Aryl hydrocarbon receptor antagonism before reperfusion attenuates cerebral ischaemia/reperfusion injury in rats.
Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.


Cerebral columnar organization of the first nociceptive component induced by CO2 laser on the tail of the rat.
The somatotopic map of the first nociceptive component in the primary somatosensory cortex (S1) is still unclear. In this study, a CO(2) laser was applied to the tail of the rat to induce nociception without the interference from large myelinated (A(beta)) fibers. Thus, only noxious fibers could be activated. Two-dimensional current-source-density analysis was used to analyze the evoked field potentials. Using this method, the nociceptive responses of A(delta)-fibers in S1 were verified, and the somatotopic map of the first nociceptive component in S1 was identified. We found that whether light touch or laser-induced nociception was applied to the tail of the rat, the responsive topography in S1 was consistent. Discrimination of these two modalities was achieved vertically in the same column; the deeper layer represented the nociceptive response while the superficial layer encoded the response to light touch. This is quite different from that of a primate brain.


Organic micropollutants in lakes: a sedimentological approach.
Many very persistent and lipophilic compounds, considered to be of concern for chronic toxicity and bioaccumulation, are generally present in surface waters at very low and variable concentrations. Sediments represent a concentrated pool for these compounds and consequently they are often analyzed instead of water. Some theoretical models have been proposed recently (Håkanson, 1980; Galassi and Migliavacca, 1986; Provini et al., 1987) in order to estimate the concentration of these pollutants in water and their potential risk for aquatic biota and human health. In this work sediments from three subalpine lakes located in Northern Italy, very close to each other but with different anthropogenic loads, were collected at several stations for determination of the classes of organic micropollutants of urban, industrial, and agricultural origin. Results show that urban and industrial pollution are predominant in this area. Two classes of micropollutants seem to be most related to anthropogenic activities: PAH and trichloroalkylphosphates. The first reaches lake sediments through atmospheric deposition and point sources; the second, present only in two lakes, is more likely to be due to industrial effluents. The advantages and limitations of the sedimentological approach for risk assessment in the aquatic environment are discussed.


Cost Analysis of Outpatient Anterior Cervical Discectomy and Fusion at an Academic Medical Center without Dedicated Ambulatory Surgery Centers.
Anterior cervical discectomy and fusion (ACDF) are increasingly performed at ambulatory surgical centers (ASCs). Academic centers lacking dedicated ASCs must perform these at large university hospitals, which pose unique challenges to cost savings and efficiency. To describe the safety and cost of outpatient ACDF at a major academic medical center without a dedicated ASC. ACDFs performed from 2015 to 2018 were retrospectively reviewed. Cases were performed at the major tertiary university hospital or a satellite university hospital dedicated to outpatient surgery. Patient demographics, surgical characteristics, perioperative complications, fusion at 12 months, and cost were collected. A total of 470 patients were included. The mean age was 56 years, with 255 women (54.3%). When comparing same-day discharge, overnight observation, or inpatient admission, there were no differences in age, gender, or number of levels fused. Same-day and overnight observation cases were associated with shorter procedure duration and less estimated blood loss. There were no differences in perioperative complications, 30-day readmissions, or fusion at 12 months. Direct and total costs were lowest for same-day cases, followed by overnight observation and inpatient admissions (P < 0.001). Academic centers without dedicated ASCs can safely perform ACDF as a same-day or overnight observation procedure with significant reductions in cost. The lack of a dedicated ASC should not preclude academic centers from allocating appropriately selected patients into same-day or overnight observation care pathways. This strategy can improve resource utilization and preserve precious hospital resources for the most critically ill patients while also allowing these centers to build viable outpatient spine practices.


Sulfhydryl oxidation: a potential strategy to achieve neuroprotection during severe hypoxia?
Previously we reported that sulfhydryl (SH) modulation affects the susceptibility of rat hippocampal slices to severe hypoxia. SH-oxidation by DTNB (5,5'-dithiobis 2-nitrobenzoic acid) or H2O2 postponed the onset of hypoxia-induced spreading depression (HSD), thereby delaying the loss of neuronal function, whereas SH-reduction by DTT (1,4-dithio-dl-threitol) hastened HSD onset. To judge the neuroprotective merit that might arise from a postponement of HSD by oxidants, we have extended our earlier observations by multiparametric recordings and screened for changes in the extracellular K+ accumulation, HSD propagation velocity, and its maximum spread. As parameters for neuronal network function, the failure of synapses during hypoxia and their posthypoxic recovery were analyzed. DTNB (2 mM) or H2O2 (5 mM) postponed HSD but did not attenuate the rise in extracellular K+ concentration ([K+](o)), HSD propagation velocity or its maximum spread. H2O2 slightly postponed the synaptic failure during hypoxia; the posthypoxic recovery of synapses was, however, incomplete. DTNB slowed the synaptic recovery upon reoxygenation. DTT (2 mM) hastened HSD onset, but HSD propagation velocity and tissue invasion were not affected. Upon reoxygenation, however, normalization of [K+](o) was disturbed and synaptic recovery failed. Therefore, SH-reducing conditions at the onset of HSD proved to be devastating for the hippocampal network. In conclusion, the only merit of DTNB or H2O2 treatment is a delayed HSD onset, i.e. some extra time before neuronal function is lost during severe hypoxia. Attenuation of the severe changes during HSD or an improved outcome was not observed. Nevertheless, combination of SH-oxidants with established neuroprotectants might be a potential therapeutic approach.


[Membrane control of the photodeblocking reaction of cytochrome oxidase in the mitochondrial electron transport chain].
Hyperosmotic shrinkage and hypoosmotic swelling of the internal mitochondrial membrane decrease considerably the efficiency of the reaction of the cyanide photodissociation from the cytochrome oxidase. The osmotic effect increases after the reduction of the membrane potential by a protonophore uncoupler. This suggests that the local photochemical reaction is subject to membrane control.


Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice.
The pathophysiology of the NO/NO synthase system and dysfunctional changes in the endothelium in the early phases of the atherogenic process are incompletely understood. In this study, we investigated the effects of the nitrosothiol NO donor S-nitroso-N-acetylcysteine (SNAC) in the early prevention of plaque development in the hypercholesterolemic LDLr-/- mice as well as the changes in endothelium-dependent relaxation and NO synthase expression. LDLr-/- mice were fed a 1.25% cholesterol-enriched diet for 15 days. Plasma cholesterol/triglyceride levels increased and this increase was accompanied by the development of aortic root lesions. Aortic vasorelaxation to acetylcholine was increased, although endothelium-independent relaxation in response to sodium nitroprusside did not change, which suggest stimulated NO release enhanced. This dysfunction was associated with enhanced aortic superoxide production and with increased levels of constitutive NOS isoform expression, particularly neuronal NOS. SNAC (S-nitroso-N-acetylcysteine) administration (0.51 micromol/kg/day i.p. for 15 days) decreased the extent of the plaque by 55% in hypercholesterolemic mice, but had no effects on vasomotor changes. It did, however, lead to a decrease in constitutive NOS expression. The SNAC induced only minor changes in plasma lipid profile. The present study has shown that, in early stages of plaque development in LDLr-/- mice, specific changes in NO/NO synthase system develop, that are characterized by increased endothelium-dependent vasorelaxation and increased constitutive NOS expression. Since the development of plaque and the indicator of endothelial cell dysfunction were prevented by SNAC, such treatment may constitute a novel strategy for the halting of progression of early plaque.


Comparison of the effects of lidocaine and amiodarone for out-of-hospital cardiac arrest patients with shockable rhythms: a retrospective observational study from a multicenter registry.
Out-of-hospital cardiac arrest (OHCA) with shockable rhythms, including ventricular fibrillation and pulseless ventricular tachycardia, is associated with better prognosis and neurological outcome than OHCA due to other rhythms. Antiarrhythmic drugs, including lidocaine and amiodarone, are often used for defibrillation. This study aimed to compare the effects of lidocaine and amiodarone on the prognosis and neurological outcome of patients with OHCA due to shockable rhythms in a real-world setting. We conducted a retrospective observational study using a multicenter OHCA registry of 91 participating hospitals in Japan. We included adult patients with shockable rhythms, such as ventricular fibrillation and pulseless ventricular tachycardia, who were administered either lidocaine or amiodarone. The primary outcome was 30-day survival, and the secondary outcome was a good neurological outcome at 30 days. We compared the effects of lidocaine and amiodarone for patients with OHCA due to shockable rhythms for these outcomes using logistic regression analysis after propensity score matching (PSM). Of the 51,199 patients registered in the OHCA registry, 1970 patients were analyzed. In total, 105 patients (5.3%) were administered lidocaine, and 1865 (94.7%) were administered amiodarone. After performing PSM with amiodarone used as the reference, the odds ratios and 95% confidence intervals of lidocaine use for 30-day survival and 30-day good neurological outcome were 1.44 (0.58-3.61) and 1.77 (0.59-5.29), respectively. The use of lidocaine and amiodarone for patients with OHCA due to shockable rhythms within a real-world setting showed no significant differences in short-term mortality or neurological outcome. There is no evidence that either amiodarone or lidocaine is superior in treatment; thus, either or both drugs could be administered.


Vein graft-coated stents for endovascular occlusion of canine experimental arteriovenous fistulae.
To evaluate different vein graft-coated stent systems in the endovascular treatment of experimental arteriovenous fistulae (AVF) in a canine model. Bilateral carotid-to-external jugular vein AVF were created. Two balloon-expandable tantalum stents (Strecker stent), two self-expanding nitinol stents (Strecker stent), and one stainless-steel stent (Wallstent) were coated with autologous vein grafts and placed using a transfemoral approach. Angiography was performed immediately after stent placement and at week 1 and 3, as well as at months 3, 6, and 9. All stents were removed and underwent histologic examination. Occlusion of the AVF succeeded with the Wallstent and both tantalum stents. The nitinol stents were misplaced, maintaining the AVF. One undersized tantalum stent and the Wallstent were occluded after 3 weeks. One nitinol stent was occluded at 3 months, whereas the two remaining stents were patent during the whole observation period. No inflammatory tissue response was seen, and no host-versus-graft reaction was present. Preparation and implantation of vein graft-coated stents, especially in the case of self-expanding stent systems, is cumbersome. This restricts the common use of such a coating, which shows an excellent biocompatibility. Vein graft-coated stents might be of use in infected endangered vessels.


Somatostatin modulates generation of inspiratory rhythms and determines asphyxia survival.
Breathing and the activity of its generator (the pre-Bötzinger complex; pre-BötC) are highly regulated functions. Among neuromodulators of breathing, somatostatin (SST) is unique: it is synthesized by a subset of glutamatergic pre-BötC neurons, but acts as an inhibitory neuromodulator. Moreover, SST regulates breathing both in normoxic and in hypoxic conditions. Although it has been implicated in the neuromodulation of breathing, neither the locus of SST modulation, nor the receptor subtypes involved have been identified. In this study, we aimed to fill in these blanks by characterizing the SST-induced regulation of inspiratory rhythm generation in vitro and in vivo. We found that both endogenous and exogenous SST depress all preBötC-generated rhythms. While SST abolishes sighs, it also decreases the frequency and increases the regularity of eupnea and gasping. Pharmacological experiments showed that SST modulates inspiratory rhythm generation by activating SST receptor type-2, whose mRNA is abundantly expressed in the pre-Bötzinger complex. In vivo, blockade of SST receptor type-2 reduces gasping amplitude and consequently, it precludes auto-resuscitation after asphyxia. Based on our findings, we suggest that SST functions as an inhibitory neuromodulator released by excitatory respiratory neurons when they become overactivated in order to stabilize breathing rhythmicity in normoxic and hypoxic conditions.


LC-MS/MS method for denosumab quantitation in human serum with rapid protein digestion using immobilized trypsin.
Proteomics-based LC-MS/MS methods using trypsin solution have some problems including ion suppression and long protein digestion times. Few practical methods to quantify denosumab in human serum have been published. Immunoglobulins in serum were extracted using immobilized protein G. Denatured, reduced and alkylated serum samples were digested with immobilized trypsin for 14 min. A denosumab-unique peptide was identified using a Fourier transform mass spectrometer as a signature peptide. The signature peptide was quantitated with a hybrid triple-quadrupole/linear ion-trap mass spectrometer. A rapid and practical proteomics-based LC-MS/MS method using immobilized trypsin for denosumab quantitation in human serum was developed. The present method has an acceptable analytical performance and can be helpful for the determination of serum denosumab in clinical settings.


Diagnostic accuracy of urine dipstick for proteinuria category in Japanese workers.
Urine dipstick tests are often used to evaluate proteinuria during health checkups. We examined the dipstick's accuracy in assessing the proteinuria levels among Japanese workers. We assessed subjects aged ≥ 18 years who had a health checkup at the University of Tokyo in 2016 or 2017 (n = 5383). Proteinuria was stratified by urine protein-to-creatinine ratio (PCR): A1, < 150 mg/gCre; A2, 150-499 mg/gCre; and A3, ≥ 500 mg/gCre. The accuracy of a dipstick result of ± or higher to detect a PCR level of ≥ A2 was examined. We compared changes in dipstick results and PCR level in 136 subjects evaluated twice with a median interval of 119 days. The subjects' mean age was 40 years, and half were women. The dipstick results were - in 94.9%, ± in 4.1%, and ≥ 1 + in 1.0%. The PCR level was A1, A2, A3 in 98.6%, 1.2%, and 0.2% of the subjects, respectively. The sensitivity, specificity, and positive and negative predictive values of a ± or higher dipstick result to detect A2 or higher were 66.2%, 95.6%, 17.5%, and 99.5%, respectively. Among the 136 subjects examined twice, 134 (98.5%) had no change in PCR level (A1 in all cases) despite a decrease or increase in dipstick results. Urine dipstick results of ± or above had a high specificity but low sensitivity and positive predictive value to detect PCR proteinuria of A2 or higher. Confirmation by quantitative protein measurement should be recommended for individuals at high risk of chronic kidney disease.


Primary Ewing sarcoma of the adrenal gland: A rare cause of abdominal mass.
Ewing sarcoma is a malignant tumor that more commonly affects the long bones. Primary Ewing sarcoma of the adrenal gland is a rare diagnosis. We report an unusual case of primary Ewing sarcoma of the adrenal gland in a 34-year-old man who initially presented with abdominal as well as flank pain and abdominal mass. Computed tomography and magnetic resonance imaging showed a heterogeneous, hemorrhagic right adrenal mass with inferior vena cava extension and thrombosis. Thus, a major open surgery including right adrenalectomy, right nephrectomy, inferior vena cava thrombectomy with resection, and a retroperitoneal lymph node dissection was necessitated. Early recognition with radiological imaging and treatment of extraosseous Ewing sarcoma of the adrenal gland with a multimodality approach reduces morbidity and mortality.


Wnt5A exerts immunomodulatory activity in the human ovarian cancer cell line SKOV-3.
The purpose of this study was three fold: (1) to reveal the implications of Wnt5A for cytokine and chemokine production by human ovarian cancer cell line SKOV-3 cells, (2) to determine the influence of Wnt5A on chemotactic SKOV-3 cell migration, and (3) to assess the effect of inflammatory mediators on Wnt5A expression levels and to describe its underlying molecular mechanisms. A cytokine array was performed using a conditioned medium harvested from SKOV-3 cells transfected with specific siRNAs against Wnt5A or with scrambled siRNA and a transfection reagent alone as negative controls for 48 h. Chemotactic cell migration was performed using transwells. Inflammation-induced Wnt5A expression was determined by treating cells with recombinant human (rh) IL-1β, IFNβ, or TNFα alone or in combination with STAT3 and NF-κB inhibitors for different time durations. The cytokine array showed the suppression of GCSF, GM-CSF, IL-1α, IL-2, IL-13, and MCP-3 production, whereas cell RANTES and IL-7 showed increased levels in Wnt5A knock-down cells compared with those in controls. Chemotactic migration decreased significantly when the conditioned medium from Wnt5A knock-down cells was applied to the upper chamber of the transwell. Compared with the control, there were 30-fold and five-fold increases in Wnt5A mRNA levels in cells treated, with rhIL-1β and rhIFNβ, respectively after 8 h (P < 0.001). Compared with the control, TNF-α had a 1.8-fold increased levels of Wnt5A mRNA after 4 h (P < 0.01). Both NF-κB and STAT3 inhibitors decreased inflammation-induced Wnt5A expression. This study revealed a previously unrecognized immunomodulatory role of endogenous Wnt5A in ovarian cancer cells, which could further influence chemotactic cell migration.


Alterations in sleep, sleep spindle, and EEG power in mGluR5 knockout mice.
The type 5 metabotropic glutamate receptor (mGluR5) represents a novel therapeutic target for schizophrenia and other disorders. Schizophrenia is associated with progressive abnormalities in cortical oscillatory processes including reduced spindles (8-15 Hz) during sleep and increased delta (0.5-4 Hz)- and gamma-band activity (30-80 Hz) during wakefulness. mGluR5 knockout (KO) mice demonstrate many schizophrenia-like behaviors, including abnormal sleep. To examine the effects of mGluR5 on the maintenance of the neocortical circuitry responsible for such neural oscillations, we analyzed sleep/wake electroencephalographic (EEG) activity of mGluR5 KO mice at baseline, after 6 h of sleep deprivation, and during a visual method of cortical entrainment (visual steady state response). We hypothesized mGluR5-KO mice would exhibit translationally relevant abnormalities in sleep and neural oscillations that mimic schizophrenia. Power spectral and spindle density analyses were performed across 24-h EEG recordings in mGluR5-KO mice and wild-type (WT) controls. Novel findings in mGluR5 KO mice include deficits in sleep spindle density, wake alpha power, and 40-Hz visual task-evoked gamma power and phase locking. Sigma power (10-15 Hz), an approximation of spindle activity, was also reduced during non-rapid eye movement sleep transitions. Our observations on abnormal sleep/wake are generally in agreement with previous reports, although we did not replicate changes in rapid eye movement sleep. The timing of these phenotypes may suggest an impaired circadian process in mGluR5 KO mice. In conclusion, EEG phenotypes in mGluR5 KO mice resemble deficits observed in patients with schizophrenia. These findings implicate mGluR5-mediated pathways in several translationally relevant phenotypes associated with schizophrenia, and suggest that agents targeting this receptor may have harmful consequences on sleep health and daily patterns of EEG power.NEW & NOTEWORTHY Metabotropic glutamate receptor type 5 (mGluR5) knockout (KO) mice show several translationally relevant abnormalities in neural oscillatory activity associated with schizophrenia. These include deficits in sleep spindle density, sigma and alpha power, and 40-Hz task-evoked gamma power. The timing of these phenotypes suggests an impaired circadian process in these mice. Previously reported rapid eye movement sleep deficits in this model were not observed. These findings suggest mGluR5-enhancing drugs may improve sleep stability and sleep spindle density, which could impact memory and cognition.


Nanocomposite scaffolds composed of Apacite (apatite-calcite) nanostructures, poly (ε-caprolactone) and poly (2-hydroxyethylmethacrylate): The effect of nanostructures on physico-mechanical properties and osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro.
Nanocomposite scaffolds were fabricated from poly (ε-caprolactone) (PCL), Poly (2-hydroxyethylmethacrylate) (PHEMA), and Apacite (Apatite-calcite) nanostructures (15 and 25 wt%). The nanoscale structure, physical and chemical properties, mechanical properties, hydrophilic behavior, degradability and osteogenic properties of the fabricated scaffolds were evaluated. The results showed that the mechanical strength, degradation, wetting ability, and mechanical strength of PCL-PHEMA scaffolds significantly increases upon inclusion of Apacite nanoparticles up to 25 wt%. Accordingly, the best mechanical values (E ~ 7.109 MPa and σ ~ 0.414 MPa) and highest degradability (32% within 96 h) were recorded for PCL-PHEMA scaffolds containing 25 wt% of Apacite. Furthermore, highest porosity and roughness were observed in the PCL-PHEMA/25% Apacite as a result of the Apacite nanoparticles inclusion. There was no cytotoxicity recorded for the fabricated scaffolds based on the results obtained from MTT assay and acridine orange staining. Alkaline phosphatase activity, calcium content quantification, Van Kossa staining, FESEM and real time PCR tests confirmed the biomineralization, and the differentiation potential of the nanocomposite scaffolds. Overall, the 3D structure, optimum porosity and balanced dissolution rate of PCL-PHEMA/25% Apacite providing a balanced microenvironment resulted in improved cell adhesion, cell behavior, and replication, as well as osteogenic induction of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs).


The impact of anastomotic leakage on oncology after curative anterior resection for rectal cancer: A systematic review and meta-analysis.
Anastomotic leakage (AL) is a serious clinical complication after anterior resection for rectal cancer and will lead to an increase in postoperative mortality. However, the effect on long-term oncology outcomes remains controversial. We searched the PubMed, Embase, and Cochrane library databases for related articles. The included studies assessed local recurrence, distant recurrence, overall survival, cancer-specific survival and disease-free survival. The systematic reviews and meta-analyses was conducted in accordance with the PRISMA guidelines. The combined RRs with 95% CI were then calculated using a fixed effects model or a randomized effect model. A total of 18 cohort studies included 34,487 patients who met the inclusion criteria. The meta-analysis demonstrated that AL was associated with increased local recurrence (RR 1.47, 95% CI 1.14-1.90, I = 57.8%). Anastomotic leakage decreased overall survival (RR 0.92, 95% CI 0.88-0.96, I = 58.1%), cancer-specific survival (RR 0.96, 95% CI 0.92-1.00, I = 30.4%), and disease-free survival (RR 0.85, 95% CI 0.77-0.94, I = 80.4%). Distant recurrence may had no significant effects of AL (RR 1.16, 95% CI 0.91-1.46, I = 58.4%). AL has a negative effect on local recurrence and long-term survival (including overall survival, cancer-specific survival, and disease-free survival) after anterior resection for rectal cancer, but not related to distant recurrence.


Molecular adsorbent recirculating system treatment for patients with liver failure: the Hong Kong experience.
The molecular adsorbent recirculating system (MARS) is an extracorporeal liver dialysis system that allows selective removal of bilirubin and other albumin-bound toxins. We reported here our experience with the use of this technique for management of liver failure at Queen Mary Hospital, Hong Kong. From December 2002 to 2004, a total of 74 MARS sessions were performed on 22 patients. The cause of liver failure included acute liver failure (n = 2), acute on chronic liver failure (n = 12), posthepatectomy liver failure (n = 4), and posttransplantation allograft failure (n = 4). MARS treatment showed significant reduction in total bilirubin level, serum ammonia level and blood urea, and nitrogen (P < 0.001 for all three parameters). Five patients (22.7%) were able to bridge to transplantation and one patient (4.5%) made a spontaneous recovery. The 30-day mortality rate was 72.7%. Our results indicated that MARS can effectively improve serum biochemistry and is suitable for temporarily supporting patients with liver failure where transplantation is not immediately available. There is, however, no clear evidence showing that MARS can increase survival, improve the chance of transplantation or assist liver regeneration. Future studies in the form of randomized-controlled trials are crucial to characterize the true potential of this treatment.


An innovative LC/MS approach applied to the determination of zeralenone in maize: Alternate Isotope-coded Derivatization Assay (AIDA).
Zearalenone is a mycotoxin mainly produced by severalFusarium species, which are known to colonize grains in temperate climates. The purpose of the study is to provide a reliable isotope dilution method for the quantification of this mycotoxin. A derivative of the analyte to be used as standard is obtained by reaction with acetic anhydride, which is available in two pure isotopic forms, a protonated ("light") and a hexadeuterated ("heavy"). The derivatized standards are added to the matrix split intwo parts. Then, the derivatization procedure is repeated on both matrices derivatizing the part containing the "heavy" labelled standard with the "light" acetic anhydride and the part containing the "light" labelled standard with the "heavy" acetic anhydride. Both extracted mixtures are analyzed by LC/MS, monitoring the "light" and the "heavy" labelled analytes and using the former as standard for the latter in one case and viceversa in the other case. The method allowed to obtain very good results, without the need of IAC purification.


A new high-yield synthetic route to PET CB1 radioligands [11C]OMAR and its analogs.
OMAR analogs reference standards and their corresponding desmethylated precursors were synthesized from substituted anilines either in 4 and 5 steps with 27-32% and 24-31% yield, or in 3 and 4 steps with 21-30% and 19-28% yield, respectively. [(11)C]OMAR and its analog radioligands were prepared from their desmethylated precursors with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50-65% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.


Real-time Markerless Tracking of Lung Tumors based on 2-D Fluoroscopy Imaging using Convolutional LSTM.
To investigate the feasibility of tracking targets in 2D fluor images using a novel deep learning network. Our model design aims to capture the consistent motion of tumors in fluoroscopic images by neural network. Specifically, the model is trained by generative adversarial methods. The network is a coarse-to-fine architecture design. Convolutional LSTM (Long Short-term Memory) modules are introduced to account for the time correlation between different frames of the fluoroscopic images. The model was trained and tested on a digital X-CAT phantom in two studies. Series of coherent 2D fluoroscopic images representing the full respiration cycle were fed into the model to predict the localized tumor regions. In first study to test on massive scenarios, phantoms of different scales, tumor positions, sizes, and respiration amplitudes were generated to evaluate the accuracy of the model comprehensively. In second study to test on specific sample, phantoms were generated with fixed body and tumor sizes but different respiration amplitudes to investigate the effects of motion amplitude on the tracking accuracy. The tracking accuracy was quantitatively evaluated using intersection over union (IOU), tumor area difference, and centroid of mass difference (COMD). In the first comprehensive study, the mean IOU and dice coefficient achieved 0.93±0.04 and 0.96±0.02. The mean tumor area difference was 4.34%±4.04%. And the COMD was 0.16 cm and 0.07 cm on average in SI (superior-interior) and LR (left-right) directions, respectively. In the second amplitude study, the mean IOU and dice coefficient achieved 0.98 and 0.99. The mean tumor difference was 0.17%. And the COMD was 0.03cm and 0.01 cm on average in SI and LR directions, respectively. Results demonstrated the robustness of our model against breathing variations. Our study showed the feasibility of using deep learning to track targets in x-ray fluoroscopic projection images without the aid of markers. The technique can be valuable for both pre- and during-treatment real-time target verification using fluoroscopic imaging in lung SBRT treatments.


Comment regarding: what is the efficacy of aerobic exercise versus strength training in the treatment of migraine? A systematic review and network meta‑analysis of clinical trials.
In Woldeamanuel and Oliveira (2022)'s article about the efficacy of exercise in the treatment of migraine, the ranking of the efficacy of strength training (mean difference, - 3.55), aerobic exercise (mean difference, - 2.18 to - 3.13), topiramate (mean difference, - 0.98), and amitriptyline (mean difference, 3.82) using network meta-analysis can mislead readers. First, the inclusion criteria were reported at a monthly frequency of migraine and the end of the intervention, but some article did not meet the inclusion criteria or had data inconsistency. Second, there was an inconsistency in the placebos used in the included studies, which can be problematic in network meta-analysis. Third, all three articles on strength training were rated as high-risk or exhibited some risk of bias. Finally, the effectiveness of this statistical method is questionable for assessing physical activities because strength training, aerobic exercise, and preventive medications can be simultaneously recommended for possible synergistic effects in the prevention of migraine.


Slower spontaneous excitatory postsynaptic currents in spiny versus aspiny hilar neurons.
In the hilar region of the rat hippocampus, large spontaneous excitatory postsynaptic currents (sEPSCs) mediated by non-NMDA glutamate receptors are present in both excitatory spiny mossy cells and inhibitory aspiny hilar interneurons, making these neurons ideal candidates for a comparative study using the tight seal whole-cell recording technique. Although sEPSCs have similar amplitude distributions, the rise and decay times are significantly slower in spiny versus aspiny neurons. Similar kinetic differences are observed in synaptic currents evoked by mossy fiber stimulation. These results demonstrate a physiological difference between the excitatory drive to excitatory and inhibitory neurons in the hilus that certainly contributes to differences in synaptic strength and that may be applicable to other brain regions. Furthermore, since the development or modification of individual spines or groups of spines may affect synaptic strength, these results may be pivotal in establishing a role for spines in modulating synaptic activity.


Neuroprotection and aging of the cholinergic system: a role for the ergoline derivative nicergoline (Sermion).
The aging brain is characterized by selective neurochemical changes involving several neural populations. A deficit in the cholinergic system of the basal forebrain is thought to contribute to the development of cognitive symptoms of dementia. Attempts to prevent age-associated cholinergic vulnerability and deterioration therefore represent a crucial point for pharmacotherapy in the elderly. In this paper we provide evidence for the protective effect of nicergoline (Sermion) on the degeneration of cholinergic neurons induced by nerve growth factor deprivation. Nerve growth factor deprivation was induced by colchicine administration in rats 13 and 18 months old. Colchicine induces a rapid and substantial down-regulation of choline acetyltransferase messenger RNA level in the basal forebrain in untreated adult, middle-aged and old rats. Colchicine failed to cause these effects in old rats treated for 120 days with nicergoline 10 mg/kg/day, orally. Moreover, a concomitant increase of both nerve growth factor and brain-derived neurotrophic factor content was measured in the basal forebrain of old, nicergoline-treated rats. Additionally, the level of messenger RNA for the brain isoform of nitric oxide synthase in neurons of the basal forebrain was also increased in these animals. Based on the present findings, nicergoline proved to be an effective drug for preventing neuronal vulnerability due to experimentally induced nerve growth factor deprivation.


On the contribution of polycyclic aromatic hydrocarbons to the carcinogenic impact of automobile exhaust condensate evaluated by local application onto mouse skin.
The objective of this investigation was to identify the substances chiefly responsible for the carcinogenicity of automobile exhaust condensate using topical application onto the skin of mice. This was performed by comparing the carcinogenic effect of various fractions with that of an unseparated sample of automobile exhaust condensate, tested in 3 different doses. The probit and Weibull analysis of the result shows: (a) The condensate, emitted from a gasoline-driven automobile provokes local tumors after long-term application to the dorsal skin of mice. The tumor incidence demonstrates a clear cut dose-response relationship. (b) The fraction of polycyclic aromatic hydrocarbons (PAH) containing more than 3 rings accounts for about 84-91% of the total carcinogenicity of automobile exhaust condensate. This fraction represents only about 3.5% by wt of the condensate. (c) The content of benzo[a]pyrene (BaP) (0.414 mg/g) accounts for 6-7.6% of the total carcinogenicity of automobile exhaust condensate, 15 selected PAHs for about 41%. (d) Regarding the minor effect of the PAH-free fraction (about 83% by wt), no hints for a cocarcinogenic activity were observed.


Incidence of aplastic anemia: the relevance of diagnostic criteria. By the International Agranulocytosis and Aplastic Anemia Study.
The incidence of aplastic anemia was estimated in a 4-year study conducted in Israel and seven areas in Europe. Strict definition criteria were used, and all data and bone marrow specimens were reviewed by a panel of experienced hematologists. Complete ascertainment of cases was attempted by establishing a telephone network including all relevant hospitals in the study areas. The incidence of aplastic anemia was estimated to be less than three per million per year, a figure lower than previously reported. The most likely explanation for the differences among studies is variation in diagnostic criteria, which might lead to an overestimation of the incidence in some previous studies.


Variable Message Signs for road tunnel emergency evacuations.
This paper investigates the design of Variable Message Signs (VMS) as a way-finding aid for road tunnel emergency evacuations. The use of the Theory of Affordances is suggested to provide recommendations on the design of VMS. A preliminary evaluation of 11 selected VMS systems was performed and 6 of them were further evaluated using an affordance-based within subject stated-preference questionnaire administered to a sample of 62 participants. Results are used to provide recommendations on the characteristics of the VMS systems, such as (1) size of the sign (large or small); (2) use of flashing lights; (3) colour scheme; (4) message coding (i.e., text, pictograms or a combination of them). The best performing VMS features for road tunnel emergency evacuation included the use of larger signs, flashing lights, the combination of emergency exit pictorial symbol in green in one panel and text in amber in the other panel.


Occurrence, fate, and risk assessment of typical tetracycline antibiotics in the aquatic environment: A review.
Tetracyclines (TCs), used as human and veterinary medicines, are the most widely used antibiotics. More than 75% of TCs are excreted in an active form and released into the environment through human and animal urine and feces, causing adverse effects on the ecological system and human health. Few articles review the environmental occurrence and behaviors of TCs, as well as their risks and toxicities. Here, we comprehensively summarized the recent advances on the following important issues: (1) Environmental occurrence of TCs. TCs are used globally and their occurrence in the aquatic environment has been documented, including surface water, groundwater, drinking water, wastewater, sediment, and sludge. (2) Environmental behaviors of TCs, particularly the fate of TCs in wastewater treatment plants (WWTPs). Most WWTPs cannot effectively remove TCs from wastewater, so alternative methods for efficient removal of TCs need to be developed. The latest degradation methods of TCs are summarized, including adsorption, photocatalytic, photochemical and electrochemical, and biological degradations. (3) Toxicities and possible risks of TCs. The toxicological data of TCs indicate that several TCs are more toxic to algae than fish and daphnia. Risk assessments based on individual compound exposure indicate that the risks arising from the current concentrations of TCs in the aquatic environment cannot be ignored.


Childhood maltreatment and impulsivity in offenders: Examining the mediating roles of self-compassion and cognitive reappraisal.
The higher impulsivity of offenders in prison is a challenge for prison intervention. Childhood maltreatment, one of the factors closely related to the generation and development of impulsivity, is also prevalent in offenders. Therefore, it is critical to investigate the underlying paths that generate impulsivity in offenders who have experienced childhood abuse. Targeting positive protective factors, this study aimed to probe the mediating roles of self-compassion and cognitive reappraisal in the relationship between childhood maltreatment and impulsivity in offenders. The participants included 2643 offenders, 1534 males and 1109 females. Each participant completed the appropriate questionnaires to measure childhood maltreatment, impulsivity, self-compassion, and cognitive reappraisal. The PROCESS macro was used to perform the mediation analysis and hypothesis testing. The findings showed that childhood maltreatment indirectly affected offenders' impulsivity through self-compassion and cognitive reappraisal, and the mediating effect of self-compassion was stronger than that of cognitive reappraisal. Further analyses found that sexual abuse indirectly affected impulsivity through self-compassion, and the remaining types of childhood maltreatment were associated with impulsivity in indirect pathways through self-compassion and cognitive reappraisal. The results suggest that reinforcing practical training in self-compassion and cognitive reappraisal, especially the former, might facilitate the reduction of impulsive symptoms among offenders with backgrounds of childhood maltreatment.


[Roentgen examination after oesophageal surgery (author's transl)].
Sutureinsufficiency has to be sought postoperatively. Later, tumors, passage disturbances and reflux must be looked for. Antirefluxsurgery with fundoplication may lead to a roentgenmorphology with tumoraspect. After transoesophageal sclerosis of varices passage disturbances and perforations may be seen. After perforations by endoscopic procedures the oesophageal roentgen examination with water-soluble substances completes the clinical surveillance.


Wood sawdust waste-derived nano-cellulose as a versatile reinforcing agent for nano silica cement composites: a systematic study on its characterization and performance.
The development of sustainable construction materials is a pressing concern for researchers worldwide, as the cement industry is a major contributor to environmental degradation. The incorporation of nano-materials with cement composites has emerged as a promising solution to sustainable materials production. In this study, the effect of the addition of nano cellulose produced from wood sawdust waste on the performance of cement-based nano-silica composite was investigated. The nano-materials were incorporated at low concentrations and in gel form to eliminate the need for any advanced dispersion techniques. The results indicated that the addition of even low concentrations of nano cellulose significantly enhanced the compactness and mechanical properties of the cement matrix. The crack propagation was observed to be arrested with better adherence to the cement hydration product, which resulted from the presence of nano-silica. The nano cellulose fibers were found to bridge the calcium silicate hydrate products, arresting the propagation of cracks at their initial condition. The high pozzolanic reactivity of nano-silica ensured a minimal amount of calcium hydroxide, which is a significant contributor to the carbon footprint of cement production. Overall, the findings of this study suggest that the incorporation of nano cellulose from wood sawdust waste with cement-based nano-silica composite can lead to the development of sustainable and high-performance building materials with improved mechanical properties and reduced environmental impact.


Sex differences in stress-related psychiatric disorders: neurobiological perspectives.
Stress is associated with the onset and severity of several psychiatric disorders that occur more frequently in women than men, including posttraumatic stress disorder (PTSD) and depression. Patients with these disorders present with dysregulation of several stress response systems, including the neuroendocrine response to stress, corticolimbic responses to negatively valenced stimuli, and hyperarousal. Thus, sex differences within their underlying circuitry may explain sex biases in disease prevalence. This review describes clinical studies that identify sex differences within the activity of these circuits, as well as preclinical studies that demonstrate cellular and molecular sex differences in stress responses systems. These studies reveal sex differences from the molecular to the systems level that increase endocrine, emotional, and arousal responses to stress in females. Exploring these sex differences is critical because this research can reveal the neurobiological underpinnings of vulnerability to stress-related psychiatric disorders and guide the development of novel pharmacotherapies.


Effects of ADAM10 and ADAM17 Inhibitors on Natural Killer Cell Expansion and Antibody-dependent Cellular Cytotoxicity Against Breast Cancer Cells In Vitro.
The inhibition of a disintegrin and metalloproteinase (ADAM) has the potential to become a novel approach for natural killer (NK) cell-based cancer immunotherapy. Thus, the aim of this study was to investigate the influence of ADAM10 and ADAM17 inhibitors on expanded NK cell to enhance antibody-dependent cellular cytotoxicity (ADCC) in breast cancer cell lines. NK cells were expanded in medium supplemented with an ADAM10 or ADAM17 inhibitor to prevent the shedding of soluble CD16/FcγRIII. The expression level of CD16 and production of interferon-gamma (IFN-γ) was detected by flow cytometry using specific antibodies. ADCC activity of expanded NK cells was estimated in trastuzumab treated breast cancer cell lines such as MCF-7, MDA-MB-231, SKBR3, and BT-474 cells. The ADAM17 inhibitor increased the purity of expanded NK cells to 90% after 14 days at 5 and 10 μM in vitro (p=0.043). However, the expansion rate of NK cells was decreased at 10 μM of the ADAM 17 inhibitor (p=0.043). Inhibition of ADAM10 suppressed the expansion of NK cells, although the NK purity was increased at 1 μM of the inhibitor. The expression of CD16 was significantly increased at 1 and 5 μM of the ADAM17 inhibitor (p=0.046, 0.028, respectively) during the culturing period. Inhibition of ADAM10 reduced the expression of CD16 on NK cells. The cytotoxic activity of the ADAM17 inhibitor treated NK cells against MCF-7 (p=0.039) and BT-474 (p=0.027) cells was significantly elevated. The ADCC activity of NK cells treated with 5 μM of ADAM17 inhibitor was significantly increased against SKBR-3 and BT-474 (p=0.027). Inhibition of ADAM17 increased the production of IFN-γ in expanded NK cells. The inhibition of ADAM17 enhanced the purity of expanded NK cells and the ADCC activity of these cells against trastuzumab treated breast cancer cell lines.


Mesh on the move: a case report of total transmural surgical mesh migration causing bowel obstruction.
We present the case of a 60-year-old man with a complex medical history, presenting to the hospital with generalized weakness and found to be markedly hyperglycemic. Early in the patient's hospital course, he developed abdominal pain and was found to have a small bowel obstruction secondary to intraluminal migrated surgical mesh entrapped in the terminal ileum. The bowel obstruction was relieved surgically with uncomplicated mesh removal and ileocecectomy. Surgical mesh migration is a relatively rare complication of hernia repair and abdominal wall reconstruction, and intraluminal mesh migration is an even more rare variant. Our case demonstrates key clinical and imaging features and serves as an important example of how such cases may present.


Effectiveness of Therapeutic Education in Patients with Cancer Pain: Systematic Review and Meta-Analysis.
(1) Objective: To review the existing evidence on pain education in patients with pain derived from an oncological process. (2) Methods: A systematic review was conducted using the databases Pubmed, Web of Science, PEDro, and Scopus. The selected studies had to incorporate instruction about the neurophysiology of pain into their educational program. The target population was cancer patients who had suffered pain for at least one month. The methodological quality of the articles collected was assessed using the PEDro scale. (3) Results: Some 698 studies were initially identified, of which 12 were included in this review. Four different models of pain education programs were found in the studies' interventions. Pain intensity, pain experience, quality of life, pain tolerance, and catastrophism were the variables that appeared most frequently. (4) Conclusions: This review demonstrates that pain education in patients with cancer pain may produce effects such as decreased pain intensity and catastrophism. Knowledge about pain also seems to increase. However, no benefit was reported for patients' overall quality of life. Therefore, more research is needed to clarify the effects of these interventions on the oncology population.


Withania somnifera ameliorates sexual arousal and impotence in stressed sexually sluggish male rats by modulating neurotransmitters and NO/cGMP/PDE5α pathway.
Psychological stress is a growing global threat to male sexual potency and erection efficiency. Withania somnifera (L.) Dunal (WS), also known as Ashwagandha, is a well-known Ayurvedic herb. The roots of Withania somnifera improve the body's ability to handle stress, strengthen the immune system, promote healthy ageing, and have aphrodisiac properties with male sexual stimulation effects. Despite its widespread acceptance as an Ayurvedic stress-relieving drug with beneficial effects on male reproductive health, Withania somnifera has yet to be studied for its potential role in improving the sexual arousal and erectile dysfunction of psychologically stressed sexually sluggish males. To investigate the therapeutic effects of purified root powder of Withania somnifera on sexual behaviour and erectile efficiency in stressed sexually sluggish male rats. Sexually sluggish male rats were screened by premating tests after being exposed to a psychological stressor, restraint stress, 3 h/day for 30 days. Subsequently, these rats were treated with purified root powder of WS (150 or 300 mg/kg/day-PO) or sildenafil (5 mg/kg/day-PO) for 30 days. The rats were sacrificed after 24 h of the last treatment, and the effects on various factors related to sexual behaviour, penile histomorphology, serum hormones, and neurotransmitters associated with sexual arousal and penile erection were examined. WS treatment improves prosexual and sexual behaviour in psychologically stressed sexually sluggish male rats by increasing non-contact erections and mounts, intromission, and ejaculation frequencies, while decreasing sexual exhaustion by decreasing post-ejaculation intervals and latencies. WS also modulates neurotransmitters and hormones associated with sexual desire and stress, including dopamine, serotonin, corticosterone, and prolactin. Additionally, there was also a dose-dependent increase in serum LH, FSH, and testosterone levels. The administration of WS to sexually sluggish rats resulted in significant improvements in penile histomorphology, specifically by increasing the ratio of smooth muscle (SM) to collagen. Furthermore, in sexually sluggish rats, WS treatment increased the expression of markers associated with penile erection facilitation, such as nNOS, eNOS, p-Akt, nitric oxide, acetylcholine, and cGMP. Notably, WS treatment decreased the expression of penile PDE5α in these rats in a dose-dependent manner. Remarkably, the therapeutic effects of WS are comparable to those of sildenafil. Purified root powder of Withania somnifera was found to improve sexual arousal and erection efficiency in stressed, sexually sluggish male rats. This improvement was achieved by modulating the HPG and HPA axes as well as the NO/cGMP/PDE5α pathway involved in penile erection. Thus, our findings strongly support the potent therapeutic potential of purified root powder of WS in improving the sexual health of stressed sexually sluggish rats.


Increased incidence of renal cell carcinoma with hypertension.
Of 276 patients who underwent evaluation to determine the cause of hypertension 2 were found to have unsuspected renal cell carcinoma. This prevalence of 0.73 per cent is 16 times higher than expected for an age-matched population. Both patients exhibited abnormalities of plasma renin activity before radical nephrectomy but they remained hypertensive postoperatively. The data suggest an unexplained association between hypertension and renal cell carcinoma. Furthermore, abnormalities on excretory urograms in hypertensive people should be defined by selective renal arteriography.


Synthesis of methanediol [CH2(OH)2]: The simplest geminal diol.
Geminal diols-organic molecules carrying two hydroxyl groups at the same carbon atom-have been recognized as key reactive intermediates by the physical (organic) chemistry and atmospheric science communities as fundamental transients in the aerosol cycle and in the atmospheric ozonolysis reaction sequence. Anticipating short lifetimes and their tendency to fragment to water plus the aldehyde or ketone, free geminal diols represent one of the most elusive classes of organic reactive intermediates. Here, we afford an exceptional glance into the preparation of the previously elusive methanediol [CH2(OH)2] transient-the simplest geminal diol-via energetic processing of low-temperature methanol-oxygen ices. Methanediol was identified in the gas phase upon sublimation via isomer-selective photoionization reflectron time-of-flight mass spectrometry combined with isotopic substitution studies. Electronic structure calculations reveal that methanediol is formed via excited state dynamics through insertion of electronically excited atomic oxygen into a carbon-hydrogen bond of the methyl group of methanol followed by stabilization in the icy matrix. The first preparation and detection of methanediol demonstrates its gas-phase stability as supported by a significant barrier hindering unimolecular decomposition to formaldehyde and water. These findings advance our perception of the fundamental chemistry and chemical bonding of geminal diols and signify their role as an efficient sink of aldehydes and ketones in atmospheric environments eventually coupling the atmospheric chemistry of geminal diols and Criegee intermediates.


Examination of nutritional factors associated with urolithiasis risk in plant based meat alternatives marketed to children and infants.
The global prevalence of pediatric nephrolithiasis continues to rise amidst increased sodium and animal protein intake. Plant-based meat alternatives (PBMAs) have recently gained popularity due to health benefits, environmental sustainability, and increased retail availability. PBMAs have the potential to reduce the adverse metabolic impact of animal protein on kidney stone formation. We analyzed PBMAs targeted to children to characterize potential lithogenic risk vs animal protein. We performed a dietary assessment using a sample of PBMAs marketed to or commonly consumed by children and commercially available at national retailers. Nutrient profiles for PBMAs were compiled from US Department of Agriculture databases and compared to animal protein sources using standardized serving sizes. We also analyzed nutrient profiles for plant-based infant formulas against typical dairy protein-based formulas. Primary protein sources were identified using verified ingredient lists. Oxalate content was extrapolated from dietary data sources. A total of 41 PBMAs were analyzed: chicken (N = 18), hot dogs (N = 3), meatballs (N = 5), fish (N = 10), and infant formula (N = 5). Most products (76%) contained a high-oxalate ingredient as the primary protein source (soy, wheat, or almond). Average oxalate content per serving was substantially higher in these products (soy 11.6 mg, wheat 3.8 mg, almond 10.2 mg) vs animal protein (negligible oxalate). PBMAs containing pea protein (24%) had lower average oxalate (0.11 mg). Most PBMAs averaged up to six times more calcium and three times more sodium per serving compared to their respective animal proteins. Protein content was similar for most categories. Three-quarters of the examined plant-based meat products for children and infants contain high-oxalate protein sources. Coupled with higher per-serving sodium and calcium amounts, our findings raise questions about possible lithogenic risk in some PBMAs, and further studies are needed to assess the relationship between PBMAs and nephrolithiasis.


Erratum: surgical experience of neglected lower cervical spine fracture in patient with ankylosing spondylitis.
[This corrects the article on p. 66 in vol. 48, PMID: 20717515.].


Mechanisms of hydrazine toxicity in rat liver investigated by proteomics and multivariate data analysis.
A proteomics approach combined with multivariate data analysis was used to examine the hepatotoxic effect of hydrazine in 30 male Sprague Dawley rats, assigned to four treatment groups and two control groups. Liver samples from the individual animals were resolved by two-dimensional differential gel electrophoresis (2-D DIGE) and protein patterns from the 2-D gels were analyzed by principal component analysis (PCA) and partial least squares regression (PLSR). The PCA plot was able to describe the variation in the protein expression related to dose and time, by separation or clustering of different animal groups. PLSR followed by variable selection (Jack-knifing) was used to select proteins that varied significantly in relation to the dose related response of the hydrazine treatment. The 10 up-regulated and 10 down-regulated proteins with highest rank in the PLSR model were identified by mass spectrometry. Hydrazine treatment induced altered expression of proteins related to lipid metabolism, Ca(2+) homeostasis, thyroid hormone pathways and stress response. Several of the identified proteins have not previously been implicated in hydrazine toxicity and may thus be regarded as new potential biomarkers of induced liver toxicity.


The expression of rat GAP-43 cDNA in transgenic carp.
To understand more about growth-associated protein-43 (GAP-43), we produced transgenic carp by introduction of a rat GAP-43 cDNA linked to the Rous sarcoma virus-long terminal repeat into fertilized eggs. Of 180 eggs microinjected with exogenous gene, 59 embryos hatched and 4 fish were found to contain the exogenous gene sequences in the genomic DNA. From a mature female transgenic carp, parthenogenetically, 126 progeny were derived and 52 of them survived for more than 90 days. The exogenous gene sequences were detected in 22 F1 progeny, and its messenger RNA was detected in all of 10 transgenic F1 carp examined. In serum-free medium, cultured retinal ganglion cells isolated from transgenic carp elongated their axons, while non-transgenic cells did not elongate axons.


Noninvasive determination of the fetal cardiac interatrial pressure gradients by Doppler ultrasonography: preliminary results.
In 2000, Johnson et al. measured the atrial pressures puncturing the atria invasively in 19 fetuses that will be terminated. In this study, it is aimed to define the fetal cardiac interatrial pressure gradient noninvasively. The pressure gradients were calculated using the ductus venosus (DV) and pulmonary vein (PV) blood flow velocities and Bernoulli equation for flowing fluids. "S," "a," and the time-averaged maximum velocities in both veins of 246 fetuses were used in the simplified Bernoulli equation; Δp=4 (VDV2-VPV2). Additionally, the umbilical vein maximum velocity is measured in order to calculate ducto-umbilical pressure gradient. The average interatrial pressure gradient was biggest in the ventricular systole and the least gradient was in the atrial systole of a cardiac cycle. The pressure gradient changes throughout the second and the third trimester have four periods with two increases and two decreases. The interatrial and ducto-umbilical pressure gradients can be measured noninvasively in order to follow the hemodynamic of the fetal circulatory system.


Central Nervous System Prophylaxis Strategies in Diffuse Large B Cell Lymphoma.
Central nervous system (CNS) relapse is an undesirable event in the course of patients with diffuse large B cell lymphoma (DLBCL) with a median survival of approximately 6 months following CNS relapse. CNS prophylaxis for the prevention of CNS recurrence, in addition to the standard R-CHOP chemotherapy, is thus preferable. For an overall relapse risk of 2-5%, administration of CNS-directed therapies for all patients with DLBCL is unnecessary and prophylaxis should be targeted for the high-risk patients. CNS-International Prognostic Index (CNS-IPI) score has enabled risk stratification with risk ranging < 1% (low-risk group) compared to > 10% (high-risk group). The latter could be considered for CNS prophylaxis. CNS-IPI, however, is not perfect and may not capture patients with high-risk extra-nodal sites such as testicular DLBCL. Cell-of-origin and MYC/BCL2 expression can further build on CNS-IPI to narrow higher risk patients. CNS prophylaxis strategies are controversial. Common strategies include intrathecal (IT) chemotherapy and systemic CNS penetrants such as methotrexate. IT chemotherapy does not adequately penetrate the brain parenchyma and hence it is insufficient in preventing parenchymal CNS recurrences. Most experts promote systemic methotrexate for high-risk groups, which penetrates both the leptomeningeal and parenchymal CNS compartments. Even though systemic CNS prophylaxis is widely promoted over IT alone, its efficacy is unclear. Ongoing efforts in search for appropriate CNS prophylaxis strategies are warranted. My personal practice is to administer systemic high-dose methotrexate in conjunction with R-CHOP chemotherapy for eligible patients deemed at a high risk of CNS recurrence, especially those with high-risk CNS-IPI and extra-nodal involvement.


Intercostal aneurysm causing spinal cord compression in an NF1 patient.
The authors illustrate a case where an intercostal aneurysm was observed in a patient with type 1 neurofibromatosis. A 32-year-old man with NF1 presented with thoracic back pain. The patient's symptoms progressed to include myelopathic symptoms, including difficulty urinating, numbness in the lower extremities, and increased weakness. Imaging revealed what appeared to be a neurofibroma at the T4-T5 level and a plan to resect the mass was formulated. Upon initial limited hemilaminotomy, significant arterial blood was encountered. The patient was then taken to the interventional suite and angiography was performed, revealing a left T4 intercostal aneurysm. The aneurysm was coil-embolized with no residual filling. By 6 months post-surgery, the patient had regained full strength and sensation in his lower extremities and no longer had difficulty urinating. There has been no recurrence of symptoms 3 years postoperatively. Intercostal artery lesions must be considered as a possible diagnosis in NF1.


Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin.
In the cross-bridge theory, contractile force is produced by cross-bridges that form between actin and myosin filaments. However, when a contracting muscle is stretched, its active force vastly exceeds the force that can be attributed to cross-bridges. This unexplained, enhanced force has been thought to originate in the giant protein titin, which becomes stiffer in actively compared with passively stretched sarcomeres by an unknown mechanism. We investigated this mechanism using a genetic mutation (mdm) with a small but crucial deletion in the titin protein. Myofibrils from normal and mdm mice were stretched from sarcomere lengths of 2.5 to 6.0 μm. Actively stretched myofibrils from normal mice were stiffer and generated more force than passively stretched myofibrils at all sarcomere lengths. No increase in stiffness and just a small increase in force were observed in actively compared with passively stretched mdm myofibrils. These results are in agreement with the idea that titin force enhancement stiffens and stabilizes the sarcomere during contraction and that this mechanism is lost with the mdm mutation.


Genetic approaches to study aging in Drosophila melanogaster.
The process of aging can be described as a progressive decline in an organism's function that invariably results in death. This decline results from the activities of intrinsic genetic factors within an organism. The relative contributions of the biological and environmental components to senescence are hard to measure, however different strategies have been devised in Drosophila melanogaster to isolate and identify genetic influences on aging. These strategies include selective breeding, quantitative trait loci (QTL) mapping and single gene mutant analysis. Selective breeding effectively demonstrated a genetic, heritable component to aging while QTL mapping located regions within the Drosophila genome carrying loci that influence the aging process. Within the past decade, single gene mutant analysis has facilitated the identification of specific genes whose activities play a determinative role in Drosophila aging. This review will focus on the application of selective breeding, QTL mapping and single gene mutant analysis used in Drosophila to study aging as well as the results obtained through these strategies to date.


DCAF1-targeting microRNA-3175 activates Nrf2 signaling and inhibits dexamethasone-induced oxidative injury in human osteoblasts.
Activation of nuclear-factor-E2-related factor 2 (Nrf2) signaling can protect human osteoblasts from dexamethasone-induced oxidative injury. DDB1 and CUL4 associated factor 1 (DCAF1) is a novel ubiquitin E3 ligase for Nrf2 protein degradation. We identified a novel DCAF1-targeting miRNA, miR-3175. RNA pull-down, Argonaute 2 RNA-immunoprecipitation, and RNA fluorescent in situ hybridization results confirmed a direct binding between miR-3175 and DCAF1 mRNA in primary human osteoblasts. DCAF1 3'-untranslated region luciferase activity and its expression were significantly decreased after miR-3175 overexpression but were augmented with miR-3175 inhibition in human osteoblasts and hFOB1.19 osteoblastic cells. miR-3175 overexpression activated Nrf2 signaling, causing Nrf2 protein stabilization, antioxidant response (ARE) activity increase, and transcription activation of Nrf2-dependent genes in human osteoblasts and hFOB1.19 cells. Furthermore, dexamethasone-induced oxidative injury and apoptosis were largely attenuated by miR-3175 overexpression in human osteoblasts and hFOB1.19 cells. Importantly, shRNA-induced silencing or CRISPR/Cas9-mediated Nrf2 knockout abolished miR-3175 overexpression-induced osteoblast cytoprotection against dexamethasone. Conversely, DFAC1 knockout, by the CRISPR/Cas9 method, activated the Nrf2 cascade and inhibited dexamethasone-induced cytotoxicity in hFOB1.19 cells. Importantly, miR-3175 expression was decreased in necrotic femoral head tissues of dexamethasone-taking patients, where DCAF1 mRNA was upregulated. Together, silencing DCAF1 by miR-3175 activated Nrf2 signaling to inhibit dexamethasone-induced oxidative injury and apoptosis in human osteoblasts.


Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo[a]pyrene-diol-epoxide and dibenzo[a,l]pyrene-diol-epoxide.
Mutations induced by polycyclic aromatic hydrocarbons (PAH) are expected to be produced when error-prone DNA replication occurs across unrepaired DNA lesions formed by reactive PAH metabolites such as diol epoxides. The mutagenicity of the two PAH-diol epoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and (+/-)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. We applied the (32)P-postlabelling assay to analyze adduct levels and the hprt gene mutation assay for monitoring mutations. It was found that the mutagenicity per target dose was 4 times higher for DBPDE compared to BPDE in NER proficient cells while in NER deficient cells, the mutagenicity per target dose was 1.4 times higher for BPDE. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the hprt gene. The results suggest that NER of BPDE lesions are 5 times more efficient than for DBPDE lesions, in NER proficient cells. However, DBPDE adducts block replication more efficiently and also induce 6 times more recombination events in the hprt gene than adducts of BPDE, suggesting that DBPDE adducts are, to a larger extent, bypassed by homologous recombination. The results obtained here indicate that the mutagenicity of PAH is influenced not only by NER, but also by replication bypass fidelity. This has been postulated earlier based on results using in vitro enzyme assays, but is now also being recognized in terms of forward mutations in intact mammalian cells.


Biomarker discovery and applications for foods and beverages: proteomics to nanoproteomics.
Foods and beverages have been at the heart of our society for centuries, sustaining humankind - health, life, and the pleasures that go with it. The more we grow and develop as a civilization, the more we feel the need to know about the food we eat and beverages we drink. Moreover, with an ever increasing demand for food due to the growing human population food security remains a major concern. Food safety is another growing concern as the consumers prefer varied foods and beverages that are not only traded nationally but also globally. The 21st century science and technology is at a new high, especially in the field of biological sciences. The availability of genome sequences and associated high-throughput sensitive technologies means that foods are being analyzed at various levels. For example and in particular, high-throughput omics approaches are being applied to develop suitable biomarkers for foods and beverages and their applications in addressing quality, technology, authenticity, and safety issues. Proteomics are one of those technologies that are increasingly being utilized to profile expressed proteins in different foods and beverages. Acquired knowledge and protein information have now been translated to address safety of foods and beverages. Very recently, the power of proteomic technology has been integrated with another highly sensitive and miniaturized technology called nanotechnology, yielding a new term nanoproteomics. Nanoproteomics offer a real-time multiplexed analysis performed in a miniaturized assay, with low-sample consumption and high sensitivity. To name a few, nanomaterials - quantum dots, gold nanoparticles, carbon nanotubes, and nanowires - have demonstrated potential to overcome the challenges of sensitivity faced by proteomics for biomarker detection, discovery, and application. In this review, we will discuss the importance of biomarker discovery and applications for foods and beverages, the contribution of proteomic technology in this process, and a shift towards nanoproteomics to suitably address associated issues. This article is part of a Special Issue entitled: Translational plant proteomics.


CRISPR/sgRNA-directed synergistic activation mediator (SAM) as a therapeutic tool for Parkinson´s disease.
Parkinson`s disease (PD) is the second most prevalent neurodegenerative disease, and different gene therapy strategies have been used as experimental treatments. As a proof-of-concept for the treatment of PD, we used SAM, a CRISPR gene activation system, to activate the endogenous tyrosine hydroxylase gene (th) of astrocytes to produce dopamine (DA) in the striatum of 6-OHDA-lesioned rats. Potential sgRNAs within the rat th promoter region were tested, and the expression of the Th protein was determined in the C6 glial cell line. Employing pseudo-lentivirus, the SAM complex and the selected sgRNA were transferred into cultures of rat astrocytes, and gene expression and Th protein synthesis were ascertained; furthermore, DA release into the culture medium was determined by HPLC. The DA-producing astrocytes were implanted into the striatum of 6-OHDA hemiparkinsonian rats. We observed motor behavior improvement in the lesioned rats that received DA-astrocytes compared to lesioned rats receiving astrocytes that did not produce DA. Our data indicate that the SAM-induced expression of the astrocyte´s endogenous th gene can generate DA-producing astrocytes that effectively reduce the motor asymmetry induced by the lesion.


An automatic and personalized recommendation modelling in activity eCoaching with deep learning and ontology.
Electronic coaching (eCoach) facilitates goal-focused development for individuals to optimize certain human behavior. However, the automatic generation of personalized recommendations in eCoaching remains a challenging task. This research paper introduces a novel approach that combines deep learning and semantic ontologies to generate hybrid and personalized recommendations by considering "Physical Activity" as a case study. To achieve this, we employ three methods: time-series forecasting, time-series physical activity level classification, and statistical metrics for data processing. Additionally, we utilize a naïve-based probabilistic interval prediction technique with the residual standard deviation used to make point predictions meaningful in the recommendation presentation. The processed results are integrated into activity datasets using an ontology called OntoeCoach, which facilitates semantic representation and reasoning. To generate personalized recommendations in an understandable format, we implement the SPARQL Protocol and RDF Query Language (SPARQL). We evaluate the performance of standard time-series forecasting algorithms [such as 1D Convolutional Neural Network Model (CNN1D), autoregression, Long Short-Term Memory (LSTM), and Gated Recurrent Units (GRU)] and classifiers [including Multilayer Perceptron (MLP), Rocket, MiniRocket, and MiniRocketVoting] using state-of-the-art metrics. We conduct evaluations on both public datasets (e.g., PMData) and private datasets (e.g., MOX2-5 activity). Our CNN1D model achieves the highest prediction accuracy of 97[Formula: see text], while the MLP model outperforms other classifiers with an accuracy of 74[Formula: see text]. Furthermore, we evaluate the performance of our proposed OntoeCoach ontology model by assessing reasoning and query execution time metrics. The results demonstrate that our approach effectively plans and generates recommendations on both datasets. The rule set of OntoeCoach can also be generalized to enhance interpretability.


Movement disorders at a university hospital emergency room. An analysis of clinical pattern and etiology.
We prospectively evaluated the clinical features and etiologies of all common categories of movement disorder seen in the emergency room (ER) of an urban university hospital over a period of 12 months. We divided movement disorders according to the presenting phenomenology likely to dominate the clinical presentation, that is, gait disorder, tremor, dystonia, myoclonus, and acute akinetic crisis and classified a specific etiology in the individual phenomenology. In one year, there were 60,002 ER visits; of these, 58 (0.09 %) were diagnosed as a primary movement disorder. The most common clinical presentation was gait disorder (n = 21, 36.2 %), followed by myoclonus (n = 16, 27.6 %), dystonia (n = 10, 17.2 %), tremor (n = 8, 13.8 %), and acute akinetic crisis (n = 3, 5.2 %). Comparing the movement disorders, the mean age of the patients with dystonia was significantly lower than that of patients with other movement disorders (P < 0.001). Of the patients, 37 (63.8 %) had drug-related movement disorders. The contribution of drugs was significantly higher in patients with dystonia compared with the other movement disorders (P < 0.01). Our study showed that a large proportion of the movement disorders seen in the ER are drug-related. Careful selection of drugs while prescribing would decrease movement disorder-related visits to the ER.


Refinement of HLA gene mapping with induced B-cell line mutants.
The lymphoma cell line BJAB.B95.8.6 was gamma-irradiated to induce mutations of major histocompatibility complex (MHC) encoded genes. Cloned "wild-type" cells were phenotyped HLA-A1, A2, B13, B35, Bw4, Bw6, Cw4, DR5, DRw52, DQw1, DQw3, DPw2, DPw4, GLO1 1, PGM3 2-1, and ME1 0 and possessed two apparently normal chromosome 6s prior to mutagenesis. Loss mutants were selected 5 days after 3 Gy gamma-irradiation employing three complement-fixing monoclonal antibodies specific for HLA-A2 (TU101) and Bw4 (TU48, TU109). Fifteen independently arising mutants were isolated and cloned. Typing with monospecific alloantisera and cell-mediated lympholysis revealed the presence of HLA-A1, B35, Bw6, Cw4, DR5, DRw52, DQw3, and DPw4 specificities on all mutant clones. HLA-A2, B13, and Bw4 were absent. Mutants differed in their expression of class II antigens. One group retained DQw1 and DPw2, another was DQw1-, DPw2+, and a third was DQw1-, DPw2-. Karyotyping of the "wild-type" line and selected mutant clones showed that the loss of HLA specificities correlated with deletions which map the HLA-A and -B loci directly to the distal part of the 6p21.33 region and the class II genes to the region 6p21.33 (proximal) to 6p21.31 (distal) on the short arm of chromosome 6.


Evaluating best educational practices, student satisfaction, and self-confidence in simulation: A descriptive study.
The National League for Nursing (NLN) has endorsed simulation as a necessary teaching approach to prepare students for the demanding role of professional nursing. Questions arise about the suitability of simulation experiences to educate students. Empirical support for the effect of simulation on patient outcomes is sparse. Most studies on simulation report only anecdotal results rather than data obtained using evaluative tools. The aim of this study was to examine student perception of best educational practices in simulation and to evaluate their satisfaction and self-confidence in simulation. This study was a descriptive study designed to explore students' perceptions of the simulation experience over a two-year period. Using the Jeffries framework, a Simulation Day was designed consisting of serial patient simulations using high and medium fidelity simulators and live patient actors. The setting for the study was a regional campus of a large Midwestern Research 2 university. The convenience sample consisted of 199 participants and included sophomore, junior, and senior nursing students enrolled in the baccalaureate nursing program. The Simulation Days consisted of serial patient simulations using high and medium fidelity simulators and live patient actors. Participants rotated through four scenarios that corresponded to their level in the nursing program. Data was collected in two consecutive years. Participants completed both the Educational Practices Questionnaire (Student Version) and the Student Satisfaction and Self-Confidence in Learning Scale. Results provide strong support for using serial simulation as a learning tool. Students were satisfied with the experience, felt confident in their performance, and felt the simulations were based on sound educational practices and were important for learning. Serial simulations and having students experience simulations more than once in consecutive years is a valuable method of clinical instruction. When conducted well, simulations can lead to increased student satisfaction and self-confidence.


Future orientation in justice-involved youth: The effects of adverse and positive childhood experiences, and being dual-status.
Justice-involved youth face diverse challenges and are likely to experience more adverse childhood experiences (ACEs) and fewer positive childhood experiences (PCEs), which can have implications for their orientation toward their future. Future orientation is thought to influence behavior, but little is known about how it is shaped. While future orientation and its correlates likely matter for all justice-involved youth, the recently recognized subcategory of Dual Status Youths (DSYs) might be especially sensitive to influences on future orientation. This study explores the effects of cumulative adverse childhood experiences (ACEs), cumulative positive childhood experiences (PCEs), and DSY classification on the likelihood of having a positive orientation toward the future. The researchers analyze a sample of 3604 justice-involved youth on probation in a large metropolitan area in Texas. The sample includes juveniles who received the full Positive Achievement Change Tool (PACT) risk/needs assessment. The analytical plan included t-tests and two logistic regression analyses. Findings were that DSY are exposed to more ACEs and fewer PCEs than non-dual status justice-involved youth. Results indicated that a greater number of PCEs is associated with future orientation, but DSY status and ACEs are not. Juvenile justice programming must strive to cultivate PCEs in justice-involved youth prior to the completion of their probation supervision.


Involvement of caveolae in hyperglycemia-induced changes in adiponectin and leptin expressions in vascular smooth muscle cells.
Hyperglycemia exerts various harmful effects on the vasculature. Studies have shown an association between the levels of the adipokines leptin and adiponectin (APN) and vascular complications in diabetes mellitus. The aim of our study was to investigate the molecular mechanisms mediated by APN and leptin that are involved in hyperglycemia-induced vascular remodeling, especially at the level of oxidative stress and actin cytoskeleton dynamics. Rat aorta organ culture was used to investigate the effect of hyperglycemia on APN and leptin protein expression in vascular smooth muscle cells (VSMCs) using Western blot analysis and immunohistochemistry. Hyperglycemia lead to a significant increase in APN synthesis in VSMCs, mainly through caveolae, but this increase failed to provide vascular protection because of the decreased expression of APN receptors, especially AdipoR2, which was assessed by qPCR. In addition, hyperglycemia significantly upregulated leptin expression in VSMCs through caveolae and the RhoA/ROCK pathway. These variations lead to a marked increase in reactive oxygen species (ROS) production, detected by dihydroethidium (DHE) staining, and in NADPH oxidase type 4 (Nox4) expression. Moreover, Nox4 mediated the synthesis of APN in hyperglycemia in VSMCs. Finally, hyperglycemia activated the RhoA/ROCK pathway and subsequently induced the polymerization of globular actin (G-actin) into filamentous actin (F-actin), decreasing the G/F-actin ratio. Taken together, these data show that hyperglycemia increases oxidative stress and changes actin cytoskeleton dynamics in the aorta via caveolae, favoring vascular remodeling.


A transport environmental Kuznets curve analysis for Malaysia: exploring the role of corruption.
Validity of the environmental Kuznets curve (EKC) hypothesis is consistently and widely debated among economists and environmentalists alike throughout time. In Malaysia, transport is one of the "dirtiest" sectors; it intensively consumes energy in powering engines by using fossil fuels and poses significant threats to environmental quality. Therefore, this study attempted an examination into the impact of corruption on transport carbon dioxide (CO2) emissions. By adopting the fully modified ordinary least squares, canonical cointegrating regression, and dynamic ordinary least squares in performing long-run estimations, the results obtained based on the annual data spanning from 1990 to 2017 yielded various notable findings. First, more corruption would be attributable towards increased transport CO2 emissions. Second, a monotonic increment of transport CO2 emission was seen with higher economic growth and thus invalidated the presence of EKC. Overall, this study suggests that Malaysia has yet to reach the level of economic growth synonymous with transport CO2 emission reduction due to the lack of high technology usage in the current system implemented. Therefore, this study could position policy recommendations of use to the Malaysian authorities in designing the appropriate economic and environmental policies, particularly for the transport sector.


Assessing the utility of transcriptome data for inferring phylogenetic relationships among coleoid cephalopods.
Historically, deep-level relationships within the molluscan class Cephalopoda (squids, cuttlefishes, octopods and their relatives) have remained elusive due in part to the considerable morphological diversity of extant taxa, a limited fossil record for species that lack a calcareous shell and difficulties in sampling open ocean taxa. Many conflicts identified by morphologists in the early 1900s remain unresolved today in spite of advances in morphological, molecular and analytical methods. In this study we assess the utility of transcriptome data for resolving cephalopod phylogeny, with special focus on the orders of Decapodiformes (open-eye squids, bobtail squids, cuttlefishes and relatives). To do so, we took new and previously published transcriptome data and used a unique cephalopod core ortholog set to generate a dataset that was subjected to an array of filtering and analytical methods to assess the impacts of: taxon sampling, ortholog number, compositional and rate heterogeneity and incongruence across loci. Analyses indicated that datasets that maximized taxonomic coverage but included fewer orthologs were less stable than datasets that sacrificed taxon sampling to increase the number of orthologs. Clades recovered irrespective of dataset, filtering or analytical method included Octopodiformes (Vampyroteuthis infernalis + octopods), Decapodiformes (squids, cuttlefishes and their relatives), and orders Oegopsida (open-eyed squids) and Myopsida (e.g., loliginid squids). Ordinal-level relationships within Decapodiformes were the most susceptible to dataset perturbation, further emphasizing the challenges associated with uncovering relationships at deep nodes in the cephalopod tree of life.


A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination. We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m(2) on days 3 and 10, and cisplatin 60 mg/m(2) on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC). Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤ 2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL-1). No DLTs were seen in six patients at DL-1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration. Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy.


Structure reassignment of laurefurenynes A and B by computation and total synthesis.
The originally assigned stereostructures of laurefurenynes A and B have been reassigned on the basis of DFT calculations of NMR chemical shifts, synthesis of model compounds and total synthesis of laurefurenyne B, demonstrating the power of this combined approach for stereostructure elucidation/confirmation.


Evaluation of contact exposure as a method for acclimatizing growing pigs to porcine reproductive and respiratory syndrome virus.
To determine whether 6.5-week-old gilts that have not previously been exposed to porcine reproductive and respiratory syndrome (PRRS) virus can be acclimatized to an endemic strain of the virus by commingling with age-matched gilts inoculated with the endemic PRRS virus strain and whether 10.5-week-old gilts can be acclimatized by commingling with age-matched inoculated or contact-exposed animals. Randomized controlled longitudinal study. 80 gilts seronegative for PRRS on a farm in the Midwestern United States with a history of PRRS. 20 gilts were inoculated with the endemic PRRS virus strain at 6.5 weeks of age (group 1) and were commingled with 20 gilts that were not inoculated (group 2). Four weeks later, the remaining 40 gilts (group 3) were commingled with gilts in groups 1 and 2. Presence of viral RNA in the tonsils, seroconversion rate, serum neutralizing antibody titers, interferon-gamma-mediated cellular immunity, and reproductive outcomes were analyzed. Acclimatization of PRRS virus-naïve pigs was achieved by means of contact exposure at both 6.5 and 10.5 weeks of age. No differences were observed among the 3 groups with respect to development of anti-PRRS virus-specific immune responses or reproductive outcomes. Results suggested that contact exposure of 6.5- to 10.5-week-old pigs that had not previously been exposed to PRRS virus to pigs inoculated with endemic PRRS virus may be an efficient acclimatization strategy for controlling outbreaks on commercial farms on which PRRS is endemic.


Self-reported experience of hospitalized children: an integrative review.
To identify available evidence about the self-reported experience of hospitalized children. An integrative review was carried out, and the survey occurred between September and November 2017, in the electronic sources DLTD-USP, CAPES, IBICT, MEDLINE, LILACS and BDENF. Ten studies were found, prevailing samples with descriptive design and approach in qualitative and mixed methods research. The literature evidenced the experience of hospitalized children through the report of parents and health professionals; few were self-reported by the child itself. Five themes were identified: Understanding the time of hospital admission, relevance of care received, feeling of pain, importance of the patient companion, information received about hospitalization. It was found that experiences in childhood are able to have repercussions throughout life, and it is relevant that nursing is attentive to their clients' perception in order to have more satisfaction and the negative impact is diminished.


[Anatomical features concerning the spinal accessory nerve. Apropos of 106 dissections of the neck in cadavers].
Surgical treatment of cervical metastases from head and neck cancer involves different techniques as a function of indication. An anatomical structure of major importance during this surgery is the spinal accessory nerve, and 106 dissections were performed to examine relations of this nerve with cervical plexus, jugular vein, sterno-cleido-mastoid muscle and mastoid tip. Interesting conclusions were drawn with regard to technical procedures of value to surgeons involved in cervicofacial cancerology.


The Effect of Different Starch Liberation and Saccharification Methods on the Microbial Contaminations of Distillery Mashes, Fermentation Efficiency, and Spirits Quality.
The aim of this study was to evaluate the influence of different starch liberation and saccharification methods on microbiological contamination of distillery mashes. Moreover, the effect of hop α-acid preparation for protection against microbial infections was assessed. The quality of agricultural distillates was also evaluated. When applying the pressureless liberation of starch (PLS) and malt as a source of amylolytic enzymes, the lactic acid bacteria count in the mashes increased several times during fermentation. The mashes obtained using the pressure-thermal method and malt enzymes revealed a similar pattern. Samples prepared using cereal malt exhibited higher concentrations of lactic and acetic acids, as compared to mashes prepared using enzymes of microbial origin. The use of hop α-acids led to the reduction of bacterial contamination in all tested mashes. As a result, fermentation of both mashes prepared with microbial origin enzyme preparations and with barley malt resulted in satisfactory efficiency and distillates with low concentrations of aldehydes.


Modulation of intramolecular charge transfer emission inside micelles: a fluorescence probe for studying microenvironment of micellar assemblies.
Modulation of intramolecular charge transfer reaction of ethyl ester of N,N-dimethylaminonaphthyl-(acrylic)-acid (EDMANA) in anionic sodium dodecyl sulfate (SDS), cationic cetyltrimethylammonium bromide (CTAB) and non-ionic p-tert-octylphenoxy polyoxyethanol (Triton-X 100, TX-100) micelles has been addressed using steady state and time resolved spectroscopy. The interaction of the CT probe EDMANA with micelles and its location inside the micelles have been investigated by the study of fluorescence spectral band position of EDMANA in micelle, the effective polarity of micelle-water interface and cetyl pyridinium chloride induced fluorescence quenching measurement. The effects of urea on the properties of the micelles such as Critical Micelle Concentration and the interaction between EDMANA and micelles have been explored using EDMANA as emission probe.


Molecular forms of human chorionic gonadotropin in serum, urine, and placental extracts.
The molecular forms of human chorionic gonadotropin (hCG) were assessed in serum, urine, and placental extracts by gel filtration chromatography using radioimmunoassays for hCG, hCGalpha, and hCGbeta and a radioreceptor assay for hCG. The predominant form in all three biologic specimens was native-sized hCG. An excess of free alpha-subunit was also found in all three specimens. A small molecular weight fragment, reactive in the hCGbeta assay, was noted in urine and placental extracts. A large molecular form, reactive in all three radioimmunoassays and in the radioreceptor assay, was found in placental extracts. This large molecular species could not be dissociated by conditions that totally dissociate hCG.


The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs.
Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150 mg/kg, i.p.), tamoxifen (1.0 mg/kg, i.p.) and chelerythrine (1 microg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0 mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0 mg/g) and higher (6.0 mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.


Therapeutic efficacies of Coriandrum sativum aqueous extract against metronidazole-induced genotoxicity in Channa punctatus peripheral erythrocytes.
Metronidazole (MTZ), a nitroimidazole drug, is primarily used as an anti-protozoan or an anti-bacterial agent in humans, although its genotoxic and carcinogenic effects have been widely reported, particularly in aquatic organisms. MTZ may induce DNA damages through single-strand breaks, modification of bases, DNA-DNA and DNA-protein cross-links, ultimately leading to apoptosis or necrosis. Here, we have assessed the genotoxicity of MTZ in the peripheral erythrocytes of Channa punctatus, using micronucleation (MN) and binucleation (BN) as genotoxicity markers. The therapeutic potential of aqueous extract of Coriandrum sativum against MTZ-induced genotoxicity has also been examined. The results show significant (P<0.05) increase in both MN and BN formation due to MTZ treatment. Such aberrations were higher in smaller fish samples for a particular dosage of MTZ, as established by correlation analysis between fish body weight and MN/BN count at P<0.05. However, such degenerative damages were found to be alleviated by a great extent due to treatment with C. sativum leaf extract. Hence, we establish that MTZ can produce considerable degrees of micronucleus and binucleus formation in peripheral erythrocytes of C. punctatus, and such deleterious effect of MTZ treatment can be mitigated by aqueous extract of C. sativum leaves.


Congenital erosive and vesicular dermatosis healing with reticulated supple scarring.
Three children had an extensive erosive and vesicular dermatosis at birth that healed with supple reticulated scarring. This article discusses the differential diagnosis and pathogenesis of the disorder in these patients, and makes recommendations for medical evaluation and parent counseling.