A comparison of regional versus systemic drug injection. Adriamycin concentration in peripheral blood and gastric stump (post-Billroth II gastrectomy) in the dog.
Gastric stump cancer has a low resection rate and poor response to systemic chemotherapy. This study attempted to achieve higher drug concentrations in target tissues by way of regional arterial injection instead of systemic venous administration. A total of 12 male mongrel dogs that had undergone post-Billroth II gastrectomies were randomly divided into two groups: in group A, 1.27 mg/kg adriamycin (ADM) was injected through the left gastric artery; in group B, the same dose of ADM was injected into a vein in the left front leg. Blood samples were taken at various time intervals, and the dogs were sacrificed 2 h after drug administration. Tissues were removed from various parts of the gastric stump for measurement of the ADM concentration. The ADM content in the jejunum, heart, liver, spleen, and pancreas was also determined. The results were as follows: (1) the ADM concentration in the gastric stump near its lesser curvature and stomal mucosa was significantly higher in group A than in group B (P less than 0.05). (2) The ADM concentrations in the adjacent organs (heart, liver, and pancreas) were also significantly higher in group A than in group B (P less than 0.05). (3) The ADM levels in the venous blood were significantly higher in group B than in group A (P less than 0.05). These results indicate that a chemotherapeutic drug given through the left gastric artery provides a higher drug concentration in the area where gastric stump cancer frequently occurs and that a lower systemic blood level may cause fewer adverse drug effects. The high concentration of ADM in the heart may not be a good indication, but it may serve as an important signal either to select a less cardiotoxic drug or to monitor heart function cautiously during drug therapy.


Regional localization of the interferon-beta 2/B-cell stimulatory factor 2/hepatocyte stimulating factor gene to human chromosome 7p15-p21.
The human interferon-beta 2 gene (IFNB2) is identical to the genes encoding the B-cell stimulatory factor (BSF-2), the hybridoma growth factor (HGF), and the hepatocyte stimulating factor (HSF). This protein mediates major alterations in the secretion of a wide spectrum of plasma proteins by the liver in response to tissue injury (the acute-phase response). We have used a cDNA probe specific to the human IFNB2 gene in DNA hybridization experiments and report the regional localization of this gene to human chromosome 7p15-p21. Southern blot analyses of DNA extracted from a panel of mouse X human somatic cell hybrids localized this gene to human chromosome 7p. In situ hybridization of the IFNB2 cDNA probe to prebanded human metaphase chromosome spreads allowed the further localization of this gene to 7p15-p21.


Insights from late-onset familial parkinsonism on the pathogenesis of idiopathic Parkinson's disease.
Disease-modifying therapies that slow or halt the progression of Parkinson's disease are an unmet clinical need. Many hypotheses have been put forward to explain the pathogenesis of the disease, but none has led to the development of disease-modifying drugs. Here we focus on familial forms of late-onset parkinsonism that most closely resemble idiopathic Parkinson's disease and present a synthesis of emerging molecular advances. Genetic discoveries and mechanistic investigations have highlighted early alterations to synaptic function, endosomal maturation, and protein sorting that might lead to an intracellular proteinopathy. We propose that these cellular processes constitute one pathway to pathogenesis and suggest that neuroprotection, as an adjunct to current symptomatic treatments, need not remain an elusive goal.


Selecting ordered environments in NMR of spin 3/2 nuclei via frequency-sweep pulses.
We demonstrate that frequency-swept pulses can be used for the selective and enhanced detection of quadrupolar nuclei located in anisotropic environments. The primary driving force for this technique development is the field of sodium-MRI, where sodium signals from locally ordered environments are known to be diagnostic of cartilage defects. We demonstrate here simple one-dimensional images of model systems, in which the signals from free sodium ions are suppressed, while ordered sodium is detected via the narrow central transition signal.


The Impact of Visceral Adiposity on Testosterone Levels in American Adult Men: A Cross-Sectional Analysis.
BACKGROUND Testosterone decline and deficiency importantly affect men's health, and may be associated with excessive deposition of visceral adipose tissue. This study was conducted to explore the association between visceral adiposity index (VAI) and testosterone level. MATERIAL AND METHODS A total of 1551 participants from the NHANES 2013-2013 cycle and 2015-2016 cycle were selected for our analyses. The VAI index was calculated based on waist circumference (WC), body mass index (BMI), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-c), and serum testosterone was measured by isotope dilution liquid chromatography tandem mass spectrometry. Multivariable adjusted linear and logistic regression were utilized to investigate the associations between VAI index and testosterone level and testosterone deficiency, respectively. Additionally, subgroup analyses were performed to identify sensitive populations. RESULTS A total of 1551 participants with mean VAI index of 1.95±0.08 were eligible for our analysis. After adjusting for all potential cofounders, men with higher VAI index displayed a lower level of total testosterone level (ß: -11.74, 95% CI: -17.33, -6.15, P<0.0001), and higher risk of testosterone deficiency (OR: 1.24, 95% CI: 1.09, 1.40, P=0.0022). Comparing to VAI quartile 1, quartile 4 showed the most decreased testosterone level (ß: -94.59, 95% CI: -130.04, -59.14, P<0.0001), and highest risk of testosterone deficiency (OR: 5.07, 95% CI: 2.41,10.63, P<0.0001). Subgroup analysis demonstrated that VAI index was strongly related to testosterone level and testosterone deficiency in aged and obese men. CONCLUSIONS Men with higher VAI index displayed lower testosterone levels and higher risk of testosterone deficiency, especially in aged men and obese men.


Synthesis and Structural Characterization of the New Clathrates K₈Cd₄Ge42, Rb₈Cd₄Ge42, and Cs₈Cd₄Ge42.
This paper presents results from our exploratory work in the systems K-Cd-Ge, Rb-Cd-Ge, and Cs-Cd-Ge, which yielded the novel type-I clathrates with refined compositions K₈Cd3.77(7)Ge42.23, Rb₈Cd3.65(7)Ge42.35, and Cs7.80(1)Cd3.65(6)Ge42.35. The three compounds represent rare examples of clathrates of germanium with the alkali metals, where a d10 element substitutes a group 14 element. The three structures, established by single-crystal X-ray diffraction, indicate that the framework-building Ge atoms are randomly substituted by Cd atoms on only one of the three possible crystallographic sites. This and several other details of the crystal chemistry are elaborated.


Identification of underlying and transfusion-related platelet qualitative alterations in the hemato-oncologic patient.
Hemato-oncologic patients with chemotherapy-induced thrombocytopenia are one of the populations receiving platelet transfusions. The general practice with these patients is to give prophylactic platelet transfusions when platelet counts fall below 10×109PLT/L. However, in more than 40% of these patients, platelet transfusion does not prevent bleeding. The reason of the low efficacy of platelet transfusion in the context of chemotherapy patients is not entirely understood. We therefore aimed at immunophenotyping the expression of platelet surface and activation markers and thrombopoietin levels from hemato-oncologic patients before and after transfusion. A more detailed follow-up was performed in three patients that underwent autologous bone marrow transplantation. As previously reported, basal platelet activation was observed in hemato-oncologic patients. Based on flow cytometry parameters, i.e. the percentage of positivity and mean fluorescence intensity (MFI) distribution, our data provide an additional interpretation of platelet acquired qualitative changes in the hemato-oncologic patient. From our results we propose: first, the underlying activation of platelets in the hemato-oncologic patient is accompanied by loss of expression of the platelet receptors that are susceptible to protease-mediated shedding; second, soon after transfusion, the newly circulating donor platelets show additional activation, which may result in subsequent platelet receptor recycling and potential accelerated clearance of these activated platelets. In conclusion, the immunophenotype of circulating platelets changes after prophylactic platelet transfusion. Next to platelet count increment, exploration of this immunophenotype might help to explain transfusion refractory bleeding in hemato-oncologic patients. Eventually this may lead to personalization and improvement of the present platelet transfusion support regime.


Dopamine-induced astrocytic Ca2+ signaling in mPFC is mediated by MAO-B in young mice, but by dopamine receptors in adult mice.
Dopamine (DA) plays a vital role in brain physiology and pathology such as learning and memory, motor control, neurological diseases, and psychiatric diseases. In neurons, it has been well established that DA increases or decreases intracellular cyclic AMP (cAMP) through D1-like or D2-like dopamine receptors, respectively. In contrast, it has been elusive how astrocytes respond to DA via Ca2+ signaling and regulate synaptic transmission and reward systems. Previous studies suggest various molecular targets such as MAO-B, D1R, or D1R-D2R heteromer to modulate astrocytic Ca2+ signaling. However, which molecular target is utilized under what physiological condition remains unclear. Here, we show that DA-induced astrocytic Ca2+ signaling pathway switches during development: MAO-B is the major player at a young age (5-6 weeks), whereas DA receptors (DARs) are responsible for the adult period (8-12 weeks). DA-mediated Ca2+ response in the adult period was decreased by either D1R or D2R blockers, which are primarily known for cyclic AMP signaling (Gs and Gi pathway, respectively), suggesting that this Ca2+ response might be mediated through Gq pathway by D1R-D2R heterodimer. Moreover, DAR-mediated Ca2+ response was not blocked by TTX, implying that this response is not a secondary response caused by neuronal activation. Our study proposes an age-specific molecular target of DA-induced astrocytic Ca2+ signaling: MAO-B in young mice and DAR in adult mice.


Post burn pruritus--a review of current treatment options.
Post burn pruritus is a well recognised symptom in almost all burn patients. Yet, there is insufficient awareness about the etiopathogenesis and a lack of a systematic approach in the assessment and treatment of this distressing symptom. The current standard therapies include antihistamines, which are effective as sole therapy in only 20% patients, and emollients. There is a lacunae of clear consensus on the care of patients not responding to antihistamines. We review the literature on the etiology and pathogenesis of post burn pruritus, which has both central and peripheral pathways. The published studies on the currently available therapeutic options to treat itch in burns are discussed. On the basis of current evidence in literature, gabapentin used in the treatment of neuropathic pain, has demonstrated great promise, and is suggested as the next option for this subset of patients, not relieved with antihistamines.


Continuous chromogenic tissue factor assay: comparison to clot-based assays and sensitivity established using pure tissue factor.
The continuous chromogenic tissue factor assay has been compared to one-stage and two-stage coagulation assays, and its sensitivity has been established using purified human placental tissue factor. Log-log plots of the clot-times versus A405/min2 are linear over the mutually useful ranges of tissue factor concentration. Using human placental tissue factor reconstituted into phosphatidylserine-phosphatidylcholine (30:70) vesicles, the chromogenic assay quantitatively detected tissue factor in dilutions containing from 3 femtomoles to less than 10 attomoles of protein.


Population regulation in the land snail Arianta arbustorum: density effects on adult size, clutch size and incidence of egg cannibalism.
The relationships between local population density and adult size, clutch size and spatial distribution of egg batches were investigated in 11 natural populations of the land snail Arianta arbustorum in a forest near Uppsala, Sweden. Shell size of adults decreased with increasing population density as did clutch size. Within populations, clutch size scaled allometrically with shell size indicating size-specific fecundity. It is hypothesized that food unpalatability caused by mucus deposition slows down juvenile growth rate in high density populations, resulting in small adults and thus reducing their fecundity in subsequent years. The influence of the distance between batches on the incidence of egg cannibalism by hatchlings was examined in a laboratory experiment. In this experiment the number of eggs cannibalized increased with decreasing distance to the batch of hatching snails. Thus, in the field, eggs of highly aggregated batches suffer a high risk of cannibalism. In the 3 populations with the highest snail density, 21-39% of all batches were deposited close to each other (nearest neighbour distance ≤5 cm, i.e. less than hatchlings more within 1 day). These findings indicate that egg cannibalism can act as a population regulating factor.


Optimizing the Spinal Interbody Implant: Current Advances in Material Modification and Surface Treatment Technologies.
Interbody implants allow for fusion of the anterior column of the spine between vertebral body endplates. As rates of spinal fusion surgery have increased over the past several years, significant research has been devoted to optimizing both the mechanical and biologic properties of the interbody implant in order to promote bony fusion. The first interbody implants used decades ago were fashioned from cortical autograft. Currently, titanium alloy and polyetheretherketone (PEEK) are the most widely used and studied materials for this purpose. This review focuses on recent innovations in material modification and surface treatment techniques for both titanium and PEEK implants to maximize fusion rates in spinal surgery. Titanium has an elastic modulus much higher than native bone and however has better osseointegrative properties than PEEK. PEEK, however, has an elastic modulus closer to that of bone without any of the advantageous biologic properties that titanium has. Increasing porosity and surface roughness of titanium implants have been shown to improve the mechanical properties of titanium implants, while the biologic properties of PEEK have been enhanced using surface coating technology, either with titanium or with hydroxyapatite (HA). Techniques such as increasing porosity, surface roughening, and surface coating are just some of the recent innovations aimed at optimizing both mechanical and biologic properties of interbody implants to promote spinal fusion. The future of interbody implant design will rely on continued improvements of PEEK and titanium implants as well as exploring new implant materials altogether.


Grain Refinement Efficiency in Commercial-Purity Aluminum Influenced by the Addition of Al-4Ti Master Alloys with Varying TiAl₃ Particles.
A series of Al-4Ti master alloys with various TiAl₃ particles were prepared via pouring the pure aluminum added with K₂TiF₆ or sponge titanium into three different molds made of graphite, copper, and sand. The microstructure and morphology of TiAl₃ particles were characterized and analyzed by scanning electron microscope (SEM) with energy dispersive spectroscopy (EDS). The microstructure of TiAl₃ particles in Al-4Ti master alloys and their grain refinement efficiency in commercial-purity aluminum were investigated in this study. Results show that there were three different morphologies of TiAl₃ particles in Al-4Ti master alloys: petal-like structures, blocky structures, and flaky structures. The Al-4Ti master alloy with blocky TiAl₃ particles had better and more stable grain refinement efficiency than the master alloys with petal-like and flaky TiAl₃ particles. The average grain size of the refined commercial-purity aluminum always hereditarily followed the size of the original TiAl₃ particles. In addition, the grain refinement efficiency of Al-4Ti master alloys with the same morphology, size, and distribution of TiAl₃ particles prepared through different processes was almost identical.


Interface engineering of Ni/NiO heterostructures with abundant catalytic active sites for enhanced methanol oxidation electrocatalysis.
Designing efficient and stable non-noble metal electrocatalysts with good performance in reaction kinetics is desirable yet challenging for the study of methanol oxidation reaction (MOR). Herein, we have reported well-defined nanoscale nickel/nickel oxide (Ni/NiO) heterostructures supported by a three-dimensional (3D) porous graphene network (RG) via a delicate interface engineering technique. The as-prepared 3D Ni/NiO/RG composites achieve outstanding catalytic activity (79.5 mA cm-2/1262.1 mA mg-1) for MOR in alkaline solution, outperforming most reported non-precious catalysts. A combined experimental and computational investigation shows that such a good performance benefits from the specific Ni/NiO interface, which not only bears abundant accessible active sites but also improves the energetics of MOR. Moreover, this interface contributes to favorable kinetic and improved structural stability during electrocatalysis, ensuring superior catalytic performance after 1000 consecutive cyclic voltammetry tests for MOR. Our work demonstrates the potential of interface engineering in the rational design of efficient precious-metal-free electrocatalysts.


Possible effects of whole body vibration on bone properties in growing rats.
To examine the effects of whole body vibration (WBV) on bone properties in growing rats, and to explore the optimal conditions for enhancing bone properties. Thirty-six 4-week-old male rats were divided into 1 control and 5 experimental groups. Each experimental group underwent WBV at 15, 30, 45, 60, and 90 Hz (0.5 g, 15 min/d, 5 d/wk) for 8 weeks. We measured bone size, muscle weight and bone mechanical strength of the right tibia. Trabecular bone mass and trabecular bone microstructure (TBMS) of the left tibia were analyzed by micro-computed tomography. Serum levels of bone formation/resorption markers were also measured. WBV at 45 Hz and 60 Hz tended to enhance trabecular bone mass and TBMS parameters. However, there was no difference in maximum load of tibias among all groups. Serum levels of bone resorption marker were significantly higher in the 45-Hz WBV group than in the control group. WBV at 45-60 Hz may offer a potent modality for increasing bone mass during the period of rapid growth. Further studies are needed to explore the optimal WBV conditions for increasing peak bone mass and TBMS parameters. WBV modality may be a potent strategy for primary prevention against osteoporosis.


BOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER-Associated Degradation.
The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins. Rather, BOK is controlled at the level of protein stability by components of the endoplasmic reticulum (ER)-associated degradation pathway. BOK is ubiquitylated by the AMFR/gp78 E3 ubiquitin ligase complex and targeted for proteasomal degradation in a VCP/p97-dependent manner, which allows survival of the cell. When proteasome function, VCP, or gp78 activity is compromised, BOK is stabilized to induce MOMP and apoptosis independently of other BCL-2 proteins.


Clinical significance of NUCB2 mRNA expression in prostate cancer.
Nucleobindin 2 (NUCB2) abnormal expression has been reported in gastric cancer and breast cancer. However, the role of NUCB2 in prostate cancer (PCa) remains unclear. The aim of the present study was to investigate the NUCB2 expression in PCa tissues and adjacent non-cancerous tissues and its potential relevance to clinicopathological variables and prognosis. NUCB2 mRNA expression was determined by real-time quantitative real time reverse transcriptase polymerase chain reaction in 180 pairs of fresh frozen PCa tissues and corresponding non-cancerous tissues. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between NUCB2 expression and prognosis of PCa patients. Our results showed that the expression level of NUCB2 mRNA in PCa tissues was significantly higher than those in non-cancerous tissues. Our results indicated that the high expression of NUCB2 in PCa was associated with lymph node metastasis, preoperative PSA, Gleason score, and angiolymphatic invasion. Kaplan-Meier survival analysis showed that patients with high NUCB2 expression have shorter biochemical recurrence (BCR)-free survival time compared to patients with low NUCB2 expression. Multivariate analysis revealed that NUCB2 expression was an independent predictor of BCR-free survival. NUCB2 might play a positive role in PCa development and could serve as an independent predictor of BCR-free survival.


Bias was reduced in an open-label trial through the removal of subjective elements from the outcome definition.
To determine whether modifying an outcome definition to remove subjective elements reduced bias in a trial that could not use blinded outcome assessment. Reanalysis of an open-label trial comparing a restrictive vs. liberal transfusion strategy for gastrointestinal bleeding. The usual definition of the primary outcome, further bleeding, allows subjective clinical symptoms to be used alone for diagnosis, whereas the definition used in the trial required more objective confirmation by endoscopy. We compared treatment effect estimates for these two definitions. Fewer subjective symptom-identified events were confirmed using more objective methods in the restrictive arm (18%) than in the liberal arm (56%), indicating differential assessment between arms. An analysis using all events (both subjective and more objective) led to an odds ratio of 0.83 (95% confidence interval [CI]: 0.50-1.37). When only events confirmed using more objective methods were included, the odds ratio was 0.50 (95% CI: 0.32-0.78). The ratio of the odds ratios was 1.66, indicating that including unconfirmed events in the definition biased the treatment effect upward by 66%. Modifying the outcome definition to exclude subjective elements substantially reduced bias. This may be a useful strategy for reducing bias in trials that cannot blind outcome assessment.


Decreased Na,K-ATPase gene expression in cardiomyopathic hamster hearts.
We studied Na,K-ATPase mRNA expression in cardiomyopathic (Bio 14.6) and normal (F1b) Syrian hamster ventricles. In Northern blot analysis, Na,K-ATPase alpha 1, alpha 2, alpha 3 and beta 1 isoform mRNAs were detected in 3-week-old Bio 14.6 and F1b hamster ventricles. We then investigated the expression of alpha 1 subunit mRNA in Bio 14.6 hamster ventricles at the ages of 3 weeks prehypertrophic and 30 weeks hypertrophic, and in age-matched F1b hamster ventricles. The alpha 1 subunit mRNA levels in Bio 14.6 hamster ventricles were approximately 50% lower than those in F1b hamster ventricles at both 3 and 30 weeks of age. Na,K-ATPase activity measured in membrane fractions from the ventricles of 3-week-old Bio 14.6 hamsters was also approximately 20% lower than that of F1b hamsters, suggesting that the differences in the mRNA level were associated with the differences in the protein level. We conclude that Na,K-ATPase mRNA expression and enzyme activity are significantly decreased in the hearts of Bio 14.6 hamsters even before the onset of hypertrophy and cardiomyopathy, suggesting that the altered expression of Na,K-ATPase gene is an early event in the pathogenesis of cardiomyopathy in this animal model.


Interactome of Obesity: Obesidome : Genetic Obesity, Stress Induced Obesity, Pathogenic Obesity Interaction.
Obesity is a chronic disease of increasing prevalence reaching epidemic proportions. Genetic defects as well as epigenetic effects contribute to the obesity phenotype. Investigating gene (e.g. MC4R defects)-environment (behavior, infectious agents, stress) interactions is a relative new field of great research interest. In this study, we have made an effort to create an interactome (henceforth referred to as "obesidome"), where extrinsic stressors response, intrinsic predisposition, immunity response to inflammation and autonomous nervous system implications are integrated. These pathways are presented in one interactome network for the first time. In our study, obesity-related genes/gene products were found to form a complex interactions network.


Postural Control Deficits in Autism Spectrum Disorder: The Role of Sensory Integration.
We investigated the nature of sensory integration deficits in postural control of young adults with ASD. Postural control was assessed in a fixed environment, and in three environments in which sensory information about body sway from visual, proprioceptive or both channels was inaccurate. Furthermore, two levels of inaccurate information were used within each channel (gain 1 and 1.6). ASD participants showed greater postural sway when information from both channels was inaccurate. In addition, control participants' ellipse area at gain 1.6 was identical to ASD participants' at gain 1, reflecting hyper-reactivity in ASD. Our results provide evidence for hyper-reactivity in posture-related sensory information, which reflects a general, rather than channel-specific sensory integration impairment in ASD.


Carbonic anhydrase gating of attention: memory therapy and enhancement.
Enhancement of memory acquisition and recall represents an important pharmacological goal in the treatment of cognitive disorders. In addition to its involvement in pH regulation, HCO3- reabsorption and CO2 expiration, carbonic anhydrase plays a crucial role in signal processing, long-term synaptic transformation and attentional gating of memory storage. Carbonic anhydrase dysfunction impairs cognition and is associated with mental retardation, Alzheimer's disease and aging. The pharmacological profile of carbonic anhydrase has been refined and specific activators have been developed. In this article, an integrated view of the involvement of carbonic anhydrase activity in synaptic plasticity and cognition will be presented, with particular focus on attentional gating of spatial learning and memory.


Improved radioimmunolocalization of carcinomas using Fab fragments with anti-CEA specificity.
A model system with human colonic grafts containing carcinoembryonic antigen (CEA) in nude mice was used to improve specificity and sensitivity of the radioimmunolocalization method. Monoclonal antibody MAb I-38S1 and monkey anti-CEA appeared to have high in vitro and in vivo specificity. Fab fragments of MAb I-38S1 improved localization ratios. A reduced time for optimal immunolocalization was obtained with Fab compared with MAb of the same specificity. Combinations of Fab:s, vasoactive compounds or anti-IgG treatment to reduce background levels did not further improve speed of localization or sensitivity.


Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.
Although hepatocellular carcinoma (HCC) primarily arises in the background of liver cirrhosis, the development of HCC in nonalcoholic fatty liver disease (NAFLD) without cirrhosis is increasingly recognized. The pathogenesis of NAFLD associated non-cirrhotic HCC is distinct from that of cirrhotic HCC because the metabolic syndrome (MS) along with obesity and insulin resistance (IR) underlie several unique mechanisms that promote tumorigenesis. IR associated with MS, NAFLD, and type 2 diabetes mellitus lead to the release of multiple pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, leptin and resistin, as well as decreased amounts of adiponectin. These processes favor the development of hepatic steatosis and inflammation within the liver, which precede HCC development. Nevertheless, further investigation is necessary to elucidate the determinants for development of HCC in patients with NAFLD in the absence of cirrhosis.


β2-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia.
β2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β2-adrenoceptor, induced Cl- secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood. We investigated β2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of β-arrestin2 was examined using siRNA knockdown. Isoprenaline and formoterol (both β2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (β2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of β-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used. Our results suggest that activation of the β2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that β2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.


Charge Density Overcomes Steric Hindrance of Ferrocene Surfactant in Switchable Oil-in-Dispersion Emulsions.
A ferrocene surfactant can be switched between single and double head form (FcN+ C12 /Fc+ N+ C12 ) triggered by redox reaction. FcN+ C12 can neither stabilize an O/W emulsion alone nor an oil-in-dispersion emulsion in combination with alumina nanoparticles due to the steric hindrance of the ferrocene group. However, such steric hindrance can be overcome by increasing the charge density in Fc+ N+ C12 , so that oil-in-dispersion emulsions can be co-stabilized by Fc+ N+ C12 and alumina nanoparticles at very low concentrations (1×10-7 M (≈50 ppb) and 0.001 wt %, respectively). Not only can reversible formation/destabilization of oil-in-dispersion emulsions be achieved by redox reaction, but also reversible transformation between oil-in-dispersion emulsions and Pickering emulsions can be obtained through reversing the charge of alumina particles by adjusting the pH. The results provide a new protocol for the design of surfactants for stabilization of smart oil-in-dispersion emulsions.


Haemopoietic growth factors: their role in cell development and their clinical use.
Mature blood cells are derived from haemopoietic stem cells which grow and proliferate to give rise to progenitor cells more restricted in their proliferation and differentiation capacity. These in turn give rise to cells belonging to any of the haemopoietic lineages. The haemopoietic growth factors interleukin 3, granulocyte-macrophage colony-stimulating factor, granulocyte colony stimulating factor, macrophage colony-stimulating factor and erythropoietin act on haemopoietic cells to promote cell survival, proliferation, differentiation and maturation, as well as many functions of the mature cells. These factors, now purified to homogeneity and molecularly cloned have recently become available. This has facilitated studies of their roles in cell production, and the range of target cells sensitive to them in vitro and in vivo in several species. The latter experimental data led to the first clinical trials where these factors have been used successfully in several clinical settings: erythropoietin to correct the anaemia of renal disease; granulocyte and granulocyte-macrophage colony-stimulating factors to accelerate haemopoietic regeneration after chemotherapy and bone marrow transplantation, and in other situations where increase in the numbers of white cells and stimulation of their function were required. The results to date allow optimism; the clinical use of growth factors not only in haematology and oncology, but in wider fields of medicine may well constitute a major breakthrough in the near future.


The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis.
The mechanism by which sulindac causes regression of adenomas in patients with familial adenomatous polyposis (FAP) is unclear. Conflicting data on the drug's effects on colorectal epithelial proliferation have been reported. An alternative mechanism, and one not previously studied, is via induction of colorectal epithelial cell apoptosis (programmed cell death). This hypothesis was tested by studying the effects of sulindac on colorectal epithelial proliferation and apoptosis in patients with FAP. Cell proliferation was studied via immunohistochemistry for cell nuclear antigen in a group of 22 patients randomized to either sulindac (150 mg twice a day) or placebo in a previously published trial. The rectal epithelium from 7 additional patients with FAP treated with sulindac was examined by flow cytometry to assess changes in cell-cycle distribution and apoptosis. Although sulindac caused a significant decrease in polyp size and number, there was no significant change in cytokinetic variables or cell cycle distribution 3 months after treatment. However, the subdiploid apoptotic fraction was increased significantly 3 months after treatment with sulindac (31.3% +/- 4.8% compared with 10% +/- 4.3% at baseline; P = 0.01). Our findings suggest that sulindac does not affect colorectal epithelial proliferation and that its effects in patients with FAP may instead result from induction of apoptosis.


Pulmonary function and clinical course in patients with cystic fibrosis after pulmonary colonization with Pseudomonas aeruginosa.
To evaluate the relationship between Pseudomonas aeruginosa colonization and the development of lung disease, we studied 895 patients who attended our cystic fibrosis clinic between 1975 and 1988. The prevalence of P. aeruginosa colonization was 82%. Patients who acquired P. aeruginosa in the first year of life had a similar 10-year survival rate (85%) to that in patients who were colonized between the ages of 1 and 7 years (87%), and to that in patients colonized after the age of 7 years (78%). One year before colonization, mean age, forced expiratory volume in 1 second (FEV1), forced vital capacity, and forced expiratory flow in the mid-expiratory phase were similar to those in a group of patients who remained free of P. aeruginosa. No significant change in pulmonary function variables could be demonstrated 1 year and 2 years after the colonization. The rate and duration of hospitalization did not increase in the years after P. aeruginosa colonization compared with the years before colonization. By the age of 7 years, the mean percentage of predicted FEV1 was lower by 10% in patients who were already colonized by P. aeruginosa compared with those who were not colonized (p less than 0.01). A similar reduction in FEV1 was observed at all ages from 7 to 35 years, but no precipitate rate of decline in FEV1 could be associated with P. aeruginosa colonization. We conclude that although P. aeruginosa colonization is associated with 10% lower lung function, it does not cause an immediate and rapid reduction, as has been previously reported. The clinical course and the pulmonary deterioration in cystic fibrosis after P. aeruginosa colonization is a gradual and variable process.


Retrospective analysis of the cholesterol levels in a European mid-latitude population between 2007 and 2018: controversies and therapeutic implications.
Coronary heart disease is the leading cause of morbidity and mortality in developed countries and its association with LDL-cholesterol has been well established. During the last decades statin therapy, and an healthy lifestyle, has proven highly effective in reducing cardiovascular event rates. Yet, there is still controversy among national guidelines and clinical practice with regard to LDL-cholesterol measurements. The aim of this study was to verify whether significant changes in cholesterol levels were observed over a relatively long (12 years) period. We also compared the Friedewald-calculated with directly-measured LDL cholesterol in order to verify whether the two methods were equivalent. We retrospectively analyzed 288000 data (total cholesterol, HDL, LDL both directly-measured and Friedewald-calculated, and triglycerides), from 57600 individuals, collected at the San Raffaele Hospital in Milan between 2007 and 2018. Data were statistically analyzed using a linear regression over the 12 years long period of time. We observed a general decreasing trend in total cholesterol (and an increasing trend in HDL) and a decrease in triglycerides only in the male group. Directly-measured LDL did not correlate well with calculated LDL. The total cholesterol decrease and the corresponding increment in HDL was attributed to either an increased use of statin and/or an improvement of the general population dietary habits. The latter was further confirmed by the decrease in triglycerides observed in the male group. Based on our data, an alternative method for assessing atherogenics lipoproteins level has been proposed.


Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening.
Cortical neurons of the superficial layers (II-IV) represent a pivotal neuronal population involved in the higher cognitive functions of the human and are particularly affected by psychiatric diseases with developmental manifestations such as schizophrenia and autism. Differentiation protocols of human pluripotent stem cells (PSC) into cortical neurons have been achieved, opening the way to in vitro modeling of neuropsychiatric diseases. However, these protocols commonly result in the asynchronous production of neurons typical for the different layers of the cortex within an extended period of culture, thus precluding the analysis of specific subtypes of neurons in a standardized manner. Addressing this issue, we have successfully captured a stable population of self-renewing late cortical progenitors (LCPs) that synchronously and massively differentiate into glutamatergic cortical neurons of the upper layers. The short time course of differentiation into neurons of these progenitors has made them amenable to high-throughput assays. This has allowed us to analyze the capability of LCPs at differentiating into post mitotic neurons as well as extending and branching neurites in response to a collection of selected bioactive molecules. LCPs and cortical neurons of the upper layers were successfully produced from patient-derived-induced PSC, indicating that this system enables functional studies of individual-specific cortical neurons ex vivo for disease modeling and therapeutic purposes.


Changes in brain microstructure during infancy and childhood using clinical feasible ADC-maps.
The purpose of this study was to examine age-related changes in apparent diffusion coefficient (ADC) during infancy and childhood using routine MRI data. A total of 112 investigations of patients aged 0 to 17.2 years showing a normal degree of myelination and no signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations at 1.5T. ADC maps based on our routinely included axial diffusion weighted sequence were created from the scanner. ADC values were measured in 35 different brain regions investigating normal age-related changes during the maturation of the human brain in infancy and childhood using clinical feasible sequences at 1.5T. The relationship between ADC values and age in infancy and childhood can be described as an exponential function. With increasing age, the ADC values decrease significantly in all brain regions, especially during the first 2 years of life. Except in the peritrigonal white matter, no significant differences were found between both hemispheres. Between 0 and 2 years of life, no significant gender differences were detected. Using ADC maps based on a routinely performed axial diffusion weighted sequence, it was possible first to describe the relationship between ADC values and age in infancy and childhood as exponential function in the whole brain and second to determine normative age-related ADC values in multiple brain regions.


Gene expression profiling in chemoresistant variants of three cell lines of different origin.
Drug resistance is a major problem in clinical cancer chemotherapy. Several mechanisms of resistance have been identified, but the underlying genomic changes are still poorly understood. Gene expression profiling, using cDNA microarray, was performed in eight cell lines (K562 leukemia, MCF-7 breast cancer and S1 colon cancer) with acquired resistance against five cytostatic drugs; daunorubicin (DNR), doxorubicin (DOX), vincristine (VCR), etoposide (VP) and mitoxantrone (MX). The resistant cell lines clustered together based on their type of origin. Several genes encoding ABC transporters were highly up-regulated, most notably ABCB1 (MDR1) and ABCB4 in several cell lines and ABCG2 (MXR) specifically in MX-resistant cell lines. A pronounced down-regulation of several histones was noted in the MCF-7-derived resistant sublines. Altered expression was also seen in, e.g., GSTs, topoisomerases, caveolins, annexins and CD44. These results will constitute a platform for further studies on specific pathways and biological processes involved in chemotherapy resistance.


Evidence that the insulin resistance of pregnancy may not involve a post-receptor defect in human adipocytes.
Insulin binding and the capacity of insulin to stimulate the conversion of glucose to carbon dioxide and lipid, and to activate the protein tyrosine kinase associated with the insulin receptor have been investigated in adipocytes isolated from pregnant and non-pregnant women. Insulin binding and the conversion of glucose to lipid were the same for both groups. However, conversion of glucose to CO2 was higher in the non-pregnant group due to an elevated basal activity, and the increase produced by insulin was similar in both groups. The tyrosine kinase activity of the isolated receptor preparations was higher in the pregnant group due to an increase in the basal non-insulin dependent activity, and the increase produced by insulin was similar in both groups. These findings show the in vitro insulin responsiveness of isolated adipocytes is similar for both groups, and suggests that the in vivo insulin resistance of late pregnancy, as far as adipose tissue is concerned, is not due to any inherent defect in insulin action at the receptor or post-receptor level. In vivo insulin resistance may result from an increased level of circulating insulin antagonists.


[On the surface-anesthetic activity of some ether alcohols (author's transl)].
An account of the preparation and surface anesthetic potency of 12 ether alcohols of the type X-O-Y-OH is given in this paper. The anaesthetic intensity and effective duration of a chloronaphthalene derivative of this type lie within the range of action of cocain.


A series of patients with subpial hemorrhage: clinical manifestation, neuroradiological presentation and therapeutic implications.
Subpial hemorrhage is a rare finding in patients with a variable spectrum of neurological symptoms and signs. Here we present a series of 10 patients with subpial hemorrhage, 53 to 80 years old, diagnosed and treated within the last 4 years at a single center. Patients were identified based on imaging criteria with either magnetic resonance imaging (MRI) or computed tomography (CT) showing blood along the cortical surface. Presenting symptoms were diverse, with seizures being the most frequent followed by headaches and focal neurological signs such as sensory or motor deficits. Of 7 patients undergoing lumbar puncture, none showed fresh blood or cerebrospinal fluid (CSF) xanthochromia. Neither digital subtraction angiography (DSA) nor MR venography (MRV) confirmed cerebral vein thrombosis as a possible etiologic factor for subpial hemorrhage. Patients for whom follow-up was available (n=8), showed complete recovery indicating an excellent prognosis. Overall, the etiology of subpial hemorrhage remains obscure. Treatment should be symptomatic with particular attention to antiepileptic medication.


Methionine sulfoxide reductases and methionine sulfoxide in the subterranean mole rat (Spalax): characterization of expression under various oxygen conditions.
The blind subterranean mole rat (Spalax ehrenbergi) exhibits a relatively long life span, which is attributed to an efficient antioxidant defense affording protection against accumulation of oxidative modifications of proteins. Methionine residues can be oxidized to methionine sulfoxide (MetO) and then enzymatically reduced by the methionine sulfoxide reductase (Msr) system. In the current study we have isolated the cDNA sequences of the Spalax Msr genes as well as 23 additional selenoproteins and monitored the activities of Msr enzymes in liver and brain of rat (Rattus norvegicus), Spalax galili, and Spalax judaei under normoxia, hypoxia, and hyperoxia. Under normoxia, the Msr activity was lower in S. galili in comparison to S. judaei and R. norvegicus especially in the brain. The pattern of Msr activity of the three species was similar throughout the tested conditions. However, exposure of the animals to hypoxia caused a significant enhancement of Msr activity, especially in S. galili. Hyperoxic exposure showed a highly significant induction of Msr activity compared with normoxic conditions for R. norvegicus and S. galili brain. It was concluded that among all species examined, S. galili appears to be more responsive to oxygen tension changes and that the Msr system is upregulated mainly by severe hypoxia.


Molecular evolution of haemagglutinin (H) gene in measles virus.
We studied the molecular evolution of the haemagglutinin (H) gene (full length) in all genotypes (24 genotypes, 297 strains) of measles virus (MeV). The gene's evolutionary timescale was estimated by the Bayesian Markov chain Monte Carlo (MCMC) method. We also analysed positive selection sites. The MCMC tree indicated that the MeV H gene diverged from the rinderpest virus (same genus) about 250 years ago and that 24 MeV genotypes formed 3 lineages dating back to a 1915 ancestor (95% highest posterior density [HPD] 1882-1941) with relatively rapid evolution (mean rate: 9.02 × 10(-4) substitutions/site/year). The 3 lineages diverged in 1915 (lineage 1, 95% HPD 1882-1941), 1954 (lineage 2, 95% HPD 1937-1969), and 1940 (lineage 3, 95% HPD 1927-1952). These 24 genotypes may have diverged and emerged between the 1940s and 1990 s. Selective pressure analysis identified many negative selection sites on the H protein but only a few positive selection sites, suggesting strongly operated structural and/or functional constraint of changes on the H protein. Based on the molecular evolution of H gene, an ancestor MeV of the 24 genotypes emerged about 100 years ago and the structure of H protein has been well conserved.


Hypermutation in shark immunoglobulin light chain genes results in contiguous substitutions.
Among 631 substitutions present in 90 nurse shark immunoglobulin light chain somatic mutants, 338 constitute 2-4 bp stretches of adjacent changes. An absence of mutations in perinatal sequences and the bias for one mutating V gene in adults suggest that the diversification is antigen dependent. The substitutions shared no patterns, and the absence of donor sequences, including from family members, supports the idea that most changes arose from nontemplated mutation. The tandem mutations as a group are distinguished by consistently fewer transition changes and an A bias. We suggest this is one of several pathways of hypermutation diversifying shark antigen-receptor genes--point mutations, tandem mutations, and mutations with a G-C preference--that coevolved with or preceded gene rearrangement.


Gunshot residues found at the exit wound: a case report.
Gunshot residues (GSRs) play an important role in forensic investigations of gun-related violence. The presence of GSRs has been described to help to identify the bullet entry area, as it was supposed not to be found at exit wounds. This report details the suicidal headshot of an 84-year-old male where unburned tube-like, cuboid and flake-formed powder particles have been found not only at the inside of the muzzle but also circular around the exit wound. With very short-barrelled weapons, it must be expected that part of the propellant charge leaves the barrel unburned behind the bullet. In contrast to that, the barrel length of the used weapon should lead to a complete burn-up of powder particles. The surprisingly large number of unburned powder particles present at the exit wound of the injury gave reason for further investigation to understand the underlying ballistic aspects and outlines the importance of having a close look at incidence scene photos during an investigation.


Release of 5-hydroxytryptamine by pentagastrin and its role in the 'fade' of stimulated gastric secretion in cats.
1. The release of 5-hydroxytryptamine (5-HT) by pentagastrin and the 'fade' phenomenon seen in acid gastric secretion during a continuous intravenous infusion of pentagastrin have been studied in anaesthetized cats. 2. During an intravenous infusion of pentagastrin, acid secretion rose steeply to a maximum at 45 min. It was maintained at this rate for only 15-30 min, after which it decreased gradually. Meanwhile there was a marked increase in the 5-HT content of the plasma which reached a peak at 120 min and remained just below the peak concentration for the rest of the experiment. 3. Acid secretion due to an intravenous infusion of histamine on the other hand, steadily increased over the 3 h collection period. Meanwhile there was only a gradual small increase in the 5-HT content of the plasma. 4. Whereas there was a continuous steady increase in acid secretion in response to an intravenous infusion of pentagastrin in cats pre-treated with reserpine, acid secretion rose to a sharp peak and then decreased gradually when reserpinized cats were given a simultaneous infusion of 5-HT along with the pentagastrin. 5. It is concluded that 5-HT is released by pentagastrin and that it is responsible for the 'fade' phenomenon seen in acid secretion during infusions of pentagastrin, first of all augmenting acid secretion and then inhibiting it.


Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells.
The malignant phenotype of prostatic tumor cells correlates with the expression of both uPA and its cell-membrane receptor (uPAR); however, there is little information concerning the role of cell-bound uPA in matrix degradation and invasion. Our results suggest that cell-associated uPA plays a key role in regulating the amount of plasmin present at the surface of prostatic carcinoma (PRCA) cells and show that differential production of uPA corresponds with the capacity to bind and activate plasminogen. In addition, we provide direct evidence that both uPA secretion and the presence of uPA-uPAR complexes characterize the invasive phenotype of PRCA cells and suggest the existence of several pathways by which tumor cells acquire plasmin activity. LNCaP cells (which do not produce uPA but express uPAR) may activate plasmin through exogenous uPA. In vivo, the source of uPA may be infiltrating macrophages and/or fibroblasts as observed in several other systems. PAI-1 accumulation in the conditioned medium (CM) limits plasmin action to the pericellular microenvironment. Our results indicate that MMP-9 and MMP-2 are also activated by plasmin generated by cell-bound but not by soluble, extracellular uPA. Plasmin activation and triggering of the proteolytic cascade involved in Matrigel invasion is blocked by antibodies against uPA (especially by anti- A-chain of uPA which interacts with uPAR) and by PA inhibitors such as p-aminobenzamidine which may regulate levels of cell-bound uPA. uPA may also regulate growth in PRCA cells. Indeed, antibodies against uPA A-chain (and also p-aminobenzamidine treatment) interfere with the ATF domain and inhibit cell growth in uPA-producing PC3 and DU145 prostate cancer cell lines, whereas exogenous uPA (HMW-uPA with ATF) induces growth of LNCaP prostate tumor cell line. These data support the hypothesis that in prostatic cancer patients at risk of progression, uPA/plasmin blockade may be of therapeutic value by blocking both growth of the primary tumor and dissemination of metastatic cells.


Burnout among staff on specialized eating disorder units in Norway.
Burnout is commonly associated with low workplace wellbeing. Patients with eating disorders are frequently referred to as a particularly challenging group to treat. It is therefore important to study healthcare providers´ workplace wellbeing in settings which treat eating disorders. The aims of the current study were to (a) measure burnout among healthcare providers working on specialized eating disorder units in Norway, and (b) explore factors predicting burnout. 186 participants from 11 specialized eating disorder units in Norway completed an online survey including the Mashlach Burnout Inventory, and eating disorder-specific factors related to burnout, job satisfaction, work environment, emotional dissonance and stress. Multiple regression analysis was used to identify predictors of burnout. Overall, low levels of burnout were found among the participants. Eating disorder-specific factors and emotional dissonance predicted the three central aspects of burnout, namely, emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. Findings suggest a relatively low level of burnout across age, gender, and professional categories working at specialized eating disorder units, contrary to commonly-held assumptions pertaining to the challenges involved in treating individuals with eating disorders.


Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients.
Conjunctival and Tenon's capsule biopsies from two patient groups were quantitatively analyzed by light microscopy. Group A consisted of 20 patients with a primary glaucoma for whom surgery was a planned primary treatment modality. Group B was comprised of 20 patients with a primary glaucoma who had received at least two types of antiglaucoma topical medication, for a minimum of 1 year (mean, 7.7 years) before surgery. All slides were examined by two masked observers. A significant increase in the number of macrophages, lymphocytes, mast cells, and fibroblasts in the conjunctiva and Tenon's capsule and a significant decrease in the number of epithelial goblet cells were seen in the group that received long-term drop therapy. These results suggest that exhaustive medical therapy, before surgery is offered, increases the number of tissue inflammatory cells. It is possible this may enhance the risk of external bleb scarring and filtration surgery failure.


The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network.
The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP) (#NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. One hundred twenty-seven patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60 years, elevated LDH and low serum albumin were independent prognostic factors. The model identified 3 groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-year OS of 78% (95% confidence interval [95% CI], 29-127), 46% (95% CI, 24-68), and 25% (95% CI, 20-30), respectively (P < 0.001) and 5-year PFS of 66% (95% CI, 33-99), 37% (95% CI, 9-65), and 17% (95% CI, 9-25), respectively (P < 0.001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the 3 groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T-Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.


Interfacing transition metal dichalcogenides with chromium germanium telluride quantum dots for controllable light-matter interactions.
In this work, we unravel a facile solution-based method to prepare chromium germanium telluride, Cr2Ge2Te6 (CGT) quantum dots (QDs), which present strong light-matter interactions with monolayer transition metal dichalcogenides (TMDs) in their CGT/TMD vertical heterostructures. The heterostructures' optoelectronic properties were controlled by simply varying the QDs thickness. We observed contrasting emissions from monolayer TMDs in the various CGT QDs-TMDs (of WS2, WSe2 and MoS2) heterostructures depending on the density of QDs in the heterostructures. Low-density CGT QDs-based heterostructures demonstrated a reduced light emission intensity compared to the isolated monolayers, but with an increased trion ratio due to the electron doping effect of CGT QDs. In contrast, high-density CGT QDs-based heterostructures showed an increased light emission intensity and a broadened, red-shifted emission peak in comparison to the bare TMDs, attributed to the enhanced optical absorption in the heterostructures arising from the assembled CGT QDs. Finally, proof-of-concept field-effect transistor (FET) and photodetector devices based on the created CGT QDs-WS2 heterostructures were designed, which showed an enhanced optoelectronic performance.


An ecological perspective on water shedding from leaves.
Water shedding from leaves is a complex process depending on multiple leaf traits interacting with rain, wind, and air humidity, and with the entire plant and surrounding vegetation. Here, we synthesize current knowledge of the physics of water shedding with implications for plant physiology and ecology. We argue that the drop retention angle is a more meaningful parameter to characterize the water-shedding capacity of leaves than the commonly measured static contact angle. The understanding of the mechanics of water shedding is largely derived from laboratory experiments on artificial rather than natural surfaces, often on individual aspects such as surface wettability or drop impacts. In contrast, field studies attempting to identify the adaptive value of leaf traits linked to water shedding are largely correlative in nature, with inconclusive results. We make a strong case for taking the hypothesis-driven experimental approach of biomechanical laboratory studies into a real-world field setting to gain a comprehensive understanding of leaf water shedding in a whole-plant ecological and evolutionary context.


Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase.
Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of tetrapyrroles (such as heme and chlorophyll). Although the predominant oligomeric form of this enzyme, as inferred from many crystal structures, is that of a homo-octamer, a rare human PBGS allele, F12L, reveals the presence of a hexameric form. Rearrangement of an N-terminal arm is responsible for this oligomeric switch, which results in profound changes in kinetic behavior. The structural transition between octamer and hexamer must proceed through an unparalleled equilibrium containing two different dimer structures. The allosteric magnesium, present in most PBGS, has a binding site in the octamer but not in the hexamer. The unprecedented structural rearrangement reported here relates to the allosteric regulation of PBGS and suggests that alternative PBGS oligomers may function in a magnesium-dependent regulation of tetrapyrrole biosynthesis in plants and some bacteria.


Efficacy of rectal progesterone on maternal and neonatal outcomes in pregnant women with Preterm Premature Rupture of membranes: a triple-blind randomised clinical trial.
This study was conducted to evaluate the efficacy of rectal progesterone suppositories on pregnancy outcomes of pregnant women diagnosed with PPROM at the gestational age of 26-34 weeks, as well as on maternal and neonatal outcomes. This is a double-blind, randomized clinical trial in pregnant women with PROM with gestational age of 26-24 weeks, conducted between February 2020 and December 2020 in Sayyad Shirazi Hospital, Gorgan, Iran. According to the results of the present study; Rectal progesterone suppository in pregnant women with PPROM is associated with improved delivery outcomes such as neonatal APGAR score, increased latent delivery stage without complications or severe and dangerous complications, without increased risk of mortality and NICU hospitalization in infants, so prescribing suppository rectal progesterone in pregnant women with PPROM with a gestational age of 26 to 34 weeks is associated with positive outcomes and is recommended based on the findings and opinions of the researchers. According to the results of the present study; Rectal progesterone suppository in pregnant women with PPROM is associated with improved delivery outcomes such as neonatal APGAR score, increased latent delivery stage without complications or severe and dangerous complications, without increased risk of mortality and NICU hospitalization in infants, so prescribing suppository rectal progesterone in pregnant women with PPROM with a gestational age of 26 to 34 weeks is associated with positive outcomes and is recommended based on the findings and opinions of the researchers.


Evaluation of relative role of LH and FSH in restoration of spermatogenesis using ethanedimethylsulphonate-treated adult rats.
Spermatogenesis is a complex process, and previous studies have clearly established the role for testosterone in its maintenance. However, the role of FSH remains controversial, although several lines of evidence suggest its importance in initiation of spermatogenesis. In the present study, the relative roles of FSH and LH have been evaluated using specific antisera capable of neutralizing endogenous hormones in adult male rats following ethanedimethylsulphonate (EDS) treatment. Restoration of spermatogenesis in EDS-treated rats was monitored following FSH or LH deprivation by histological analysis and flow cytometry. Deprivation of FSH resulted in a reduction of seminiferous tubule diameter and spermatogonial number, which was much more drastic than that observed following LH deprivation. More importantly, FSH deprivation was associated with a significant reduction in the number of pachytene spermatocytes. These results provide evidence for a definite role for FSH in regulation of spermatogenesis, in addition to confirming the role of LH in spermatogenesis via testosterone.


Antistatic treatment and salbutamol dosing have variable effect on drug delivery of valved holding chambers.
Our aim was to evaluate whether the number of puffs or antistatic treatment have significant effect on drug delivery of six different valved holding chambers (VHCs). We used simulated paediatric breathing pattern with 25/min frequency and 200 ml tidal volume. When comparing the effect of antistatic treatment, we used 100 μg of salbutamol (one puff Ventolin Evohaler 100 μg/dos) actuated into each VHC before and after detergent wash. When comparing the effect of one or two puffs (100 vs. 200 μg), all VHCs were washed prior to the measurements. All VHC were significantly affected by antistatic treatment. Washing improved drug delivery of four VHCs (1.3-2.2 fold increase in median filter dose) but had an opposite effect in two devices (54-61% decrease). The effect of dose doubling resulted in a 2.03-2.93 fold increase on filter dose in two VHCs. Four out of the six VHC showed significantly poorer performance with two puffs as opposed to one puff (ratio of two puffs to one puff varied between 1.19 and 1.77). VHCs marketed as antistatic are significantly affected by antistatic treatment. To ensure optimal drug delivery, salbutamol should be actuated to VHCs one puff at a time. Each VHC brand has its unique characteristic that affects drug delivery in a way that cannot be generalised to another VHC. There is a need for universal standardisation of VHCs. Valved holding chambers (VHCs) that are marketed as antistatic are significantly affected by antistatic treatment. Multiple actuations before inhalation tend to decrease the drug delivery efficacy of VHCs. Each VHC brand has its unique characteristic that affects drug delivery in a way that cannot be generalised to another VHC. There is a need for comprehensive and financially independent testing and standardisation of VHCs.


Morphology, crystallization and rheological behavior in poly(butylene succinate)/cellulose nanocrystal nanocomposites fabricated by solution coagulation.
Nanocomposites consisting of poly(butylene succinate) (PBS) and cellulose nanocrystals (CNC) were fabricated by solution coagulation method. Morphology analysis indicated that CNC dispersed well in PBS matrix and rheological analysis suggested that PBS and CNC showed strong interactions. Thermal analysis indicated that the nanocomposites showed slightly increased glass transition temperature, significantly enhanced crystallization temperature and different melting behavior, compared to neat PBS. Study on crystallization indicated that small loading of CNC could significantly increase overall crystallization rate of PBS, meanwhile the crystallization mechanism and crystal structure remained unchanged. The significant enhancement in overall crystallization was attributed to the increased nucleation ability by incorporation of well dispersed CNC nanoparticles. Tensile testing indicated that the tensile strength and modulus were gradually improved with increasing CNC content, while the elongation at break decreased and even brittle fracture occurred when the content of CNC increased to 1.0wt%.


Aquaporin 7 involved in GINSENOSIDE-RB1-mediated anti-obesity via peroxisome proliferator-activated receptor gamma pathway.
Obesity, characterized by the excessive accumulation of triglycerides in adipocytes and their decreased excretion from adipocytes, is closely related to various health problems. Ginsenoside Rb1 (Rb1), the most active component of the traditional Chinese medicine ginseng, has been reported to have positive effects on lipid metabolism. The aim of the present study was to determine the protective effects of Rb1 on glycolipid metabolism under obesity conditions and its mechanisms and to reveal the signaling pathways involved. In our study, male C57BL/6 mice with obesity induced by a high-fat diet (HFD) and mature 3 T3-L1 adipocytes were used to investigate the role of Rb1 in lipid accumulation and explore its possible molecular mechanism in vivo and in vitro, respectively. Rb1 reduced the body weight, fat mass, adipocytes size and serum free fatty acid (FFA) concentration of obese mice. In differentiated 3 T3-L1 adipocytes, Rb1 reduced the accumulation of lipid droplets and stimulated output of triglycerides. Additionally, the expression of peroxisome proliferator-activated receptor gamma (PPARγ), phosphorylated PPARγ (Ser112) and aquaporin 7 (AQP7) was upregulated in adipocytes and adipose tissues upon Rb1 treatment. However, intervention of GW9662, PPARγ antagonist, attenuated Rb1-mediated effects on glycolipid metabolism and AQP7 levels. These data indicated that Rb1 reduced body weight and improved glycolipid metabolism by upregulating PPARγ and AQP7 protein levels. Our study indicated a potential role for Rb1 in the prevention and treatment of obesity.


Caloric content in plants dominating maquis ecosystems in Greece.
Caloric content for 15 evergreen sclerophyllous and 8 deciduous plants dominating maquis ecosystems are presented on dry and ash-free dry weight basis. Leaves of evergreen sclerophylls contain 4,667±61, bark 4,207±78 and wood 4,250±37 cal.g-1 d.w. On ash-free basis values are: 5,959±57, 4,560±71 and 4,325±32 cal.g-1 ash-free d.w., respectively. On deciduous plants results show that leaves, bark and wood contain 4,375±47, 4,128±151 and 4,278±59 cal.g-1 d.w. respectively. Values on ash-free dry weight are: 4,719±39, 4,529±124 and 4,371±67 cal.g-1 ash-free d.w.


The Armc10/SVH gene: genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation.
Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents Aβ-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against Aβ-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.


Continuous compared with intermittent epidural infusion on progress of labor and patient satisfaction.
To compare continuous with intermittent epidural infusion on the duration of labor and patients' satisfaction in nulliparous women. Nulliparous women who requested epidural analgesia during labor were randomly allocated to receive either a continuous infusion of 0.125% bupivacaine with 2 microg/mL fentanyl at a rate of 8 mL/h (group A) or intermittent bolus of 10 mL of 0.25% bupivacaine on demand (group B). Controls were nulliparous women who did not receive epidural analgesia (group C). Included were singleton term pregnancies with cervical dilatation between 2 cm and 5 cm. A comparison was made between the groups regarding the duration of the active phase and the second stage of labor and patients' satisfaction. Secondary outcomes investigated were the mode of delivery, analgesia-related complications, and intrapartum and postpartum complications. Cord pH and Apgar score measured neonatal outcome. Sixty-three parturients were randomly assigned to receive continuous infusion, and 64 received intermittent bolus infusion. Sixty-three patients served as controls. Mean duration of the active phase and the second stage of labor were not statistically different between groups A and B. Each technique produced comparable analgesia, achieving equivalent maternal satisfaction, with no apparent complications. The active phase of labor was prolonged by an average of 60 minutes and the 2nd stage by an average of 36 minutes regardless of the type of epidural compared with controls. The mode of delivery and maternal and neonatal outcome were not significantly different among the 3 groups. This study provides evidence that both continuous and intermittent epidural infusion produce comparable analgesia achieving equivalent maternal satisfaction with no difference regarding the duration of labor between them. Although patients receiving epidural analgesia experienced longer labors compared with controls, both mothers and neonates were unharmed.


Cancer in the respiratory organs of Swedish farmers.
In a cohort of 254,417 male Swedish farmers (4,330,717 person-years) the incidence of cancer of the respiratory organs was compared to a reference cohort of 1,725,845 men (30,131,664 person-years) employed in other economic activities than agriculture or forestry. In the study cohort 1450 cases of cancer in the respiratory organs were found in 1961 to 1979 resulting in an estimated relative risk (RR) of 0.38 (95% confidence interval [CI]: 0.36-0.40). For cancer of trachea, bronchus and lung, the decreased risk was equal for adenocarcinoma and squamous cell carcinoma. No time related trend in RR for any of the histologic subtypes could be seen. However, for squamous cell carcinoma in nose and nasal sinuses RR has increased from 0.42 (95% CI: 0.20-0.80) in 1961 to 1966 to 2.06 (95% CI: 1.22-3.50) in 1974 to 1979.


A Prospective Observational Study of Antibiotic Therapy in Febrile Neutropenia Patients with Hematological Malignances from Multiple centers in Northeast China.
Febrile neutropenia (FN) is a common but lethal complication of chemotherapy in hematological malignance. The aim of this study was to identify the prognostic risk factors for antibiotic treatment outcome in PN patients, and provide the optimal choice for the initial empirical antibiotic treatment. 227 consecutive FN hematologic malignancies from four hospitals in Northeast China were enrolled. The outcome of antibiotic therapy was investigated until 14 days after the onset of FN. The factors affecting antibiotic therapy outcome were evaluated using Univariate analysis and Multivariate logistic regression analysis. Among all patients, 27 patients did not achieve favorable outcome either clinically or bacteriologically. It was shown that the risk factors for poor FN therapy outcome were associated with prolonged duration of neutropenia over 9 days during FN (P=0.019), slow neutrophil recovery (P=0.039), respiratory infection (P=0.005), and that initial monotherapy with drugs recommended by the guidelines indicated better outcome (P=0.009). Additionally, patients with multi-bacterial infection, as well as further ANC decrease after fever, had a poor prognosis. Our results indicate that early application of antibiotics and prevention of respiratory infection as well as good clinical care are able to improve clinical outcomes from empirical antibiotic treatment in FN patients with hematological malignances.


Patients' perspectives on the use of artificial intelligence in dentistry: a regional survey.
The use of artificial intelligence (AI) in dentistry is rapidly evolving and could play a major role in a variety of dental fields. This study assessed patients' perceptions and expectations regarding AI use in dentistry. An 18-item questionnaire survey focused on demographics, expectancy, accountability, trust, interaction, advantages and disadvantages was responded to by 330 patients; 265 completed questionnaires were included in this study. Frequencies and differences between age groups were analysed using a two-sided chi-squared or Fisher's exact tests with Monte Carlo approximation. Patients' perceived top three disadvantages of AI use in dentistry were (1) the impact on workforce needs (37.7%), (2) new challenges on doctor-patient relationships (36.2%) and (3) increased dental care costs (31.7%). Major expected advantages were improved diagnostic confidence (60.8%), time reduction (48.3%) and more personalised and evidencebased disease management (43.0%). Most patients expected AI to be part of the dental workflow in 1-5 (42.3%) or 5-10 (46.8%) years. Older patients (> 35 years) expected higher AI performance standards than younger patients (18-35 years) (p < 0.05). Overall, patients showed a positive attitude towards AI in dentistry. Understanding patients' perceptions may allow professionals to shape AI-driven dentistry in the future.


Model systems for regeneration: Hydra.
The freshwater polyp Hydra provides a potent model system for investigating the conditions that promote wound healing, reactivation of a developmental process and, ultimately, regeneration of an amputated body part. Hydra polyps can also be dissociated to the single cell level and can regenerate a complete body axis from aggregates, behaving as natural organoids. In recent years, the ability to exploit Hydra has been expanded with the advent of new live-imaging approaches, genetic manipulations that include stable transgenesis, gene silencing and genome editing, and the accumulation of high-throughput omics data. In this Primer, we provide an overview of Hydra as a model system for studying regeneration, highlighting recent results that question the classical self-enhancement and long-range inhibition model supposed to drive Hydra regeneration. We underscore the need for integrative explanations incorporating biochemical as well as mechanical signalling.


Cerebrovascular disorders in childhood.
Cerebrovascular problems in childhood include diverse problems of vascular supply to the brain and occur with an overall frequency of from 5 to 8/100000 children/year. Signs and symptoms at manifestation are manifold. They depend not only on localization of the infarction but also on age at injury and specific risk factors. Acute arterial ischemic insult in neonates is oligosymptomatic (short-lasting seizures); hemiparesis is the most common symptom in children. Risk factors are multiple for both neonates and children, with more thromboembolic events in neonates and (infection-related) vasculopathies or cardiac problems in children. MRI (diffusion weighted) is the golden standard for diagnosis. In the absence of evidence for treatment in both groups, guidelines suggest use of platelet aggregation. There are some special indications for anticoagulation. Thrombolysis should be evaluated. Two-thirds of children and neonates face lifelong neurological and neuropsychological problems. Spinal artery ischemia presents with acute spinal symptoms, mostly paraplegia. Risk factors and prognosis are similar to cerebral insults. Sinus venous thromboses are significantly less common. Provoking factors in newborns are mainly neonatal problems, and in children infections, especially in the ENT region. For diagnosis the delta sign in CT is less sensitive than MR/MR venography. In the absence of any evidence, LMWH or heparinization for 3-6 months are recommended. Prognosis is better in children than in neonates. Deep vein thrombosis and/or young age worsen the outcome.


Incorporating 3-dimensional models in online articles.
The aims of this article are to introduce the capability to view and interact with 3-dimensional (3D) surface models in online publications, and to describe how to prepare surface models for such online 3D visualizations. Three-dimensional image analysis methods include image acquisition, construction of surface models, registration in a common coordinate system, visualization of overlays, and quantification of changes. Cone-beam computed tomography scans were acquired as volumetric images that can be visualized as 3D projected images or used to construct polygonal meshes or surfaces of specific anatomic structures of interest. The anatomic structures of interest in the scans can be labeled with color (3D volumetric label maps), and then the scans are registered in a common coordinate system using a target region as the reference. The registered 3D volumetric label maps can be saved in .obj, .ply, .stl, or .vtk file formats and used for overlays, quantification of differences in each of the 3 planes of space, or color-coded graphic displays of 3D surface distances. All registered 3D surface models in this study were saved in .vtk file format and loaded in the Elsevier 3D viewer. In this study, we describe possible ways to visualize the surface models constructed from cone-beam computed tomography images using 2D and 3D figures. The 3D surface models are available in the article's online version for viewing and downloading using the reader's software of choice. These 3D graphic displays are represented in the print version as 2D snapshots. Overlays and color-coded distance maps can be displayed using the reader's software of choice, allowing graphic assessment of the location and direction of changes or morphologic differences relative to the structure of reference. The interpretation of 3D overlays and quantitative color-coded maps requires basic knowledge of 3D image analysis. When submitting manuscripts, authors can now upload 3D models that will allow readers to interact with or download them. Such interaction with 3D models in online articles now will give readers and authors better understanding and visualization of the results.


Effects of chlorotrifluoroethylene oligomer fatty acids on recombinant GABA receptors expressed in Xenopus oocytes.
GABA-activated Cl- current was expressed in Xenopus oocytes after injecting cRNA that had been transcribed in vitro from complementary DNA (cDNA) coding for a single GABA rho i-subunit cloned from human retina. The expressed current was insensitive to 100 microM bicuculline, but was activated by the GABA analogue trans-4-aminocrontonic acid (TACA). Anion-selective permeability of the expressed rho 1-subunit was determined by isotonically replacing the extracellular Cl- with different anions. The anion permeability was very similar to the native GABAA receptor/channel following a sequence of SCN- > I- > NO3- > Br- > or = Cl-. Halogenated fatty acids, such as chlorotrifluoroethylene (CTFE) and perfluorinated oligomer acids inhibited the GABA-induced current in oocytes expressing the human retinal GABA rho 1-subunit or rat brain GABAA receptor alpha 1,beta 2,gamma 2 subunits. The inhibitory effect of halogenated fatty acids demonstrated a carbon chain length-dependent manner of: C10 > C8 > C6 > C4. Perfluorinated C8-oligomer acid (PFOA) was less effective at blocking this channel than the C8-CTFE oligomer acid. Radiolabeled GABA binding assay indicated that CTFE oligomer acids do not interfere at the GABA binding site of the receptor. Furthermore, the C8-CTFE oligomer fatty acid did not compete with picrotoxin for binding sites within the pore of the channel. These studies demonstrated that the heterologous expression system is useful for studying the molecular interaction between potential neurotoxic agents and neuroreceptors. Our results provide detailed information that should contribute to our understanding of the structure and function of retinal GABA receptors.


SSPred: A prediction server based on SVM for the identification and classification of proteins involved in bacterial secretion systems.
Protein secretion systems used by almost all bacteria are highly significant for the normal existence and interaction of bacteria with their host. The accumulation of genome sequence data in past few years has provided great insights into the distribution and function of these secretion systems. In this study, a support vector machine (SVM)- based method, SSPred was developed for the automated functional annotation of proteins involved in secretion systems further classifying them into five major sub-types (Type-I, Type-II, Type-III, Type-IV and Sec systems). The dataset used in this study for training and testing was obtained from KEGG and SwissProt database and was curated in order to avoid redundancy. To overcome the problem of imbalance in positive and negative dataset, an ensemble of SVM modules, each trained on a balanced subset of the training data were used. Firstly, protein sequence features like amino-acid composition (AAC), dipeptide composition (DPC) and physico-chemical composition (PCC) were used to develop the SVM-based modules that achieved an average accuracy of 84%, 85.17% and 82.59%, respectively. Secondly, a hybrid module (hybrid-I) integrating all the previously used features was developed that achieved an average accuracy of 86.12%. Another hybrid module (hybrid-II) developed using evolutionary information of a protein sequence extracted from position-specific scoring matrix and amino-acid composition achieved a maximum average accuracy of 89.73%. On unbiased evaluation using an independent data set, SSPred showed good prediction performance in identification and classification of secretion systems. SSPred is a freely available World Wide Web server at http//www.bioinformatics.org/sspred.


Effects of high temperature and nitrogen availability on the growth and composition of the marine diatom Chaetoceros pseudocurvisetus.
The assimilation of inorganic nutrients by phytoplankton strongly depends on environmental conditions such as the availability of nitrogen and temperature, especially warming. The acclimation or adaptation of different species to such changes remains poorly understood. Here, we used a multimethod approach to study the viability and physiological and biochemical responses of the marine diatom Chaetoceros pseudocurvisetus to different temperatures (15, 25, and 30 °C) and different N:P ratios. Nitrogen limitation had a greater effect than high temperature on cell growth and reproduction, leading to a marked elongation of setae, decreased phosphorus assimilation, increased lipid accumulation, and decreased protein synthesis. The elongation of setae observed under these conditions may serve to increase the surface area available for the uptake of inorganic and/or organic nitrogen. In contrast, high temperatures (30 °C) had a stronger effect than nitrogen deficiency on cell death, nitrogen assimilation, chlorophyll a accumulation, the cessation of setae formation, and cell lipid remodelling. Significant changes in thylakoid lipids were observed in cells maintained at 30 °C, with increased levels of digalactosyldiacylglycerol and sulfoquinovosyldiacylglycerol. These changes may be explained by the role of galactolipids in thylakoid membrane stabilization during heat stress.


Chiroptical generation and inversion during the mirror-symmetry-breaking aggregation of dialkylpolysilanes due to limonene chirality.
We observed the emergence and inversion of chiroptical handedness in three chiroptically silent dialkylpolysilanes during aggregation in limonene-methanol-THF tersolvents.


Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
The new category of heart failure (HF), HF with mid-range left ventricular ejection fraction (LVEF) (HFmrEF), has recently been proposed. However, the clinical features of HFmrEF, with reference to HF with preserved LVEF (HFpEF) and HF with reduced LVEF (HFrEF) in the same HF cohort, remain to be fully examined. In the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study, we examined 3480 consecutive HF patients with echocardiography data consisting of 2154 HFpEF (LVEF ≥50%), 596 HFmrEF (LVEF 40-49%) and 730 HFrEF (LVEF <40%). While clinical characteristics and prognostic factors of HFmrEF were intermediate between HFpEF and HFrEF, prognosis of HFmrEF resembled HFpEF and the prognostic impact of cardiovascular medications in HFmrEF resembled that of HFrEF. Analysis of LVEF transition among the three groups revealed that HFmrEF and HFrEF dynamically transitioned to other categories, especially within 1 year, whereas HFpEF did not; HFmrEF at registration transitioned to HFpEF and HFrEF by 44% and 16% at 1 year, and 45% and 21% at 3 years, respectively. Landmark analysis demonstrated that, regardless of HF stages at registration, HFmrEF patients at 1 year had mortality comparable to that of HFpEF patients, which was better than HFrEF patients, but HFmrEF patients at registration had increased mortality when transitioned to HFrEF at 1 year. These results indicate that clinical characteristics of HFmrEF are intermediate between HFpEF and HFrEF and that HFmrEF dynamically transitions to HFpEF or HFrEF, especially within 1 year, suggesting that HFmrEF represents a transitional status or an overlap zone between HFpEF and HFrEF, rather than an independent entity of HF.


In situ detection of reactive oxygen species and nitric oxide production in normal and pathological tissues: improvement by differential interference contrast.
Reactive oxygen species (ROS), among which nitric oxide (NO) is currently included, play a plethora of (patho)physiological roles. Harman's free radical theory of aging put forth over 40 years ago received full support since then. A nitric oxide hypothesis of aging recently proposed by McCann, is very likely to be the object of widespread investigation in the near future. Therefore, the possibility of localizing at the (sub)cellular level under the light microscope the sites of ROS and NO production with simple and reliable methods appears as a powerful tool for analytic cytology and pathology. Various histochemical methods were developed for visualizing ROS production; a recently improved version to localize superoxide (and possibly also singlet oxygen), based on a DAB-Mn2+ -Co2+ reaction, appears very promising. Since the direct detection of NO is still very difficult, the action sites of NO are currently localized by the identification of NO synthase (NOS). The most widespread method to reveal the catalytic activity of NOS is that of demonstrating the fixation-resistant NADPH diaphorase activity with the tetrazolium salt method. We have improved this method by using a tetrazolium salt whose formazan particles are very thin and lipid insoluble (tetranitroblue tetrazolium, TNBT) and by including a tissue protectant, polyvinyl alcohol, in the incubation medium. Here significant examples of application of the DAB-Mn2+ -Co2+ technique for ROS and the TNBT-PVA method for NOS to normal liver and brain and to solid tumors are presented. We further document the usefulness of Nomarkis's differential interference contrast (DIC) to analyze wide tissue areas where ROS production or NOS activity is low or even nil. The improved version for NOS allowed for the first time to demonstrate NOS activity in liver fat-storing cells and in astrocyte-like cells in the brain.


The Pharmacodynamics of Prolonged Infusion β-Lactams for the Treatment of Pseudomonas aeruginosa Infections: A Systematic Review.
Pseudomonas aeruginosa is a commonly isolated nosocomial pathogen for which treatment options are often limited for multidrug-resistant isolates. In addition to newer available antimicrobial agents active against P. aeruginosa, strategies such as extended (eg, prolonged or continuous) infusion have been suggested to optimize the pharmacokinetic and pharmacodynamic profiles of β-lactams. Literature regarding clinical outcomes for extended infusion β-lactams has been controversial; however, this use seems most beneficial in patients with severe illness. Prolonged infusion of β-lactams (eg, 3- to 4-hour infusion) can enhance the pharmacodynamic target attainment via increasing the amount of time throughout the dosing interval to which the free drug concentration remains above the MIC (minimum inhibitory concentration) of the organism (fT > MIC). This systematic review summarizes current literature related to the probability of target attainment (PTA) of various antipseudomonal β-lactam regimens administered as prolonged infusions in an effort to provide guidance in selecting optimal dosing regimens and infusion times for the treatment of P. aeruginosa infections. A literature search for all pertinent studies was performed by using the PubMed database (with no year limit) through March 31, 2019. Thirty-nine studies were included. Although many standard antipseudomonal β-lactam intermittent infusion regimens can provide adequate PTA against most susceptible isolates, prolonged infusion may enhance percent fT > MIC for organisms with higher MICs (eg, nonsusceptible) or patients with altered pharmacokinetic profiles (eg, obese, critically ill, those with febrile neutropenia). Prolonged infusion β-lactam regimens can enhance PTA against nonsusceptible P. aeruginosa isolates and may provide a potential therapeutic option for multidrug-resistant infections. Before implementing prolonged infusion antipseudomonal β-lactams, institutions should consider the half-life of the antibiotic, local incidence of P. aeruginosa infections, antibiotic MIC distributions or MICs isolated from individual patients, individual patient characteristics that may alter pharmacokinetic variables, and PTA (eg, critically ill), as well as implementation challenges.


Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer.
We tested cis-ApcΔ716/Smad4+/- and cis-ApcΔ716/Smad4+/-KrasG12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-ApcΔ716/Smad4+/-KrasG12D mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-ApcΔ716/Smad4+/- and cis-ApcΔ716/Smad4+/-KrasG12D mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.


KRAS-specific Amino Acid Substitutions are Associated With Different Responses to Chemotherapy in Advanced Non-small-cell Lung Cancer.
Emerging data highlight different clinical behaviors according to KRAS amino acid substitutions (AASs) in patients with non-small-cell lung cancer (NSCLC). We aimed to evaluate whether different KRAS AASs were associated with different responses to chemotherapy. We retrospectively reviewed data from 1190 patients with KRAS mutations who underwent first-line platinum-based chemotherapy for stage IV NSCLC. The response to different chemotherapy regimens was evaluated using the Response Evaluation Criteria In Solid Tumors criteria (v 1.1). Overall survival and time to progression (TTP) were secondary endpoints. Taxane was associated with the best response in the entire cohort (odds ratio, 2.52; 95% confidence interval [CI], 1.82-3.48; P < .001), especially in G12V patients (odds ratio, 2.15; 95% CI, 1.05-4.41; P = .036). Taxane was associated with improved TTP in the entire cohort (hazard ratio [HR], 0.31; 95% CI, 0.26-0.38; P < .001), especially in G13D patients (HR, 0.47; 95% CI, 0.22-1.01; P = .054). Pemetrexed was associated with the worst TTP in the entire cohort, particularly in G12V patients, who had the worst response rates (HR, 0.55; 95% CI, 0.30-0.99; P = .049). No impact on overall survival was observed according to different chemotherapy regimens and AASs. KRAS-specific AAS appears to induce different responses to chemotherapy regimens after first-line platinum-based chemotherapy in advanced NSCLC.


Successful treatment of cytomegalovirus enteritis after unrelated allogeneic stem cell transplantation by the infusion of ex vivo-expanded CD4+ lymphocytes derived from the recipient's peripheral blood donor cells.
Adoptive immunotherapies have been developed for antiviral agent-refractory cytomegalovirus (CMV) disease after stem cell transplantation (SCT). However, the application of such strategies is limited, particularly in terms of need for donor cooperation regarding blood sampling and inaccessibility in the setting of cord blood transplantation. Herein, we describe the first successful treatment of antiviral agent-refractory CMV enteritis after allogeneic SCT by the infusion of ex vivo-expanded donor-derived CD4(+) lymphocytes obtained from the recipient's peripheral blood.