Fluorescent base analogues in gapmers enable stealth labeling of antisense oligonucleotide therapeutics.
To expand the antisense oligonucleotide (ASO) fluorescence labeling toolbox beyond covalent conjugation of external dyes (e.g. ATTO-, Alexa Fluor-, or cyanine dyes), we herein explore fluorescent base analogues (FBAs) as a novel approach to endow fluorescent properties to ASOs. Both cytosine and adenine analogues (tC, tCO, 2CNqA, and pA) were incorporated into a 16mer ASO sequence with a 3-10-3 cEt-DNA-cEt (cEt = constrained ethyl) gapmer design. In addition to a comprehensive photophysical characterization, we assess the label-induced effects on the gapmers' RNA affinities, RNA-hybridized secondary structures, and knockdown efficiencies. Importantly, we find practically no perturbing effects for gapmers with single FBA incorporations in the biologically critical gap region and, except for pA, the FBAs do not affect the knockdown efficiencies. Incorporating two cytosine FBAs in the gap is equally well tolerated, while two adenine analogues give rise to slightly reduced knockdown efficiencies and what could be perturbed secondary structures. We furthermore show that the FBAs can be used to visualize gapmers inside live cells using fluorescence microscopy and flow cytometry, enabling comparative assessment of their uptake. This altogether shows that FBAs are functional ASO probes that provide a minimally perturbing in-sequence labeling option for this highly relevant drug modality.


Kinetics and Monte Carlo simulation of UV disinfection of B. subtilis spores and SARS-CoV-2 in dried saliva droplets.
Surfaces can be contaminated by droplets produced through coughing or sneezing. In this exploratory work, the UV disinfection results of Bacillus subtilis spores in dried saliva droplets were fitted to a three-parameter kinetic model (R2 ≥ 0.97). This model has a disinfection rate constant for single organisms and a smaller one for aggregates found in droplets. The fraction of organisms found in aggregates (β) could account for the effects of different-sized droplets in the experimental work. Since a wide spectrum of droplet sizes can be produced, and some of the rate constants were uncertain, Monte Carlo simulation was used to estimate the UV inactivation performance in dried saliva droplets in a variety of conditions. Using conservative distribution for β, the model was applied to the UV disinfection of SARS-CoV-2 in dried saliva droplets. It was shown that a one-log reduction of SARS-CoV-2 was very likely (p>99.9%) and a two-log reduction was probable (p=75%) at a dose of 60 mJ/cm2. Aggregates tend to be variable and limit the log reductions that can be achieved at high UV doses.


The Reference Genome of Tea Plant and Resequencing of 81 Diverse Accessions Provide Insights into Its Genome Evolution and Adaptation.
Tea plant is an important economic crop, which is used to produce the world's oldest and most widely consumed tea beverages. Here, we present a high-quality reference genome assembly of the tea plant (Camellia sinensis var. sinensis) consisting of 15 pseudo-chromosomes. LTR retrotransposons (LTR-RTs) account for 70.38% of the genome, and we present evidence that LTR-RTs play critical roles in genome size expansion and the transcriptional diversification of tea plant genes through preferential insertion in promoter regions and introns. Genes, particularly those coding for terpene biosynthesis proteins, associated with tea aroma and stress resistance were significantly amplified through recent tandem duplications and exist as gene clusters in tea plant genome. Phylogenetic analysis of the sequences of 81 tea plant accessions with diverse origins revealed three well-differentiated tea plant populations, supporting the proposition for the southwest origin of the Chinese cultivated tea plant and its later spread to western Asia through introduction. Domestication and modern breeding left significant signatures on hundreds of genes in the tea plant genome, particularly those associated with tea quality and stress resistance. The genomic sequences of the reported reference and resequenced tea plant accessions provide valuable resources for future functional genomics study and molecular breeding of improved cultivars of tea plants.


Problems and pitfalls in providing acute and short-term pain relief with nonsteroidal anti-inflammatory agents.
NSAIDs are extremely versatile and effective analgesics and anti-inflammatory agents that are generally very safe to use in young, healthy adults. However, physicians should be aware of those patients who are at greater risk of toxicity from their use and avoid or modify NSAID treatment in these individuals. Certain newer NSAIDs seem to offer lower gastric or renal toxicity and might be preferable in high-risk patients.


Bi-Level ventilation decreases pulmonary shunt and modulates neuroinflammation in a cardiopulmonary resuscitation model.
Optimal ventilation strategies during cardiopulmonary resuscitation are still heavily debated and poorly understood. So far, no convincing evidence could be presented in favour of outcome relevance and necessity of specific ventilation patterns. In recent years, alternative models to the guideline-based intermittent positive pressure ventilation (IPPV) have been proposed. In this randomized controlled trial, we evaluated a bi-level ventilation approach in a porcine model to assess possible physiological advantages for the pulmonary system as well as resulting changes in neuroinflammation compared to standard measures. Sixteen male German landrace pigs were anesthetized and instrumented with arterial and venous catheters. Ventricular fibrillation was induced and the animals were left untreated and without ventilation for 4 minutes. After randomization, the animals were assigned to either the guideline-based group (IPPV, tidal volume 8-10 ml/kg, respiratory rate 10/min, FiO21.0) or the bi-level group (inspiratory pressure levels 15-17 cmH2O/5cmH2O, respiratory rate 10/min, FiO21.0). Mechanical chest compressions and interventional ventilation were initiated and after 5 minutes, blood samples, including ventilation/perfusion measurements via multiple inert gas elimination technique, were taken. After 8 minutes, advanced life support including adrenaline administration and defibrillations were started for up to 4 cycles. Animals achieving ROSC were monitored for 6 hours and lungs and brain tissue were harvested for further analyses. Five of the IPPV and four of the bi-level animals achieved ROSC. While there were no significant differences in gas exchange or hemodynamic values, bi-level treated animals showed less pulmonary shunt directly after ROSC and a tendency to lower inspiratory pressures during CPR. Additionally, cytokine expression of tumour necrosis factor alpha was significantly reduced in hippocampal tissue compared to IPPV animals. Bi-level ventilation with a constant positive end expiratory pressure and pressure-controlled ventilation is not inferior in terms of oxygenation and decarboxylation when compared to guideline-based IPPV ventilation. Additionally, bi-level ventilation showed signs for a potentially ameliorated neurological outcome as well as less pulmonary shunt following experimental resuscitation. Given the restrictions of the animal model, these advantages should be further examined.


Identification and quantification of nucleosides and nucleobases in Geosaurus and Leech by hydrophilic-interaction chromatography.
A simple hydrophilic-interaction chromatography (HILIC) method was developed for the identification and quantification of 14 nucleosides and nucleobases, namely cytosine, uracil, cytidine, guanine, hypoxanthine, xanthine, uridine, thymine, inosine, guanosine, thymidine, 2'-deoxyadenosine, 2'-deoxyinosine and 2'-deoxyuridine in two traditional Chinese medicines, Geosaurus and Leech. The separation was achieved on a TSKgel Amide-80 column (150 mm × 2.0 mm, 3.0 μm) with a mixture of acetonitrile and 10 mM aqueous ammonium acetate as the mobile phase at a flow rate of 0.2 mL/min. The temperature was set at 30°C and UV detection wavelength was set at 260 nm. All calibration curves showed good linearity (R(2)>0.9957) within the test ranges. The overall intra- and inter-day RSD ranged from 0.4 to 3.4% and from 0.7 to 3.3%, respectively. The LOD and LOQ were in the range of 0.07-30.49 ng/mL and 0.26-60.98 ng/mL, respectively. The repeatability of the method was in the range of 2.2-5.8% for Geosaurus and 1.4-5.5% for Leech. The recoveries of the samples were in the range of 91.4-100.9% for Geosaurus, and 91.9-99.3% for Leech. The established method was applied successfully for the analysis of nucleosides and nucleobases in 22 commercially available samples collected from different regions in China and Japan. Our data showed that HILIC had advantages as a useful tool for the study of the bioactive components in Geosaurus and Leech as well as their quality control, and could therefore be used for the determination of the analytes in pharmaceutical products and biological fluids.


Pre-operative pulmonary artery pulsatility index does not predict mortality post-cardiac transplantation.
The pulmonary artery pulsatility index (PAPi) is a novel haemodynamic marker that has previously been shown to predict right ventricular dysfunction and mortality in patients with pulmonary hypertension and advanced heart failure. Utility of the PAPi in predicting outcomes post-cardiac transplantation is unknown. The aim of this study was to compare the prognostic significance of PAPi against pulmonary vascular resistance (PVR) for the predication of morbidity and all-cause mortality post-transplantation. All patients who underwent cardiac transplantation over a 6 year period were studied. Pre-operative right heart catheter data was obtained. The PAPi was calculated as follows: (systolic pulmonary artery pressure [sPAP] - diastolic pulmonary artery pressure [dPAP])/right atrial (RA) pressure. One hundred fifty-eight patients with a mean age of 49 ± 14 years were studied (43 with a pre-transplant left ventricular assist device [LVAD]). Three patients were excluded due to missing data. In the non-LVAD group, there was no significant difference in PAPi or PVR, nor was there any association with post-operative outcome (including stratification by natural history sub-type; all P > 0.05). In the LVAD group, there was no association with PAPi and post-operative outcome; however, PVR was predictive of post-operative mortality (mortality: 2.8 ± 1.3 WU vs. alive: 1.7 ± 0.7 WU; P = 0.005). The PAPi was not able to discriminate mortality outcomes for patients post-cardiac transplantation. Pulmonary vascular resistance remains a marker of mortality in an LVAD cohort bridged to transplant (central illustration).


Mapping of rice Ur1 (Undulated rachis-1) gene with effect on increasing spikelet number per panicle and sink size, and development of selection markers for the breeding by the use of Ur1.
Ur1 enhances secondary rachis-branching, resulting in more spikelets per panicle. This genic effect can increase grain yield by enlarging sink size. We conducted mapping of Ur1 using SSR markers, and detected markers usable for the MAS (marker-assisted selection) for Ur1. Three Ur1 isogenic lines of recurrent parents Taichung 65, 'Shiokari' and 'Nishihikari'('T(U)', 'S(U)' and 'N(U)', respectively) were used. SSR-marker analysis indicated that each isogenic line had a non-substituted region containing Ur1 on chromosome 6 which was inherited from its donor parent. T(U) was crossed with a non-Ur1-carrying line, and the F(2) and F(3) populations were grown. Recombination values between the Ur1 locus and SSR-marker loci were obtained from data of the F(2) and F(3). On the basis of both the linkage relationship and the non-substituted regions in T(U), S(U) and N(U), candidate region of the Ur1 locus was narrowed to 0.139 Mb between the loci of up85938 and SSR17 on the long arm of chromosome 6. Genotypes of T(U) and other five Ur1-carrying lines at each locus of ten SSR markers near the Ur1 locus were determined, and allelic frequency at each locus was investigated for 27 japonica and 21 indica varieties. Consequently, SSR12 and SSR17 could be employed as MAS markers for Ur1.


Radiographic Results after Vertebral Body Tethering.
Vertebral body tethering (VBT), otherwise known as fusion-less anterior scoliosis correction (ASC), is a new and increasingly interesting therapeutic option for selected scoliosis patients. The available data on this surgical technique are still limited and guidelines on patient selection or surgical timing are not available. The aim of this study was to conduct a systematic review of the available literature on VBT. The analysis was performed in accordance with the PRISMA Statement. Nine studies with data from 175 patients were available. On average, 7.3 vertebrae were instrumented. Surgical time was 230 min and the estimated blood loss 153 ml. The mean correction on the coronal plane was 52%, and there was no significant change in sagittal parameters. The revision rate was 18.9%. The methodological quality assessment with the Coleman score gave unsatisfactory results, so that available data are not sufficient to propose general indications or guidelines to perform VBT.


Autonomic nervous system dysregulation in human hypertension.
An increased sympathetic drive combined with decreased parasympathetic inhibition is found in patients with borderline hypertension, who characteristically have rapid heart rates, high cardiac output and relatively normal vascular resistance (hyperkinetic state). In established hypertension, cardiac output is normal, vascular resistance is elevated and signs of increased sympathetic drive are absent. Apparently hemodynamics and sympathetic drive change during hypertension. The mechanism of the hemodynamic transition in the course of hypertension is well understood. Cardiac output returns from elevated to normal values as beta-adrenergic receptors down-regulate and stroke volume decreases (due to decreased cardiac compliance). The high blood pressure induces vascular hypertrophy, which in turn leads to increased vascular resistance. The mechanism of the change of sympathetic tone from elevated in borderline hypertension to apparently normal in established hypertension can best be explained within the conceptual framework of the "blood-pressure-seeking" properties of the brain. In hypertension, the central nervous system seeks to maintain systemic blood pressure at the higher level. As hypertension advances and vascular hypertrophy develops, arterioles become hyperresponsive to vasoconstriction. At this point, less sympathetic drive is needed to maintain pressure-elevating vasoconstriction, and the central sympathetic drive is down-regulated. The etiology of increased sympathetic drive in hypertension remains unresolved. Subjects with increased sympathetic drive are also usually overweight and have elevated levels of insulin, cholesterol and triglycerides, as well as decreased high-density lipoproteins. Future research must focus on the link between coronary risk factors and sympathetic overactivity in hypertension.


Passive electrical properties of the membrane and cytoplasm of cultured rat basophil leukemia cells. II. Effects of osmotic perturbation.
The effects of osmotic perturbation on the dielectric behavior of cultured rat basophilic leukemia (RBL-1) cells were examined. Cells exposed to osmolalities (pi) of 145-650 mosmolal showed dielectric dispersions of the following characteristics: Permittivity increment delta epsilon(= epsilon l - epsilon h where epsilon l and epsilon h refer to the low- and high-frequency limit values) for a fixed volume concentration increased with pi; gross permittivity behavior was apparently of a typical Cole-Cole type; however, frequency dependence of conductivity was undulant and could be simulated by a superposition of two separate Cole-Cole type dispersions; separation of these subdispersions along the frequency axis was an increasing function of pi, and so was conductivity increment in the high-frequency region. As examined by light microscopy, the cells were spherical in spite of imposed anisotonic stresses and behaved as osmometers at 200-410 mosmolal. When normalized by dividing by number (not volume) concentration, delta epsilon remained relatively constant irrespective of pi. Apparent membrane capacities (Cm), analyzed by applying a single-shell model, increased systematically from a hypotonic value of approx. 1 microF/cm2 up to 5 microF/cm2 at 650 mosmolal. This increase was interpreted as due to increased cellular 'surface/volume' ratios that were confirmed by scanning electron microscopy. Cole-Cole's beta parameter, which culminated around 0.9 for isotonic cells and declined to approx. 0.8 for anisotonic cells, did not parallel the broadening of cell volume distribution but appeared to reflect changes in the intracellular conductivity caused by the anisotonic challenge. The results indicate that the dispersion method can probe changes in surface morphology as well as subcellular organelles' constitution of living cells.


Inhaled nitric oxide after left ventricular assist device implantation: a prospective, randomized, double-blind, multicenter, placebo-controlled trial.
Used frequently for right ventricular dysfunction (RVD), the clinical benefit of inhaled nitric oxide (iNO) is still unclear. We conducted a randomized, double-blind, controlled trial to determine the effect of iNO on post-operative outcomes in the setting of left ventricular assist device (LVAD) placement. Included were 150 patients undergoing LVAD placement with pulmonary vascular resistance ≥ 200 dyne/sec/cm(-5). Patients received iNO (40 ppm) or placebo (an equivalent concentration of nitrogen) until 48 hours after separation from cardiopulmonary bypass, extubation, or upon meeting study-defined RVD. For ethical reasons, crossover to open-label iNO was allowed during the 48-hour treatment period if RVD criteria were met. RVD criteria were met by 7 of 73 patients (9.6%; 95% confidence interval, 2.8-16.3) in the iNO group compared with 12 of 77 (15.6%; 95% confidence interval, 7.5-23.7) who received placebo (p = 0.330). Time on mechanical ventilation decreased in the iNO group (median days, 2.0 vs 3.0; p = 0.077), and fewer patients in the iNO group required an RVAD (5.6% vs 10%; p = 0.468); however, these trends did not meet statistical boundaries of significance. Hospital stay, intensive care unit stay, and 28-day mortality rates were similar between groups, as were adverse events. Thirty-five patients crossed over to open-label iNO (iNO, n = 15; placebo, n = 20). Eighteen patients (iNO, n = 9; placebo, n = 9) crossed over before RVD criteria were met. Use of iNO at 40 ppm in the perioperative phase of LVAD implantation did not achieve significance for the primary end point of reduction in RVD. Similarly, secondary end points of time on mechanical ventilation, hospital or intensive care unit stay, and the need for RVAD support after LVAD placement were not significantly improved.


Kinematic fundamentals of a biomechatronic laparoscopy system.
Optical assistance in laparoscopic surgery is essential for an optimal procedure. Unlike conventional surgery, it requires new systems to reduce spatial location time, navigation and cleanliness without compromising surgical quality. This article shows the kinematic analysis of a new bio-mechatronic design to assist laparoscopic visual perspective in real time, either during training or in surgery. The bio-mechatronic system is analyzed in order to get the kinematic model of the system. The set of kinematic equations for the bio-mechatronic system are presented here. The system has been tested functionally in several surgical procedures successfully. The analysis shows the workspace under postural conditions of navigation in real time, where it is possible to get visually self assistance during training or specific surgeries. The new bio-mechatronic system has been tested in training with inanimate and biological models, in veterinary surgery and pediatrics, with the appropriate consent and respecting the Treaty of Helsinki.


Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study.
This study examines B-type natriuretic peptide (BNP) levels in patients with systolic versus non-systolic dysfunction presenting with shortness of breath. Preserved systolic function is increasingly common in patients presenting with symptoms of congestive heart failure (CHF) but is still difficult to diagnose. The Breathing Not Properly Multinational Study was a seven-center, prospective study of 1,586 patients who presented with acute dyspnea and had BNP measured upon arrival. A subset of 452 patients with a final adjudicated diagnosis of CHF who underwent echocardiography within 30 days of their visit to the emergency department (ED) were evaluated. An ejection fraction of greater than 45% was defined as non-systolic CHF. Of the 452 patients with a final diagnosis of CHF, 165 (36.5%) had preserved left ventricular function on echocardiography, whereas 287 (63.5%) had systolic dysfunction. Patients with non-systolic heart failure (NS-CHF) had significantly lower BNP levels than those with systolic heart failure (S-CHF) (413 pg/ml vs. 821 pg/ml, p < 0.001). As the severity of heart failure worsened by New York Heart Association class, the percentage of S-CHF increased, whereas the percentage of NS-CHF decreased. When patients with NS-CHF were compared with patients without CHF (n = 770), a BNP value of 100 pg/ml had a sensitivity of 86%, a negative predictive value of 96%, and an accuracy of 75% for detecting abnormal diastolic dysfunction. Using Logistic regression to differentiate S-CHF from NS-CHF, BNP entered first as the strongest predictor followed by oxygen saturation, history of myocardial infarction, and heart rate. We conclude that NS-CHF is common in the setting of the ED and that differentiating NS-CHF from S-CHF is difficult in this setting using traditional parameters. Whereas BNP add modest discriminatory value in differentiating NS-CHF from S-CHF, its major role is still the separation of patients with CHF from those without CHF.


Edge sensitive mechanisms in humans with abnormal visual experience.
Detection of broadband, aperiodic stimuli (edges) was investigated in normal observers, and in observers with abnormal visual experience which resulted in amblyopia. The spatial properties of the mechanisms used to detect an edge were investigated by a method of subthreshold addition. The method involved the determination of the threshold contrast for detecting an edge in the presence of a subthreshold line at various distances from the edge. In normal eyes, the one dimensional sensitivity profile of the edge detecting mechanism was: (1) approximately antisymmetric, (2) very localized, with sensitivity changes restricted to +/- 6'--8' on either side of the edge, and (3) phase dependent, showing an abrupt change in sign between +/- 1.5'. The sensitivity profiles of the amblyopic eyes were also approximately antisymmetric and showed the same steep rate of change from plus to minus as the fellow (nonamblyopic) eyes. However, in every case, the spatial extent of the profile was much broader than that of the nonamblyopic eyes. In normal eyes, the narrowest edge sensitivity profile was associated with the fovea; however, in two amblyopes with eccentric fixation, the narrowest edge sensitivity profile coincided with the locus of eccentric fixation. Moreover, the grating sensitivity function of the edge detecting mechanism of the amblyopic eye was similar to that of the non-amblyopic eye, but was shifted toward lower spatial frequencies. Control experiments show that these results are not accounted for on the basis of optics, eccentric fixation, or abnormal eye movements. The findings are discussed in terms of current models for the detection of aperiodic stimuli, and in the context of animal models of amblyopia.


Pathology of human metapneumovirus infection: insights into the pathogenesis of a newly identified respiratory virus.
Human metapneumovirus (hMPV) is a recently discovered human virus that causes significant respiratory infections. Pathologic features of hMPV infection have not been described. A total of 1257 pediatric respiratory samples submitted for routine clinical virologic testing were additionally tested for hMPV by reverse transcriptase polymerase chain reaction (PCR). Pathology specimens, available in 6 of 53 hMPV-positive patients, were examined by light and electron microscopy and included 6 bronchoalveolar lavage (BAL) and 3 lung biopsy specimens from 6 patients (3 girls and 3 boys) ranging in age from 1 to 16 years. BAL from three patients performed within 4 days of the positive hMPV assay showed epithelial degenerative changes and eosinophilic cytoplasmic inclusions within epithelial cells, multinucleate giant cells, and histiocytes. Inclusions were not seen in three patients with BAL performed = 1 month from the time of their positive assay. Lung biopsy, performed in three patients, all = 1 month from the time of their positive assay, showed chronic airway inflammation and intraalveolar foamy and hemosiderin-laden macrophages; all three patients had an underlying pulmonary/systemic disorder. Our findings delineate the clinicopathologic features in hMPV-infected patients undergoing anatomic sampling, which may provide diagnostic guidance to a practicing pathologist. Further, they contribute toward understanding the pathogenesis of hMPV infection.


Lymphoma presenting as small bowel obstruction: A case report.
Small bowel lymphoma accounts for 10%-30% of gastro-intestinal tumors. Clinical presentation is not specific. CT scans helps the diagnosis showing some characteristic appearances such as wall thickening of the loops, enlarged lymph nodes and infiltration of mesenteric fat. Pseudoaneurysmal intestinal dilatation is uncommon and may cause bowel obstruction which is a diagnostic and therapeutic emergency. We report the case of a 73-year-old man, who presented for occlusive syndrome revealing hail lymphoma. Pseudoaneurysmal intestinal dilatation is an uncommon presentation of lymphoma that should evoke the diagnosis especially when associated to wall thickening of the loops and lymphadenopathy.


Risk factors for 30-day readmission in general medical patients admitted from the emergency department: a single centre study.
Overcrowding in emergency departments (ED) around the world is an increasingly serious problem with an adverse impact on both patient flow and patient outcomes. A significant contributing factor to ED overcrowding is possibly due to readmission. Risk factors for readmission in patients admitted from ED are rarely studied, particularly in Asian countries where the length of stay is reportedly longer. A retrospective study of patients admitted to general medical wards from the ED of a referral centre in northern Taiwan from November 2009 to April 2010 was conducted. The primary outcome was 30-day hospital readmission and clinical characteristics were analysed for predictors of readmission. Of the recruited 2698 patients, 451 (16.7%) were readmitted within 30 days after discharge. Age, gender, marital status and the activities of daily living (Barthel's score) were not associated with 30-day readmission. Higher Charlson score ((score 2-4) hazard ratio (HR): 1.42, 95% confidence interval (CI): 1.07-1.89; (score >4) HR: 1.93, 95% CI: 1.37-2.73), longer hospital stay ((8-14 days) HR: 1.51, 95% CI: 1.17-1.95; (15-28 days) HR: 1.64, 95% CI: 1.22-2.19; (>28 days) HR: 1.97, 95% CI: 1.43-2.71), and presence of underlying active malignancy (HR: 1.66, 95% CI: 1.27-2.16) and anaemia (HR: 1.26, 95% CI: 1.02-1.55) were independently associated with readmission. Medical patients admitted from the ED of a referral centre have a 30-day readmission rate of 16.7%. Post-discharge care should focus on patients with higher Charlson score, longer hospitalisation, anaemia and underlying active malignancy, which are independent predictive factors for 30-day readmission.


The way to a man's heart is through his stomach: much 'diaphragmatic' attenuation is likely gastric, and effervescent granules enhance cardiac imaging.
Avoidance of falsely positive results depends on distinguishing reality from artifact, in turn depending on images of highest quality. In radionuclide cardiac imaging, an inferior wall artifactual defect, so called "diaphragmatic attenuation", is particularly common and vexing. Despite the historically held view, analysis and review of the literature suggest the defect is likely not diaphragmatic but rather primarily due to attenuation by nearby stomach wall. The explanation is based on gravity and anatomy. With this improved understanding, effervescent granules were given as a clinical, nonresearch measure to nine patients during myocardial scanning. It was observed that two-thirds demonstrated moderate or marked lessening of attenuation. An additional benefit is lessening of artifact by extracardiac activity. These benefits may also apply to other sorts of cardiac radionuclide imaging. The significance of this new imaging method is discussed and various avenues of research are proposed.


Polytene chromosomes of Oxytricha: biochemical and morphological changes during macronuclear development in a ciliated protozoan.
After conjugation in the ciliated protozoan, Oxytricha, polytene chromosomes are formed during the development of a macronucleus from a micronucleus. Here we report a microscopic study of these chromosomes and an analysis of their DNA. The polytene chromosomes of Oxytricha bear a strong morphological resemblance to the polytene chromosomes of the Dipteran salivary gland. The nucleus of a developing macronuclear anlage contains 120 +/- 2 polytene chromosomes and each chromosome has an average of 81 hands; a total of about 10,000 bands per nucleus. At a later stage in development, the number of bands per chromosome is reduced by a factor of four, presumably due to fusion of adjacent bands. The polytene chromosomes then break up into their constituent bands, each of which is encased in a vesicle. There are about 2,700 vesicles per nucleus.--During the growth of polytene chromosomes, there is a change in the relative proportion of sequences in the DNA. The DNA from polytene nuclei has a buoyant density of 1.695 g/cc, significantly lighter than the density of the original micronuclear DNA (1.698 G/cc to 1.702 g/cc). We interpret this buoyant density change to be the result of differential replication of DNA sequences during polytene chromosome growth. A second change in DNA composition occurs after the polytene stage of development, shown by a shift in buoyant density to 1.701 g/cc in the DNA of the mature macronucleus. During this second process, the molecular weight of the DNA is reduced from greater than 50 x 10(6) daltons to about 2 x 10(6) daltons.


Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context.
Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro-drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in naive animals, a far cry from the clinical pathologic context of paracetamol use. Moreover, FAAH is a ubiquitous enzyme expressed both in the central nervous system and in the periphery. Thus, we explored: (i) the involvement of FAAH in the analgesic action of paracetamol in a mouse model of inflammatory pain; and (ii) the contributions of central versus peripheral FAAH in this action. The analgesic effect of paracetamol was evaluated in thermal hyperalgesia, mechanical allodynia and hyperalgesia induced by an intra-plantar injection of carrageenan (3%) in FAAH knock-out mice or their littermates. Moreover, the contribution of the central and peripheral enzymes was explored by comparing the effect of a global FAAH inhibitor (URB597) to that of a peripherally restricted FAAH inhibitor (URB937) on paracetamol action. Here, we show that in a model of inflammatory pain submitted to different stimuli, the analgesic action of paracetamol was abolished when FAAH was genetically or pharmacologically inhibited. Whereas a global FAAH inhibitor, URB597 (0.3 mg/kg), reduced the anti-hyperalgesic action of paracetamol, a brain-impermeant FAAH inhibitor, URB937 (0.3 mg/kg), had no influence. However, administered intracerebroventricularly, URB937 (5 μg/mouse) reduced the action of paracetamol. These results demonstrate that the supra-spinally-located FAAH enzyme is necessary for the analgesic action of paracetamol.


Lesion of nucleus basalis magnocellularis decreases [3H]hemicholinium-3 binding (as measured by autoradiography) in the amygdala and frontal cortex of the rat.
The effects of a unilateral electrolytic lesion of the nucleus basalis magnocellularis on [3H]hemicholinium-3 binding sites in discrete brain regions of the rat were studied through the use of quantitative autoradiography. When compared to the contralateral side this lesion caused a decrease in the density of [3H]hemicholinium-3 binding sites in the medial prefrontal cortex, frontoparietal cortex and basolateral nucleus of the amygdala but not in the caudate-putamen, nucleus accumbens, olfactory tubercle, hippocampus and auditory cortex. These results add further weight to the view that the cholinergic innervation of the rostral cerebral cortex and amygdala originates from the nucleus basalis magnocellularis and suggest that [3H]hemicholinium-3 autoradiography is a suitable means of visualizing cholinergic nerve terminals.


LncRNA TUG1 Promoted Stabilization of BAG5 by Binding DDX3X to Exacerbate Ketamine-Induced Neurotoxicity.
As a clinically widely used anesthetic, ketamine (KET) has been reported to cause neurotoxicity in patients. Our work aimed to probe the function of long-chain non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) in KET-induced neurotoxicity. HT22 cells were subjected to KET to build the cell model. 3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide (MTT) assay was employed to determine cell viability. Additionally, cell apoptosis was evaluated by flow cytometry. The binding relationships among TUG1, DEAD-box RNA helicase 3X (DDX3X), and Bcl-2-associated athanogene 5 (BAG5) were verified by RIP and RNA pull-down assays. Cell viability was impaired and cell apoptosis was increased in KET-treated HT22 cells accompanied by increased TUG1, DDX3X, and BAG5 expressions. TUG1 knockdown dramatically enhanced cell viability and repressed the of KET-induced apoptosis in HT22 cells, while TUG1 overexpression presented the opposite effects. In addition, we found that TUG1 promoted DDX3X expression via directly binding with DDX3X. As expected, DDX3X overexpression abolished the palliative effect of TUG1 knockdown on KET-induced neurotoxicity. Further research proved that TUG1 increased the stability of BAG5 through interacting with DDX3X. Finally, as expected, the moderating effect of TUG1 knockdown on KET-induced neuron injury was abolished by BAG5 overexpression. Taken together, TUG1 promoted BAG5 expression by binding DDX3X to exacerbate KET-induced neurotoxicity.


Small-bowel resection. Oral intake is the stimulus for hyperplasia.
Small-bowel resection leads to hyperplasia of the residual small intestine, However, the factors initiating small-bowel hyperplasia are not clearly understood, although oral intake either by direct contact with the small bowel or via hormonal or neurovascular factors has been suggested as the major stimulus. In order to determine whether oral intake is an obligatory prerequisite for small-intestinal hyperplasia, we compared rats one week after undergoing a 70-cm proximal intestinal resection with sham-operated animals. Resected, orally fed rats demonstrated small-intestinal hyperplasia, whereas resected and sham-operated intravenously alimented rats did not. There were no differences in gut weight, mucosal weight, mucosal protein, or DNA between resected or sham-operated intravenously alimented rats. These data provide direct experimental proof that oral intake is a necessary stimulus for small-intestinal hyperplasia after resection.


Remediation of Cd contaminated paddy fields by intercropping of the high- and low- Cd-accumulating rice cultivars.
Intercropping cadmium (Cd) hyperaccumulators with crops have been widely applied in the remediation of contaminated farmland soils. However, most studies were done on drylands since the majority of the hyperaccumulators are susceptible to the aquatic environment, making the remediation of Cd-contaminated paddy fields particularly difficult. Our study attempts to address the issue by intercropping the high-Cd-accumulating (henceforth, "high-Cd") rice cultivars with the low-Cd-accumulating (henceforth, "low-Cd") ones, and to study the Cd removal, uptake and translocation during the remediation process. The results indicated that intercropping mode with 20-cm row spacing (intercropping-20 treatment) performed better than the that with 30-cm row spacing (intercropping-30 treatment), while intercropping had stronger impact on late rice compared to early rice. In general, the physiological condition of rice was stable under the intercropping-20 treatment, suggesting the growth of rice was not impeded. For late rice, as the intercropping-20 treatment can significantly reduce soil pH and increase the diethylenetriaminepentaacetic acid extracted Cd (DTPA-extracted Cd) from the rhizosphere soil, Cd accumulated more in the tissues of the high-Cd rice cultivars (H2), and its dry biomass increased. As a result, a drastic improvement in the total Cd removal rate by 38.55 % was noticed. Therefore, the reduction of total Cd concentration in 0-20 cm profile caused by removal, thus it could provide safer soil environment for the growth of low Cd-rice cultivars (L2), leading to a significant drop in the root Cd concentration and safer production of L2. Interestingly, intercropping had no effect on the yield per plant of low-Cd rice cultivars. For early rice, intercropping-20 treatment exerted trivial effects to all aspects. The intercropping-30 treatment has poor representativeness of all indicators because of the large intercropping distance. Our results demonstrate that intercropping of the high-Cd and the low-Cd rice cultivars is a potential mode for Cd remediation in paddy fields.


Effectiveness and safety of lenvatinib plus anti-programmed death-1 antibodies in patients with hepatocellular carcinoma: A real-world cohort study.
Lenvatinib plus anti-programmed death-1 (anti-PD-1) antibody combinations have shown potent anti-tumor effect in phase I/II trials in advanced or unresectable hepatocellular carcinoma (HCC), but real-world data are limited. To investigate the effectiveness and safety of lenvatinib plus anti-PD-1 antibodies in a real-world cohort, we retrospectively evaluated 210 patients with unresectable or advanced HCC treated with these regimens between October 2018 and February 2022. The objective response rate and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were 28.1% and 75.2%. Median overall survival (OS) and progression-free survival (PFS) in the overall cohort were 17.2 and 8.4 months, respectively. Median OS and PFS of patients receiving first-line treatment reached 18.9 and 9.6 months. Median OS was significantly longer in patients with Child-Pugh class A versus B (18.8 vs. 5.9 months, respectively), as was median PFS (9.1 vs. 4.4 months). Patients with albumin-bilirubin (ALBI) grade 1 versus grade 2/3 also had significantly greater median OS (23.5 vs. 13.4 months). Treatment-related adverse events (AEs) occurred in 79.5% of patients. Patients with ALBI grade 2/3 had a higher rate of grade 3/4 AEs than patients with ALBI grade 1 (57.5% vs. 38.5%). Lenvatinib combined with anti-PD-1 antibody therapy was effective in patients with sufficient liver function reserve. Further study is needed to improve therapeutic efficacy and AE management in patients with Child-Pugh class B or ALBI grade 2/3.


The chameleon-like nature of elusive cobalt-oxygen intermediates in C-H bond activation reactions.
High-valence metal-oxo (M-O, M = Fe, Mn, etc.) species are well-known reaction intermediates that are responsible for a wide range of pivotal oxygenation reactions and water oxidation reactions in metalloenzymes. Although extensive efforts have been devoted to synthesizing and identifying such complexes in biomimetic studies, the structure-function relationship and related reaction mechanisms of these reaction intermediates remain elusive, especially for the cobalt-oxygen species. In the present manuscript, the calculated results demonstrate that the tetraamido macrocycle ligated cobalt complex, Co(O)(TAML) (1), behaves like a chameleon: the electronic structure varies from a cobalt(III)-oxyl species to a cobalt(IV)-oxo species when a Lewis acid Sc3+ salt coordinates or an acidic hydrocarbon attacks 1. The dichotomous correlation between the reaction rates of C-H bond activation by 1 and the bond dissociation energy (BDE) vs. the acidity (pKa) was rationalized for the first time by different reaction mechanisms: for normal C-H bond activation, the Co(III)-oxyl species directly activates the C-H bond via a hydrogen atom transfer (HAT) mechanism, whereas for acidic C-H bond activation, the Co(III)-oxyl species evolves to a Co(IV)-oxo species to increase the basicity of the oxygen to activate the acidic C-H bond, via a novel PCET(PT) mechanism (proton-coupled electron transfer with a PT(proton-transfer)-like transition state). These theoretical findings will enrich the knowledge of biomimetic metal-oxygen chemistry.


Association of body mass index and waist circumference with high blood pressure in older adults.
The relationship between obesity and prevalent high blood pressure in older adults has predominantly been estimated using categorical measures of body mass index (BMI) and waist circumference (WC), masking the shape of the dose-response relationship. We aimed to examine the precise relationship of BMI, WC with high blood pressure and to assess the appropriate level of BMI and WC for high blood pressure. We examined data for 126,123 individuals in Xinzheng city aged ≥60 years from a population based study from January to December 2019. Logistic regression and restricted cubic spline models were applied to assess the relationship and the appropriate level of BMI and WC for high blood pressure. An additive interaction analysis was used to test synergistic effects between a higher BMI and WC for high blood pressure. The full-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of an increase of 1 kg/m2 in BMI and 1 cm in WC for high blood pressure were 1.084 (1.080-1.087) and 1.026(1.024-1.027), respectively. Multivariable adjusted restricted cubic spline analyses showed the nonlinear relationships of BMI and WC with high blood pressure in both men and women (all P < 0.001). The risk of high blood pressure increased steeply with increasing BMI from ≥25 kg/m2 and WC ≥ 88 cm or 86 cm for males and females, respectively. And we observed a significant additive interaction between a higher BMI and WC such that the prevalence of high blood pressure was significantly enhanced. These findings suggest increased high blood pressure prevalence in the older adults with increased BMI and WC. BMI ≤ 25 kg/m2 and WC ≤ 88 cm or 86 cm for males and females may be the best suggestion with regard to primary prevention of high blood pressure in older adults.


Application of the conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats.
The conditioned taste aversion (CTA) paradigm is one of the reliable methods to evaluate the discriminative stimulus properties of drugs and is characterized by a short conditioning period and no need for special equipment. This method, however, has not yet been fully investigated for psychostimulants such as cocaine and methamphetamine. In the present study, rats were trained to discriminate between cocaine and a vehicle using CTA and substitution tests with various psychostimulants were conducted to evaluate the usefulness of the method for assessing the discriminative stimulus properties of this pharmacological class. Male rats received an intraperitoneal (i.p.) injection of cocaine (10mg/kg) 10 min prior to access saccharin for 20-min, and immediately after the saccharin access they received an i.p. dose of LiCl (1.8 mEq; n=8, Group CL) or the vehicle (n=8, Group CW) on the day of conditioning; on the other days (2 or 3 days between the cocaine conditioning days), they were injected with saline prior to access to saccharin without the LiCl or vehicle injection after the access. By the fifteenth cocaine conditioning trial, all animals acquired discrimination. In the substitution test, cocaine dose dependently decreased saccharin consumption. The psychostimulants, methamphetamine, methylphenidate, bupropion and sibutramine, substituted for cocaine, whereas the opioid μ agonist morphine and the cannabinoid agonist, Δ9-tetrahydrocannabinol, did not substitute for cocaine. Mazindol did not substitute for cocaine although it has CNS stimulant activities. These results suggest that discriminative stimulus properties of psychostimulants can be evaluated using the CTA paradigm.


Anaerobic co-digestion of glycerol and wastewater derived from biodiesel manufacturing.
The anaerobic co-digestion of glycerol and wastewater derived from biodiesel manufacturing, in which COD was found to be 1054 and 428 g/L, respectively, was studied in batch laboratory-scale reactors at mesophilic temperature (35 degrees C). Glycerol was acidified with H(3)PO(4) in order to recover the alkaline catalyst employed in the transesterification reaction (KOH) as agricultural fertiliser (potassium phosphates). Wastewater was subjected to an electrocoagulation process in order to reduce its oil content. After mixing, the anaerobic revalorisation of the wastewater was studied employing inoculum-substrate ratios ranging from 5.02 to 1.48 g VSS/g COD and organic loading rates of 0.27-0.36 g COD/g VSS d. Biodegradability was found to be around 100%, while the methane yield coefficient was 310 mL CH(4)/g COD removed (1 atm, 25 degrees C). At the equilibrium time, the proportionality between r' and the load was constant, showing 1.55 mL CH(4)/(g VSS g COD h). The results showed that anaerobic co-digestion reduces the clean water and nutrient requirement, with the consequent economical and environmental benefit.


Primary Hyperaldosteronism and Renal Medullary Nephrocalcinosis: A Controversial Association.
Primary hyperaldosteronism (PA) is a common disease with a prevalence of 5-10% in unselected patients with hypertension. Medullary nephrocalcinosis is a radiological diagnosis and refers to diffuse calcification in the renal parenchyma. The three commonest causes of nephrocalcinosis are hyperparathyroidism, distal renal tubular acidosis, and medullary sponge kidney. PA is not a recognized cause of nephrocalcinosis. There are a few case reports linking PA with nephrocalcinosis published till date. In this case series, we report three cases where PA was possibly associated with medullary nephrocalcinosis. In all three cases, the common causes of nephrocalcinosis were excluded by careful clinical history, biochemical evaluation, and radiological findings. We conclude and emphasize that a diagnosis of PA as an etiology of medullary nephrocalcinosis should be sought after common causes have been excluded, at least in those with hypertension that is difficult to control.


Male mouse submaxillary gland secretes highly toxic proteins.
Submaxillary gland saliva induced by phenylephrine from male mice was highly toxic to guinea-pigs, rats and hamsters, whereas the toxicity was relatively low to mice. One of the toxic components in the saliva was isolated as a kallikrein-like enzyme.


[Tuberculosis in a cohort of patients with systemic lupus erythematosus].
1) To study tuberculosis (TB) infection in a cohort of patients with systemic lupus erythematosus (SLE) and to compare its frequency and characteristics with that of others series. 2) To look for differential characteristic among SLE patients with and without TB. 3) To investigate if there was any relationship between TB's most severe forms and higher doses of glucocorticoids (GC) or other immunosuppressants. Retrospective review of medical records of 789 SLE patients and description of the clinical characteristics of 13 cases of active TB infection among them. Bibliographical search in MEDLINE-PubMed of the SLE/TB series published, using the terms: infection, tuberculosis, systemic lupus erythematosus. Comparative study of clinical, biological and therapeutic differences between cases (SLE/TB+) and controls (SLE/TB) using χ(2) and Fisher exact test. Thirteen patients with active tuberculosis were detected (10 women, average age 36 years/SD 11,2/prevalence 1,6%). Nine (69,2%) of them were primary infections and 4 (30,8%) reactivations. Microbiological diagnosis (smear examination for acid-fast bacilli and/or culture on Lowestein-Jensen medium) was established in 11 patients (84,6%). TB Pulmonary manifestations was present in 9 patients (69,2%) and extra-pulmonary manifestations were found in 8 [(61,5%); 6 of them (46%) were disseminated forms]. Nine (69,2%) patients were on GC therapy at the moment TB was diagnosed. Four of the TB patients died (30,8%). Myositis was more frequent in TB cases (p < 0,05). This data is similar to that reported in the literature. In our series, TB mortality was high (30,8%) in a patients with SLE. Frequency of extrapulmonary forms was double than that described in the Spanish population. Patients with higher GC dose had more severe forms of TB.


Liver transplantation for hereditary hemorrhagic telangiectasia: a systematic review.
To evaluate the indications, timing and results of liver transplantation in patients affected by hereditary hemorrhagic telangiectasia (HHT), by undertaking a systematic review of the current literature. Electronic bibliographical databases were searched on MEDLINE and Pubmed according to the PRISMA criteria. A total of 58 articles were initially found, 11 have been excluded because of single center series later included in the European Liver transplant Registry (ELTR), already reported in this study. Thirty-eight articles have been excluded because they did not report specifically new cases of liver transplantation for hereditary hemorrhagic telangiectasia. Finally 9 articles were included in the analysis. A total of 56 patients who underwent liver transplantation for HHT are present in the English literature. One additional patient is presented in this article, for a total of 57 patients worldwide. To date, the most consistent published series is the one of the ELTR, including patients from 15 liver transplantation centers in the period 1985-2003 with a mean follow-up of 69 months. Ten-year patient and graft survival is 82.5% CONCLUSION: Liver transplantation should be considered as a radical but definitive treatment option in patients affected by HHT with liver or cardiac involvement not responsive to medical treatment.


Meta-analysis of vitamin D supplementation and hemoglobin concentration: methodological faults obscure the interpretation of the data.
We read the review by Arabi et al. with great interest which tried to examine the effects of vitamin D supplementation on hemoglobin concentration. It seems that the article suffers from fundamental methodological issues and the conclusions are likely to be erroneous. In this regard, we would like to ask the authors to address the mentioned limitations and to update the analysis in order to provide robust and trustful results. We are concerned that such meta-analyses may lead to the biased findings and conclusions.


Microarray data and gene expression statistics for Saccharomyces cerevisiae exposed to simulated asbestos mine drainage.
Here we describe microarray expression data (raw and normalized), experimental metadata, and gene-level data with expression statistics from Saccharomyces cerevisiae exposed to simulated asbestos mine drainage from the Vermont Asbestos Group (VAG) Mine on Belvidere Mountain in northern Vermont, USA. For nearly 100 years (between the late 1890s and 1993), chrysotile asbestos fibers were extracted from serpentinized ultramafic rock at the VAG Mine for use in construction and manufacturing industries. Studies have shown that water courses and streambeds nearby have become contaminated with asbestos mine tailings runoff, including elevated levels of magnesium, nickel, chromium, and arsenic, elevated pH, and chrysotile asbestos-laden mine tailings, due to leaching and gradual erosion of massive piles of mine waste covering approximately 9 km2. We exposed yeast to simulated VAG Mine tailings leachate to help gain insight on how eukaryotic cells exposed to VAG Mine drainage may respond in the mine environment. Affymetrix GeneChip® Yeast Genome 2.0 Arrays were utilized to assess gene expression after 24-h exposure to simulated VAG Mine tailings runoff. The chemistry of mine-tailings leachate, mine-tailings leachate plus yeast extract peptone dextrose media, and control yeast extract peptone dextrose media is also reported. To our knowledge this is the first dataset to assess global gene expression patterns in a eukaryotic model system simulating asbestos mine tailings runoff exposure. Raw and normalized gene expression data are accessible through the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) Database Series GSE89875 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89875).


The role of DDE and polychlorinated biphenyl levels in preterm birth.
Maternal serum levels of DDE and polychlorinated biphenyls (PCB) and their congeners were compared for 20 women who had a spontaneous preterm delivery and 20 matched women who had delivered at term at Mount Sinai Medical Center in New York between October 1990 and August 1993. Since no substantial case-control differences were evident, these findings do not indicate that increased DDE or PCB levels are associated with spontaneous preterm birth.


Expression of green fluorescent protein and its inheritance in transgenic oat plants generated from shoot meristematic cultures.
The expression of green fluorescent protein (GFP) and its inheritance were studied in transgenic oat ( Avena sativa L.) plants transformed with a synthetic green fluorescent protein gene [sgfp(S65T)] driven by a rice actin promoter. In vitro shoot meristematic cultures (SMCs) induced from shoot apices of germinating mature seeds of a commercial oat cultivar, Garry, were used as a transformation target. Proliferating SMCs were bombarded with a mixture of plasmids containing the sgfp(S65T) gene and one of three selectable marker genes, phosphinothricin acetyltransferase (bar), hygromycin phosphotransferase (hpt) and neomycin phosphotransferase (nptII). Cultures were selected with bialaphos, hygromycin B and geneticin (G418), respectively, to identify transgenic tissues. From 289 individual explants bombarded with the sgfp(S65T) gene and one of the three selectable marker genes, 23 independent transgenic events were obtained, giving a 8.0% transformation frequency. All 23 transgenic events were regenerable, and 64% produced fertile plants. Strong GFP expression driven by the rice actin promoter was observed in a variety of tissues of the T(0) plants and their progeny in 13 out of 23 independent transgenic lines. Stable GFP expression was observed in T(2) progeny from five independent GFP-expressing lines tested, and homozygous plants from two lines were obtained. Transgene silencing was observed in T(0) plants and their progeny of some transgenic lines.


Strengthening the predictive power of screening for adverse childhood experiences (ACEs) in younger and older children.
There is increasing interest in routine screening for Adverse Childhood Experiences (ACEs) to help identify high-risk children who would benefit from interventions. However, there has not yet been sufficient research concerning which particular set of ACEs would be most predictive as a potential screening tool. This study compared 40 Adverse Childhood Experiences (ACEs), covering 11 different conceptual domains, in their ability to predict trauma symptoms in childhood. The current study uses pooled data from three National Surveys of Children's Exposure to Violence (NatSCEV) conducted in 2008, 2011, and 2014. Each survey collected information on children aged one month to 17 years. Samples were obtained from a mix of random digit dialing and address based sampling methods. Telephone interviews were conducted with children 10 years and older and with caregivers, if the randomly selected child was under age 10. A different set of 15 items best predicted trauma symptoms for younger (2-9-year-old) compared to older (10-17-year-old) youth. Some conventional ACEs, like physical and emotional abuse, proved important for both age groups. However, family-related factors were more predictive for younger children, while community and peer violence exposures were more predictive for older children. Our new proposed measures explained substantially more variance in subsequent trauma symptoms than did the original ACE measure (R2 = .31 vs .18 for 2-9 year olds; R2 = .43 vs .26 for 10-17 year olds; p < .001 for all) and identified a larger percentage of children with high levels of trauma.


Evidence for extensive and non-specific translocation of oligopeptides across plasma membranes of mammalian cells.
After exposure of bovine aortic endothelial cells to various small peptides (tetra- to undeca-mer), extensive transport of the peptides across the plasma membrane was observed in the concentration range 10(-7) to 10(-2) M. The observed transport events, which contradict the generally anticipated poor permeability of peptides across plasma membranes, exhibited high complexity and showed no saturability up to a concentration of 10(-2) M. Evidence was found for the involvement of mdrp-like transporters as well as of energy-independent facilitated diffusion events. The peptide levels within the cells approximated those of the incubation solution within 30 min, indicating high capacity and velocity for the involved transport processes. Correspondingly, preloaded cells exported about 80% of the internalized peptide within 5 min at 37 degrees C. Analogous results were found after peptide exposure to several other mammalian cell types, indicating a more general importance of the transport phenomena described here. Our findings contradict the prevailing opinion that the often observed lack of activity of externally administered peptides against their targets within intact cells is accounted for primarily by poor cellular uptake and point to export processes counteracting the uptake to be more important in this context.


Electrical neuromodulation in bladder dysfunction: Mapping the state-of-the-art with bibliometric analysis of field and top 100 cited articles.
Electrical neuromodulation of bladder function has been extensively investigated in the literature. To date, there has been no characterization of the field, and there is a lack of bibliometric literature to guide future studies. We directed this scientometric analysis to characterize the distribution, characteristics and relationships of the field, with subanalysis of top 100 articles. The Web of Science Core Collection of the Thompson Reuters Web of Science was searched and analyzed to determine distributions and characteristics of clinical research investigating electrical neuromodulation in bladder dysfunction. Field citation and coauthorship networks were mapped, and recent citation bursts of the past decade are described. The top 100 cited articles were categorized, with level of evidence rating system applied. A total of 872 articles published from 1949 until October 2020 were included in field analysis. Europe demonstrated the highest continental productivity within field (n = 539, 61.81%), and the United States the top nation (35.55% of field, 39.24% of top 100 articles). The Journal of Urology has historically published the most articles in the field (n = 150, 17.20%), and top 100 articles (n = 41, 40.20%). Top 100 articles reported studies of neuromodulation effects via sacral neuromodulation (n = 59); of non-neurological bladder dysfunction (n = 72); urinary incontinence (n = 92), frequency (n = 73) and urgency (n = 68) symptomology. Analysis of electrical neuromodulation of bladder dysfunction literature reveals historical development, core research clusters and relationships, and an increase in publication activity over past decades.


Status epilepticus stimulates peroxisome proliferator-activated receptor γ coactivator 1-α/mitochondrial antioxidant system pathway by a nitric oxide-dependent mechanism.
Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1-α (PGC-1α) is a transcriptional coactivator identified as an upstream regulator of lipid catabolism, mitochondrial number and function. PGC-1α protects neurons against oxidative damage by inducing several members of the mitochondrial antioxidant system such as superoxide dismutase 2 (SOD2) and uncoupling protein 2 (UCP2). Its role in seizure-induced oxidative stress has not been studied. Here we showed that pilocarpine-induced status epilepticus (SE) stimulates the PGC-1α/mitochondrial antioxidant system signaling pathway in the rat hippocampus. Because nitric oxide (NO) is the key factor of mitochondrial biogenesis through the transcriptional induction of PGC-1α, we investigated whether NO is involved in activation of the PGC-1α/mitochondrial antioxidant system after SE. Treatment with the NO synthase (NOS) inhibitor N(G)-nitro-l-argininemethyl ester (l-NAME) attenuated the increased expression of the PGC-1α/mitochondrial antioxidant system after SE and enhanced oxidative stress. These results suggest that SE can induce the PGC-1α/mitochondrial antioxidant system signaling pathway, which may represent a protective mechanism against SE-induced oxidative stress. Furthermore, NO may positively regulate the mitochondrial antioxidant system by inducing PGC-1α in pilocarpine-induced SE.


Blood and faecal lead levels in children with various functional gastrointestinal disorders.
To investigate the blood lead levels (BLLs) and faecal lead levels (FLLs) in children with various functional gastrointestinal disorders (FGIDs) and compare them with controls. One hundred and two children with FGIDs defined by the Rome IV criteria, aged 4-18 years, and one hundred and two sex matched healthy children were enrolled in the study. Children with FGIDs were divided into three subgroups as functional constipation (FC) (n = 36), functional abdominal pain (FAP) (n = 36) and functional nausea (FN) (n = 30). The lead levels were measured using atomic absorption spectrometer. The median BLLs in the FGIDs group was significantly higher than in controls (5.12 and 1.77 µg/dL, respectively). The BLLs were above 5 µg/dL in 51,9% of children with FGIDs. There was statistically significant difference in BLLs between FC subgroup and the other subgroups (FAP and FN) (p = 0.003, p < 0.001 respectively). The FLLs in the FGIDs group was significantly higher than in controls (28.08 and 0.01 µg/g, respectively). There was no significant difference in FLLs between FC subgroup and the other subgroups (p = 0.992, p = 0.989 respectively). No significant relation found between BLLs and FLLs of the FGIDs group (p = 0.123). This study revealed that children with FGIDs had higher BLLs and FLLs than controls and also more than half of children with FGIDs had BLLs ≥5 µg/dL which is considered as toxic level. These results might revive the question of whether or not clinicians need to evaluate routine BLLs in children with FGIDs.


Unmasking latent thioesters under hydrophobic-compatible conditions.
Hydrophobic latent C-terminal thioesters were converted into thioesters, and were also coupled with cysteine in one-pot reactions, using conditions generally compatible with hydrophobic materials. The reaction conditions (ethanethiol and triethylamine in a mixture of DMF and THF) are compatible with acid-labile protecting groups (Boc/t-Bu) that are standard in Fmoc peptide synthesis.


Analytical artefacts in the speciation of arsenic in clinical samples.
Urine and blood samples of cancer patients, treated with high doses of arsenic trioxide were analysed for arsenic species using HPLC-HGAFS and, in some cases, HPLC-ICPMS. Total arsenic was determined with either flow injection-HGAFS in urine or radiochemical neutron activation analysis in blood fractions (in serum/plasma, blood cells). The total arsenic concentrations (during prolonged, daily/weekly arsenic trioxide therapy) were in the microg mL(-1) range for urine and in the ng g(-1) range for blood fractions. The main arsenic species found in urine were As(III), MA and DMA and in blood As(V), MA and DMA. With proper sample preparation and storage of urine (no preservation agents/storage in liquid nitrogen) no analytical artefacts were observed and absence of significant amounts of alleged trivalent metabolites was proven. On the contrary, in blood samples a certain amount of arsenic can get lost in the speciation procedure what was especially noticeable for the blood cells although also plasma/serum gave rise to some disappearance of arsenic. The latter losses may be attributed to precipitation of As(III)-containing proteins/peptides during the methanol/water extraction procedure whereas the former losses were due to loss of specific As(III)-complexing proteins/peptides (e.g. cysteine, metallothionein, reduced GSH, ferritin) on the column (Hamilton PRP-X100) during the separation procedure. Contemporary analytical protocols are not able to completely avoid artefacts due to losses from the sampling to the detection stage so that it is recommended to be careful with the explanation of results, particularly regarding metabolic and pharmacokinetic interpretations, and always aim to compare the sum of species with the total arsenic concentration determined independently.


Effects of enrofloxacin on the human intestinal microbiota in vitro.
An anaerobic, continuous-flow culture method has been developed to assess the effects of different levels of enrofloxacin (ENR) on the human intestinal microbiota. Chemostats containing human faecal flora were exposed to 1.25, 12.5 and 125 μg/mL ENR. Before and during drug exposure, samples aspirated from culture vessels were analysed using viable cell counting and denaturing gradient gel electrophoresis (DGGE). In addition, the colonisation resistance (CR) of the microbiota to Candida albicans SC5314 was evaluated. When exposed to 1.25 μg/mL ENR, total counts of aerobic bacteria, anaerobic bacteria, Lactobacillus, enterococci, Escherichia coli and Bacteroides fragilis were similar to the control group, except for Bifidobacterium; when exposed to 12.5 μg/mL and 125μg/mL ENR, numbers of categorised microorganisms changed significantly, except for B. fragilis. DGGE indicated that although 1.25 μg/mL ENR had little effect on the total number of microbiota, several bands representing dominant bacteria disappeared. The bands disappeared more quickly when exposed to 12.5 μg/mL and 125 μg/mL ENR. In addition to their influence on microbial diversity, different levels of ENR reduced the CR of the intestinal microbiota to C. albicans SC5314.


Detection of Giardia lamblia by immunofluorescence.
High-titer immune sera to cysts of Giardia lamblia, produced in guinea pigs, were labeled with fluorescein isothiocyanate. The resulting conjugates were used to detect G. lamblia in stool specimens by fluorescence microscopy. The sera also reacted with cysts of Chilomastix mesnili, but the two organisms could be differentiated by their size.


[Response distortion or symptom severity? Symptom description by psychiatric patients and sociomedical assessment subjects].
Psychiatric disorders are the most frequent cause for premature retirement; however, trying to verify claims of performance deficits due to psychiatric disorders without the actual existence of the latter in sociomedical assessments is problematic. For this reason, differentiation between actual psychiatric disorders with real presence of symptoms and simulated or aggravated symptoms is of importance in sociomedical assessments. In recent years, symptom validity tests (SVT) have been increasingly utilized in psychiatric/psychological assessments; however, knowledge of the validity of these tests and the relation to symptom severity is still lacking. This study aimed to compare the validity of different SVTs depending on symptom severity (Structured Inventory of Malingered Symptomatology (SIMS), Word Memory Test (WMT), Symptom Checklist-90-R (SCL-90‑R), Minnesota Multiphasic Personality Inventory‑2 (MMPI-2)). Clinically treated inpatient psychiatric patients (n = 30) were compared with subjects of sociomedical assessments (n = 29) regarding their tendency to simulate or aggravate symptoms. It could be shown that the WMT and the SIMS both failed in the differentiation between psychiatric patients and subjects of sociomedical assessments, regarding description of symptoms or (un)restricted performance motivation. Furthermore, 20% of psychiatric patients were classified as false positive in WMT. The results of the SIMS were significantly related to the severity of psychiatric symptoms in SCL-90‑R, therefore the severity of symptoms was assessed rather than the response distortion. The results underline the importance of further research on SVTs in sociomedical assessments, especially regarding symptom severity and response distortion.


House-dust mite allergen Der p 1: amount or concentration?
There is a lack of consensus as to the best way to quantify settled house-dust mite Der p 1 allergen from planar and nonplanar surfaces. To investigate the most appropriate measure of settled house-dust mite Der p 1 allergen, we determined the relationship between Der p 1 allergen content and collected dust weight from planar-surface (mattress) and nonplanar-surface (living-room) samples in 58 homes. There was a direct relationship between Der p 1 content and dust weight for both planar-surface (mattress, n = 217) samples (r = 0.50, P < 0.0001) and nonplanar-surface (living-room, n = 48) samples (r = 0.61, P < 0.0001). Correction for the surface area of the planar surface (mattress) vacuum-cleaned resulted in no additional benefit. We conclude that expression of Der p 1 levels per weight of collected dust appears to be the best method for both planar and nonplanar surfaces.


Long-term life and partnership satisfaction in infertile patients: a 5-year longitudinal study.
To describe the long-term effects of infertility on life and partnership satisfaction. Longitudinal cohort study. A university outpatient andrology and gynecology infertility clinic. 275 men and 272 women treated for infertility between August 2000 and December 2001. None. The Life Satisfaction Questionnaire (FLZ), the Partnership Questionnaire (PFB), and sociodemographic items at baseline (T1) and 5 years later (T2). Compared with a representative sample, our male and female participants had higher Finance and Partnership scores and lower Health scores on the FLZ at T1. They also had markedly higher PFB scores, with the exception of Conflict Behavior. After 5 years (T2), 101 men and 113 women rated the Partnership and Sexuality FLZ subscales as well as all the PFB subscales statistically significantly lower than at baseline. Only the women rated the Self-esteem FLZ subscale lower than at baseline (T1). Participants who became parents had lower Leisure and Partnership FLZ subscale scores, and fathers had lower Finance FLZ subscale scores. Satisfaction declined over 5 years for both men and women, but only in the partnership-related domains. Women were more affected than men. The success of infertility treatment had only a minor influence on a couple's future satisfaction.


Emergence of multiple drug-resistant human cytomegalovirus variants in 2 patients with human immunodeficiency virus infection unresponsive to highly active antiretroviral therapy.
In 2 patients infected with human immunodeficiency virus (HIV), highly active antiretroviral therapy was unable to suppress HIV replication as a result of the emergence of drug-resistant HIV variants. Human cytomegalovirus (HCMV) retinitis developed in both patients, and an unusually complex mixture of drug-resistant HCMV variants was detected in both patients.


NMR imaging of solids with magic angle spinning.
Different aspects of solid state NMR imaging are reviewed, with emphasis on imaging in combination with line narrowing, especially in combination with magic angle spinning. Experimental results obtained with the latter technique are discussed, along with the implications of magic angle spinning on slice selection.


Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma.
Diagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy. A 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy. This report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment.


Beta-2 adrenergic receptor gene (ADRB2) polymorphism and risk for lung adenocarcinoma: a case-control study in a Chinese population.
The incidence of lung adenocarcinoma (AC) has been increasing over recent decades. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent carcinogens and reproducibly induces a high incidence of lung AC in laboratory animals. In addition to its genotoxic effects, NNK has also epigenetic effects on lung cells by functioning as an agonist for beta adrenergic receptors and stimulating the signal pathways that lead to lung AC. Beta-2 adrenergic receptor (ADRB2) expressed on bronchial smooth muscle is a well-defined target for asthma treatment that has epidemiological implications in lung cancer development. And biochemical effect and pharmacogenetic relevance of regulatory and coding variants of ADRB2 have been well documented. Aiming to test whether the genetic variants of ADRB2 modify risk of lung AC, we compared the manifestation of three common single nucleotide polymorphisms (SNPs) of ADRB2 (G-1023A, G-654A, and A46G (Gly16Arg)) between 313 patients with lung AC and 321 controls. Overall association was not observed between risk and either individual of the three SNPs or their combined haplotypes. However, in the subgroup of young subjects < or =50 years old, significant association was observed for G-1023A (allele based OR, 1.82; 95% CI, 1.12-2.95), A46G (Gly16Arg) (allele based OR, 0.64; 95% CI, 0.40-1.03), and the haplotype A(-1023)A(46) (OR 2.62; 95% CI 1.30-5.27). Our results do not support a major independent role of ADRB2 polymorphisms in lung AC risk, suggesting that functional variants of other genes involved in the NNK epigenetic pathway of carcinogenesis should be investigated.


Treatment of acute HCV infection.
In developed nations, the majority of new HCV infections are acquired by injection drug users. Acute HCV infection is generally asymptomatic and is followed by spontaneous viral clearance in approximately 25% of individuals. However, given the asymptomatic nature of infection and difficulties in identifying and following those at risk of acquiring infection, our knowledge of treatment for acute HCV infection has been hampered. Much of what is known about the timing, optimal regimen and duration of therapy comes from small, prospective, observational studies and randomized, controlled trials in selected populations. Furthermore, data on the treatment of acute HCV infection among injection drug users and patients co-infected with HCV and HIV are limited. Genetic testing for variations in IL28B may provide an additional diagnostic tool for the optimal management and treatment of acute HCV infection. This Review highlights current knowledge of the epidemiology, diagnosis, natural history and treatment of acute HCV infection, including proposed recommendations for the assessment and treatment of this infection.


Selective familiarity deficits after left anterior temporal-lobe removal with hippocampal sparing are material specific.
Research has firmly established a link between recognition memory and the functional integrity of the medial temporal lobes (MTL). Dual-process models of MTL organization maintain that there is a division of labour within the MTL, with the hippocampus (HC) supporting recollective processes and perirhinal cortex (PRc) supporting familiarity assessment. An older neuropsychological literature suggested a different type of division of labour within the MTL, with left-sided structures playing a critical role in memory for verbal materials and right-sided structures being differentially involved in memory for material that cannot easily be verbalized. Research that has related predictions made by these two accounts to each other is limited. Evidence from research in patients with selective recollection impairments and fMRI data in healthy individuals suggests that lateralization of recollection for verbal materials is not clear-cut. Here we examined lateralization of familiarity processes in the MTL by asking whether selective familiarity impairments after unilateral anterior temporal-lobe removal with hippocampal sparing are material specific. We examined this issue in NB, an individual who was previously shown to exhibit selective familiarity impairments with such a lesion (Bowles et al., 2007). We administered three similar recognition memory tests in combination with the same Remember-Know procedure for three different types of novel stimuli without pre-existing semantic representations. Analyses focused on discrimination and on possible differences in response criterion, and included an ROC based approach as well. We found that NB exhibited a deficit in overall recognition of aurally presented pronounceable non-words that reflected a specific impairment of familiarity assessment with preservation of recollective processes. Examination of recognition memory for visually presented abstract pictures and faces did not reveal any impairment, neither at the level of overall recognition nor, more specifically, at the level of familiarity assessment. These findings suggest that the neural mechanisms that support familiarity assessment in the temporal lobe operate in a manner that is tied to the specific stimulus class being assessed.


[Effectiveness of an intervention to improve demand management of laboratory tests related to anaemia in primary care].
To evaluate the appropriateness oflaboratory test requests for the diagnosis and monitoring of anaemia in Primary Care. As a secondary objective, a decrease in variability was sought byunifying the test profile performed. A decision algorithm based on scientific evidence for test requests related to anaemia in Primary Care was implemented, so that the profile of tests performed is conditioned by haemoglobin results and mean corpuscular volume. A multidisciplinary laboratory-Primary Care team was created for the design, execution and evaluation of the results obtained. In addition, there was computer support for the development and inclusion of the rules in the laboratory and Primary Care computer systems. Through the directed algorithm, the necessary tests for the diagnosis and follow-up of anaemia were performed sequentially, even so this meant an average monthly decrease in the number of tests of 70% for folic acid, 66% for vitamin B12, 92% for transferrin, 43% foriron and 42% for ferritin. It was also possible to unify the profile of tests performed, regardless of the centre of origin. Better use of the biochemical tests related to anaemia was achieved, since only the necessary tests for the patient were performed. Variability is reduced by unifying the request profile in all centres.


Cytoreduction and HIPEC after neoadjuvant chemotherapy in stage IIIC-IV ovarian cancer. Critical analysis in elderly patients.
The aim of our study was to evaluate postoperative morbidity and mortality, disease-free and overall survival in patients older than 75 years undergoing interval debulking after neoadjuvant chemotherapy and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). Were included a series of consecutive patients diagnosed with stages IIIC/IV ovarian carcinoma, intervened after neoadjuvant systemic chemotherapy (paclitaxel and carboplatin) between January 2008 and June 2013. After completion of cytoreduction HIPEC was administered using paclitaxel (60mg/m(2)) or cisplatin (75mg/m(2)). We analyzed and compared the results of postoperative morbidity and mortality, disease-free survival and overall survival in patients ≥75 years compared to patients with lower ages intervened in the same time period. From a total of 66 patients tested, 9 patients were ≥75 years (14%). Grade I-IV morbidity was significantly higher in patients ≥75 years (78% vs 35%, p<0.05) as well as grade III-IV disease (56% vs 16%, p<0.05). There were no procedure-related mortality. In patients ≥75 years the median disease-free survival was 6 months (95% CI: 3.5-8.5 months) vs 24 months (95% CI: 10.5-37.5 months) in younger patients. The median overall survival in patients ≥75 years was 13 months (95% CI: 4.7-21.3), not having reached at time of analysis of the database in younger patients. Patients ≥75 years received no benefit in prognosis after interval cytoreduction with HIPEC and paid a high price in terms of postoperative morbidity. This age group should be excluded from this therapeutic procedure.


Sensory-motor modality compatibility in multitasking: The influence of processing codes.
Sensory-motor modality compatibility is defined as the similarity between the sensory modality and the modality of response-related effects. Previous dual-task and task-switching studies have shown higher performance costs for coordinating relatively incompatible sensory-motor modality mappings (i.e., auditory-manual and visual-vocal) compared to more compatible mappings (i.e., auditory-vocal and visual-manual). Until now, however, little attention has been paid to potential variability in effects of modality compatibility depending on different processing codes. In the present study, we independently varied the processing codes of input and output (nonverbal-spatial, nonverbal-nominal, verbal-spatial, verbal-nominal) while participants switched between incompatible and compatible sensory-motor modality mappings. Beside higher switch costs for switching between incompatible sensory-motor modality mappings than for switching between compatible mappings, the results revealed stronger effects of modality compatibility on switch costs for verbal input than for nonverbal input codes. This suggests that priming mechanisms between sensory input and compatible motor output are modulated by the processing code of the sensory input. As possible explanations, we assume a higher degree of concordance with output processing codes as well as stronger associations with potential response effects for verbal than for nonverbal input.


Neural activities in the monkey basal ganglia related to attention, memory and anticipation.
Discharges of single neurons were recorded in the caudate nucleus of an awake monkey. The monkey was trained to perform a series of behavioral tasks which required him to fixate on a spot of light on a screen and if the spot jumped to another location to make a saccade to refixate it. A significant portion of the neurons in the head and body of the caudate nucleus showed increases in their activities in relation to the behavioral tasks. While some neurons responded to the visual stimulus (light spot), others showed activities preceding a saccade. Another group of neurons showed activities not directly related to such sensory or motor events but presumably related to monkey's cognitive states. Even the visual or saccade-related activities were highly dependent on the behavioral context in which a given visual stimulus was presented or a given saccade was elicited. This report presents typical examples of caudate neural activities related to selective attention, short-term memory and anticipation of future events, and explains how such complex signals in the caudate are converted to oculomotor outputs through a major efferent pathway of the basal ganglia, namely caudate--substantia nigra pars reticulate--superior colliculus.


Sudden unexpected death.
Sudden unexpected death is a major public health problem. Many cases could be prevented if they were anticipated through means of a better awareness among the medical community, new therapies based on early genetic screening, or corrected by countershock.


Lethal paradoxical cerebral vein thrombosis due to suspicious anticoagulant rodenticide intoxication with chlorophacinone.
Superwarfarin exposure is a growing health problem, described in many countries. The authors report a case of suspicious chlorophacinone poisoning with a problematic diagnosis. They review the literature and discuss particularities of anticoagulant rodenticide intoxication, as well as the apparent contradiction between anticoagulant intoxication and lethal thrombosis.


Flow regulation by dams impacts more than land use on water quality and benthic communities in high-gradient streams in a semi-arid region.
In semi-arid regions, water policy has strongly promoted the construction of water reservoirs with little or no consideration for their ecological consequences. In order to quantify the effect induced by flow discontinuity on environmental conditions, water quality, and invertebrate communities at high-gradient streams, we investigated unregulated and regulated reaches at 13 watercourses, located in the Dry Chaco Ecoregion (South America). Dams differed in the dominant land uses (rangeland, agriculture, and urban) of the related catchment area. We assessed on-site hydro-geomorphic features, water quality and bacteriological parameters, habitat condition, chlorophyll a, macrophytes cover, and macroinvertebrate communities. Significant increases in mineral parameters and organic contamination indicators were detected at regulated reaches, such as: conductivity, total solids, turbidity, color, and phosphates. Dams negatively affected habitat condition, and macrophyte cover increased at regulated sites. Macroinvertebrates showed a diminution in most of the metrics analyzed, with a decrease of sensitive groups and an increase in the more tolerant ones. Redundancy Analysis revealed that SWQI (physicochemical based index) and the proportion of coarse gravel were stronger predictors on metrics arrangement. Variance partitioning analyses proved that regulation effects prevailed over land use in explaining metrics variation. Invertebrate community was positively related to better ecological conditions, which suggests that restitution of ecological integrity at regulated reaches should include habitat restoration. These results are relevant for the management of regulated water resources in arid and semi-arid regions in a context of climate change.


A one-year pragmatic trial of naltrexone vs disulfiram in the treatment of alcohol dependence.
To compare the efficacy of naltrexone and disulfiram in preventing an alcoholic relapse in routine clinical practice in an Indian metropolis. Hundred alcohol-dependent men, for whom a family member would accompany the patient to follow-up appointments, were randomly allocated to a year of treatment with either naltrexone or disulfiram. Patients, the accompanying family member and the treating psychiatrist were aware of the nature of treatment given. Alcohol consumption, craving and adverse events were recorded weekly for the first three months, then fortnightly for the rest of the year, by the treating psychiatrist. Serum gamma-glutamyl transferase (GGT) was measured at the start and the end of the study. At the end of the year, 97 patients were still in contact. Relapse, the consumption of >5 drinks (40 g of ethanol) in a 24 h period, occurred at a mean of 119 days with disulfiram and at 63 days with naltrexone (P = 0.020). Mean serum GGT, which had not differed between the two groups initially, was 117 U/l with naltrexone and 85 U/l with disulfiram (P = 0.038) at the end of the study. Eighty-six per cent of the patients remained abstinent throughout the study with disulfiram compared to 44% with naltrexone (P = 0.0009). However, patients allocated to naltrexone had significantly lower craving than those allocated to disulfiram. Disulfiram is superior to naltrexone in preventing a relapse among alcohol-dependent men with family support. Comparison between these treatments in other settings and in different types of alcoholics is warranted.


Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury.
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.


Dual pretreatment of mixing H2O2 followed by torrefaction to upgrade spent coffee grounds for fuel production and upgrade level identification of H2O2 pretreatment.
Biochar is a carbon-neutral solid fuel and has emerged as a potential candidate to replace coal. Meanwhile, spent coffee grounds (SCGs) are an abundant and promising biomass waste that could be used for biochar production. This study develops a biochar valorization strategy by mixing SCGs with hydrogen peroxide (H2O2) at a weight ratio of 1:0.75 to upgrade SCG biochar. In this dual pretreatment method, the H2O2 oxidative ability at a pretreatment temperature of 105 °C contributes to an increase in the higher heating value (HHV) and carbon content of the SCG biochars. The HHV and carbon content of biochar increase by about 6.5% and 7.8%, respectively, when compared to the unpretreated one under the same conditions. Maximized biochar's HHV derived via the Taguchi method is 30.33 MJkg-1, a 46.9% increase compared to the raw SCG, and a 6.5% increase compared to the unpretreated SCG biochar. The H2O2 concentration is 18% for the maximized HHV. A quantitative identification index of intensity of difference (IOD) is adopted to evaluate the contributive level of H2O2 pretreatment in terms of the HHV and carbon content. IOD increases with increasing H2O2 pretreatment temperature. Before torrefaction, SCGs' IOD pretreated at 50 °C is 1.94%, while that pretreated at 105 °C is 8.06%. This is because, before torrefaction, H2O2 pretreatment sufficiently weakens SCGs' molecular structure, resulting in a higher IOD value. The IOD value of torrefied SCGs (TSCG) pretreated at 105 °C is 10.71%, accounting for a 4.59% increase compared to that pretreated at 50 °C. This implies that TSCG pretreated by H2O2 at 105 °C has better thermal stability. For every 1% increase in IOD of TSCG, the carbon content of the biochar increases 0.726%, and the HHV increases 0.529%. Overall, it is demonstrated that H2O2 is a green and promising pretreatment additive for upgrading SCG biochar's calorific value, and torrefied SCGs can be used as a potential solid fuel to approach carbon neutrality.


[Pain management in patients with chronic rheumatic pain--a model for primary medical care].
A rheumatologist and a medical psychotherapist collaborate in offering periodically a cognitive behavioral treatment program for pain control for the patients of a rheumatological practice. The program consists of a biopsychosocial model of chronic pain, individualized relaxation training combining progressive muscle relaxation and some elements of autogenous training and meditation, several attention-related techniques and cognitive restructuring. From 1993 to 1995, 50 patients took part in five training courses. The compliance of the patients was satisfactory and the drop-out rate low (8%). In a post hoc interview 4 weeks later and another 2 years after the end of the training most of the patients assessed the program as useful for reduction of pain, increase of activity and enhancement of mood. Psychotherapeutic experience in group therapy or special training for non-psychotherapeutic physicians with continuous supervision is necessary in order to conduct a qualified treatment program. Within medical primary care, rheumatologists can motivate their patients towards active pain management, which can help to prepare patients for further psychotherapy in cases with psychiatric disorders and/or severe psychosocial strains.


[Absence of photoperiodism and digestive enzymes in rats: the role of the age and endogenous melatonin level.]
We studied the effect of prolonged absence of a photoperiodic signal (constant lighting and constant darkness) on the changes of digestive enzymes' activity in late postnatal ontogenesis of rats. Age-related alterations are characterized as a change in activity of enzymes, as well as a redistribution of the functional activity between the amylo- and lipolytic links, the upper and lower divisions of the gastrointestinal tract. It was shown that along with age, the activity of enzymes is affected both by the absence of photoperiodism and by the level of melatonin associated with the light regime. In conditions of light deprivation the age-related changes characterizing the «aging» of the digestive system are observed later compared with standard illumination and especially constant illumination.


The evolution and immunomodulatory role of Zc3h12 proteins in zebrafish (Danio rerio).
Zc3h12 family is an important RNA-binding protein family regulating mRNA of inflammatory cytokines in mammals. However, there are few studies on their post-transcriptional level regulation of inflammatory cytokines in fish. Here, we investigated the evolution of zebrafish Zc3h12 family and explored their immunomodulatory role. Phylogenetic and syntenic analysis indicated the number of zc3h12 family members had increased ranging from a single member in invertebrates to a single copy of four members in mammals. As the most evolutionarily diverse group of vertebrates, the number of zc3h12 family members was more complex and diverse in the teleost, each member experienced different fates and followed different rules in multiple rounds of whole-genome duplication events. Thereinto, zebrafish contained three zc3h12 genes, among which zc3h12aa and zc3h12ab were duplicated from the same gene. Zebrafish Zc3h12 family could recognize the 3'-UTR regions of inflammatory cytokines through binding to the specific RNA secondary structure and negatively regulate their expression. Deletion of either Zc3h12 domains or mutation of the key amino acid in RNAase domain attenuated their modulatory effect, suggesting both domain and RNAase activity are important to the immunomodulatory role. These results elucidated the evolution of Zc3h12 family and uncovered Zc3h12-mediated post-transcriptional regulation of cytokines in zebrafish.


Production of BRO beta-lactamases and resistance to complement in European Moraxella catarrhalis isolates.
Of the 419 Moraxella catarrhalis isolates collected during the 1997-1999 European SENTRY surveillance study, 385 (92%) were beta-lactamase positive. Twenty-two (5.7%) produced BRO-2 beta-lactamase. Twenty-one new mutations were found in the putative promoter region of the bro genes. Nineteen percent of all isolates tested were complement sensitive. Resistance to beta-lactams is not linked to the phylogenetic lineages associated with susceptibility to complement.