Pharmacokinetics of an extended-release human interferon alpha-2b formulation.
The in vivo half-life of human interferon alpha-2b (hIFN-alpha-2b) is relatively short, and frequent injections over prolonged periods are required for efficacy. An extended-release formulation of hIFN-alpha-2b (Depo/IFN) was created by encapsulation into a lipid-based drug-delivery system. The capture efficiency was 51% +/- 13% and the release half-life in human plasma at 37 degrees C was 16 days. The pharmacokinetics of Depo/IFN was compared with that of unencapsulated standard hIFN-alpha-2b (Std/IFN) in the peritoneal cavity of male BDF1 mice. Depo/IFN exhibited a 13-fold longer intraperitoneal (i.p.) half-life as compared with Std/IFN (20 vs 1.5 h). The release of free hIFN-alpha-2b from Depo/IFN into the peritoneal cavity was slow and protracted, with a 10-fold lower peak concentration and a 13-fold longer apparent half-life being observed in comparison with Std/IFN. The areas under the curve of free hIFN-alpha-2b in the peritoneal cavity were comparable for Depo/IFN and Std/IFN. hIFN-alpha-2b was detectable in plasma only after the i.p. administration of Std/IFN. These data suggest the possibility that Depo/IFN may be useful as an extended-release formulation of hIFN-alpha-2b.


Perioperative management and prevention of postoperative complications in patients undergoing cranioplasty with polyetheretherketone.
This study aimed to compare the incidence of postoperative complications in patients undergoing cranioplasty with polyetheretherketone (PEEK) materials under different perioperative management schemes and summarize and describe a perioperative bundle to reduce patients' postoperative complications and improve patient outcomes. We retrospectively analyzed the clinical data of 69 patients who had undergone craniotomy with PEEK materials in the neurosurgery department of our hospital between June 2017 and June 2021. Patients who had received conventional treatment were defined as the conventional group (29 cases), and those who had received the improved scheme were defined as the improved group (40 cases). The early complications of the two groups were compared, and the long-term effects were observed. The early total complication rates of the conventional and the improved groups were 55.2% and 32.5%, respectively, without any significant difference (P = 0.06), and the long-term complication rates were 24.1% and 7.5%, respectively, with no significant difference (P = 0.112). The incidence of epidural effusion in the improved group was significantly lower than that in the conventional group, with no significant difference in the incidence of complications, such as intracranial pneumatosis, epidural hemorrhage, new seizures and intracerebral hemorrhage. There was no difference in long-term complications, such as seizures, incision infections, and implant exposure. Epidural effusion after cranioplasty with PEEK materials is common. This study's improved perioperative bundle can effectively reduce the occurrence of epidural effusion after skull repair.


Raynaud's phenomenon.
Treatment of Raynaud's phenomenon in any one individual depends on the severity of symptoms and whether or not there is an underlying disease process requiring specific intervention. Many patients with primary (idiopathic) Raynaud's phenomenon respond well to treatment with general measures, perhaps with the addition of a calcium channel blocker. Conversely, others with underlying structural vascular abnormality (as occurs in connective tissue diseases such as systemic sclerosis ) are often refractory to treatment and may progress to irreversible tissue injury, sometimes with gangrene. Because these patients are the most challenging and because a large proportion of the research into Raynaud's phenomenon has been conducted in patients with SSc-spectrum disorders, much of this review is weighted toward them. The key principles of management are removal/treatment of any triggering factor/underlying cause, general (nondrug) measures, drug treatment, and surgery, although the last is rarely indicated. New insights into pathogenesis have led, and continue to lead, to new approaches to treatment, including endothelin-1 receptor antagonism and nitric oxide supplementation.


Design and preparation of a simple and effective palladium catalyst and the hydrogenation performance toward dibenzylbiotinmethylester.
A series of well-dispersed carbon supported Pd catalysts were prepared by a simple and effective method under mild conditions. The functionalized carbon supported Pd catalyst (Pd/AC-H) demonstrated a enhanced performance to original carbon supported Pd catalyst (Pd/AC) in the probe reaction hydrogenation of 3,4-(1',3'-Dibenzyl-2'-oxoimidazolido)-2-(4-carboxybutylidene)thiophane to dibenzylbiotinmethylester. The results of various characterization techniques revealed that the improvement of Pd dispersion on Pd/AC-H catalyst surface could be associated to the presence of abundant oxygen-containing groups available for anchorage. Furthermore, the role of the surface groups of carbon supports was indispensable since they could provide an efficient pathway for the reaction. The oxygen-containing groups located at the Pd-supports interface were able to adjust the strength of reactant adsorption/activation on the Pd active sites, which was responsible for the high yield of dibenzylbiotinmethylester.


Determination of topotecan in human whole blood and unwashed erythrocytes by high-performance liquid chromatography.
A reversed-phase HPLC method for the quantitative determination of total topotecan in human whole blood and unwashed erythrocytes has been developed and validated in terms of sensitivity, specificity, precision and accuracy. Linear calibration curves were constructed in the range of 0.20 to 50.0 ng/ml. The sample pre-treatment for whole blood involved a two-step extraction with methanol and perchloric acid. Prior to extraction, erythrocytes were separated from other blood components by centrifugation in MESED instruments. Separations were achieved on an Inertsil ODS-80A analytical column (150x4.6 mm, 5 microm particle size), eluted at 50 degrees C and a flow-rate of 1.00 ml/min, with a mixture of 100 mM ammonium acetate (pH 6.0)-tetrahydrofuran (94.6:5.4, v/v). Fluorescence detection was performed using excitation and emission wavelengths of 381 and 525 nm, respectively. With the applied method, 80% of topotecan was extracted out of whole blood. The lower limit of quantitation in whole blood was established at 0.20 ng/ml with within-run and between-run precisions, respectively, ranging from 1.7 to 9.3% and 1.5-6.1%, while the accuracy ranged from 100 to 113%. The described method will be used in clinical studies to explore the role of erythrocytes in the overall kinetic behavior of topotecan.


TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20-7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32-4.16) and complex karyotype (P = 0.038, HR = 1.07-9.78) were associated with shorter OS in AML patients. In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.


New type of alginate/chitosan microparticle membranes for highly efficient pervaporative dehydration of ethanol.
A new type of composite alginate membranes filled with chitosan (CS) and three different modified chitosan submicron particles, i.e. phosphorylated (CS-P), glycidol (CS-G) or glutaraldehyde (CS-GA) crosslinked ones, were prepared, and the pervaporation of water/ethanol mixture was investigated. The influence of various chitosan particles and their content on the transport properties of membranes was discussed. It was found that the addition of chitosan particles into the alginate matrix has a prominent effect on the ethanol/water separation efficiency. All tested membranes are characterized simultaneously by a high flux and selectivity, exhibiting advantageous properties, and outperforming numerous conventional materials. The best results were achieved for alginate membranes filled with phosphorylated chitosan particles at 10 wt%, for which separation factor, flux and PSI were equal to 136.2, 1.90 kg m-2 h-1 and 256.9 kg m-2 h-1, respectively.


Targeted neonatal echocardiography service in neonatal intensive care in Manitoba, Canada.
To evaluate the impact of a targeted neonatal echocardiography (TNE) service on patient management in the neonatal intensive care units (NICU) in Winnipeg, Canada. Retrospective cohort study of neonates who had TNEs from 2014 to 2019. The primary outcome was the change in clinical management based on TNE recommendation. Multivariate logistic regression analysis was used to identify predictors of the primary outcome. A total of 747 echos were performed on 307 neonates. Patent ductus arteriosus assessment was the most common indication for TNE followed by evaluation of pulmonary hypertension and systemic hemodynamics. TNE led to a change in clinical management following 492 (66%) echos. Mechanical ventilation [Odds ratio (OR) 2.4, 95% CI: 1.7-3.4, P < 0.001) and receiving inhaled nitric oxide (1.9, 95% CI: 1.3-3.0, P = 0.003) were the predictors for the change in clinical management following TNE. TNE has enhanced patient care by altering the management of patients in the NICU.


Prolonged survival of allogeneic islets in cynomolgus monkeys after short-term triple therapy.
Preclinical studies in nonhuman primates (NHP) are particularly useful to evaluate the safety and efficacy of new therapeutic proteins developed for use in clinical transplantation. We hypothesized that a treatment that selectively destroys activated cytopathic donor reactive T cells while sparing resting and immunoregulatory T cells in a mouse model might also produce long-term drug-free engraftment and tolerance without the hazards of lymphopenia in the challenging nonhuman primate islet allograft model. Short-term treatment with a regimen consisting of rapamycin, and IL-2.Ig plus mutant antagonist-type IL-15.Ig cytolytic fusion proteins (triple therapy) posttransplantation results in prolonged, drug-free engraftment of cynomolgus islet allografts. Moreover slow progressive loss of islet function in some recipients was not associated with obvious pathologic evidence of rejection.


[Robust low-dose CT myocardial perfusion deconvolution via high-dimension total variation regularization].
To develop a computed tomography myocardial perfusion (CT-MP) deconvolution algorithm by incorporating high-dimension total variation (HDTV) regularization. A perfusion deconvolution model was formulated for the low-dose CT-MPI data, followed by HDTV regularization to regularize the consistency of the solution by fusing the spatial correlation of the vascular structure and the temporal continuation of the blood flow signal. Both qualitative and quantitative studies were conducted using XCAT and pig myocardial perfusion data to evaluate the present algorithm. The experimental results showed that this algorithm achieved hemodynamic parameter maps with better performances than the existing methods in terms of streak-artifacts suppression, noise-resolution tradeoff, and diagnosis structure preservation. The proposed algorithm can achieve high-quality hemodynamic parameter maps in low-dose CT-MPI.


Japanese macaque (Macaca fuscata) mothers huddle with their young offspring instead of adult females for thermoregulation.
It is unclear whom animals select to huddle with for thermoregulation. In this study, we investigated whom Japanese macaque (Macaca fuscata) mothers huddled with-their young offspring or other adult group members-when there is need for thermoregulation. We used a focal-animal sampling method, targeting 17 females at Katsuyama, Okayama Prefecture, Japan. A majority of huddling among adult females was recorded during winter season (December, January, and February). Females who had young (0- or 1-year-old) offspring huddled less frequently with other adult females compared to females who did not have young offspring in winter. However, including young offspring, the frequency of huddling with any other individuals did not differ by whether females had young offspring. Moreover, the females who did not have young offspring huddled with other adult females more often in cloudy than in sunny weather during winter season. In contrast, females who had young offspring increased huddling with their young offspring in cloudy than in sunny weather, but did not do so with other adult females. This study indicates that Japanese macaque mothers huddle with their young offspring instead of other adult females when there is need for thermoregulation.


Fabrication of novel core-shell hybrid alginate hydrogel beads.
Novel hybrid alginate hydrogel beads with shells of porous CaCO3 microparticles were fabricated by templating water-in-oil emulsion and subsequent in situ gelation. Porous CaCO3 microparticles were self-assembled at interfaces of water-in-oil emulsion. Water droplets containing alginate in the emulsion were subsequently in situ gelated by Ca2+ released from CaCO3 through decreasing pH with slow hydrolysis of d-glucono-delta-lactone (GDL). The resulting hybrid beads with alginate gel cores and shells of porous CaCO3 microparticles were called colloidosomes. The packed density of CaCO3 microparticles in the shell increased with increasing the ratio of the CaCO3 microparticle weight to the water phase volume Mp/Vw and decreased with addition of NaCl into water. The size of the produced colloidosome beads was independent of Mp/Vw. Increasing the volume fraction of water Phi w to 0.5, some colloidosome beads deformed to nonspheral shape and even broken. Brilliant blue (BB) as a drug model was loaded into the colloidosome beads by being dissolved in the alginate aqueous solution before gelation. The BB release from the colloidosome beads was slowed down because of the formation of the shells of CaCO3 microparticles. The colloidosome beads may find applications as delivery vehicles for drugs, cosmetics, food supplements and living cell.


Biofeedback treatment increases heart rate variability in patients with known coronary artery disease.
To determine if cardiorespiratory biofeedback increases heart rate variability (HRV) in patients with documented coronary artery disease (CAD). Diminished HRV has been associated with increased cardiac morbidity and mortality. Evidence suggests that various lifestyle changes and pharmacologic therapies can improve HRV. The objective of this study was to determine if biofeedback increases HRV in patients with CAD. Patients with established CAD (n = 63; mean age, 67 years) were randomly assigned to conventional therapy or to 6 biofeedback sessions consisting of abdominal breath training, heart and respiratory physiologic feedback, and daily breathing practice. HRV was measured by the standard deviation of normal-to-normal QRS complexes (SDNN) at week 1 (pretreatment), week 6 (after treatment), and week 18 (follow-up). Baseline characteristics were similar for the treatment and control groups. The SDNN for the biofeedback and control groups did not differ at baseline or at week 6 but were significantly different at week 18. The biofeedback group showed a significant increase in SDNN from baseline to week 6 (P <.001) and to week 18 (P =.003). The control subjects had no change from baseline to week 6 (P =.214) and week 18 (P =.27). Biofeedback increases HRV in patients with CAD and therefore may be an integral tool for improving cardiac morbidity and mortality rates.


Neovagina construction by combined laparoscopic-perineal sigmoid colpoplasty in a patient with Rokitansky syndrome.
We created a neovagina by sigmoid colpoplasty using a combined laparoscopic-perineal approach in a 19-year-old woman with Rokitansky syndrome. Operating time was 4 hours and 45 minutes. No perioperative or postoperative complications occurred. Hemoglobin level fell by 1 g/dl. Total doses of morphine, nonsteroidal antiinflammatory drugs (NSAIDs), and paracetamol were 20 mg, 350 mg, and 28 g, respectively. Hospital stay was 7 days. The length of the neovagina was 12 cm. By comparison, in the three reported cases of laparotomic-perineal sigmoid vaginoplasty, mean operating time was 5 hours and 40 minutes; 24-hour fall in hemoglobin was 3.2 g/dl (range 2.1-4.3 g/dl); mean doses of morphine, NSAIDs, and paracetamol were 42.6 mg, 300 mg, and 40 g, respectively; mean hospital stay was 11.3 days; and length of neovaginas was 10, 12, and 12 cm. Although sigmoid colpoplasty is a reliable and reproducible technique, it requires experience in laparoscopic colonic surgery. The combined laparoscopic-perineal approach is associated with less analgesic requirement, shorter hospital stay, and similar anatomic results compared with the laparotomic-perineal approach.


Freezing of gait in Parkinson's disease: Classification using computational intelligence.
Parkinson's disease (PD) is a neurodegenerative disease represented by the progressive loss of dopamine producing neurons, with motor and non-motor symptoms that may be hard to distinguish from other disorders. Affecting millions of people across the world, its symptoms include bradykinesia, tremors, depression, rigidity, postural instability, cognitive decline, and falls. Furthermore, changes in gait can be used as a primary diagnosis factor. A dataset is described that records data on healthy individuals and on PD patients, including those who experience freezing of gait, in both the ON and OFF-medication states. The dataset is comprised of data for four separate tasks: voluntary stop, timed up and go, simple motor task, and dual motor and cognitive task. Seven different classifiers are applied to two problems relating to this data. The first problem is to distinguish PD patients from healthy individuals, both overall and per task. The second problem is to determine the effectiveness of medication. A thorough analysis on the classifiers and their results is performed. Overall, multilayer perceptron and decision tree provide the most consistent results.


Small-molecule protein and lipid kinase inhibitors in inflammation and specific models for their evaluation.
The inflammatory response requires complex and coordinated cooperation of different signaling pathways and cell types. Therefore, more than 40 different protein or lipid kinases can be regarded as potential small-molecule inhibitor targets to approach a therapy of acute inflammation, such as septic syndrome, and especially chronic inflammation, such as rheumatoid arthritis or inflammatory bowel disease. Besides the general considerations about selectivity and potency of small-molecule kinase inhibitors, in this chapter special emphasis is put on the inflammation-specific methods and assays available for testing potential small-molecule inhibitors for their anti-inflammatory activity. Examples for human cell-based assays for characterization of the effect of inhibitors on contribution of various cell types, such as monocytes, neutrophils, mast cells, T-cells, and synovial fibroblasts, to the inflammatory scenario are given. It is further demonstrated how these assays are complemented by rodent models for septic syndrome, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and systemic lupus erythematosus. Finally, it is discussed how the results obtained by these methods can be further validated and which future strategies for the treatment of chronic inflammation will exist.


Factors associated with sexually transmitted diseases amongst female prison inmates in Peru.
The number of women in prison is rapidly increasing every year and it is important to establish what factors are related to the probability of presenting STDs in this population to enable health control policies to be established. An analysis was carried out on the open database of the national prison population survey conducted in 2016 in all Peruvian prisons. The study was based on the census and all female and male adults in prison were surveyed using a validated questionnaire. The sample consisted of 4,574 inmates in 67 institutions, covering 98.8% of the inmate population. It was found that presenting tuberculosis (PR: 2.64; CI 95%, 1.32-5.26), HIV/AIDS (PR 6.54, CI 95% 1.52-28.18), hepatitis (PR: 4.01; CI 95%, 1.23-13.11) and drug use (PR: 2.44; CI 95%, 1.32-4.52), are statistically related (P ≤0.05) are factors associated with the presence of STDs in the multivariate model with a P ≤0.05. The inclusion of associated factors (tuberculosis, HIV/AIDS, hepatitis and drug use) should be part of the strategy to control and treat STD in women's prisons in Peru.


Influence of the operating conditions on highly oxidative radicals generation in Fenton's systems.
In this work, an indirect method for estimating the total amount and concentration of oxidative radicals in aqueous and slurry-phase Fenton's systems was developed. This method, based on the use of benzoic acid as probe compound, was applied for evaluating the effect of the operating conditions on the radicals amount produced, their production efficiency (i.e. moles of radicals generated per mole H2O2 and their concentration. A Rotatable Central Composite design (RCC) was used to select the operating conditions in order to get a statistically meaningful data set. Hydrogen peroxide and ferrous ion concentrations ranged between 0.2-1mM and 0.2-0.5mM, respectively; humic acid concentration between 0 and 15mg/L, whereas the soil/water weight ratio in slurry-phase systems between 1:10 and 9:10. The probe compound concentration was 9 or 0.1mM in experiments aimed to evaluate the total amount or concentration of oxidative radicals, respectively. The obtained results indicated that the amount of radicals generated in both aqueous and soil slurry Fenton's system increased with higher H2O2 concentration and, more specifically, that their production efficiency increased with increasing Fe(II):H2O2 molar ratio. Addition of dissolved organic compounds as humic acid did not notably affect the oxidative radicals amount and concentration. On the contrary, a one order of magnitude reduction in both radicals amount generated and concentration was observed when soil was added to the reaction environment.


Role of the high-affinity leukotriene B4 receptor signaling in fibrosis after unilateral ureteral obstruction in mice.
Leukotriene B4 (LTB4) is a lipid mediator that acts as a potent chemoattractant for inflammatory leukocytes. Kidney fibrosis is caused by migrating inflammatory cells and kidney-resident cells. Here, we examined the role of the high-affinity LTB4 receptor BLT1 during development of kidney fibrosis induced by unilateral ureteral obstruction (UUO) in wild-type (WT) mice and BLT1 knockout (BLT1-/-) mice. We found elevated expression of 5-lipoxygenase (5-LOX), which generates LTB4, in the renal tubules of UUO kidneys from WT mice and BLT1-/- mice. Accumulation of immunoreactive type I collagen in WT UUO kidneys increased over time; however, the increase was less prominent in BLT1-/- UUO kidneys. Accumulation of S100A4-positive fibroblasts increased temporally in WT UUO kidneys, but was again less pronounced in-BLT1-/- UUO kidneys. The same was true of mRNA encoding transforming growth factor-β (TGF)-β and fibroblast growth factor (FGF)-2. Finally, accumulation of F4/80-positive macrophages, which secrete TGF-β, increased temporally in WT UUO and BLT1-/- UUO kidneys, but to a lesser extent in the latter. Following LTB4 stimulation in vitro, macrophages showed increased expression of mRNA encoding TGF-β/FGF-2 and Col1a1, whereas L929 fibroblasts showed increased expression of mRNA encoding α smooth muscle actin (SMA). Bone marrow (BM) transplantation studies revealed that the area positive for type I collagen was significantly smaller in BLT1-/-BM→WT than in WT-BM→WT. Thus, LTB4-BLT1 signaling plays a critical role in fibrosis in UUO kidneys by increasing accumulation of macrophages and fibroblasts. Therefore, blocking BLT1 may prevent renal fibrosis.


Decreased plasma testosterone concentrations and weight gain in young bulls affected by ryegrass staggers.
Ryegrass staggers caused a significant depression of plasma testosterone concentrations in prepubertal bulls, and the most severely affected animals had a marked reduction in liveweight gain.


Meloxicam emulgel potently suppressed cartilage degradation in knee osteoarthritis: Optimization, formulation, industrial scalability and pharmacodynamic analysis.
Meloxicam (MLX) is prescribed for the management of pain and inflammation allied with osteoarthritis (OA). However, MLX causes intestinal damage in long term administration. Hence, meloxicam loaded emulgel (MLX-emulgel) was optimized, formulated and examined under stringent parameters in monosodium-iodoacetate (MIA) induced knee OA in Wistar rats. Nanoemulsion of MLX was fabricated by ultrasonication and microfluidization method with a droplet size of 66.81 ± 5.31-nm and zeta potential of -24.6 ± 0.72-mV. Further, MLX nanoemulsion was optimized with centrifugation, heating-cooling cycles and transmittance parameters in addition to scale-up feasibility with microfluidizer. Post optimization, MLX-nanoemulsion was tailored as emulgel with Carbopol Ultrez 10 NF and assessed for pH, rheology, textural properties, assay and stability features. The in-vitro release study revealed the Korsmeyer-Peppas release kinetics and ex-vivo skin permeation was improved by 6.71-folds. The skin distribution of MLX-emulgel evinced the transfollicular mode of permeation. In-vivo study indicated the protective action of MLX-emulegl expressed in terms of inflammatory cyctokines level, X-ray analysis of knee joints of rats, histopathology and OARSI (Osteoarthritis Research Society International) scoring. MLX-emulgel treated group displayed lower (P < 0.001) level of COX-2 intensity as compared to positive control group. However, it was comparable (P > 0.05) to the normal control group, MLX oral dispersion, i.v. solution and etoricoxib gel groups. MLX-emulgel showcased an alternative to the long term usage of analgesics for relieving the symptoms of knee OA. MLX-emulgel may be a potential candidate for translating in to a clinically viable dosage form in the management of knee OA.


Relevance of Arg457 for the nucleotide affinity of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase.
Phosphoenolpyruvate carboxykinases catalyze one of the first steps in the biosynthesis of glucose and depending on the enzyme origin, preferentially use adenine or guanine nucleotides as substrates. The Saccharomyces cerevisiae enzyme has a marked preference for ADP (or ATP) over other nucleotides. Homology models of the enzyme in complex with ADP or ATP show that the guanidinium group of Arg457 is close to the adenine base, suggesting that this group might be involved in the stabilization of the nucleotide substrate. To evaluate this we have performed the mutation Arg457Met, replacing the positively charged guanidinium group by a neutral residue. The mutated enzyme retained the structural characteristics of the wild-type protein. Fluorescence titration experiments showed that mutation causes a loss of 1.7 kcal mol(-1) in the binding affinity of the enzyme for ADPMn. Similarly, kinetic analyses of the mutated enzyme showed 50-fold increase in K(m) for ADPMn, with minor alterations in the other kinetic parameters. These results show that Arg457 is an important factor for nucleotide binding by S. cerevisiae PEP carboxykinase.


A multicenter interventional program to reduce the incidence of anal sphincter tears.
In Norway, we have experienced a gradual increase in the incidence of obstetric anal sphincter injuries from under 1% in the late 1960s to 4.3% in 2004. This study was aimed to assess whether an interventional program causes a decrease in the frequency of anal sphincter tears. In all, 40,152 vaginal deliveries between 2003 and 2009 were enrolled in the interventional cohort study from four Norwegian obstetric departments. The focus of the intervention was on manual assistance during the final part of the second stage of labor. Data were analyzed in relation to occurrence of obstetric anal sphincter tears. The proportion of parturients with anal sphincter tears decreased from 4-5% to 1-2% during the study period in all four hospitals (P<.001). The tears associated with both noninstrumental and instrumental deliveries decreased dramatically. The number of patients with grades 3 and 4 anal sphincter ruptures decreased significantly, and the reduction was most pronounced in grade 4 tears (-63.5%) and least in 3c tears (-47.5%) (both P<.001). The number of episiotomies increased in two hospitals but remained unchanged in the other two. The lowest proportion of tears at the end of the intervention (1.2% and 1.3%, respectively) was found in the two hospitals with an unchanged episiotomy rate. The multicenter intervention caused a highly significant decrease in obstetric anal sphincter injuries. II.


Dishabituation with component transitions may contribute to the interactions observed during multiple schedules.
Rates of responding by rats were usually higher during the variable interval (VI) 30-s component of a multiple VI 30-s fixed interval (FI) 30-s schedule than during the same component of a multiple VI 30-s VI 30-s schedule (Experiment 1). Response rates were also usually higher during the FI 30-s component of a multiple VI 30-s FI 30-s schedule than during the same component of a multiple FI 30-s FI 30-s schedule (Experiment 2). The differences in response rates were not observed when the components provided VI or FI 120-s schedules. These results were predicted by the idea that differences in habituation to the reinforcer between multiple schedules contribute to behavioral interactions, such as behavioral contrast. However, differences in habituation were not apparent in the within-session patterns of responding. Finding differences in response rates in both experiments violates widely-held assumptions about behavioral interactions, including that behavioral contrast does not occur for rats and that improving the conditions of reinforcement decreases, rather than increases, response rate in the alternative component.


Nuclear oncology 1984.
New developments in nuclear oncology, based on monoclonal antibodies and position emission tomography measurement of glucose metabolism promise to broaden the range of applications of nuclear medicine methods in the clinical management of patients with tumor. Perhaps of greatest importance, is the prospect of both diagnosing and treating common solid tumors, with the same radiolabeled (monoclonal antibody) pharmaceutical preparation.


Genital anomalies of males (GAM-complex).
Between 1973-1982, the Hungarian Congenital Malformation Registry recorded 165 male index patients with two or more genital anomalies of the male (GAM) without other abnormalities. Of 17 'severe' GAM cases with penile or perineal hypospadias and other anomalies of external genitalia, clinical examination detected a recognizable syndrome in all but one case. A family study of 70 'mild' GAM cases with coronal or glandular hypospadias, undescended testes, and congenital inguinal hernia with or without minor genital anomalies, showed that 8.7% of index patients had fathers and brothers with GAM-type anomalies. The mild GAM cases seem to be a monotopic developmental field defect, the so-called GAM-complex.


Natural sesquiterpene lactones as inhibitors of Myb-dependent gene expression: structure-activity relationships.
c-myb is a proto-oncogene encoding a transcription factor which is highly expressed in hematopoietic progenitor cells. It regulates the expression of genes important for lineage determination, cell proliferation, and differentiation. Deregulation of c-myb expression is known to be involved in the development of human tumors, especially certain types of leukemia and breast and colon cancer. The c-Myb protein has thus been identified as an interesting therapeutic target. We recently discovered that some sesquiterpene lactones suppress Myb-dependent gene expression which is a new mechanism for these natural products' potential anti-cancer activity. We developed a test system to screen compounds for inhibitory activity on Myb-inducible reporter gene activation. Using this system we have now investigated 60 sesquiterpene lactones for their capacity to inhibit c-Myb-dependent gene activation. The IC50 values were in a range between 0.7 and >30 μM. The furanoheliangolide goyazensolide and the pseudoguaianolide helenalin acetate (IC50 = 0.6 and 0.7 μM, respectively) represent the most active inhibitors of c-Myb dependent gene expression found up to present. Control measurements for cell viability (MTS assay) proved that the observed activity on c-Myb dependent gene expression is not a function of cytotoxicity/unspecific cell damage. Structure-activity relationships were investigated by a QSAR approach based on flexible alignment of the most active compounds and a common pharmacophore model. These investigations resulted in a QSAR model which indicates that the potency of inhibitory activity on c-Myb-dependent transcription does not only depend on the presence of reactive Michael-acceptor features but also on their optimal spatial arrangement in the molecule.


Hydraulic properties and leachate level analysis of Kimpo metropolitan landfill, Korea.
Hydraulic properties of waste and cover soil from Kimpo Metropolitan Landfill were experimentally measured by laboratory tests. The degree of compaction was changed to identify the effect on hydraulic conductivity, field capacity, and permanent wilting point. Properties were utilized in developing a reliable numerical tool for leachate analysis. HELP, a simulation model for hydrologic evaluation of landfill performance, was adopted for that purpose. For calibration, results from simulation using the parameter values measured by laboratory tests were compared against the field data. The model was applied to predict the leachate level change according to the degree of compaction and cover soil thickness variation. It was found that the increase in the degree of compaction for intermediate cover soil and waste results in the decrease of field capacity and hydraulic conductivity, hence, the increase of leachate level. The effect of cover layer thickness on the leachate level was minor. Based on the findings from laboratory and numerical experiments, a guideline for reclamation practice was recommended.


A HhaI/BstUI polymorphism in a novel gene at human chromosome 11p15.5.
We found a HhaI/BstUI polymorphism in the 3' untranslated region of a novel gene which was localized to 11p15.5. This region is one of prominent imprinting domains and contains multiple imprinted genes, such as H19, IGF2, KVLQT1, and p57KIP2, which suggests that regional factors might contribute to the imprinting. This polymorphism will be useful in the allelic analysis of expression and methylation of the novel gene.


Saikosaponins from roots of Bupleurum scorzonerifolium.
Saikosaponin u and saikosaponin v, were isolated from the roots of Bupleurum scorzonerifolium and these saponins were identified as 3-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl- (1-->3)-beta-D-fucopyranosyl]-3 beta,16 alpha,23,28-tetrahydroxy-olean- 11,13(18)-dien-30-oic acid-30-O-[pentito(1-->1)-beta-D-glucopyranosyl-(6-->)] ester and 3-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-fucopyranosyl]-3 beta,16 alpha,23,28-tetrahydroxy-olean-11,13(18)-dien-30-oic acid-30-O-[pentito(1-->1)-beta-D-glucopyranosyl(6-->)] ester, respectively.


Molecular assessment of indigenous yeast population from traditional balsamic vinegar.
To identify and describe the indigenous yeast population involved in traditional balsamic vinegar (TBV) fermentation. Using the restriction analysis of the ribosomal region 5.8S (5.8S rRNA) and the internal transcribed spacers 1 and 2 (5.8S-ITS region) we were able to group 133 strains isolated from 17 cooked grape must samples into 10 different yeast species, included into 4 genera. Moreover, we sequenced the D1/D2 domains of the 26S rRNA and confirmed the reliability of each identification at species level. Most strains belonged to the genus Zygosaccharomyces. In particular, Zygosaccharomyces bailii was found in 41% of the samples, followed by Saccharomyces cerevisiae, Zygosaccharomyces pseudorouxii and Candida stellata. Strains belonging respectively to Zygosaccharomyces mellis, Zygosaccharomyces bisporus, Zygosaccharomyces rouxii, Hanseniaspora valbyensis, Hanseniaspora osmophila and Candida lactis-condensi species were also detected. Despite the great number of species recovered, the mtDNA restriction profiles showed low variability at strain level. Saccharomyces cerevisiae isolates with an higher degree of intraspecific variance were considered an exception. Many different indigenous yeast species were recovered and TBV yeasts population seems to be far more complex than what was reported in previous literature. This study has allowed us to gain a better understanding of the indigenous yeast species of TBV cooked must.


Involvement of chromosome 9 in variant Ph1 translocation.
Cytogenetic analysis of a patient with chronic myelocytic leukemia revealed a translocation (21; 22) (q 22; q 11) without a detectable involvement of chromosome 9. By in-situ hybridization studies, however, we demonstrate a reciprocal translocation of sequences from chromosome 9 (c-abl) to Ph1 and chromosome 22 (bcr) to 9, respectively. These observations suggest a consistent participation of chromosome 9 in the Ph1 translocation, regardless of the cytogenetic subtype.


Protocol for stratification of triple-negative breast cancer patients using in silico signaling dynamics.
Personalized kinetic models can predict potential biomarkers and drug targets. Here, we provide a step-by-step approach for building an executable mathematical model from text and integrating transcriptomic datasets. We additionally describe the steps to personalize the mechanistic model and to stratify patients with triple-negative breast cancer (TNBC) based on in silico signaling dynamics. This protocol can also be applied to any signaling pathway for patient-specific modeling. For complete details on the use and execution of this protocol, please refer to Imoto et al. (2022).


Pharmacological characterization of 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[(3'-fluoro-4'-pyridyl)acetamido]morphinan (NFP) as a dual selective MOR/KOR ligand with potential applications in treating opioid use disorder.
For thousands of years opioids have been the first-line treatment option for pain management. However, the tolerance and addiction potential of opioids limit their applications in clinic. NFP, a MOR/KOR dual-selective opioid antagonist, was identified as a ligand that significantly antagonized the antinociceptive effects of morphine with lesser withdrawal effects than naloxone at similar doses. To validate the potential application of NFP in opioid addiction treatment, a series of in vitro and in vivo assays were conducted to further characterize its pharmacological profile. In calcium mobilization assays and MOR internalization studies, NFP showed the apparent capacity to antagonize DAMGO-induced calcium flux and etorphine-induced MOR internalization. In contrast to the opioid agonists DAMGO and morphine, cells pretreated with NFP did not show apparent desensitization and down regulation of the MOR. Though in vitro bidirectional transport studies showed that NFP might be a P-gp substrate, in warm-water tail-withdrawal assays it was able to antagonize the antinociceptive effects of morphine indicating its potential central nervous system activity. Overall these results suggest that NFP is a promising dual selective opioid antagonist that may have the potential to be used therapeutically in opioid use disorder treatment.


Application of the Synechococcus nirA promoter to establish an inducible expression system for engineering the Synechocystis tocopherol pathway.
Tocopherols are important antioxidants in lipophilic environments. They are synthesized by plants and some photosynthetic bacteria. Recent efforts to analyze and engineer tocopherol biosynthesis led to the identification of Synechocystis sp. strain PCC 6803 as a well-characterized model system. To facilitate the identification of the rate-limiting step(s) in the tocopherol biosynthetic pathway through the modulation of transgene expression, we established an inducible expression system in Synechocystis sp. strain PCC 6803. The nirA promoter from Synechococcus sp. strain PCC 7942, which is repressed by ammonium and induced by nitrite (S.-I. Maeda et al., J. Bacteriol. 180:4080-4088, 1998), was chosen to drive the expression of Arabidopsis thaliana p-hydroxyphenylpyruvate dioxygenase. The enzyme catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvate. Expression of this gene under inducing conditions resulted in up to a fivefold increase in total tocopherol levels with up to 20% of tocopherols being accumulated as tocotrienols. The culture supernatant of these cultures exhibited a brown coloration, a finding indicative of homogentisic acid excretion. Enzyme assays, functional complementation, reverse transcription-PCR, and Western blot analysis confirmed transgene expression under inducing conditions only. These data demonstrate that the nirA promoter can be used to control transgene expression in Synechocystis and that homogentisic acid is a limiting factor for tocopherol synthesis in Synechocystis sp. strain PCC 6803.


CAN WAIST/HIP RATIO BE USED AS A SIMPLE MEASURE OF CARDIOVASCULAR RISK IN THE ARMED FORCES : RESULTS FROM A FIELD EPIDEMIOLOGICAL STUDY.
A cross-sectional analytical epidemiologic study was undertaken in the community setting, on 1080 army personnel in a field formation, to study the association between waist/hip ratio (WHR) and certain physiological and biochemical parameters of cardiovascular risk. The study revealed that Junior Commissioned Officers, personnel aged 35 years and above, and personnel from Services had an increased probability of having higher WHR. WHR was consistently, linearly and significantly associated with increasing mean values of serum cholesterol, blood sugar and blood pressure. The optimum cut-off point of WHR from the findings of this study seems to be 0.91 and above. Beyond this value of WHR, the cardiovascular risk increases significantly and becomes more dramatic at WHR values of 0.96 and above.


Pain tolerance after stroke: The Tromsø study.
Stroke lesions might alter pain processing and modulation by affecting the widely distributed network of brain regions involved. We aimed to compare pain tolerance in stroke survivors and stroke-free persons in the general population, with and without chronic pain. We included all participants of the sixth and seventh wave of the population-based Tromsø Study who had been tested with the cold pressor test (hand in cold water bath, 3°C, maximum time 106 s in the sixth wave and 120 s in the seventh) and who had information on previous stroke status and covariates. Data on stroke status were obtained from the Tromsø Study Cardiovascular Disease Register and the Norwegian Stroke Register. Cox regression models were fitted using stroke prior to study attendance as the independent variable, cold pressor endurance time as time variable and hand withdrawal from cold water as event. Statistical adjustments were made for age, sex, diabetes, hypertension, hyperlipidaemia, body mass index and smoking. In total 21,837 participants were included, 311 of them with previous stroke. Stroke was associated with decreased cold pain tolerance time, with 28% increased hazard of hand withdrawal (hazard ratio [HR] 1.28, 95% CI 1.10-1.50). The effect was similar in participants with (HR 1.28, 95% CI 0.99-1.66) and without chronic pain (HR 1.29, 95% CI 1.04-1.59). Stroke survivors, with and without chronic pain, had lower cold pressor pain tolerance, with possible clinical implications for pain in this group. We found lower pain tolerance in participants with previous stroke compared to stroke-free participants of a large, population-based study. The association was present both in those with and without chronic pain. The results may warrant increased awareness by health professionals towards pain experienced by stroke patients in response to injuries, diseases and procedures.


Early life adversities or high fat diet intake reduce cognitive function and alter BDNF signaling in adult rats: Interplay of these factors changes these effects.
Environmental factors, like early exposure to stressors or high caloric diets, can alter the early programming of central nervous system, leading to long-term effects on cognitive function, increased vulnerability to cognitive decline and development of psychopathologies later in life. The interaction between these factors and their combined effects on brain structure and function are still not completely understood. In this study, we evaluated long-term effects of social isolation in the prepubertal period, with or without chronic high fat diet access, on memory and on neurochemical markers in the prefrontal cortex of rats. We observed that early social isolation led to impairment in short-term and working memory in adulthood, and to reductions of Na(+),K(+)-ATPase activity and the immunocontent of phospho-AKT, in prefrontal cortex. Chronic exposure to a high fat diet impaired short-term memory (object recognition), and decreased BDNF levels in that same brain area. Remarkably, the association of social isolation with chronic high fat diet rescued the memory impairment on the object recognition test, as well as the changes in BDNF levels, Na(+),K(+)-ATPase activity, MAPK, AKT and phospho-AKT to levels similar to the control-chow group. In summary, these findings showed that a brief social isolation period and access to a high fat diet during a sensitive developmental period might cause memory deficits in adulthood. On the other hand, the interplay between isolation and high fat diet access caused a different brain programming, preventing some of the effects observed when these factors are separately applied.


Autonomic contribution to the blood pressure and heart rate variability changes in early experimental hyperthyroidism.
To study the interaction between autonomic nervous activity and thyroid hormones in the control of heart rate (HR) and blood pressure (BP). Thyrotoxicosis was produced by injections of L-thyroxine (0.5 mg/kg/day for five days). Blockers were atropine (0.5 mg/kg), atenolol (1 mg/kg) or prazosin (1 mg/kg). Eight animals were studied in each group. Spectral analyses was performed using continuous BP time series obtained in conscious rats. Thyroxine treatment was sufficient to induce a significant degree of tachycardia (423+/-6 vs 353+/-4 bpm, P < 0.001, unpaired Student's t test), systolic BP elevation (142+/-3 vs 127+/-2 mmHg, P < 0.001) and cardiac hypertrophy (1.165+/-0.017 vs 1.006+/-0.012 g, P < 0.001). The intrinsic HR was markedly increased after treatment with thyroxine (497+/-16 vs 373+/-10 bpm, P < 0.05). Vagal tone was positively linearly related to intrinsic HR (r = 0.84, P< 0.01). Atenolol neither modified HR nor BP variability in rats with hyperthyroidism. The thyrotoxicosis was associated with a reduction of the 0.4 Hz component of BP variability (modulus 1.10+/-0.07 vs 1.41+/-0.06 mmHg, P < 0.01). Prazosin was without effect on this 0.4 Hz component in hyperthyroid animals. These data show a functional diminution of the vascular and cardiac sympathetic tone in early experimental hyperthyroidism. The marked rise in the intrinsic HR could be the main determinant of tachycardia. The BP elevation may reflexly induce vagal activation and sympathetic (vascular and cardiac) inhibition.


An air-assisted dispersive liquid phase microextraction method based on a hydrophobic magnetic deep eutectic solvent for the extraction and preconcentration of melamine from milk and milk-based products.
In the current research, a fast and sustainable air-assisted hydrophobic magnetic deep eutectic solvent-based dispersive liquid phase microextraction followed by UV-Vis spectrophotometry measurements was optimized for the extraction and determination of melamine in milk and milk-based products. The central composite design was applied for the optimization of factors affecting the recovery of melamine. Quantitative extraction of melamine was achieved using hydrophobic magnetic deep eutectic solvents prepared from a mixture of octanoic acid, aliquat-336, and cobalt(II) chloride. The optimum conditions for extraction were found as follows: 6 extraction cycles, pH 8.2, extraction solvent volume 260 µL, and acetone volume 125 µL.Interestingly, a centrifugation step was not required to achieve phase separation. Under the optimum conditions, melamine was determined in the linear range of 3-600 ng mL-1, the limit of detection (3Sblank/m) of 0.9 ng mL-1, and the enrichment factor of 144. The validation of the method was investigated by the analysis of reference materials. Consequently, the method was successfully applied for the analysis of melamine residues in milk and milk-based products.


The emerging phenotype of long-term survivors with infantile Pompe disease.
Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors. Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor, and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status. Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4-12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers. Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.


Histologic changes induced by intraperitoneal chemotherapy with 5-fluorouracil and mitomycin C in patients with peritoneal carcinomatosis from cystadenocarcinoma of the colon or appendix.
Intraperitoneal chemotherapy with mitomycin C and 5-fluorouracil has been used to rescue patients from peritoneal carcinomatosis after perforated cystadenocarcinoma of the large bowel or appendix. A staging celiotomy was used to asses the results of therapy. In nine patients tumor was recovered from the abdominal cavity and was subjected to careful histopathologic examination. The posttreatment appearance of the tumor was compared with that before treatment. Also, tumor deposits harvested from these same patients, but from anatomic sites not directly exposed to chemotherapy were examined. The most striking findings observed in treated patients were as follows: (1) the marked reduction in the number of foci of atypical neoplastic epithelium lining the mucin globules, and (2) atrophy and degeneration of the atypical neoplastic epithelium. All treated patients showed these effects but they were not in all sampled tumor specimens, suggesting nonuniform drug distribution in the abdominal cavity and limited penetration of chemotherapy into tumor. The authors conclude that intraperitoneal chemotherapy produces marked histologic changes in mucinous tumors when there is direct contact between tumor and intracavitary drugs.


A common variation in HCN1 is associated with heart rate variability in schizophrenia.
There is growing evidence for a shared genetic basis between schizophrenia risk and cardiovascular disease. Reduced efferent vagal activity, indexed by reduced heart rate variability (HRV), has been consistently described in patients with schizophrenia and may potentially contribute to the increased cardiovascular risk in these patients. In this study, we tested the hypothesis whether the established schizophrenia risk variant HCN1 rs16902086 (A > G) is associated with reduced HRV. We analyzed the risk status of HCN1 rs16902086 (AG/GG vs. AA genotype) in 83 unmedicated patients with schizophrenia and 96 healthy controls and investigated genotype-related impacts on various HRV parameters. We observed significantly increased resting heart rates and a marked decrease of vagal modulation in our patient cohort. Strikingly, HCN1 rs16902086 (A > G) was associated with reduced HRV parameters in patients only. A trend towards more pronounced HRV deviations was observed in homozygous (GG) compared to heterozygous patients (AG). We present first evidence for a genetic risk factor that is associated with decreased vagal modulation in unmedicated patients with schizophrenia. Moreover, our findings suggest that HCN1 might be involved in reduced vagal modulation and possibly in increased cardiac mortality in schizophrenia patients. Thus, our data indicate that reduced vagal modulation might be an endophenotype of schizophrenia.


[Retarded ejaculation and anejaculation without orgasm. Apropos of the results of studies and of treatment in 60 cases].
The physiological mechanism of ejaculation is recalled. The different kinds of abnormalities of ejaculation and their etiologies (drugs, post-surgery, neurological, endocrinological, psychological) are specified. The diagnosis and the therapeutical management of the different varieties are discussed and the results of a personal experience of 60 cases are reported.


Parameters of inflammation and infection in a community based case-control study of coronary heart disease.
increased levels of systemic inflammatory markers appear to be related to coronary heart disease (CHD) both in asymptomatic individuals and in subjects with established CHD. Whether these associations are related to confounding coronary risk factors or are explicable through chronic infectious conditions is not clear. (1) to determine whether subjects with stable CHD differ from normal controls in inflammatory markers (CRP, SAA and fibrinogen) and/or in serostatus of four infectious agents (Helicobacter pylori, Chlamydia pneumoniae, CMV and EBV), independent of classical coronary risk factors. (2) To determine whether these inflammatory markers are related to the serostatus against these four infectious agents either in patients with CHD or in normal subjects. in a large epidemiologic survey, 446 out of 16307 men at work, aged 35-59 years, had antecedents of myocardial infarction, CABG or PTCA or had prominent Q/QS waves on their resting ECG. They were compared with double the number (n=892) of men, matched for age, educational level and industry. Inflammatory biomarkers (CRP, fibrinogen and SAA) and antibodies against H. pylori, C. pneumoniae, CMV and EBV were measured, besides classical coronary risk factors. in univariate analyses, cases had higher CRP, fibrinogen and SAA levels than controls, but no differences were observed in serumantibody levels to any of the infectious agents. Markers of previous infections were not related to inflammatory biomarkers. In multivariate analyses CRP was significantly different between cases and controls independent of differences in other coronary risk factors and in the use of lipid lowering drugs and antiplatelet aggregants. in men at work with CHD, CRP levels are significantly different from controls, independent of known risk factors. No association was found between inflammatory biomarkers and positive serostatus against four infectious agents, neither in the patients nor in the healthy controls.


Synthesis of some new 2-(3-aryl-1-phenyl-4-pyrazolyl)-benzoxazoles using hypervalent iodine mediated oxidative cyclization of Schiff's bases.
Ten new 2-(3-aryl-1-phenyl-4-pyrazolyl)benzoxazoles have been synthesized by oxidative intramolecular cyclization of the corresponding Schiff's bases using iodobenzene diacetate in methanol as an oxidant.


Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia.
BCR-ABL1-positive acute lymphoblastic leukemia (ALL) cell survival is dependent on the inositol-requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response. In the current study, we have focused on exploring the efficacy of a simultaneous pharmacological inhibition of BCR-ABL1 and IRE1α in Philadelphia-positive (Ph+) ALL using tyrosine kinase inhibitor (TKI) nilotinib and the IRE1α inhibitor MKC-8866. The combination of 0.5 µM nilotinib and 30 µM MKC-8866 in Ph+ ALL cell lines led to a synergistic effect on cell viability. To mimic this dual inhibition on a genetic level, pre-B-cells from conditional Xbp1+/fl mice were transduced with a BCR-ABL1 construct and with either tamoxifen-inducible cre or empty vector. Cells showed a significant sensitization to the effect of TKIs after the induction of the heterozygous deletion. Finally, we performed a phosphoproteomic analysis on Ph+ ALL cell lines treated with the combination of nilotinib and MKC-8866 to identify potential targets involved in their synergistic effect. An enhanced activation of p38 mitogen-activated protein kinase α (p38α MAPK) was identified. In line with this findings, p38 MAPK and, another important endoplasmic reticulum-stress-related kinase, c-Jun N-terminal kinase (JNK) were found to mediate the potentiated cytotoxic effect induced by the combination of MKC-8866 and nilotinib since the targeting of p38 MAPK with its specific inhibitor BIRB-796 or JNK with JNK-in-8 hindered the synergistic effect observed upon treatment with nilotinib and MKC-8866. In conclusion, the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph+ ALL.


Acute Pancreatitis Secondary to Newly Diagnosed Intraductal Papillary Mucinous Neoplasm.
Acute pancreatitis (AP) is a common gastrointestinal cause of hospital admissions and is prevalent in the United States. AP etiologies include alcohol use, cholelithiasis, hypertriglyceridemia, hypercalcemia, autoimmune phenomena, medications, or idiopathic. Rarely, intraductal papillary mucinous neoplasms can cause AP, as we present in this case report.


A jack-of-all-trades: 2-mercaptosuccinic acid.
2-Mercaptosuccinic acid (MS) is an important and versatile substance for diverse fields of applications of which the most significant are surveyed in this article. Biological, chemical, and physical properties of MS as well as the knowledge of its synthesis and microbial degradation are illustrated. In addition, exemplary structural analogs of the organic sulfur compound are commented. The key application of MS in nanotechnology is discussed in detail with particular emphasis on quantum dots (nanocrystals) and self-assembled monolayers in combination with gold or silver. Furthermore, some medical and pharmaceutical applications are given, inter alia in bioimaging, as a nanocarrier, and with regard to the antimicrobial activity of MS-silver and MS-gold nanoparticles. Moreover, biological and chemical applications of MS are exemplified: the thiol compound can serve as an inhibitor for glutathione peroxidase, or the toxicity of substances can be increased due to the presence of MS in the respective cells or tissues. In the field of cosmetics, MS is widely utilized as a reducing agent for numerous products as explained in this article. Additionally, the microbial utilization of MS as a carbon and energy source for growth is elucidated in-depth, providing insight into different catabolic mechanisms.


Postoperative water and electrolyte changes in skeletal muscle: a clinical study with three different intravenous infusions.
Twenty-seven patients admitted for cholecystectomy were matched for age and sex in three groups for different perioperative fluid therapies over a period of 3 days. Group I was given an acetated half-isotone "balanced" saline solution with the addition of 2.5% glucose, Group II an acetated Ringer solution and Group III an isotonic glucose solution. Percutaneous muscle biopsies were performed before and on the third day after surgery for the determination of water content and the concentration of sodium, potassium, magnesium and chloride in skeletal muscle. The cumulative balance of sodium and potassium was measured daily during the study. In all three groups a significant increase in the total muscle water content was demonstrated. The concentration of sodium and chloride in skeletal muscle increased significantly in Groups II and III, whereas the concentration of potassium decreased in all groups. The cumulative sodium balance was positive in Groups I and II; the potassium balance was negative in all groups. In conclusion, the patients given the balanced saline solution showed the least change in water content and electrolyte concentrations in skeletal muscle.


Genome-wide expression profiling in pediatric septic shock.
For nearly a decade, our research group has had the privilege of developing and mining a multicenter, microarray-based, genome-wide expression database of critically ill children (≤10 y of age) with septic shock. Using bioinformatic and systems biology approaches, the expression data generated through this discovery-oriented, exploratory approach have been leveraged for a variety of objectives, which are reviewed here. Fundamental observations include widespread repression of gene programs corresponding to the adaptive immune system and biologically significant differential patterns of gene expression across developmental age groups. The data have also identified gene expression-based subclasses of pediatric septic shock having clinically relevant phenotypic differences. The data have also been leveraged for the discovery of novel therapeutic targets, as well as for the discovery and development of novel stratification and diagnostic biomarkers. Almost a decade of genome-wide expression profiling in pediatric septic shock is now demonstrating tangible results. The studies have progressed from an initial discovery-oriented and exploratory phase to a new phase in which the data are being translated and applied to address several areas of clinical need.


Berberine Affects the Proliferation, Migration, Invasion, Cell Cycle, and Apoptosis of Bladder Cancer Cells T24 and 5637 by Down-Regulating the HER2/PI3K/AKT Signaling Pathway.
To assess the anticancer effect, target, and mechanism of berberine on bladder cancer. Bladder cancer T24 and 5637 cells were treated with different concentrations of berberine. Then, cell proliferation was assessed by cell counting kit-8 (CCK8) measure, cell migration and invasion were assessed by transwell method, cell cycle and apoptosis were assessed by flow cytometry, and the expression of human epidermal growth factor receptor-2/PhosphoInositide-3 Kinase/AKT Serine/Threonine Kinase (HER2/PI3K/AKT) proteins were assessed by Western blot. Berberine molecular docking and HER2 target were performed using the AutoDock Tools 1.5.6. Finally, HER2 inhibitors CP-724714 and berberine were used independently or in combination to detect AKT and P-AKT protein downstream changes by Western blot. Berberine inhibited the proliferation of T24 and 5637 bladder cancer cells in a concentration-dependent and time-dependent manner. Berberine can significantly inhibit the migration, invasion, and cell cycle progression of T24 and 5637 bladder cancer cells, promote their apoptosis, and down-regulate the expression of HER2/PI3K/AKT proteins. Berberine showed good docking with HER2 molecular target and had a similar and synergistic effect with HER2 inhibitor in T24 and 5637 bladder cancer cells. Berberine inhibited the proliferation, migration, invasion, and cell cycle progression of T24 and 5637 bladder cancer cells and promoted their apoptosis by down-regulating HER2/PI3K/AKT signaling pathway.


Transient state kinetic studies of proton liberation by myosin and subfragment 1.
Myosin and subfragment 1 give a maximum burst size of 0.25 to 0.30 protons per active site at pH 8 with ATP, alpha,beta-methylene-ATP, ADP, and adenylyl imidodiphosphate as substrates. The proton is derived from a change in conformation of the enzyme-substrate complex since it is produced by substrates which are not hydrolyzed. The rate constants for the binding of ATP and the proton release step in 0.1 M, 0.5 M, and 1.0 M KCl have been determined by analysis of the concentration dependence of the apparent rate. (see article)


A novel electrode-pipette design for simultaneous recording of extracellular spikes and iontophoretic drug application in awake behaving monkeys.
We developed a novel design of an electrode-pipette combination (EPC) which allows access to brain structures in awake behaving primates without the need for guide tubes or to mechanically open the dura prior to electrode insertion. The EPC consists of an etched tungsten in glass electrode flanked by two pipettes which allow for local and highly controlled iontophoretic administration of neuroactive substances. These EPCs have excellent single cell isolation properties and are sturdy enough to penetrate the primate dura for up to 8 weeks following either a craniotomy or a dura scrape (i.e. even after substantial built up of fibrous scar tissue). We show that the EPCs can be used to selectively manipulate the cholinergic system in primate V1 during passive fixation and while animals perform an attentionally demanding task.


Drosophila ezoana uses morning and evening oscillators to adjust its rhythmic activity to different daylengths but only the morning oscillator to measure night length for photoperiodic responses.
Animals living at high latitudes are exposed to prominent seasonal changes to which they need to adapt to survive. By applying Zeitgeber cycles of different periods and photoperiods we show here that high-latitude D. ezoana flies possess evening oscillators and highly damped morning oscillators that help them adapting their activity rhythms to long photoperiods. In addition, the damped morning oscillators are involved in timing diapause. The flies measure night length and use external coincidence for timing diapause. We discuss the clock protein TIMELESS (d-TIM) as the molecular correlate and the small ventrolateral clock neurons (s-LNvs) as the anatomical correlates of the components measuring night length.


Cold swim stress-induced changes in the levels of opioid peptides in the rat CNS and peripheral tissues.
Endogenous opioid peptides have been implicated in stress-induced analgesia and stress-induced feeding behavior. An earlier study from our laboratory showed that rats subjected to cold swim stress consumed significantly more food compared to controls. The present study describes changes in the levels of various opioid peptides in the central nervous system and periphery due to cold swim stress. Male Sprague-Dawley rats were subjected to cold swim stress (1 degree C for 5 min), then sacrificed by decapitation; brain, pituitary, adrenals and plasma were collected. Tissue extracts were assayed for opioid peptides by RIA. Cold swim stress resulted in analgesia which could be blocked by prior administration of naloxone, as observed by a tail-flick latency test. Cold swim stress caused a 42% decrease in pituitary beta-endorphin, but increased the level of this peptide in the hypothalamus and plasma by 36% and 337%, respectively. Dynorphin level decreased by 62% in the hypothalamus, but was not affected in the pituitary. Levels of Leu-enkephalin and Met-enkephalin decreased in the adrenal gland by 37% and 18%, respectively, but were not significantly affected in the CNS. These results indicate that cold swim stress has a differential effect on the level of CNS and peripheral opioid peptides, and that both central and peripheral opioid peptides may be important in stress-induced analgesia and feeding behavior.


Systematic review of the prospective association of daily step counts with risk of mortality, cardiovascular disease, and dysglycemia.
Daily step counts is an intuitive metric that has demonstrated success in motivating physical activity in adults and may hold potential for future public health physical activity recommendations. This review seeks to clarify the pattern of the associations between daily steps and subsequent all-cause mortality, cardiovascular disease (CVD) morbidity and mortality, and dysglycemia, as well as the number of daily steps needed for health outcomes. A systematic review was conducted to identify prospective studies assessing daily step count measured by pedometer or accelerometer and their associations with all-cause mortality, CVD morbidity or mortality, and dysglycemia (dysglycemia or diabetes incidence, insulin sensitivity, fasting glucose, HbA1c). The search was performed across the Medline, Embase, CINAHL, and the Cochrane Library databases from inception to August 1, 2019. Eligibility criteria included longitudinal design with health outcomes assessed at baseline and subsequent timepoints; defining steps per day as the exposure; reporting all-cause mortality, CVD morbidity or mortality, and/or dysglycemia outcomes; adults ≥18 years old; and non-patient populations. Seventeen prospective studies involving over 30,000 adults were identified. Five studies reported on all-cause mortality (follow-up time 4-10 years), four on cardiovascular risk or events (6 months to 6 years), and eight on dysglycemia outcomes (3 months to 5 years). For each 1000 daily step count increase at baseline, risk reductions in all-cause mortality (6-36%) and CVD (5-21%) at follow-up were estimated across a subsample of included studies. There was no evidence of significant interaction by age, sex, health conditions or behaviors (e.g., alcohol use, smoking status, diet) among studies that tested for interactions. Studies examining dysglycemia outcomes report inconsistent findings, partially due to heterogeneity across studies of glycemia-related biomarker outcomes, analytic approaches, and sample characteristics. Evidence from longitudinal data consistently demonstrated that walking an additional 1000 steps per day can help lower the risk of all-cause mortality, and CVD morbidity and mortality in adults, and that health benefits are present below 10,000 steps per day. However, the shape of the dose-response relation is not yet clear. Data are currently lacking to identify a specific minimum threshold of daily step counts needed to obtain overall health benefit.


Inaccuracies in the Use of the Majeed Pelvic Outcome Score: A Systematic Literature Review.
To evaluate the accuracy with which the Majeed Pelvic Score has been reported in the English literature. Databases used to search for literature were PubMed, Embase, and Ovid, restricted to English language from inception to October 2, 2018. Search words used were: Majeed, pelvis, and outcome. Articles were assessed for descriptions of scoring and proper reporting of Majeed Pelvic Outcome Score. Descriptive statistics were used to report the outcome of our findings. Ninty-two English articles were identified. Twenty-four (26%) articles were identified as including methodology related to the use and scoring of the Majeed Pelvic score. The remaining 68 presented mean Majeed scores with no methodological information. None (0/92) discussed how the range of possible scores for the most severe function was applied. Six (7%) reported adjusted scores for patients not working. Three (3%) included a discussion of the scores as adjusted for patients working before injury compared with those not working. Ten (11%) addressed the categorization of scores by excellent to poor describing what raw scores defined those categories. We observed poor accuracy and notable inconsistency in the use and reporting of the Majeed Pelvic Outcome Score in the literature. These data demonstrate that interpretation and comparison of research reporting this score should be done cautiously. Future studies should include specific information as to how the Majeed instrument calculated to allow for verification of the presented scores and subsequent conclusions.


Bradycardia stimulates vascular growth during gradual coronary occlusion.
In cultured endothelium, stretch induces release of growth factors that contribute to angiogenesis. We tested the hypothesis that bradycardia, which prolongs ventricular diastolic filling time and volume, promotes collateral vessel growth. An ameroid occluder was placed on coronary arteries of dogs with normal heart rates (AM) or bradycardia (55 bpm; AM+BC). A third group had normal heart rates and no ameroid (control [CON]). Four weeks after occluder placement, myocardial blood flow at rest and maximal vasodilation (adenosine) at equivalent heart rates and vascular morphometry of hearts were measured. In AM dogs, conductance (myocardial flow/diastolic pressure) of collateral-dependent myocardium was similar to collateral-independent myocardium during rest but increased to only one third of CON during maximal vasodilation. In contrast, in AM+BC dogs, conductance was similar in collateral-dependent and -independent regions during maximal vasodilation. Arteriolar length density in collateral-dependent myocardium was 80% greater in AM+BC than AM dogs. Capillary length density in collateral-dependent region of AM dogs was lower than CON but normal in AM+BC dogs. The angiopoietin receptor Tie-2 increased in collateral-dependent regions of AM and AM+BC groups, whereas vascular endothelial growth factor increased in collateral-dependent and -independent regions only in AM+BC dogs. Chronic bradycardia during gradual coronary artery occlusion facilitates angiogenesis/arteriogenesis in collateral-dependent myocardium and preserves maximal perfusion.


Naturally occurring hydroxy napthoquinones and their iron complexes as modulators of radiation induced lipid peroxidation in synaptosomes.
The modulation of radiation induced lipid peroxidation in synaptosomes by iron (II) and iron (III) complexes of two naturally occurring and therapeutically relevant naphthoquinones viz. 5,hydroxy-1,4 naphthoquinone; juglone and 2,hydroxy-1,4 naphthoquinone; lawsone, have been studied. At lower concentrations the complexes enhance lipid peroxidation predominantly through redox cycling as observed for Fe(II)- juglonate while at higher concentrations the complexes tend to limit lipid peroxidation through fast recombinations.


Viral Decay Dynamics and Mathematical Modeling of Treatment Response: Evidence of Lower in vivo Fitness of HIV-1 Subtype C.
Despite the high prevalence of HIV-1 subtype C (HIV-1C) worldwide, information on HIV-1C viral dynamics and response to antiretroviral therapy (ART) is limited. We sought to measure viral load decay dynamics during treatment and estimate the within-host basic reproductive ratio, R0, and the critical efficacy, εc, for successful treatment of HIV-1C infection. Individuals initiated on first-line ART in India and monitored for 6 months of treatment were considered. Viral load, CD4 count, and adherence data were collected at baseline, 4, 12, 16 and 24 weeks after ART initiation. Drug resistance genotyping was performed at baseline. R0 and εc were estimated using a mathematical model. Among 257 patients with complete data, mean baseline viral load was 5.7 log10 copies per milliliter and median CD4 count was 165 cells per cubic millimeter. Primary drug resistance was present in 3.1% at baseline. At 6 months, 87.5% had undetectable viral load, indicating excellent response to ART despite high baseline viremia. After excluding those with transmitted resistance, suboptimal adherence and viral rebound, data from 112 patients were analyzed using a mathematical model. We estimated the median R0 to be 5.3. The corresponding εc was ∼0.8. These estimates of R0 and εc are smaller than current estimates for HIV-1B, suggesting that HIV-1C exhibits lower in vivo fitness compared with HIV-1B, which allows successful treatment despite high baseline viral loads. The lower fitness, and potentially lower virulence, together with high viral loads may underlie the heightened transmission potential of HIV-1C and its growing global spread.


Nanohybrid of antimonene@Ti3C2Tx-based electrochemical aptasensor for lead detection.
Lead ions (Pb2+), as one of many common heavy metallic environmental pollutants, can cause serious side-effects and result in chronic poisoning to people's health, so it is highly significant to monitor Pb2+ efficiently and sensitively. Here, we proposed an antimonene@Ti3C2Tx nanohybrid-based electrochemical aptamer sensor (aptasensor) for high sensitive Pb2+ determination. The sensing platform of nanohybrid was synthesized by ultrasonication, possessing the advantages of both antimonene and Ti3C2Tx, which not only can vastly enlarge the sensing signal of the proposed aptasensor, but also greatly simplified its manufacturing flow, because antimonene can strongly interact with aptamer through noncovalently bound. The surface morphology and microarchitecture of the nanohybrid were perused by several methods such as scanning electron microscope (SEM), energy-dispersive X-ray mapping spectroscopy (EDS), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and atomic force microscope (AFM). Under optimal empirical conditions, the proposed aptasensor exhibited a wide linear correlation of the current signals with the logarithm of CPb2+ (Log CPb2+) over the span from 1 × 10-12 to 1 × 10-7 M and provided a trace discernment limit of 3.3 × 10-13 M. Moreover, the constructed aptasensor displayed superior repeatability, great consistency, eminent selectivity, and beneficial reproducibility, implying its extreme potential application for water quality control and the environmental monitoring of Pb2+.


Transposable elements potentiate radiotherapy-induced cellular immune reactions via RIG-I-mediated virus-sensing pathways.
Radiotherapy (RT) plus immunotherapy is a promising modality; however, the therapeutic effects are insufficient, and the molecular mechanism requires clarification to further develop combination therapies. Here, we found that the RNA virus sensor pathway dominantly regulates the cellular immune response in NSCLC and ESCC cell lines. Notably, transposable elements (TEs), especially long terminal repeats (LTRs), functioned as key ligands for the RNA virus sensor RIG-I, and the mTOR-LTR-RIG-I axis induced the cellular immune response and dendritic cell and macrophage infiltration after irradiation. Moreover, RIG-I-dependent immune activation was observed in ESCC patient tissue. scRNA sequencing and spatial transcriptome analysis revealed that radiotherapy induced the expression of LTRs, and the RNA virus sensor pathway in immune and cancer cells; this pathway was also found to mediate tumour conversion to an immunological hot state. Here, we report the upstream and ligand of the RNA virus sensor pathway functions in irradiated cancer tissues.


Acyl lipid composition variation related to culture age and nitrogen concentration in continuous culture of the microalga Phaeodactylum tricornutum.
The influence of culture age and nitrogen concentration on the distribution of fatty acids among the different acyl lipid classes has been studied in continuous cultures of the microalga Phaeodactylum tricornutum. The culture age was tested in the range of 1.15-7 days, controlled by adjusting the dilution rate of fresh medium supplied. The effect of nitrogen concentration was tested from saturating conditions to starvation by modifying nitrate concentration in the fresh medium. Culture age had almost no influence on the fatty acid content; 16:0, 16:3 and 20:5 increased moderately wherein the level of 16:1 decreased when the culture age decreased. Culture age had no effect on the total fatty acid content that remained around 11% of dry weight. Conversely, culture age had a greater impact on lipid classes, producing changes in amounts of triacylglycerols (TAG) which ranged between 43% and 69%, and galactolipids (GLs) that oscillated between 20% and 40%. In general, the content of polar lipids of the biomass decreased with culture age. The other factor assayed, nitrogen content, affected the fatty acid profile. Saturated and monounsaturated fatty acids accumulated when the nitrogen concentration was decreased. The experiments regarding the effect of nitrogen concentration on lipid species were carried out with cells of an average age of 3.5 days. A decrease of the nitrogen concentration caused the GL fraction to decrease from 21 to 12%. Conversely, both neutral lipids (NLs) and phospolipids (PLs) increased from about 73 to 79% and from 6 to 8%, respectively. In these experiments, TAG was the lipid class with the highest increase, from 69 to 75%.


Measurement of Pi dissociation from actin filaments following ATP hydrolysis using a linked enzyme assay.
Using glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase as a linked enzyme assay for determination of free inorganic phosphate, as described by Trentham et al. (1972, Biochem. J. 126, 635-644) we have been able to monitor the time course of Pi release from F-actin following ATP hydrolysis that accompanies ATP-actin polymerization. The rate constant for Pi dissociation from Mg-F-actin is 0.006 s-1 at 25 degrees C and pH 7.8, both in the presence of 1 mM Mg and 0.1 M KCl + 1 mM Mg. This result confirms the existence of ADP-Pi-F-actin as a major intermediate in the polymerization of ATP-actin (Carlier and Pantaloni, 1986, Biochemistry 25, 7789-7792). The method is potentially useful for other enzymes hydrolyzing triphosphate nucleotides, provided that the rate of Pi release is appreciably lower than 0.1 s-1.


Cytotoxic terpenoids and flavonoids from Artemisia annua.
The cytotoxic activity of nine terpenoids and flavonoids isolated from Artemisia annua was tested in vitro on several human tumor cell lines. These compounds are artemisinin, deoxyartemisinin, artemisinic acid, arteannuin-B, stigmasterol, friedelin, friedelan-3 beta-ol, artemetin, and quercetagetin 6,7,3',4'-tetramethyl ether. Friedelane-type triterpenoids were isolated for the first time from this plant. Artemisinin and quercetagetin 6,7,3',4'-tetramethyl ether showed significant cytotoxicity against P-388, A-549, HT-29, MCF-7, and KB tumor cells.


Are teeth evidence in acid environment.
Teeth are the most durable structures that resist destruction more than skeletal tissue Commercially available acids can be used to destroy the body or a part, to mask human identification. The present study examines the effect of caustic acids on human dentition. Ten upper anterior teeth each were immersed in 37% hydrochloric acid (conc. HCl), 65% nitric acid (conc. HNO3) and 96% sulfuric acid (conc. H2SO4). Teeth were retrieved, washed in distilled water, dried, photographed and radiographed at intervals of 15 min, 30 min, 1 hr, 3 hr, 5 hr and 8 hr. Teeth placed in conc. HCl and conc. HNO3 dissolved completely after 8 hours, while that placed in conc. H2SO4 retained its morphology and radiographic dimension even after 8 hours. Hence teeth can serve as a tool in identification (age estimation and sex determination) of the victim when in contact with conc. H2SO4.


Animal Models Correlating Immune Cells for the Development of NAFLD/NASH.
This review mainly elaborates on the animal models available for understanding the pathogenesis of the second hit of non-alcoholic fatty liver disease (NAFLD) involving immune system. This is known to be a step forward from simple steatosis caused during the first hit, which leads to the stage of inflammation followed by more serious liver conditions like non-alcoholic steatohepatitis (NASH) and cirrhosis. Immune-deficient animal models serve as an important tool for understanding the role of a specific cell type or a cytokine in the progression of NAFLD. These animal models can be used in combination with the already available animal models of NAFLD, including dietary models, as well as genetically modified mouse models. Advancements in molecular biological techniques enabled researchers to produce several new animal models for the study of NAFLD, including knockin, generalized knockout, and tissue-specific knockout mice. Development of NASH/NAFLD in various animal models having compromised immune system is discussed in this review.


[Effect of alcohol on hepatocyte mitochondria].
The authors studied ultrastructural changes of hepatocytes under the effect of alcohol. The greatest changes were revealed in the mitochondria. Physical activity and hypoprotein diet produced a significant influence on the results of alcohol poisoning. The first factor reduced, and the second enhanced the deleterious effect of alcohol.


Catecholamines and Parkinson's disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview.
The author identified the genes and proteins of human enzymes involved in the biosynthesis of catecholamines (dopamine, norepinephrine, epinephrine) and tetrahydrobiopterin (BH4): tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and GTP cyclohydrolase I (GCH1). In Parkinson's disease (PD), the activities and levels of mRNA and protein of all catecholamine-synthesizing enzymes are decreased, especially in dopamine neurons in the substantia nigra. Hereditary GCH1 deficiency results in reductions in the levels of BH4 and the activities of TH, causing decreases in dopamine levels. Severe deficiencies in GCH1 or TH cause severe decreases in dopamine levels leading to severe neurological symptoms, whereas mild decreases in TH activity in mild GCH1 deficiency or in mild TH deficiency result in only modest reductions in dopamine levels and symptoms of DOPA-responsive dystonia (DRD, Segawa disease) or juvenile Parkinsonism. DRD is a treatable disease and small doses of L-DOPA can halt progression. The death of dopamine neurons in PD in the substantia nigra may be related to (i) inflammatory effect of extra neuronal neuromelanin, (ii) inflammatory cytokines which are produced by activated microglia, (iii) decreased levels of BDNF, and/or (iv) increased levels of apoptosis-related factors. This review also discusses progress in gene therapies for the treatment of PD, and of GCH1, TH and AADC deficiencies, by transfection of TH, AADC, and GCH1 via adeno-associated virus (AAV) vectors.


Video Laryngoscope Screen Visualization and Tracheal Intubation Performance: A Video-Based Study in a Pediatric Emergency Department.
Our study objectives were to describe patterns of video laryngoscope screen visualization during tracheal intubation in a pediatric emergency department (ED) and to determine their associations with procedural performance. We conducted a prospective, observational, video-based study of pediatric ED patients undergoing tracheal intubation with a standard geometry video laryngoscope (Storz C-MAC; Karl Storz, Tuttlingen, Germany). Our primary exposure was video screen visualization patterns, measured by the percentage of each attempt spent viewing the screen and the number of times the proceduralist changed their gaze between the patient and screen (gaze switches). Our primary outcome was first-pass success. We compared measures of screen visualization between successful and unsuccessful first attempts using a generalized linear mixed model. From December 2019 to October 2021, we collected data on 153 patients. The first-pass success rate was 79.1%. Proceduralists viewed the video screen during 80.4% of attempts; the median percentage of each attempt spent viewing the video screen was 42.1% (interquartile range 8.7% to 65.5%). The median number of gaze switches per attempt was 3 (interquartile range 1 to 6, maximum 22). The percentage of each attempt spent viewing the video screen was not associated with success (adjusted odds ratio 1.00, 95% confidence interval 0.93 to 1.08); additional gaze switches were associated with a lower likelihood of success (adjusted odds ratio 0.80, 95% confidence interval 0.71 to 0.90). We found wide variation in how proceduralists viewed the video laryngoscope screen during intubations in a pediatric ED. We illustrate the application of 2 objective screen visualization measures to quantify and understand how clinicians actually use video laryngoscopy.


MARCKS for maintenance in dendritic spines.
Synapses in the brain must maintain a balance between learning-related plasticity and the stability necessary for reliable function. In this issue of Neuron, Calabrese and Halpain describe cell-transfection experiments implicating MARCKS, a protein that binds to both the cell surface and actin cytoskeleton, in the maintenance of dendritic spines.


I'm angry that I'm not perfect! aggression mediates the relationship between perfectionism and eating pathology in men and women.
The link between maladaptive perfectionism and eating disorder (ED) pathology is well-established, yet less is known about factors that contribute to this relationship. The current study examined the mediating effect of aggression on the relationship between maladaptive perfectionism and ED pathology in a mixed-gender sample. Three-hundred and thirty-six participants (47.3% women) with a mean age of 35.75 (SD = 10.00) were recruited online through Amazon Mechanical Turk. Self-reported data were collected on ED pathology (Eating Disorder Examination-Questionnaire), perfectionism (Frost Multidimensional Perfectionism Scale), aggression (Buss-Perry Aggression Questionnaire), and demographic information. Mediation analyses were performed separately for men and women using the SPSS PROCESS macro (Hayes in Introduction to mediation, moderation, and conditional process analysis: a regression-based approach, Guilford Press, New York, 2018). To test gender differences for specific model parameters, multiple-group structural equation modeling was used. Findings indicate that aggression partially mediated the relationship between maladaptive perfectionism and ED pathology in both men and women. There were no significant gender differences in the strength of the indirect effect or direct effect of perfectionism on ED pathology. Findings from this study suggest that aggression may partially account for the relationship between maladaptive perfectionism and ED pathology. Additional research is needed to determine the temporal sequence of maladaptive perfectionism and aggression as it relates to ED pathology. Nonetheless, given their interrelationships, treatment research may benefit from examining interventions targeting aggression as a potential avenue for reducing ED symptoms. Level V, cross-sectional study.


Increasing patient-reported allergies are not associated with pain, functional outcomes, or satisfaction following medial patellofemoral ligament reconstruction: a retrospective comparative cohort study.
Patient-reported allergies (PRAs) are often stigmatized as a potential nonmodifiable risk factor for increased pain and worse functional outcomes following surgery. However, there is a dearth of literature directly assessing the impact of PRAs on outcomes in sport surgeries such as medial patellofemoral ligament reconstruction (MPFLR). The purpose of our study was to determine whether PRAs were associated with worse outcomes following MPFLR. We conducted a retrospective review of patients who underwent MPFLR at our institution from 2011 to 2019. Patients were included if they had at least 12 months of follow-up. PRAs were obtained from preoperative medical assessments and categorized by drug class. Demographic and perioperative data were obtained from electronic medical records. Postoperative outcomes were measured using a telephone survey and included recurrent instability, Visual analog scale (VAS) for pain, VAS for sports, Kujala score, MPFL-Return to Sport after Injury (MPFL-RSI) score, and overall satisfaction score. Multiple linear regression was used to determine association between PRAs and outcome measures, and p-values less than 0.05 were considered significant. The cohort included 141 MPFLR. Most patients were female (98, 70%) with an average age of 25 years (range 12-56 years). Average follow-up time was 47 months. Forty-seven patients (33%) reported at least one PRA. There were no significant differences in postoperative pain, functional outcomes, satisfaction, or return to sport between patients with or without PRAs (all p > 0.05). Absence of antibiotic PRAs was predictive of higher VAS (p < 0.007), but there were no other differences. There were no significant differences in outcomes between patients without PRAs, PRAs without a concomitant psychiatric disorder, or PRAs with a concomitant psychiatric disorder (all p > 0.05). In conclusion, PRAs with or without concomitant psychiatric diagnoses are not associated with worse postoperative pain, functional outcomes, or satisfaction following MPFLR with allograft, dispelling common misconceptions that increased number of allergies or psychiatric diagnoses lead to inferior surgical outcomes. Presence of antibiotic allergies was associated with lower VAS postoperative pain score. Future research should investigate the relationship between PRAs and other surgeries in the field of sports medicine.


Role of pylorus in the control of the canine migrating motor complex.
The cyclic myoelectric activity of the gastroduodenal area and the antral mucosal ionic permeability, measured by the transmural potential difference, were simultaneously evaluated in the dog. These parameters were recorded before and after section of the omental attachments to the pyloric area, section of the terminal antrum, and excision of a 2-cm segment at the pylorus. None of the surgical procedures modified the duration of the postprandial disruption of the migrating motor complexes, whereas the potential difference was increased. In fasted dogs resection of the omentum increased the migrating motor complex intervals and the duration of the phase of regular spiking activity; however, the regular spiking activities still occurred in a sequential manner. Transection of the terminal antrum was associated with a decrease in duration of the regular spiking activity phases that started simultaneously on the antrum and duodenum, without changes in the migrating motor complex intervals, and prevented the occurrence of the increase in potential difference associated with feeding. After pylorectomy, the migrating motor complex intervals were reduced by 46% on both antrum and duodenum. Our observation that only pylorectomy was able to consistently increase the frequency of migrating motor complexes suggests a pyloric inhibition of the normal pacing of the cyclic motor events at both antral and duodenal levels.


Gossypol activates pancreatic polyamine catabolism in normal rats and induces acute pancreatitis in transgenic rats over-expressing spermidine/spermine N1-acetyltransferase.
The male antifertility agent gossypol has been reported to induce spermidine/spermine N1-acetyltransferase (SSAT) in canine prostate cells. As SSAT is the rate-controlling enzyme in the catabolism of the polyamines and is involved in the development of acute pancreatitis in a recent transgenic rat model, we exposed normal and transgenic rats over-expressing SSAT to gossypol to evaluate its effect on pancreatic polyamine metabolism and organ integrity. Pancreatic SSAT activity, polyamine pools, pancreatic histology and plasma 2-amylase activity were determined after different doses of gossypol. Gossypol increased pancreatic putrescine and decreased spermidine and spermine pools in normal rats accompanied by tissue oedema and significantly elevated plasma amylase activity. In transgenic rats, the drug strikingly induced SSAT, profoundly depleted the higher polyamines and caused distinct pancreatitis. The combination of gossypol at doses harmless to transgenic pancreas with an inhibitor of polyamine oxidase caused massive synergistic induction of SSAT, profound depletion of the polyamine pools and acute pancreatitis. The results indicate that gossypol induces pancreatitis through an activation of polyamine catabolism.