCaP tumor-bearing mice. The best candidate HTK03149 was selected and radiolabeled with 177Lu, and SPECT imaging and biodistribution studies were performed in LNCaP tumor-bearing mice. Radiation dosimetry calculation was conducted using the OLINDA software. Radioligand therapy study was performed in LNCaP tumor-bearing mice treated with [177Lu]Lu-HTK03149 (9.3-148 MBq), [177Lu]Lu-PSMA-617 (37 MBq) or natLu-HTK03149 (500 pmol). Results: PSMA binding affinities (Ki) of Ga-HTK03161, Ga-HTK03149, Ga-HTK03189A and Lu-HTK03149 were 3.88±0.66, 6.99±0.80, 550±35.7 and 1.57±0.42 nM, respectively. PET imaging showed that all 68Ga-labeled HTK03161, HTK03149 and HTK03189A/B were excreted mainly via the renal pathway and had minimal uptake in all organs/tissues including kidneys and salivary glands. Tumor xenografts were clearly visualized in PET images of [68Ga]Ga-HTK03161 and [68Ga]Ga-HTK03149 but were barely visualized using [68Ga]Ga-HTK03189A/B. Tumor uptake values for [68Ga]Ga-HTK03161, [68Ga]Ga-HTK03149, [68Ga]Ga-HTK0189A and [68Ga]Ga-HTK03189B were 12.7±1.91, 19.1±6.37, 2.10±0.28 and 0.67±0.15 %IA/g, respectively at 1h post-injection, and their average kidney and salivary gland uptake values were 2.13-4.41 and 0.20-0.23 %IA/g, respectively. Longitudinal SPECT imaging studies showed that [177Lu]Lu-HTK03149 was excreted mainly through the renal pathway with high uptake in LNCaP tumors and minimal uptake in all normal organs/tissues. The tumor uptake of [177Lu]Lu-HTK03149 peaked at 4h post-injection (20.9±2.99 %IA/g) and the uptake was sustained over time. Compared to [177Lu]Lu-PSMA-617, [177Lu]Lu-HTK03149 had 145% increase in tumor absorbed dose but 70% less in kidney absorbed dose, leading to an 7.1-fold increase in tumor-to-kidney absorbed dose ratio. Radioligand therapy studies showed that only half of the [177Lu]Lu-PSMA-617 injected dosage was needed for [177Lu]Lu-HTK03149 to achieve the same median survival. Conclusion: Replacing Glu in the PSMA-targeting Lys-urea-Glu pharmacophore of [68Ga]Ga-HTK03041 with Asp and Aad generates [68Ga]Ga-HTK03161 and [68Ga]Ga-HTK03149, respectively, and the new derivatives retain high uptake in LNCaP tumors and have minimal uptake in normal organs/tissues including kidneys and salivary glands. [177Lu]Lu-HTK03149 also retain high uptake in LNCaP tumors and has minimal uptake in normal organs/tissues, and is, therefore, promising for clinical translation to treat prostate cancer.


Aneurysmal bone cysts.
Ten cases of aneurysmal bone cysts in various parts of the body are presented. Their features are analysed and the relevant literature is reviewed.


Team based learning in nursing and midwifery higher education; a systematic review of the evidence for change.
The aim of this study is to review the evidence in relation to the experiences and outcomes of students on nursing and/or midwifery higher education programmes, who experience team based learning. To examine the relationship between team based learning and attainment for nursing and midwifery students in professional higher education. To examine the relationship between team based learning and student satisfaction for nurses and midwifery students in higher education. To identify and report examples of good practice in the implementation of team based learning in Nursing and Midwifery higher education. A systematic Review of the literature was undertaken. The population were nurses and midwives studying on higher education pre and post registration professional programmes. The intervention was learning and teaching activities based on a team-based learning approach. Data sources included CINAHL and MEDLINE. ERIC and Index to Theses were also searched. International research papers published in English between 2011 and 2017 that met the inclusion criteria were included in the study. Papers that met the criteria were subjected to quality appraisal and agreement amongst authors for inclusion in the review. A total of sixteen papers were reviewed and four themes emerged for discussion. These were Student Engagement, Student Satisfaction, Attainment and Practice Development and Transformational Teaching and Learning. There is a tentative, though growing body of evidence to support TBL as a strategy that can impact on student engagement, student satisfaction, attainment, practice development and transformative teaching and learning. The literature indicates that implementing TBL within the curriculum is not without challenge and requires a sustained and structured approach. Staff and students need to understand the processes involved, and why they should be adhered to, in the pursuit of enhanced student experiences and outcomes for nurses and midwives in Higher Education.


The effect of inhalational anaesthetics on QTc interval.
The aim of this study was to assess time dependent cumulative effects of three different inhalation anaesthetics on QTc interval during the maintenance of anaesthesia. Seventy-five ASA I-II male patients undergoing inguinal herniorrhaphy were randomly allocated into three groups. No premedication was given. Anaesthesia was induced with thiopental and tracheal intubation was facilitated by vecuronium in all groups. Anaesthesia was maintained with 0.8% halothane (Group I) (n = 25), 1% isoflurane (Group II) (n = 25), or 2% sevoflurane (Group III) (n = 25) and 66% nitrous oxide in oxygen. Three lead electrocardiogram recordings were taken before induction, 2, 5, 10, 15, 30 and 45 min after induction and after extubation. Heart rate, systolic, diastolic, mean arterial pressure and SpO2 were recorded at the same time. Heart rate and corrected QT interval were evaluated by using Bazett's formula. Multivariate analysis of variance for repeated measures was used to determine intergroup and intragroup differences. There was no statistically significant difference in the baseline QTc values of the groups. There was no difference between QTc values with halothane and sevoflurane. There was a difference between QTc values with isoflurane and those with the other two inhalation anaesthetics (P < 0.05). Although QTc values in the isoflurane group were higher at all times, the critical value of 440 ms was not exceeded. We conclude that halothane 0.8%, isoflurane 1% and sevoflurane 2% do not prolong QTc interval.


Association of Bio-energy Processing-Induced Protein Molecular Structure Changes with CNCPS-Based Protein Degradation and Digestion of Co-products in Dairy Cows.
The primary objective of this study was to develop a model to predict Cornell Net Carbohydrate Protein System (CNCPS) protein degradation and digestion based on protein molecular structure changes induced by bio-energy processing in different types of co-products (CoPR, CoPC, CoPS = co-products from bioprocessing of rapeseed, canola seed, and soybean, respectively). The results showed that the inherent structure changes induced by the processing had a close relationship with CNCPS predicted protein degradable, undegradable, and digestible contents. The amide I to II ratio and α-helix to β-sheet ratio could be used to predict total degradable protein (R(2) = 0.99, RSD = 0.84, P < 0.001). Total CNCPS intestinal digestible protein could be predicted by protein structure α-helix to β-sheet ratio (R(2) = 0.93, RSD = 0.33, P < 0.001). In conclusion, the processing-induced protein molecular structure changes were highly linked to protein nutritive value of the co-products and could be used as predictors for CNCPS protein degradation and digestion in dairy cattle.


Modulation of primary orthostatic tremor by magnetic stimulation over the motor cortex.
To study the role of corticomotor neuronal pathways in primary orthostatic tremor. Transcranial magnetic stimuli at an intensity 10% above the resting motor threshold were delivered over the leg motor cortex in two patients with primary orthostatic tremor while standing still. Electromyographic responses in both tibialis anterior muscles were recorded after 20 stimuli given randomly at intervals of 120 to 180 seconds. Differences between predicted and actual times of occurrence of tremor bursts after the stimuli were used to calculate a resetting index, with a value of 0 representing no resetting and a value of 1 representing complete resetting. Transcranial magnetic stimulation evoked EMG responses in both tibialis anterior muscles, followed by transient suppression of tremor before reappearance of rhythmic EMG activity. Analysis of the timing of tremor bursts from EMG recordings before and after the magnetic stimuli disclosed that the phase of orthostatic tremor could be reset by brain stimulation (mean resetting indices 0.93 and 0.82). The results suggest that a central oscillator, involving the motor cortex, has a crucial role in either the generation or modulation of orthostatic tremor.


The secondary phosphite selenide, CpFe(CO)2P(Se)(O(i)Pr)2, as an organometalloligand in heterometallic M-Se-P-Fe(Cp)-type complexes [M = Cr(0), W(0), Pd(II), Pt(II), Au(I)].
The neutral metalloligand [CpFe(CO)2P(Se)(O(i)Pr)2] (Cp = η(5)-C5H5), which contains the rare secondary phosphite selenide moiety, reacts with different metal complex precursors to form six new heterobimetallic complexes containing M-Se-P-Fe(Cp) bond connectivity. The complexes [M(CO)5{CpFe(CO)2P(Se)(O(i)Pr)2}] (M = Cr, 1; M = W, 2), [MCl2{CpFe(CO)2P(Se)(O(i)Pr)2}2] (M = Pd, 3; M = Pt, 4), [Au4Cl4{CpFe(CO)2P(Se)(O(i)Pr)2}2], 5, and [AuI{CpFe(CO)2P(Se)(O(i)Pr)2}], 6, are all heterometallic, neutral, dinuclear (1, 2, 6), trinuclear (3, 4), and hexanuclear (5) complexes. The complexes were all prepared from straightforward substitution reactions (1-5) or as an adduct, 6. All new complexes were characterized by (1)H, (31)P, (77)Se NMR, infrared spectroscopy, elemental analysis and single crystal X-ray diffraction.


Risk reduction in road and rail LPG transportation by passive fire protection.
The potential reduction of risk in LPG (Liquefied Petroleum Gas) road transport due to the adoption of passive fire protections was investigated. Experimental data available for small scale vessels fully engulfed by a fire were extended to real scale road and rail tankers through a finite elements model. The results of mathematical simulations of real scale fire engulfment scenarios that may follow accidents involving LPG tankers proved the effectiveness of the thermal protections in preventing the "fired" BLEVE (Boiling Liquid Expanding Vapour Explosion) scenario. The presence of a thermal coating greatly increases the "time to failure", providing a time lapse that in the European experience may be considered sufficient to allow the start of effective mitigation actions by fire brigades. The results obtained were used to calculate the expected reduction of individual and societal risk due to LPG transportation in real case scenarios. The analysis confirmed that the introduction of passive fire protections turns out in a significant reduction of risk, up to an order of magnitude in the case of individual risk and of about 50% if the expectation value is considered. Thus, the adoption of passive fire protections, not compulsory in European regulations, may be an effective technical measure for risk reduction, and may contribute to achieve the control of "major accidents hazards" cited by the European legislation.


Causal Inference for Genetic Obesity, Cardiometabolic Profile and COVID-19 Susceptibility: A Mendelian Randomization Study.
Cross-sectional observational studies have reported obesity and cardiometabolic co-morbidities as important predictors of coronavirus disease 2019 (COVID-19) hospitalization. The causal impact of these risk factors is unknown at present. We conducted multivariable logistic regression to evaluate the observational associations between obesity traits (body mass index [BMI], waist circumference [WC]), quantitative cardiometabolic parameters (systolic blood pressure [SBP], serum glucose, serum glycated hemoglobin [HbA1c], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol and triglycerides [TG]) and SARS-CoV-2 positivity in the UK Biobank cohort. One-sample MR was performed by using the genetic risk scores of obesity and cardiometabolic traits constructed from independent datasets and the genotype and phenotype data from the UK Biobank. Two-sample MR was performed using the summary statistics from COVID-19 host genetics initiative. Cox proportional hazard models were fitted to assess the risk conferred by different genetic quintiles of causative exposure traits. The study comprised 1,211 European participants who were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 387,079 participants who were either untested or tested negative between 16 March 2020 to 31 May 2020. Observationally, higher BMI, WC, HbA1c and lower HDL-cholesterol were associated with higher odds of COVID-19 infection. One-sample MR analyses found causal associations between higher genetically determined BMI and LDL cholesterol and increased risk of COVID-19 (odds ratio [OR]: 1.15, confidence interval [CI]: 1.05-1.26 and OR: 1.58, CI: 1.21-2.06, per 1 standard deviation increment in BMI and LDL cholesterol respectively). Two-sample MR produced concordant results. Cox models indicated that individuals in the higher genetic risk score quintiles of BMI and LDL were more predisposed to COVID-19 (hazard ratio [HR]: 1.24, CI: 1.03-1.49 and HR: 1.37, CI: 1.14-1.65, for the top vs the bottom quintile for BMI and LDL cholesterol, respectively). We identified causal associations between BMI, LDL cholesterol and susceptibility to COVID-19. In particular, individuals in higher genetic risk categories were predisposed to SARS-CoV-2 infection. These findings support the integration of BMI into the risk assessment of COVID-19 and allude to a potential role of lipid modification in the prevention and treatment.


Mental Health and Psychosocial Problems of Medical Health Workers during the COVID-19 Epidemic in China.
We explored whether medical health workers had more psychosocial problems than nonmedical health workers during the COVID-19 outbreak. An online survey was run from February 19 to March 6, 2020; a total of 2,182 Chinese subjects participated. Mental health variables were assessed via the Insomnia Severity Index (ISI), the Symptom Check List-revised (SCL-90-R), and the Patient Health Questionnaire-4 (PHQ-4), which included a 2-item anxiety scale and a 2-item depression scale (PHQ-2). Compared with nonmedical health workers (n = 1,255), medical health workers (n = 927) had a higher prevalence of insomnia (38.4 vs. 30.5%, p < 0.01), anxiety (13.0 vs. 8.5%, p < 0.01), depression (12.2 vs. 9.5%; p< 0.04), somatization (1.6 vs. 0.4%; p < 0.01), and obsessive-compulsive symptoms (5.3 vs. 2.2%; p < 0.01). They also had higher total scores of ISI, GAD-2, PHQ-2, and SCL-90-R obsessive-compulsive symptoms (p ≤ 0.01). Among medical health workers, having organic disease was an independent factor for insomnia, anxiety, depression, somatization, and obsessive-compulsive symptoms (p < 0.05 or 0.01). Living in rural areas, being female, and being at risk of contact with COVID-19 patients were the most common risk factors for insomnia, anxiety, obsessive-compulsive symptoms, and depression (p < 0.01 or 0.05). Among nonmedical health workers, having organic disease was a risk factor for insomnia, depression, and obsessive-compulsive symptoms (p < 0.01 or 0.05). During the COVID-19 outbreak, medical health workers had psychosocial problems and risk factors for developing them. They were in need of attention and recovery programs.


Persistent illusory apparent motion in sequences of uncorrelated random dots.
We report a novel phenomenon in which long sequences of random dot arrays refreshing at 2.5 Hz lead to persistent illusory percepts of coherent apparent motion. We term this effect illusory apparent motion (IAM). To quantify this illusion, we devised a persistence task in which observers are primed with a particular motion pattern and must indicate when the motion pattern ends. In Experiment 1 (N = 119), we induced translational apparent motion patterns and show that both drifting motion (e.g., up-up-up-up) and rebounding motion (e.g., up-down-up-down) persists throughout many frames of uncorrelated random dots, although rebounding motion tends to persist for longer (a rebounding bias). In Experiment 2 (N = 60), we induced rotational IAM on an annulus-shaped display, and show that the topology of the display (whether the annulus is complete or has a gap) determines whether or not the rebounding bias is present. Based on our findings, we argue that IAM provides a powerful tool to study the mechanisms, constraints, and individual differences in the perception of illusory motion.


Co-Expression Network Analysis of Micro-RNAs and Proteins in the Alzheimer's Brain: A Systematic Review of Studies in the Last 10 Years.
MicroRNAs (miRNAs) are small non-coding nucleic acids that can regulate post-transcriptional gene expression by binding to complementary sequences of target mRNA. Evidence showed that dysregulated miRNA expression may be associated with neurological conditions such as Alzheimer's disease (AD). In this study, we combined the results of two independent systematic reviews aiming to unveil the co-expression network of miRNAs and proteins in brain tissues of AD patients. Twenty-eight studies including a total of 113 differentially expressed miRNAs (53 of them validated by qRT-PCR), and 26 studies including a total of 196 proteins differentially expressed in AD brains compared to healthy age matched controls were selected. Pathways analyses were performed on the results of the two reviews and 39 common pathways were identified. A further bioinformatic analysis was performed to match miRNA and protein targets with an inverse relation. This revealed 249 inverse relationships in 28 common pathways, representing new potential targets for therapeutic intervention. A meta-analysis, whenever possible, revealed miR-132-3p and miR-16 as consistently downregulated in late-stage AD across the literature. While no inverse relationships between miR-132-3p and proteins were found, miR-16's inverse relationship with CLOCK proteins in the circadian rhythm pathway is discussed and therapeutic targets are proposed. The most significant miRNA dysregulated pathway highlighted in this review was the hippo signaling pathway with p = 1.66 × 10-9. Our study has revealed new mechanisms for AD pathogenesis and this is discussed along with opportunities to develop novel miRNA-based drugs to target these pathways.


Medical versus surgical treatment of unstable angina.
Unstable angina is an important symptom of coronary artery disease. Two general clinical presentations may occur: (1) stable angina with a recent increase in severity or angina of recent onset, or (2) acute coronary insufficiency or angina at rest with chest pain resembling that of acute infarction. The risk of death or infarction is greater in patients who have recurrent chest pain and ST-T wave abnormalities despite hospital treatment. In patients without electrocardiographic or serum enzyme evidence of a completed infarct, coronary arteriography and bypass graft surgery can be performed with an acceptably low mortality rate. Surgical treatment provides better symptomatic relief than medical management in many patients, but the significant incidence of perioperative infarction makes it difficult to determine if surgery prevents infarction. Some studies indicate that surgery improves survival in subgroups, but data from large scale randomized studies will be needed to answer this question securely. Patients with disease of the left main coronary artery should probably have surgical treatment. Medical treatment will relieve symptoms in most patients with unstable angina and on a long-term basis may obviate the need for surgery. A preliminary period of intensive medical treatment before surgery may be advantageous since there is little evidence that survival rates are improved by treating unstable angina as an acute surgical emergency.


pSBVB: A Versatile Simulation Tool To Evaluate Genomic Selection in Polyploid Species.
Genomic Selection (GS) is the procedure whereby molecular information is used to predict complex phenotypes and it is standard in many animal and plant breeding schemes. However, only a small number of studies have been reported in horticultural crops, and in polyploid species in particular. In this paper, we have developed a versatile forward simulation tool, called polyploid Sequence Based Virtual Breeding (pSBVB), to evaluate GS strategies in polyploids; pSBVB is an efficient gene dropping software that can simulate any number of complex phenotypes, allowing a very flexible modeling of phenotypes suited to polyploids. As input, it takes genotype data from the founder population, which can vary from single nucleotide polymorphisms (SNP) chips up to sequence, a list of causal variants for every trait and their heritabilities, and the pedigree. Recombination rates between homeologous chromosomes can be specified, so that both allo- and autopolyploid species can be considered. The program outputs phenotype and genotype data for all individuals in the pedigree. Optionally, it can produce several genomic relationship matrices that consider exact or approximate genotype values. pSBVB can therefore be used to evaluate GS strategies in polyploid species (say varying SNP density, genetic architecture or population size, among other factors), or to optimize experimental designs for association studies. We illustrate pSBVB with SNP data from tetraploid potato and partial sequence data from octoploid strawberry, and we show that GS is a promising breeding strategy for polyploid species but that the actual advantage critically depends on the underlying genetic architecture. Source code, examples and a complete manual are freely available in GitHub https://github.com/lauzingaretti/pSBVB.


Quantitative steps in the evolution of metabolic organisation as specified by the Dynamic Energy Budget theory.
The Dynamic Energy Budget (DEB) theory quantifies the metabolic organisation of organisms on the basis of mechanistically inspired assumptions. We here sketch a scenario for how its various modules, such as maintenance, storage dynamics, development, differentiation and life stages could have evolved since the beginning of life. We argue that the combination of homeostasis and maintenance induced the development of reserves and that subsequent increases in the maintenance costs came with increases of the reserve capacity. Life evolved from a multiple reserves - single structure system (prokaryotes, many protoctists) to systems with multiple reserves and two structures (plants) or single reserve and single structure (animals). This had profound consequences for the possible effects of temperature on rates. We present an alternative explanation for what became known as the down-regulation of maintenance at high growth rates in microorganisms; the density of the limiting reserve increases with the growth rate, and reserves do not require maintenance while structure-specific maintenance costs are independent of the growth rate. This is also the mechanism behind the variation of the respiration rate with body size among species. The DEB theory specifies reserve dynamics on the basis of the requirements of weak homeostasis and partitionability. We here present a new and simple mechanism for this dynamics which accounts for the rejection of mobilised reserve by busy maintenance/growth machinery. This module, like quite a few other modules of DEB theory, uses the theory of Synthesising Units; we review recent progress in this field. The plasticity of membranes that evolved in early eukaryotes is a major step forward in metabolic evolution; we discuss quantitative aspects of the efficiency of phagocytosis relative to the excretion of digestive enzymes to illustrate its importance. Some processes of adaptation and gene expression can be understood in terms of allocation linked to the relative workload of metabolic modules in (unicellular) prokaryotes and organs in (multicellular) eukaryotes. We argue that the evolution of demand systems can only be understood in the light of that of supply systems. We illustrate some important points with data from the literature.


[Thermal radiotherapy in the treatment of a locally disseminated rectal carcinoma].
The results of thermoradiotherapy of 48 patients with local extended carcinoma of the rectum are discussed. The tumor was heated four to five times up to 42 to 43,5 degrees C by using electromagnetic waves with a frequency of 915 MHz. Total tumor dose of ionizing radiation made up 40 Gy (TDF = 88). The obtained results were compared with those in control group consisted of 74 patients with local extended carcinoma of the rectum, who underwent only radiation therapy. Basing of clinical and morphological findings the authors evaluated effects of radiation treatment and thermoradiotherapy. The comparison between two methods of preoperative treatment of local extended carcinoma of the rectum resulted in conclusion that thermoradiotherapy is a preferable method as it causes more marked regressive changes in tumor and raises operability.


The effect of the glycemic index of an evening meal on the metabolic responses to a standard high glycemic index breakfast and subsequent exercise in men.
The present study investigated the effect of the glycemic index of an evening meal on responses to a standard high glycemic index (HGI) breakfast the following morning. The metabolic responses to exercise 3 h after breakfast were also investigated. Seven active males completed 2 trials. In each trial, participants were provided with an evening meal on day 1, which was composed of either HGI or LGI (high or low glycemic index) carbohydrates. On day 2, participants were provided with a standard HGI breakfast and then performed a 60 min run at 65% VO(2max) 3 h later. Plasma glucose and serum insulin concentrations following breakfast were higher in the HGI trial compared to the LGI trial (P < 0.05). During exercise, there were no differences in substrate utilization. The results suggest that consuming a single LGI evening meal can improve glucose tolerance at breakfast but the metabolic responses to subsequent exercise were not affected.


Distinct perceptual rhythms for feature and conjunction searches.
Feature and conjunction searches are widely used to study attentional deployment. However, the spatiotemporal behavior of attention integration in these tasks remains under debate. Are multiple search stimuli processed in parallel or sequentially? Does sampling of visual information and attentional deployment differ between these two types of search? If so, how? We used an innovative methodology to estimate the distribution of attention on a single-trial basis for feature and conjunction searches. Observers performed feature- and conjunction-search tasks. They had to detect and discriminate a tilted low-spatial-frequency grating among three low-spatial-frequency vertical gratings (feature search) or low-spatial-frequency vertical gratings and high-spatial-frequency tilted gratings (conjunction search). After a variable delay, two probes were flashed at random locations. Performance in reporting the probes was used to infer attentional deployment to those locations. By solving a second-degree equation, we determined the probability of probe report at the most (P1) and least (P2) attended locations on a given trial. Were P1 and P2 equal, we would conclude that attention had been uniformly distributed across all four locations. Otherwise, we would conclude that visual information sampling and attentional deployment had been nonuniformly distributed. Our results show that processing was nonuniformly distributed across the four locations in both searches, and was modulated periodically over time at ∼5 Hz for the conjunction search and ∼12 Hz for the feature search. We argue that the former corresponds to the periodicity of attentional deployment during the search, whereas the latter corresponds to ongoing sampling of visual information. Because different locations were not simultaneously processed, this study rules out a strict parallel model for both search types.


An evaluation of diagnostic methods for bovine brucellosis in Libya.
A total of 8,607 animals were examined for detection of brucellosis using blood serum agglutination as well as complement fixation tests. out of 8,607 sera samples examined, 125 sera played positive serum agglutination reactions in significant levels for brucella (1.45%). The percentage of reactors to the complement fixation test in the examined cattle was 1.82%. The relation between positive or doubtful cases of serum tube agglutination as regards to their complement fixation results were discussed in detail.


Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.
Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.


Respiratory virus infection of peripheral blood monocytes: correlation with ageing of cells and interferon production in vitro.
The ability of respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) to replicate in peripheral blood monocytes cultured in vitro for 1, 2, 4 or 7 days prior to infection was investigated. Inoculation of 1-day old monocytes produced at least tenfold less new virus than infection of the older, more macrophage-like cells for both viruses. PIV3 induced extensive syncytium formation, whereas RSV caused a cytopathic effect manifest by increased rounding of the cells with minimal syncytium formation. Supernatants of infected monocytes were assayed for human interferon-alpha (HuIFN-alpha) in an attempt to explain the restricted viral replication in the youngest monocytes. In PIV3-infected cells, HuIFN-alpha production was inversely correlated with new virus formation. Monocytes infected after 1 day in culture produced 800 IU/ml of HuIFN-alpha; the older cells produced 100 to 200 IU/ml. In contrast, monocytes infected on day 1 with RSV produced minimal amounts (1.5 IU/ml) of HuIFN-alpha. Increasing amounts of HuIFN-alpha were detected in cells infected with RSV after 2, 4 or 7 days in culture, reaching a maximum of 400 IU/ml on day 7. Further investigation of the apparent restriction of replication in young monocyte cultures may be helpful in understanding the pathogenesis of these respiratory infections.


[Vaccine prophylaxis of infectious diseases in adults].
The paper reviews the main problems of vaccine prophylaxis of adult infectious diseases, including the organization of adult vaccination within the national calendar of immunization and that as indicated by epidemics. It gives data on vaccine-controlled adult infectious morbidity. The problems of the training of medical workers serving the adult population in vaccine prophylaxis and those of the financing of adult immunization are discussed.


Prolong: a double-blind randomised placebo-controlled trial of broccoli sprout extract in women with early onset preeclampsia. A clinical trial protocol.
Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. There is a need for adjuvant, targeted therapies to improve outcomes. Broccoli sprout extract, rich in the antioxidant sulforaphane, reduces oxidative stress and placental secretion of the antiangiogenic factors that contribute to vascular dysfunction in preeclampsia. We propose a phase III trial investigating broccoli sprout extract. We will assess broccoli sprout extract in women with early onset (<34 weeks) preeclampsia, investigating (1) the interval between enrolment and delivery (days), (2) biomarkers of placental and endothelial function and (3) maternal and fetal outcomes. A double-blind, placebo-controlled randomised trial will be conducted at Monash Health, Melbourne, Australia. One hundred and eighty women (45 each arm of each stratum) with early onset preeclampsia (defined as per Society for Obstetric Medicine of Australia and New Zealand guidelines) will be recruited. Consenting women will be randomised to receive an oral dose of either broccoli sprout extract (24 mg of activated sulforaphane) or identical placebo, twice daily until delivery. Maternal blood will be collected antenatally for measurement of biomarkers of preeclampsia, including soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin (sEng) and activin A, as well as circulating sulforaphane metabolites. Maternal and perinatal outcomes will be monitored throughout. All clinical care decisions, including the timing of delivery, will be made by the treating team, blinded to treatment allocation. Participation in this trial will not affect routine care. At delivery, maternal and cord blood and placentae will be collected to measure sulforaphane metabolites and sFlt-1, PlGF, sEng and activin A. Approval to conduct the trial has been granted by Monash Health Human Research and Ethics Committee (RES-18-0000-109A). Deidentified data will be published in peer-reviewed journals and presented at learnt society conferences, both nationally and internationally. This study has not yet commenced and is pre-results.Trial registration numberACTRN12618000216213.


The effect of triiodothyronine on maturation and differentiation of oligodendrocyte progenitor cells during remyelination following induced demyelination in male albino rat.
Demyelination was induced by two weeks cuprizone treatment. Rats of +ve control and triiodothyronine (T3) then received three subcutaneous injections of either saline or T3 day after day and sacrificed at the end of the third and fifth weeks. Animals in -ve control group received only standard rodent chow. After one week of cuprizone withdrawal the corpus callosum in +ve control and T3 treated rats was still demyelinated as revealed by MBP immunohistochemistry. The assay of PLP gene showed significant increase of T3 treated group compared to both the -ve control and +ve control groups. After three weeks, significant improvement in myelination was detected in T3-treated group compared to +ve control as detected by both MBP immunohistochemistry and electron microscopy. After one week of cuprizone withdrawal, PDGFRα positive cells and gene expression showed significant increase in +ve control and T3-treated groups as compared to -ve control with insignificant difference in between the former two groups. After three weeks of cuprizone withdrawal, PDGFRα positive cells in T3-treated and +ve control groups decreased to the control levels. These results suggest that T3 was effective in improving remyelination when administered during acute phase and might direct progenitor lineage toward oligodendrocytes.


Iliac Telangiectatic Osteosarcoma - A Rare Presentation and Diagnostic Pitfall: A Case Report.
Telangiectatic osteosarcoma is a rare variant of osteosarcoma and can be easily misdiagnosed as aneurysmal bone cyst. We report an atypical case of iliac telangiectatic osteosarcoma in a young healthy female, who presents with painful slow growing expansile lytic septate lesion in the left hemipelvis, which is initially treated as aneurysmal bone cyst. The diagnosis of aneurysmal bone cyst is made after histopathological examination of core needle biopsy. Her condition became unstable and massive bleeding is noted at the lesion site after sclerosant injection. She undergoes emergency hemipelvectomy and eventually the biopsy turns up to be telangiectatic osteosarcoma. Our case highlights that core needle biopsy is not useful in making diagnosis for iliac telangiectatic carcinoma. Hence, an open biopsy should be carried out in our case. This case also emphasises on careful evaluation for malignancy which is mandatory because bleeding from pelvis after an unsuitable treatment can be grave, to the extent that major amputation hemipelvectomy is an option. Even though telangiectatic osteosarcoma has the same prognosis and treatment with conventional osteosarcoma, the outcome of delayed treatment for telangiectatic osteosarcoma is not good due to the dilemma in establishing an early correct diagnosis.


The Effect of Cognitive Load and Task Complexity on Automation Bias in Electronic Prescribing.
Determine the relationship between cognitive load (CL) and automation bias (AB). Clinical decision support (CDS) for electronic prescribing can improve safety but introduces the risk of AB, where reliance on CDS replaces vigilance in information seeking and processing. We hypothesized high CL generated by high task complexity would increase AB errors. One hundred twenty medical students prescribed medicines for clinical scenarios using a simulated e-prescribing system in a randomized controlled experiment. Quality of CDS (correct, incorrect, and no CDS) and task complexity (low and high) were varied. CL, omission errors (failure to detect prescribing errors), and commission errors (acceptance of false positive alerts) were measured. Increasing complexity from low to high significantly increased CL, F(1, 118) = 71.6, p < .001. CDS reduced CL in high-complexity conditions compared to no CDS, F(2, 117) = 4.72, p = .015. Participants who made omission errors in incorrect and no CDS conditions exhibited lower CL compared to those who did not, F(1, 636.49) = 3.79, p = .023. Results challenge the notion that AB is triggered by increasing task complexity and associated increases in CL. Omission errors were associated with lower CL, suggesting errors may stem from an insufficient allocation of cognitive resources. This is the first research to examine the relationship between CL and AB. Findings suggest designers and users of CDS systems need to be aware of the risks of AB. Interventions that increase user vigilance and engagement may be beneficial and deserve further investigation.


HIV and amenorrhea: a meta-analysis.
There is conflicting literature to support a link between HIV and amenorrhea. Here, we conduct a meta-analysis to summarize the results from landmark studies in this area and shed light on this important clinical association. Using a search of Ovid Medline and Embase, a total of 322 articles were screened for controlled matched observational studies of amenorrhea in premenopausal women living with HIV (WLWH). For inclusion, amenorrhea was defined as absence of menses for 3 months or longer. The meta-analysis used a random-effects model with an I2 calculated to assess heterogeneity. Six studies from 1996 to 2010 were included in our analysis for a total of 8925 women (6570 WLWH). There was a significant association between HIV status and amenorrhea (OR 1.68, P value 0.0001) without evidence of heterogeneity (I2: 0.0%). In the majority of studies, there was no significant difference in substance use, smoking, or socioeconomic status between WLWH and controls. Additionally, in the majority of studies, amenorrhea in the setting of low BMI was significantly more frequent in WLWH than controls. This meta-analysis provides a large population assessment of amenorrhea in HIV to suggest increased prevalence of menstrual disturbances in WLWH. It lends evidence suggestive that this relation is independent of substance use and socioeconomic status, but may be related to low BMI. Our findings reinforce the importance of routine assessment of reproductive health and time of last menstrual period as part of the health assessment of women, especially those living with HIV.


Dissemination of high-level penicillin-, extended-spectrum cephalosporin-, and erythromycin-resistant Streptococcus pneumoniae clones in Taiwan.
Sixty-seven clinical isolates of Streptococcus pneumoniae (40 of serotype 23F, 19 of serotype 19F, and 8 of serotype 6B) with decreased susceptibilities to penicillin and erythromycin were characterized by antimicrobial susceptibility patterns; DNA restriction endonuclease cleavage profiles of the penicillin-binding protein genes pbp1a, pbp2b, and pbp2x; random amplified polymorphic DNA (RAPD) patterns generated by arbitrarily primed PCR; and chromosomal macrorestriction profiles based on pulsed-field gel electrophoresis. A total of 22 clones (identical or closely related pulsotypes and identical RAPD patterns) were identified; 14 clones of 23F, 6 of 19F, and 2 of 6B. Three 23F clones (26 isolates) and one 19F clone (9 isolates) expressed high-level resistance to penicillin, cefotaxime, and erythromycin (MICs >/= 256 microg/ml). These data strongly suggest that multiple high-level penicillin-, extended-spectrum cephalosporin-, and macrolide-resistant clones of S. pneumoniae have been disseminated in Taiwan.


5-HT3 receptor antagonists regulate autonomic cardiac dysfunction in primary fibromyalgia syndrome.
Fibromyalgia syndrome (FMS) frequently presents with autonomic and/or functional symptoms. Tropisetron, a selective serotonin-3 antagonist, is widely used for the treatment of this disease. However, its effects on autonomic function are not well known. In the present study, we evaluated whether tropisetron improved cardiac autonomic symptoms in FMS. Thirty-six patients were treated with physiotherapy and 5 mg tropisetron intravenously for 5 days. An additional 36 patients were treated with physiotherapy alone. Thirty-six volunteers served as healthy controls. The ISAX apparatus was used for spectral analyses of cardiac R-R intervals. High frequencies and mid frequencies were analysed to assess sympathetic and parasympathetic activity. The findings were correlated with pain intensity. ISAX findings were significantly different in FMS patients compared to healthy controls and did not correlate with pain perception. Ten of 12 pathological parameters disappeared during treatment in the tropisetron group. Our results indicate that tropisetron reduced not only pain perception but also had a favourable effect on cardiac dysfunction during treatment.


Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes.
Exendin-4 (Ex-4) is a Glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of Type 2 Diabetes (T2DM), which requires daily subcutaneous administration. In T2DM patients, GLP-1 administration is reported to reduce glycaemia and HbA1c in association with a modest, but significant weight loss. The aim of present study was to characterize the site-specific profile and metabolic effects of Ex-4 levels expressed from salivary glands (SG) in vivo, following adeno-associated virus-mediated (AAV) gene therapy in two different animal models of obesity prone to impaired glucose tolerance and T2DM, specifically, Zucker fa/fa rats and high fed diet (HFD) mice. Following percutaneous injection of AAV5 into the salivary glands, biologically active Ex-4 was detected in the blood of both animal models and expression persisted in salivary gland ductal cell until the end of the study. In treated mice, Ex-4 levels averaged 138.9±42.3 pmol/L on week 6 and in treated rats, mean circulating Ex-4 levels were 238.2±72 pmol/L on week 4 and continued to increase through week 8. Expression of Ex-4 resulted in a significant decreased weight gain in both mice and rats, significant improvement in glycemic control and/or insulin sensitivity as well as visceral adipose tissue adipokine profile. In conclusion, these results suggest that sustained site-specific expression of Ex-4 following AAV5-mediated gene therapy is feasible and may be useful in the treatment of obesity as well as trigger improved metabolic profile.