Evaluation of a low-temperature calcium phosphate particulate implant material: physical-chemical properties and in vivo bone response.
A study was conducted to evaluate the osteoconductive ability of a particulate, low-temperature hydroxylapatite (HA(LT)) material (OsteoGen; Impladent, Holliswood, NY). An implantable chamber model was used to determine the ability of this material to encourage bone ingrowth into channels lined with either rough-surfaced titanium or rough-surfaced plasma-sprayed hydroxylapatite. The HA(LT) material increased bone ingrowth into the titanium-lined channels comparable with that in plasma-sprayed hydroxylapatite-coated channels. It was incorporated into ingrowing bone without intervening soft tissue, with the bone bonding directly to the material surface in much the same fashion as it bonds at the plasma-sprayed hydroxylapatite surface. Mechanical testing of the ingrown bone showed no weakness because particles were incorporated. At 12 weeks, the particles began to show signs of dissolution. It was concluded that the HA(LT) material is a biocompatible, osteoconductive material that conducts bone ingrowth in much the same way as high-temperature particulate hydroxylapatite ceramics. This material has the additional desirable property of being slowly resorbable, a beneficial characteristic for many bone-filling applications.


Growth of autografted tendons: an experimental study in vivo.
The growth of transplanted tendons was investigated in 54 young chickens. The transplantations were done within the first week of life. The flexor digitorum profundus tendon in the digital sheath of the right third digit was replaced by a graft taken from the same tendon of the left third digit. The growth of the grafted tendons was measured and compared with control tendons at the first, fifth, tenth, fifteenth, and twentieth week after the operation. Five weeks after operation the grafted tendons showed the same growth rate as the control tendons. Although tendon growth was retarded compared with the control tendons 15 weeks after operation, it was not statistically different at 20 weeks.


Prevalence and prediction of multiple organ system failure and mortality in acute pancreatitis.
We studied the prevalence of multiple organ system failure (MOSF), the relations between age, pre-existing chronic conditions, local complications, systemic infection, organ system failure, and mortality in patients with acute pancreatitis. During the study period, 267 consecutive patients were admitted to a tertiary hospital with acute pancreatitis. Multivariate analyses were used to identify factors predictive of MOSF occurrence and mortality. Using a previously developed MOSF scoring system at our center, MOSF (> or = 2 organ systems) was found to occur in 63 (24%) of the patients. Cardiovascular, pulmonary, renal, and hepatic failure predominated. Advanced age (> 55 yr) and chronic disease were related to local complications and systemic infection (both, P < .001). Local complications and systemic infection occurred in 68% and 75% of patients, respectively. In multiple logistic regression, advanced age, chronic disease, local complications, and systemic infection independently contributed to the development of MOSF. Overall mortality was 19%. MOSF accounted for 96% of deaths; mortality increased from 1% to 79% in patients without and with MOSF, respectively. In multiple logistic regression, advanced age, chronic disease, local complications, failure of the cardiovascular, renal, hepatic, gastrointestinal, and neurological systems independently contributed to mortality prediction. Advanced age and prior chronic disease may reflect diminished physiological reserve and predispose to local complications, systemic infection, and MOSF. Although local complications and systemic infection are important predisposing factors for MOSF, a host-dependent response to unknown specific or nonspecific factors may have a role in the pathogenesis of the syndrome in 25% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Response of Suidasia pontifica (Acaridida: Suidasiidae) to phosphine fumigation.
The present study evaluated the level of phosphine toxicity of various strains of Suidasia pontifica, infesting stored agricultural products in the Philippines. The bioassays for the efficacy of phosphine fumigation followed the FAO standard method. A full assay comprised eight concentrations ranging from 0.005 to 1.00 mg/L with 20, 72 and 144-h exposure periods. A total of 15 strains were collected, representing 15 provinces in the country. Results revealed that the most susceptible strain (MR12gsn) was recorded from a private owned warehouse in General Santos City-LC50 and LC99 were 0.009 and 0.025 mg/L, respectively. On the other hand, the most resistant strain (LR3tar) was collected from a private owned warehouse in Tarlac City-LC50 and LC99 were 1.501 and 2.407 mg/L, based on discrimination dose tests. Eggs were more tolerant than the adults; complete mortality of eggs was achieved at 0.50 mg/L for 72 h and 0.35 mg/L for 144 h, whereas complete mortality of adults was obtained with 0.10 and 0.20 mg/L for 144 and 72 h exposure, respectively. The estimated minimum effective concentration (MEC) of phosphine to give complete kill of S. pontifica at various exposure periods must exceed 0.50 mg/L for 72 and 144 h. These results simply illustrate the increased efficiency (i.e., increased mortality) of phosphine fumigation of longer exposure of S. pontifica to lower concentrations.


The epipharynx-kidney axis triggers glomerular vasculitis in immunoglobulin A nephropathy.
Macroscopic hematuria concomitant with acute pharyngitis is a characteristic feature of immunoglobulin A nephropathy (IgAN). Although the underlying mechanism of worsening hematuria has not been fully elucidated, activation of the innate immune system of nasopharynx-associated lymphoid tissue is thought to play an important role. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. As latent but significant epipharyngitis presents in most IgAN patients, it is plausible that acute pharyngitis due to airway infection may contribute as a trigger of the epipharyngeal innate immune system, which is already upregulated in the chronically inflamed environment. The aim of this review was to discuss the mechanism of epipharynx-kidney axis involvement in glomerular vasculitis responsible for the worsening of hematuria in IgAN.


Apolipoprotein E receptors mediate the effects of beta-amyloid on astrocyte cultures.
We have previously shown that beta-amyloid (Abeta) induces astrocyte activation in vitro and that this reaction is attenuated by the addition of exogenous apolipoprotein E (apoE)-containing particles. However, the effects of Abeta on endogenous apoE and apoJ levels and the potential role of apoE receptors in astrocyte activation have not been addressed. Three activating stimuli (lipopolysaccharide, dibutyryl cAMP, and aged Abeta 1-42) were used to induce activation of rat astrocyte cultures, as assessed by changes in morphology and an increase in interleukin-1beta. However, only Abeta also induced approximately 50% reduction in the amount of released apoE and apoJ and an 8-fold increase in the levels of cell-associated apoE and apoJ. Experiments using two concentrations of receptor-associated protein, an inhibitor of apoE receptors with a differential affinity for the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), suggest that LRP mediates Abeta-induced astrocyte activation, whereas LDLR mediates the Abeta-induced changes in apoE levels. Receptor-associated protein had no effect on apoJ levels or on activation by either dibutyryl cAMP or lipopolysaccharide. These data suggest that apoE receptors translate the presence of extracellular Abeta into cellular responses, both initiating and modulating the inflammatory response induced by Abeta.


Optimizing Perioperative Blood and Coagulation Management During Cardiac Surgery.
Bleeding and transfusion are common in cardiac surgery and associated with poorer outcome. Bleeding is frequently due to coagulopathy caused by the complex interaction between cardiopulmonary bypass, major surgical trauma, anticoagulation management, and perioperative factors. Patient blood management has emerged to improve outcome by the prediction, prevention, monitoring, and treatment of bleeding and transfusion. Each part of this chain has several individual modalities and when combined leads to result in a better outcome. This article reviews the hemostasis disturbances in cardiac surgery with cardiopulmonary bypass and gives an overview of the most important patient blood management strategies.


CD105 expression is associated with invasive capacity in ovarian cancer and promotes invasiveness by inhibiting NDRG1 and regulating the epithelial-mesenchymal transition.
This study investigates the association of CD105 (endoglin) with the invasiveness of paclitaxel-resistant ovarian cancer (OC) cells and explores the potential mechanism. A paclitaxel-resistant OC cell line OC3/TAX300, which expresses the stem cell marker CD105 and has a high invasive potential, was established in our previous study. After CD105 knockdown using CD105 siRNA, the invasiveness of the OC cells was decreased, and the chemo-resistance was reversed, but the CD105 overexpression was related to the poor survival of the primary OC patients. The differentially expressed genes were investigated in the OC cells after the CD105 knockdown. The results showed that, in the CD105-siRNA transfected cells, the expressions of some genes (such as KIAA0125, SSTR5-AS1, CDH18, MIAT, NDRG1, E-cadherin, DUSP1, MAL, MYC, and JAK3) were significantly upregulated, but the expressions of other genes (such as PRKAR2B, KLK10, DDX17, and lncRNA SNHG7) were markedly downregulated. Several genes, such as NDRG1 and E-cadherin, are known to be related to cancer metastasis and the epithelial-mesenchymal transition (EMT). A KEGG analysis found that 264 signaling pathways changed after the CD105 knockdown, of which 27 signaling pathways showed significant enrichment. Our results show that CD105 is related to the metastasis of OC and may promote the EMT of OC by inhibiting NDRG1 and E-cadherin. MYC, JAK3, and IKBKB mediate the CD105-induced metastasis of OC via the MAPK/PI3K/AKT and JAK/STAT signaling pathways in the OC cells. Therefore, inhibiting the CD105 expression may be useful for treating OC.


Dyrk2 gene transfer suppresses hepatocarcinogenesis by promoting the degradation of Myc and Hras.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and has a poor prognosis. However, the molecular mechanisms underlying hepatocarcinogenesis and progression remain unknown. In vitro gain- and loss-of-function analyses in cell lines and xenografts revealed that dual-specificity tyrosine-regulated kinase 2 (DYRK2) influences tumour growth in HCC. To investigate the role of Dyrk2 during hepatocarcinogenesis, we developed liver-specific Dyrk2 conditional knockout mice and an in vivo gene delivery system with a hydrodynamic tail vein injection and the Sleeping Beauty transposon. The antitumour effects of Dyrk2 gene transfer were investigated in a murine autologous carcinogenesis model. Dyrk2 expression was reduced in tumours, and that its downregulation was induced before hepatocarcinogenesis. Dyrk2 gene transfer significantly suppressed carcinogenesis. It also suppresses Myc-induced de-differentiation and metabolic reprogramming, which favours proliferative, and malignant potential by altering gene profiles. Dyrk2 overexpression caused Myc and Hras degradation at the protein level rather than at the mRNA level, and this degradation mechanism was regulated by the proteasome. Immunohistochemical analyses revealed a negative correlation between DYRK2 expression and MYC and longer survival in patients with HCC with high-DYRK2 and low-MYC expressions. Dyrk2 protects the liver from carcinogenesis by promoting Myc and Hras degradation. Our findings would pave the way for a novel therapeutic approach using DYRK2 gene transfer. Hepatocellular carcinoma (HCC) is one of the most common cancers, with a poor prognosis. Hence, identifying molecules that can become promising targets for therapies is essential to improve mortality. No studies have clarified the association between DYRK2 and carcinogenesis, although DYRK2 is involved in tumour growth in various cancer cells. This is the first study to show that Dyrk2 expression decreases during hepatocarcinogenesis and that Dyrk2 gene transfer is an attractive approach with tumour suppressive activity against HCC by suppressing Myc-mediated de-differentiation and metabolic reprogramming that favours proliferative and malignant potential via Myc and Hras degradation.


Erxian decoction inhibits apoptosis by activating Akt1 and repairs spinal cord injury in rats.
Spinal cord injury (SCI) often leads to severe physiological and pathological changes in patients. Erxian Decoction (EXD) is effective in the postoperative treatment of spinal cord injury, but its specific mechanism of action is poorly defined. Network pharmacology and molecular docking were used to predict the potential mechanisms of EXD in SCI. In vivo studies were used to validate the above predictions. For in vivo study, the rats were pretreated with or without EXD (5.76 g/kg, by intragastric gavage). Multiple molecular biological test methods to identify molecular mechanisms. One-way analysis of variance (ANOVA) was used with Bonferroni's post-hoc test to identify the differences between groups. In vivo studies have shown that EXD improved motor function at 7dpi in SCI rats (P < 0.0001), significantly reduced spinal cord edema (P = 0.0139), upregulated 5-HT, GFAP, and TMEM119 expression. Through network pharmacology analysis, we found that Akt1 in EXD plays a role in treating SCI. The underlying mechanism may be the inhibition of apoptosis after activation of Akt1 phosphorylation. Molecular docking revealed that the key compounds could spontaneously bind to the Akt1 protein. Pharmacological inhibition of Akt1 activation by MK-2206, attenuated the anti-apoptotic effect of EXD on SCI in rats (P < 0.0001). EXD inhibits apoptosis by activating Akt1, reduce spinal cord edema and restore behavioral function after SCI in rats.


Response properties of the perioral reflex in Parkinson's disease.
Analyses of the response magnitudes of the short-latency perioral reflex were made in a group of Parkinson disease patients and control subjects. As a group, the parkinsonian subjects manifested reflex magnitudes which were increased relative to normal. For low-acceleration, mechanical displacements of perioral tissue (less than 500 cm/s2), the perioral reflex was not elicited in normal controls. However, such low-acceleration stimuli did elicit the perioral reflex in more than half of the parkinsonian subjects studied. These findings are consistent with earlier findings of increased sensitivity of facial and perioral reflexes associated with disturbances of the basal ganglia. These results contribute to the understanding of specific stimulus-response characteristics of the facial reflex and the role of the basal ganglia in orofacial motor control. The finding of increased sensitivity to mechanical stimuli in Parkinson's disease supports the hypothesis of basal ganglia gating or regulation of afferent information.


Diagnostics to support mycetoma management-Development of two target product profiles.
Mycetoma is a neglected tropical disease caused by more than 70 different microorganisms and identified by the WHO as one of the high-priority diseases for developing diagnostic tests. To ensure the production of diagnostic assays for use by clinical staff in endemic regions, target product profiles (TPPs) were designed. We describe the development of two TPPs: one for a diagnostic test able to identify the causative agent of mycetoma and another that would determine when treatment could be stopped. The TPPs were developed by considering product use, design, performance, product configuration and costs. Version 1.0 TPPs for two uses were posted by WHO for a 1-month online public consultation on 25 October 2021, and the final TPP was posted online on 5 May 2022. A major difficulty encountered in developing both TPPs was the large number of agents able to cause mycetoma and the lack of specific biomarkers for most of them.


An Update on the Role of Cardiac Magnetic Resonance Imaging in Cancer Patients.
Cardiac magnetic resonance imaging has a significant and expanding role to play in contemporary cardio-oncology. This review seeks to explore the current and future roles of this imaging modality in the cardio-oncology setting. Cardiac magnetic resonance imaging is required in diagnosing, monitoring and treating all types of cardiotoxicities (acute coronary syndromes, arrhythmias, myocarditis, pericardial disease, heart failure) and in all types of cancers (breast, gastrointestinal, renal, prostate, haematological etc.). Newer imaging sequences and techniques can help provide additional information and shorten imaging times. Cardiac magnetic resonance imaging is an integral part of the holistic management of cardio-oncology patients, with increasingly expanding applications in the area.


Compartmentalization of lysosomal enzymes in cauda epididymis of normal and castrated rats.
The mammalian epididymis is an organ particularly rich in acid hydrolases, consistent with a developed lysosomal apparatus. However, some of these enzymes could also play a role in an extracellular environment, since they are actively secreted by the epithelium. In this study the authors measured the activity of five acid hydrolases distributed between the epithelium, fluid, small vesicles, and spermatozoa of the rat cauda epididymis in adult rats, and compared with that distribution under conditions of deprivation of luminal testosterone and testicular compounds (hemicastration). Lysosomal enzymes are differently compartmentalized in rat cauda epididymis. Most of beta-galactosidase (beta-GAL) and aryl sulfatase (approximately 70%) were found in soluble form within the fluid. Some 60% of N-acetyl-beta-D-glucosaminidase (beta-NAG) and alpha-mannosidase (alpha-MAN) become transiently bound to sperm, and beta-glucuronidase (beta-GLU) was mostly concentrated in the epithelium. After remotion of testis this distribution changed, as the retention of alpha-MAN, beta-GAL, beta-GLU, and beta-NAG by the epididiymal tissue increased. The increase of beta-GLU followed an increase of synthesis of the enzyme. The distribution of enzymes in the epididymis from the contralateral side was similar to that in normal rats. The different roles for each enzyme in the epididymis are discussed.


Regulation of cellular redox homeostasis in Arabidopsis thaliana seedling by atmospheric pressure cold plasma-generated reactive oxygen/nitrogen species.
Atmospheric pressure cold plasma (APCP) holds great potential as an efficient, economical and eco-friendly approach for improving crop production. Although APCP-induced plant growth promotion is undisputedly attributed to the reactive oxygen and nitrogen species (RONS), how these RONS regulate the intracellular redox state and plant growth is still largely unknown. This study systematically investigates the regulation mechanism of APCP-generated RONS on intracellular redox homeostasis in Arabidopsis thaliana seedling by measuring the RONS compositions in APCP-treated solutions and intracellular RONS and antioxidants in Arabidopsis seedlings. The results show that APCP exhibited a dual effect (stimulation or inhibition) on Arabidopsis seedling growth dependent on the treatment time. APCP-generated RONS in liquids increased in a time-dependent manner, leading to an increase of conductivity and oxidation reduction potential (ORP) and decrease of pH. APCP caused an enrichment of intracellular RONS and most of them increased with APCP treatment time. Meanwhile, APCP treatment accelerated malondialdehyde (MDA) generation, and the level of intracellular antioxidants were enhanced by low-dose APCP treatment while decreased at high doses. The results of correlation analysis showed that the extracellular RONS produced by APCP were positively correlated with the intracellular RONS and negatively correlated with the antioxidants. These results demonstrate that the improved antioxidant capacity induced by moderate APCP-generated RONS plays an important role in the growth promotion of Arabidopsis seedlings, which may be a promising alternative for fertilizers in agricultural production.


Intensity-based nonrigid endomicroscopic image mosaicking incorporating texture relevance for compensation of tissue deformation.
Image mosaicking has emerged as a universal technique to broaden the field-of-view of the probe-based confocal laser endomicroscopy (pCLE) imaging system. However, due to the influence of probe-tissue contact forces and optical components on imaging quality, existing mosaicking methods remain insufficient to deal with practical challenges. In this paper, we present the texture encoded sum of conditional variance (TESCV) as a novel similarity metric, and effectively incorporate it into a sequential mosaicking scheme to simultaneously correct rigid probe shift and nonrigid tissue deformation. TESCV combines both intensity dependency and texture relevance to quantify the differences between pCLE image frames, where a discriminative binary descriptor named fully cross-detected local derivative pattern (FCLDP) is designed to extract more detailed structural textures. Furthermore, we also analytically derive the closed-form gradient of TESCV with respect to the transformation variables. Experiments on the circular dataset highlighted the advantage of the TESCV metric in improving mosaicking performance compared with the other four recently published metrics. The comparison with the other four state-of-the-art mosaicking methods on the spiral and manual datasets indicated that the proposed TESCV-based method not only worked stably at different contact forces, but was also suitable for both low- and high-resolution imaging systems. With more accurate and delicate mosaics, the proposed method holds promises to meet clinical demands for intraoperative optical biopsy.


Episodic-like memory is sensitive to both Alzheimer's-like pathological accumulation and normal ageing processes in mice.
Episodic memory depends on the hippocampus and is sensitive to both Alzheimer's disease (AD) pathology and normal ageing. We showed previously that 3xTgAD mice express a specific, episodic-memory deficit at 6 months of age in the What-Where-Which occasion (WWWhich) task (Davis, Easton, Eacott and Gigg, 2013). This task requires the integration of object-location and contextual cues to form an episodic-like memory. Here, we explore the cumulative effect of AD pathology on WWWhich memory by testing very young and middle-aged mice (3 and 12 months old, respectively). For comparison, we included an alternative episodic-like task (What-Where-When; WWWhen) and an object temporal order (Recency) task to explore claims that WWWhen types of memory are open to non-episodic solutions. We found that in contrast to their performance at 6 months, 3-month-old 3xTgAD mice formed WWWhich episodic-like memories; however, their performance at this age was poorer than in matched controls. In contrast, 3xTgAD and control animals aged 12 months were both impaired on the WWWhich task. Finally, 3xTgAD mice with a WWWhich deficit were unimpaired in both Recency and WWWhen tasks. These results support conclusions that: (1) young 3xTgAD mice express episodic-like memory, albeit depressed relative to controls; (2) age-related changes result in a deficit on the hippocampal-dependent WWWhich episodic memory task; and (3) control and 3xTgAD mice can use recency (trace strength) rather than episodic-like memory for tasks that contain a temporal 'When' component. These results, in combination with our previous findings, support an age-related decline in WWWhich episodic-like memory in mice. Furthermore, this decline is accelerated in the 3xTgAD model.


Does clinical testing support the current guidance definition of prolonged contact for nickel allergy?
The European Chemical Agency (ECHA) definition of prolonged contact was introduced in 2014 and has not been evaluated clinically. To assess whether nickel-sensitized individuals react on patch testing with high nickel-releasing metal discs for short and repetitive periods. We patch tested 45 nickel-sensitized individuals double-blind with 2 different types of high nickel-releasing discs for 10, 30 and 60 minutes on 3 occasions over a period of 2 weeks, and for 1 longer period. Discs were tested for nickel release. Nickel release from both discs significantly exceeded the 0.5 μg Ni/cm2 /week limit of the EU REACH nickel restriction. However, only 1 individual tested had a largely dose-dependent allergic reaction. The majority of nickel-allergic subjects did not react to nickel discs after 2 hours or after repetitive exposures of up to 30 minutes on 3 occasions over a period of 2 weeks. The length of time needed to cause nickel allergic contact dermatitis in most nickel-allergic individuals is longer than the ECHA guidance definition. Longer test times are needed to define the time required to cause dermatitis in most nickel-allergic individuals. As a limitation, the test conditions did not adequately assess real-life factors such as friction, which is relevant for some uses of nickel.


Monitoring of RNA clearance in a novel plasmid DNA purification process.
As the field of plasmid DNA-based vaccines and therapeutics matures, improved methods for impurity clearance monitoring are increasingly valuable for process development and scale-up. Residual host-cell RNA is a major impurity in current large-scale separation processes for the production of clinical-grade plasmid DNA. Current RNA detection technologies include quantitative rtPCR, HPLC, and fluorescent dye-based assays. However, these methodologies are difficult to employ as in-process tests primarily as a result of impurity and buffer interferences. To address the need for a method of measuring RNA levels in various process intermediates, a sample pretreatment strategy has been developed that utilizes spermidine affinity precipitation to eliminate a majority of solution impurities, followed by a quantitative precipitation with alcohol to concentrate RNA and allow detection at lower concentrations. RNA concentrations as low as 80 ng/mL have been measured using detection with gel electrophoresis and 20 ng/mL if microplate-based detection with Ribogreen fluorescent dye is used. The assay procedure has been utilized to troubleshoot RNA clearance issues encountered during scale-up of a novel, non-chromatographic purification process for plasmid DNA. Assay results identified residual liquor removal inadequacies as the source of elevated RNA levels, enabling process modifications in a timely fashion.


Prevalence of Human Immunodeficiency Virus and Opportunistic Infections Among Transgender Patients in the Clinical Setting: An All-Payer Electronic Health Record Database Study.
We performed a cross-sectional analysis of the prevalence of HIV and opportunistic infections among transgender patients in clinical care. Of 10,160 transgender patients identified, 3.9% had a diagnosis of HIV, compared to 0.32% in the non-transgender cohort (p<0.0001). Transgender patients experience the burden of all opportunistic infection compared to non-transgender patients in this analysis, although prevalence of pneumocystis pneumonia was not significant. This cohort-based, all-payer electronic health record study of HIV patients connected to care revealed that transgender patients have a higher prevalence of HIV infection and opportunistic infections compared to the non-transgender cohort.


Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study.
We sought to investigate whether the use of balanced solutions reduces the incidence of hyperchloraemic acidosis without increasing the risk for intracranial hypertension in patients with severe brain injury. We conducted a single-centre, two-arm, randomised, double-blind, pilot controlled trial in Nantes, France. Patients with severe traumatic brain injury (Glasgow Coma Scale score ≤8) or subarachnoid haemorrhage (World Federation of Neurosurgical Society grade III or higher) who were mechanically ventilated were randomised within the first 12 hours after brain injury to receive either isotonic balanced solutions (crystalloid and hydroxyethyl starch; balanced group) or isotonic sodium chloride solutions (crystalloid and hydroxyethyl starch; saline group) for 48 hours. The primary endpoint was the occurrence of hyperchloraemic metabolic acidosis within 48 hours. Forty-two patients were included, of whom one patient in each group was excluded (one consent withdrawn and one use of forbidden therapy). Nineteen patients (95%) in the saline group and thirteen (65%) in the balanced group presented with hyperchloraemic acidosis within the first 48 hours (hazard ratio = 0.28, 95% confidence interval [CI] = 0.11 to 0.70; P = 0.006). In the saline group, pH (P = .004) and strong ion deficit (P = 0.047) were lower and chloraemia was higher (P = 0.002) than in the balanced group. Intracranial pressure was not different between the study groups (mean difference 4 mmHg [-1;8]; P = 0.088). Seven patients (35%) in the saline group and eight (40%) in the balanced group developed intracranial hypertension (P = 0.744). Three patients (14%) in the saline group and five (25%) in the balanced group died (P = 0.387). This study provides evidence that balanced solutions reduce the incidence of hyperchloraemic acidosis in brain-injured patients compared to saline solutions. Even if the study was not powered sufficiently for this endpoint, intracranial pressure did not appear different between groups. EudraCT 2008-004153-15 and NCT00847977.


Some descriptive characteristics of a new goat breed called Honamli in Turkey.
This study has been carried out in the Western Mediterranean Region of Turkey on seven different Honamli goat flocks. The aim of this study was to determine the growth characters, survival rate (till weaning, 105th day), some reproductive characteristics and marketable milk yield. The data were collected from 516 does and 210 kids (125 buckling and 85 doelings). The results indicate that the numbers of multiple birth and litter size were 32.8 % and 1.35 respectively. Survival rates of kids at the 30th, 90th, and 105th days were 98.5, 97.2, and 97.2 %, respectively. The average birth weight for the buckling and doelings was 4.1 and 3.7 kg, respectively. The average weaning weights for buckling and doelings were 26.9 and 23.4 kg, respectively. The effects of dams' age, on sex and birth type on the growth of Honamli kids were statistically significant (p < 0.05, p < 0.01, and p < 0.001). While the diameters of erythrocytes of Honamli goats are smaller, the density of hemoglobin in the erythrocytes is more than Asian, Indian, and American caprine breeds. The average lactation length and marketable milk yield was assessed to be at 210.3 days and was 89 L, respectively. The growth characteristics of Honamli kids at weaning age were assessed to be higher than most of the other goat breeds in Turkey. The results further indicated that there is a significant variation in the production traits among the different Honamli goat flocks. Production traits of Honamli goats at different breeding conditions should further be investigated to come to a definite conclusion.


Ascending Aorta Elastography After Kawasaki Disease Compared to Systemic Hypertension.
Kawasaki disease (KD) is a systemic vasculitis, classically affecting large- and medium-size arteries. The coronary arteries draw most of the clinical attention, whereas few studies have taken interest in the ascending aorta. Using a proprietary imaging-based mechanical biomarker (ImBioMark), we sought to determine aortic stiffness in KD compared to systemic hypertension (HTN) and healthy children. We evaluated parasternal long-axis views focused on the ascending aorta in 20 controls, 12 KD, and 8 HTN as a comparative clinical model of vascular stiffness. We calculated systolic and diastolic aortic wall strain with ImBioMark. Strain was tested for normality against height, systolic, and diastolic blood pressure in normal subjects. Strain from KD and HTN was normalized (Z score) accordingly. Z score comparisons were performed using nonparametric statistics. Age was similar between KD and HTN (9.1 ± 5.3 and 9.9 ± 5.3 years old; p = NS). Systolic and diastolic strain values were normally distributed against height, systolic blood pressure, and diastolic blood pressure in healthy subjects. HTN subjects had abnormal systolic and diastolic strain values (p < 0.0001). Whereas KD subjects had normal diastolic strain, systolic strain was significantly lower (p < 0.001), and systolic strain was intermediate between controls and HTN. There were no significant differences in aortic strain among KD, however, according to the presence of coronary artery aneurysms. Despite normal blood pressure, the ascending aorta in KD exhibits reduced strain during systole. This may reflect in situ rigidity of the aorta. The normal diastolic strain in KD may, in contrast, reflect normal peripheral vascular resistance.


Effects of Danggui-Shaoyao-San on central neuroendocrine and pharmacokinetics in female ovariectomized rats.
The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to have estrogen-like effects and therapeutic effects on the symptoms of Alzheimer's disease (AD). To explore whether the central oxytocin and neuroendocrine system is involved in the modulating effects of DSS on the cognition and neuropsychiatric hebaviors in female AD rats, and to investigate the pharmacokinetics of paeoniflorin and ferulic acid in female AD rats with DSS treatment. DSS (1.2, 3.2, 8.6 g/kg/day) was orally administered to ovariectomized (OVX) rats, and saline was orally administered to sham operation rats as control group. The Morris water maze test, novel object recognition test, and passive avoidance test were conducted for evaluation of learning and memory abilities, while elevated plus maze test and forced swim test were performed to assess anxiety- and depressive-like behaviors. ELISA kits were used to detect the levels of estrogen (E), estrogen receptor α (ERα), oxytocin (OT), oxytocin receptor (OTR), acetylcholine (Ach), acetylcholin esterase (AchE), and choline acetyl transferase (ChAT) in the cortex. The concentrations of Ach, glutamate (Glu), γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) in the hippocampus were assessed by HPLC-MS. The changes of neuronal morphology in the hippocampus were observed by Nissl staining. The pharmacokinetics of paeoniflorin and ferulic acid in OVX rats with DSS treatment were studied by HPLC. In the Morris water maze test, novel object recognition test, and passive avoidance test, OVX rats showed cognitive impairment. In the elevated plus maze test and forced swim test, the anxiety- and depressive-like behaviors of OVX rats were significant as compared to the control group. Treatment of DSS significantly imporved the cognitive deficits, and ameliorated anxiety- and depressive-like behaviors of OVX rats. The expression of E, ERα, OT, OTR, AchE and ChAT in the cortex of model group were significantly decreased, and DSS significantly reversed these changes. The concentrations of Ach, Glu, GABA, 5-HT and NE in the hippocampus of OVX rats were significantly decreased, whereas DSS significantly increased the levels of Ach, Glu, GABA, 5-HT and NE. There was no significant difference in the concentration of DA in the hippocampus among groups. Degenerating neurons in the hippocampal CA3 region were observed in OVX rats, and the number of neurons was decreased. DSS treatment reduced the degenerating neurons, and incresed the number of neurons. The MRT (0 - ∞), AUC (0 - ∞), Cmax and t1/2z values of paeoniflorin, and the AUC 0-∞ and Cmax value of ferulic acid were higher in DSS-treated OVX rats than those in the DSS-treated control rats. DSS improves the learning and memory ability, and attenuates anxiety- and depressive-like behaviors of OVX rats. The mechanism may be through increasing estrogen, reducing cholinergic damage, and modulating neurotransmitters. The increase in absorption and elimination time of paeoniflorin and ferulic acid in OVX rats may enhance the efficacy of DSS.


Identification and chromosomal localization of mariner-like elements in the cabbage moth Mamestra brassicae (Lepidoptera).
A complete mariner-like element has been identified in the lepidopteran Mamestra brassicae. This element, called Mbmar, represents a new type of mariner transposon. It has a transposase similar to that of other insect mariner coding sequences but its inverted terminal repeats differ from typical mariner ones. This observation is unique since generally both mariner coding region and ITRs are evolutionarily conserved in insects. Mbmar is detectable by FISH only in the heterochromatic regions of both the sex chromosomes.


KLF16 overexpression deleteriously affects the proliferation and migration of retinoblastoma by transcriptionally repressing BCL2L15.
Krüppel-like factors (KLFs) are transcription factors that control the expression of downstream genes. The role of KLFs has been reported in cancers. KLF16 promotes the proliferation of gastric cancer cells by upregulating p21, while suppresses the tumorigenesis of glioma through targeting TFAM. The function of KLF16 is controversial in cancer development. In this study, we aimed to investigate the role of KLF16 in retinoblastoma (RB). KLF16 was highly expressed in RB tissues and cells. Overexpression of KLF16 promoted the proliferation, growth and migration of RB cells. By contrast, KLF16 interference showed opposite effects. Cell cycle arrest and apoptosis were induced or repressed by KLF16 knockdown or overexpression, respectively. Mechanistically, BCL2 like 15 (BCL2L15), an apoptosis gene, was negatively regulated by KLF16. Luciferase reporter and ChIP assay showed that KLF16 transcriptionally repressed the expression of BCL2L15 by binding to its promoter. BCL2L15 was lowly expressed in RB tissues. Additionally, overexpression of BCL2L15 inhibited the proliferation and increased the apoptosis in RB cells. Our study identifies that KLF16 contributes to RB cell proliferation and migration by negatively regulating BCL2L15.


The new demarcation problem.
There is now a general consensus amongst philosophers in the values in science literature that values necessarily play a role in core areas of scientific inquiry. We argue that attention should now be turned from debating the value-free ideal to delineating legitimate from illegitimate influences of values in science, a project we dub "The New Demarcation Problem." First, we review past attempts to demarcate the uses of values and propose a categorization of the strategies by where they seek to draw legitimacy from. Next, we propose a set of desiderata for what we take to be a satisfactory solution and present a case study where conflicting sets of values clearly impinge on science, but where the legitimacy of their influence is ambiguous. We use these desiderata and the case study to illustrate what we take to be the strengths and weaknesses of current strategies. To be clear, our goal is not to answer the question we pose, but to articulate a framework within which a solution can be judged.


Study on the relationship of protease production and luminescence in Vibrio harveyi.
To demonstrate that Vibrio harveyi produces various types of toxins and how the production of those toxins is related with luminescence. Luminescence and toxicity of eight V. harveyi were evaluated. We demonstrated that all V. harveyi emitting luminescence were isolated from marine organisms and also showed that they were highly pathogenic when compared with culture collection V. harveyi based on cytotoxic assay test. On the contrary, V. harveyi isolated from shrimp farm showed no luminescence but showed high pathogenicity based on toxicity test. The effect of protease inhibitors on pathogenicity and luminescence was also investigated. We demonstrated that light emission of pathogenic V. harveyi remarkably decreased after addition of protease inhibitor. Furthermore, extracellular proteins from cell-free culture supernatant of luminescent and nonluminescent V. harveyi were compared using SDS-PAGE analysis. Results showed that there were differences in molecular weight and amount of proteins. Vibrio harveyi parasiting marine organisms have both luminescence and pathogenicity. Based on this study, luminescence and protease toxin activity in V. harveyi are related. Moreover, this paper clarified that V. harveyi produces various types of toxins. The current study demonstrated that V. harveyi produces two kinds of toxins, haemolysin and protease toxin. It may be clear roots of V. harveyi toxin.


Gel electrophoresis in studies of protein conformation and folding.
Electrophoresis through polyacrylamide gels is a useful method for distinguishing conformational states of proteins and analyzing the thermodynamic and kinetic properties of transitions between conformations. Although the relationship between protein conformation and electrophoretic mobility is quite complex, relative mobilities provide qualitative estimates of compactness. Conformational states which interconvert slowly on the time scale of the electrophoretic separation can often be resolved, and the rates of interconversion can be estimated. If the transitions are more rapid, then the electrophoretic mobility represents the equilibrium distribution of conformations. Protein unfolding transitions induced by urea are readily studied using slab gels containing a gradient of urea concentration perpendicular to the direction of electrophoresis. Protein applied across the top of such a gel migrates in the presence of continuously varying urea concentrations, and a profile of the unfolding transition is generated directly. Transitions induced by other agents could be studied using analogous gradient gels. Electrophoretic methods are especially suited for studying small quantities of protein, and complex mixtures, since the different components can be separated during the electrophoresis.


A promoter variant in the chitinase 3-like 1 gene is associated with serum YKL-40 level and personality trait.
The chitinase 3-like 1 (CHI3L1) gene, a cellular survival factor against several environmental and psychosocial stresses, has been sown to be more highly expressed in the hippocampus and prefrontal cortex of patients with schizophrenia than unaffected individuals. We recently reported a significant association between schizophrenia and SNP rs4950928, which is located in the promoter region of the CHI3L1 gene, in a Japanese population. The G-allele at this SNP in the gene has been associated with higher transcriptional activity in a luciferase reporter assay and with higher mRNA levels in the peripheral blood cells of patients with schizophrenia. We investigated the impact of the CHI3L1 polymorphism rs4950928 on serum YKL-40 levels, the protein product of CHI3L1. We found that individuals with the G-allele, who were more prevalent among patients with schizophrenia, had significantly higher serum YKL-40 levels (p=0.043). Personality traits are considered to be an important aspect of schizophrenia primarily because they may influence symptoms and social functioning. Personality trait analyses using the temperament and character inventory (TCI) indicated that schizophrenic patients have a unique personality profile that appears to be present across cultures. We hypothesized that higher serum YKL-40 levels are associated with personality trait in patients with schizophrenia. Thus, we next examined the impact of the risk CHI3L1 polymorphism on personality traits using the TCI. We found that individuals with the G-allele had significantly higher self-transcendence scores (p=0.0054). These findings suggest possible associations between the SNP in the CHI3L1 gene, the risk for schizophrenia, and higher serum YKL-40 levels and personality traits in a Japanese population.


Sleep, Health, and Society.
Insufficient sleep and sleep disorders are highly prevalent in the population and are associated with significant morbidity and mortality. Adverse outcomes of insufficient sleep and/or sleep disorders are weight gain and obesity, cardiovascular disease, diabetes, accidents and injuries, stress, pain, neurocognitive dysfunction, psychiatric symptoms, and mortality. Exposure to sleep difficulties varies by age, sex, race/ethnicity, and socioeconomic status; significant sleep health disparities exist in the population. Societal influences, such as globalization, technology, and public policy, affect sleep at a population level.


The design of an on-line semi-preparative LC-SPE-NMR system for trace analysis.
This paper reports the design of an on-line semi-preparative LC-SPE-NMR system and its use in the structural analysis of mixture components at the 0.02-1% level. The combination provides at least a five fold mass sensitivity increase over that obtained from typical analytical LC-SPE systems and a >30-fold total NMR sensitivity enhancement over analysis by LC-NMR. This is accomplished by using a novel on-line device to store, dilute (1-100-fold) and deliver (at an optimized flow-rate) the isolated component of interest to an SPE trap unit. The SPE unit consists of two cartridges connected in parallel to increase the overall SPE capacity and also to decrease the flow-rate through each trap for enhanced trapping efficiency. As the coupling of semi-preparative LC with NMR (through SPE) is well matched in terms of optimal mass loading for both techniques, only one LC-SPE cycle is required to enrich a 50 microg ml(-1) component (1% in a 5 mg ml(-1) mixture) for the acquisition of heteronuclear (1)H-(13)C NMR data using a conventional NMR flow probe. Furthermore, analytes at the 0.02% level (approximately 1 microg ml(-1)) can be studied using 2D (1)H NMR techniques if peak cuts from replicate sample injections (> or =3) are accumulated into the storage/dilution unit and the resulting solution processed by just one SPE trap and elute cycle.


Galerucella nymphaeae (Col., Chrysomelidae) grazing increases Nuphar leaf production and affects carbon and nitrogen dynamics in ponds.
The grazing effects of the waterlily beetle Galerucella nymphaeae on Nuphar lutea stands were studied in three ponds in Central Finland. Production of floating leaves of N. lutea and growth in the G. nymphaeae population were investigated in the ponds and bioenergetics of the beetle larvae in the laboratory. Combination of field and laboratory data enabled estimation of the effect of the beetle on the production of floating leaves of N. lutea and the consequences of grazing for the input of detritus from Nuphar into the ponds. Adults and larvae of G. nymphaeae consumed 3.0-6.1% of the net annual floating leaf production during the growing period. In addition to consumption losses, feeding accelerated the degradation rate of the leaves. This was associated with an increased flow of detrital material of Nuphar origin, and also with increased production of floating leaves in the ponds. These increments were estimated to be up to 3 times greater in the presence of grazing than without it. Grazing by G. nymphaeae releases substantial amounts of carbon and nitrogen bound in Nuphar, particularly in ponds with a dense Nuphar vegetation. It is hypothesized that feeding by this beetle may markedly affect the structure and functioning of such small aquatic systems.


Performance characteristics of chimerism testing by next generation sequencing.
Chimerism testing provides informative clinical data regarding the status of a biological sample mixture. For years, this testing was achieved by measuring the peaks of informative short tandem repeat (STR) loci using capillary electrophoresis (CE). With the advent of next generation sequencing (NGS) technology, the quantification of the percentage of donor/recipient mixtures is more easily done using sequence reads in large batches of samples run on a single flow cell. In this study, we present data on using a FORENSIC NGS chimerism platform to accurately measure the percentage of donor/recipient mixtures. We were able to detect chimerism to a limit threshold of 1% using both STR and single nucleotide polymorphism (SNP) informative loci. Importantly, a significant correlation was observed between NGS and CE chimerism methods when compared at donor detection ranges from 1% to 10%. Furthermore, 100% accuracy was achieved through proficiency testing over six surveys. Its usefulness was expanded beyond this to help identify suitable donors for solid organ transplant patients using ancestry SNP profiles. In summary, the NGS method provides a sensitive and reliable alternative to traditional CE for chimerism testing of clinical samples.


Attentional processing of infant emotion during late pregnancy and mother-infant relations after birth.
The mother-infant relationship has an important influence on maternal mental health and infant development. Evidence suggests that this relationship is enhanced by a mother's sensitive response towards her infant's distress. We proposed that attentional processing of infant distress may indicate individual differences in this response. Research also suggests that maternal responses develop during pregnancy. We therefore hypothesised that more sensitive attentional processing of distressed infant stimuli during late pregnancy will be associated with more successful mother-infant relationships. Healthy pregnant women were recruited through community midwives. An established computerised paradigm measured women's ability to disengage attention from distressed or non-distressed infant faces. From this paradigm, we derived an index of women's attentional bias towards infant distress. Mother-infant relationships were measured using the postpartum bonding questionnaire (PBQ). A complete case sample of 49 women completed the attentional paradigm during late pregnancy and the PBQ 3-6 months after birth. We found that women who showed greater attentional bias towards infant distress during late pregnancy reported more successful mother-infant relationships. For every 50-ms increase on our measure of attentional bias towards infant distress during late pregnancy, the odds ratio for reporting a higher PBQ score, indicative of a weaker relationship, was 0.43 (95% confidence intervals 0.23-0.81, p = 0.01). The results suggest that women's basic attentional processing of infant emotion during pregnancy influences their relationships with their infant. In the future, women's attentional processing of infant emotion could inform early strategies to promote successful mother-infant relationships in vulnerable mothers to be.


Prognostic Role of the MicroRNA-200 Family in Various Carcinomas: A Systematic Review and Meta-Analysis.
Background/Aims. The miRNA-200 (miR-200) family may act as key inhibitors of epithelial-to-mesenchymal transition. However, the potential prognostic value of miR-200s in various human malignancies remains controversial. This meta-analysis analyzed the associations between miR-200 levels and survival outcomes in a variety of tumors. Methods. Eligible published studies were identified by searching the Embase, PubMed, CINAHL, and Google scholar databases. Patient clinical data were pooled, and pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. Results. The pooled HRs suggested that high tissue expression of miR-200 family members was associated with better survival (overall survival [OS]: HR = 0.70, 95% CI 0.54-0.91; progression-free survival [PFS]: HR = 0.63, 95% CI 0.52-0.76) in thirty-four eligible articles. In contrast, higher expression of circulating miR-200 members was significantly associated with poor clinical outcome (OS, HR = 1.68, 95% CI 1.15-2.46; PFS, HR = 2.62, 95% CI 1.68-4.07). Conclusion. The results from this meta-analysis suggest that miR-200 family members are potential prognostic biomarkers in patients with various carcinomas. To apply these findings in the clinic, large prospective studies are needed to validate the prognostic values of miR-200s in individual cancer types.


[Clinical statistics on inpatients and operations in the urological department of the Omori Red Cross Hospital (January, 1981 to December, 1985].
The statistics obtained for the 716 inpatients and 550 operations at our clinic between January 1981 and December 1985 were reviewed. The patients were most frequently in their sixties, and there was a predominance in males. The most frequent diseases of the inpatients were benign prostatic hypertrophies and bladder tumors. The most performed operations were also those for urological tumors.


Accuracy of Magnetic Resonance Imaging in Detecting Tumor Depth of Invasion in Squamous Cell Carcinoma of the Tongue: A Systematic Review.
The objective of the study was to detect the accuracy of Magnetic Resonance Imaging (MRI) in assessing tumor depth of invasion (DOI) in squamous cell carcinoma (SCC) of the tongue. The electronic search of PubMed (including MEDLINE), COCHRANE CENTRAL and Google Scholar search engine for articles published from January 1, 2000, to September 31, 2021, was conducted and also searched the lists of references of relevant articles and reviews for studies involving patients with squamous cell carcinoma of the tongue. A total of 5362 articles were retrieved in the initial search. After the initial search process, 13 full-text articles were reviewed. Out of these 13 articles, seven met the inclusion criteria and were thus included in this systematic review. The MRI-determined DOI based on T1-weighted sequences increases with increasing T stage. There is the highest correlation between the MRI-derived DOI and the histopathological DOI with increasing T stage. Therefore, MRI provides satisfactory diagnostic accuracy for measuring tumor DOI and, thus, may be considered a predictor of tumor stage.


Dermatology resident perspectives on practice ownership structures and private equity-backed group practices.
Recently, dermatology group practice ownership structures have changed, as private equity (PE) consolidates independent dermatology practices to create larger groups. Currently, little is known about how dermatology residents perceive practice ownership structures, including those that are owned by PE. One hundred thirty-seven residents from 32 dermatology residency programs responded to a 21-question anonymous survey. Approximately 65% of residents in this study were not open to working for PE-backed practices, and their negative perceptions of how PE influences quality of care, long-term salary, and physician autonomy were associated with their unwillingness to work at a PE-backed practice. Most residents in this study valued education about practice ownership structures, and approximately 43% of respondents did not feel adequately informed about practice options during residency. Future studies should evaluate how PE ownership of group practices influences practice parameters, including quality of patient care, physician autonomy, and long-term salary.


Leishmania donovani: influence of anti-leishmanial therapy on expression of lymphocyte function-associated antigen-3 and its relevance to pathogenisis in visceral leishmaniasis.
Lymphocyte function associated antigen 3 (LFA-3) is known as adhesion molecule with its role in T-cell activation signaling as well as in Foxp3 expression. Its influences on IL-10 production is also available, whose role in pathogenesis is well documented. However, this molecule is not yet directly addressed for its association with visceral leishmaniasis (VL). We investigated the relationship between Leishmania donovani infection and expression of LFA-3 in VL patients in their pre and post treatment stage through this case control study. Present study reports L. donovani mediated expression of LFA-3 on CD14(+) monocytes in human VL. Active cases of VL was observed with 2.91-fold increased mean florescence intensity (MFI) of LFA-3 expression on CD14(+) cells compared to healthy control (p = 0.0001). This increased MFI of untreated VL cases was reduced 1.92-fold in successfully treated cases (p = 0.0001). This observation was also accorded by mRNA expression for LFA-3 in monocytes of corresponding samples. The expression of LFA-3 was also observed influenced by L. donovani load in splenic aspirates, as it was 1.71-fold elevated in patients with Ld grade ≥3+ compared to patients with ≤2+ Ld grade (p = 0.0121). To evaluate the possibility that L. donovani utilize LFA-3 mediated evasion pathway in human visceral leishmaniasis; in vitro experiments were performed for measurement of pathogenic cytokine IL-10 and Foxp3 mRNA expression. The IL-10 production and Foxp3 expression in peripheral blood mononuclear cells from VL subjects were observed regulated significantly (p = 0.0131 and 0.0436 when compared with untreated samples) in presence of an antagonist to LFA-3. This study recommends further investigations to strengthen the pathogenic and prognostic significance of LFA-3 in visceral leishmaniasis.


Draft Genome Sequence of Bacillus subtilis AS2, a Heavy Crude Oil-Degrading and Biosurfactant-Producing Bacterium Isolated from a Soil Sample.
Here, we report the draft genome sequence of Bacillus subtilis AS2 that was isolated from heavy crude oil-contaminated soil samples from sludge pits of an Omani heavy-oil field. B. subtilis AS2 was able to biodegrade heavy crude oil and produce biosurfactant. In order to provide a better understanding of the biodegradation mechanism and biosynthesis of metabolites, the B. subtilis AS2 genome was sequenced and compared to those of other B. subtilis strains.


Assessing long-term performance of stabilized Zn-contaminated dredged sediment slurry treated with the PHDVPSS method.
Solidification/stabilization (S/S) has been widely used for effective treatment of dredged sediment (DS) for many years, with the objective of improving the mechanical properties of DS through the addition of inorganic cementitious materials. Most previous studies have reported the short-term performance of S/S. However, long-term effectiveness is critical, as contaminants remain underground and are subjected to a variety of environmental stresses that can degrade S/S materials. In this regard, this experimental work investigated the long-term efficacy of solidification/stabilization of dredged contaminated sediments (DCS) treated with a new integrated method, namely PHDVPSS, which uses a prefabricated horizontal drain (PHD) assisted by vacuum pressure (VP) as well as solidification/stabilization. The DCS were treated with Portland cement (PC) as binder in the PHDVPSS method (abbreviated as VP-PC) at different zinc (Zn) concentration levels and compared with the traditional cement-based solidification/stabilization method (abbreviated as SS-PC). A series of experimental tests such as unconfined compressive strength (UCS), toxicity characteristics leaching procedure (TCLP), X-ray diffraction (XRD) and scanning electron microscopy in conjunction with energy-dispersive spectroscopy (SEM-EDS) were performed to assess the long-term strength, leaching and microstructural characteristics of high-water-content DCS, respectively. The UCS test results indicated that the strength of VP-PC mixes increased significantly with curing time compared to the limited strength development of SS-PC mixes. After 180-day curing, VP-PC mixes exhibited 3.5-5.5 times higher UCS values than the SS-PC mixes. Furthermore, when compared to the SS-PC mixes, the VP-PC mixes had 14.7-36.4% lower leached Zn concentrations at different Zn levels. This is attributed to an increase in the least reactive F4 (residual) fraction and a decrease in the most mobile F1 (acid-soluble) fraction as confirmed by the BCR method. Microstructural tests including XRD and SEM-EDS revealed that calcium silicate hydrate-like compounds were identified as the main hydration products of both the VP-PC and SS-PC mixes. However, portlandite, a major hydration product of PC, was not detected in either case, which is attributed to the retardant effect of Zn on cement hydration. Overall, the experimental results showed that the PHDVPSS method, when compared to the conventional solidification/stabilization method, is a viable choice for treating high-water-content DCS at different Zn concentration levels with low cement content.


Electrically stimulating prefrontal cortex at retrieval improves recollection accuracy.
Neuroimaging and brain damage studies suggest that dorsolateral prefrontal cortex (dlPFC) is involved in the cognitive control of episodic recollection. If dlPFC is causally involved in retrieval, then transcranial direct current stimulation (tDCS) of this brain region should increase recollection accuracy, especially when recollection is difficult and requires cognitive control. Here, we report the first brain stimulation experiment to directly test this hypothesis. We administered tDCS to dlPFC immediately after studying to-be-learned material but just prior to recollection testing, thereby targeting retrieval processes. We found that stimulation of dlPFC significantly increased recollection accuracy, relative to a no-stimulation sham condition and also relative to active stimulation of a comparison region in left parietal cortex. There was no significant difference in the size of this increase between hemispheres. Moreover, these dlPFC stimulation effects were behaviorally selective, increasing accuracy only when participants needed to recollect difficult information. Electrically stimulating dlPFC allowed people to more accurately recollect specific details of their experiences, demonstrating a causal role of dlPFC in the retrieval of episodic memories.


Knee arthroplasty for acute fractures around the knee.
Results of open reduction and internal fixation for complex articular fractures around the knee are poor, particularly in elderly osteoporotic patients.Open reduction and internal fixation may lead to an extended hospital stay and non-weight-bearing period.This may lead to occurrence of complications related to decubitus such as thrombo-embolic events, pneumonia and disorientation.Primary arthroplasty can be a valuable option in a case-based and patient-specific approach. It may reduce the number of procedures and allow early full weight-bearing, avoiding the above-mentioned complications.There are four main indications: 1) Elderly (osteoporotic) patients with pre-existing (symptomatic) end-stage osteoarthritis.2) Elderly (osteoporotic) patients with severe articular and metaphyseal destruction.3) Pathological fractures of the distal femur and/or tibia.4) Young patients with complete destruction of the distal femur and/or tibia.The principles of knee (revision) arthroplasty should be applied; choice of implant and level of constraint should be considered depending on the type of fracture and involvement of stabilizing ligaments. The aim of treatment is to obtain a stable and functional joint.Long-term data remain scarce in the literature due to limited indications. Cite this article: EFORT Open Rev 2020;5:713-723. DOI: 10.1302/2058-5241.5.190059.


Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not.
Pregnenolone (P), the main precursor of the steroids, and its sulfate ester, pregnenolone sulfate (PS), are the major neurosteroids produced in the neural tissue. Many neuroendocrinological studies stressed the neuroprotective role of neurosteroids although it has been suggested that the inhibition of P and PS synthesis can delay neuronal cell death. The potential roles of P and PS in vital neuronal functions and in amyloid beta peptide (Abeta) toxicity are not clearly identified. This work aims to investigate the effects of P and PS on cell viability and Abeta peptide toxicity in a concentration and exposure time-dependent manner in rat PC-12 cells. The cells were treated with 20muM Abeta peptide 25-35 and variable concentrations of P and PS ranging from 0.5muM to 100muM. To examine the effects of steroid treatment on Abeta peptide toxicity, 0.5muM (low) and 50muM (high) neurosteroids were used. The cell viability and lactate dehydrogenase release of cells were evaluated after 24, 48 and 72h. Morphological changes of cells were also examined. The treatment with higher than 1muM concentrations of P and PS significantly decreased the cell viability comparing to untreated cells. At lower concentrations, P and PS had no toxic actions until 72h. The Abeta treatment resulted in a significant decrease in cell viability comparing to untreated cells. P showed a dose-dependent protective effect against Abeta peptide in PC-12 cells. But its sulfate ester did not have the same effect on Abeta peptide toxicity, even it significantly decreased cell viability in Abeta-treated cells. Consequently, the discrepant effects of P and PS on Abeta peptide toxicity may provide insight on the pathogenesis of Alzheimer's disease.


microRNA-542-5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen-activated protein kinase signaling pathway through the negative regulation of P21-activated kinase 1.
Severe acute pancreatitis (SAP) is a condition associated with high rates of mortality and lengthy hospital stays. In the current study, SAP mouse models were established in BALB/c wild-type and P21-activated kinase 1 (PAK1) knockdown mice with the objective of determining the expression of microRNA-542-5p (miR-542-5p) and the subsequent elucidation of the mechanism by which it influences acute lung injury (ALI) by mediating mitogen-activated protein kinase (MAPK) signaling and binding to PAK1. The targeting relationship between miR-542-5p and PAK1 was verified using the bioinformatics prediction website and by the means of a dual-luciferase reporter assay. Following the SAP model establishment, the mice were assigned into various groups with the introduction of different mimic and inhibitors in an attempt to investigate the effects involved with miR-542-5p on inflammatory reactions among mice with SAP-associated ALI. Our results indicated that PAK1 was targeted and negatively mediated by miR-542-5p. Mice with SAP-associated ALI exhibited an increased wet-to-dry weight ratio, myeloperoxidase activity, serum amylase activity, TNF-α, interleukin-1 beta (IL-1β), and intercellular adhesion molecule-1 (ICAM-1) contents, p-p38MAPK, p-ERK1/2, and p-JNK protein levels as well as PAK1 positive expression, while decreased miR-542-5p levels were observed. Functionally, overexpression of miR-542-5p improves ALI in mice with SAP via inhibition of the MAPK signaling pathway by binding to PAK1.Based on the evidence from experimental models, miR-542-5p was shown to improve ALI among mice with SAP, while suggesting that the effect may be related to the inactivation of the MAPK signaling pathway and downregulation of PAK1 gene. Thus, miR-542-5p could serve as a promising target for ALI treatment.


Machine learning-based construction of a ferroptosis and necroptosis associated lncRNA signature for predicting prognosis and immunotherapy response in hepatocellular cancer.
Liver hepatocellular carcinoma (LIHC), one of the most common malignancies worldwide, occurs with high incidence and mortality. Ferroptosis and necroptosis are critically associated with LIHC prognosis. Some long non-coding RNAs (lncRNAs) have been found to induce ferroptosis and necroptosis in hepatocellular carcinoma cells. Cox regression analysis was used to construct a risk model for LIHC based on differentially expressed ferroptosis and necroptosis related lncRNAs (F-NLRs), and their expression in SMMC7721, HepG2 and WRL68 cells was detected by qPCR. Five F-NLRs were associated with LIHC prognosis, including KDM4A-AS1, ZFPM2-AS1, AC099850.3, MKLN1-AS, and BACE1-AS. Kaplan-Meier survival analysis indicated that patients with LIHC in the high-risk group were associated with poor prognosis. The combined F-NLR signature model demonstrated a prognostic AUC value of 0.789 and was more accurate than standard clinical variables for predicting LIHC prognosis. T cell functions and immunotherapy responses differed significantly between patients in the low- and high-risk groups. Additionally, immune checkpoints and m6A-related genes were differentially expressed between patients in the two risk groups. Furthermore, proteins encoded by the five F-NLRs were overexpressed in four liver cancer cell lines compared to that in human liver cell line WRL68. Pan-cancer examination revealed that expression levels of the five F-NLRs differed between most common tumor types and normal tissues. F-NLRs identified in this study provide a predictive signature representing ferroptosis and necroptosis in LIHC, which correlated well with patient prognosis, clinicopathological characteristics, and immunotherapy responses. The study findings help to elucidate the mechanisms of F-NLRs in LIHC and provide further guidance for the selection and development of immunotherapeutic agents for LIHC.


Ultastructural analysis on acetylcholinesterase localization in the cerebellar cortex of teleosts.
The histochemical localization of acetylcholinesterase (AChE) was studied by electron microscopy in the cerebellar cortex of the goldfish and the catfish. The patterns of enzyme distribution show noticeable differences in the two teleost species at the level of the corresponding cerebellar structures. Among the most distinctive features is the prevailing intracellular localization of enzyme activity in the goldfish and the prevailing extracellular localization in the catfish in the molecular layer and, to a lesser extent, the granular layer. Only quantitative differences in the ability to synthesize AChE can be recorded among the different cerebellar neurons in the two species, since all these neurons exhibit different amounts of enzyme activity linked to their cytoplasmic structures. Comparing the results obtained with those of previous histochemical, experimental and developmental researches, the hypothesis seems well founded that the embryonic pool of cerebellar neurons is made up of AChE-synthesizing nruroblasts which, during development, loss or maintain to a different the mechanisms for AChE synthesis. In addition the light and electron microscope histochemistry reveals at different levels of resolution that the final pattern of AChE distribution in the cerebellar cortex is the sum of different degress of AChE synthesis by cerebellar neurons and different degrees of enzyme release in extracellular spaces.


Ral-Arf6 crosstalk regulates Ral dependent exocyst trafficking and anchorage independent growth signalling.
Integrin dependent regulation of growth factor signalling confers anchorage dependence that is deregulated in cancers. Downstream of integrins and oncogenic Ras the small GTPase Ral is a vital mediator of adhesion dependent trafficking and signalling. This study identifies a novel regulatory crosstalk between Ral and Arf6 that controls Ral function in cells. In re-adherent mouse fibroblasts (MEFs) integrin dependent activation of RalA drives Arf6 activation. Independent of adhesion constitutively active RalA and RalB could both however activate Arf6. This is further conserved in oncogenic H-Ras containing bladder cancer T24 cells, which express anchorage independent active Ral that supports Arf6 activation. Arf6 mediates active Ral-exocyst dependent delivery of raft microdomains to the plasma membrane that supports anchorage independent growth signalling. Accordingly in T24 cells the RalB-Arf6 crosstalk is seen to preferentially regulate anchorage independent Erk signalling. Active Ral we further find uses a Ral-RalBP1-ARNO-Arf6 pathway to mediate Arf6 activation. This study hence identifies Arf6, through this regulatory crosstalk, to be a key downstream mediator of Ral isoform function along adhesion dependent pathways in normal and cancer cells.


Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients.
Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition? We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls. NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase. Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work.


Resorption of synthetic porous hydroxyapatite and replacement by newly formed bone.
Synthetic porous hydroxyapatite (HA) is commonly used as a bone substitute for bone defects which, previously, would have been treated by autogenous bone grafting. HA has been thought to be a nonbiodegradable material that remains as it is implanted. However, after long-term follow-up, some authors report that the margin of implanted HA blocks or granules is absorbed, suggesting that HA is biodegradable. We experienced a patient in whom synthetic HA blocks implanted in a bone defect of the ilium after the harvesting of full-thickness bone for grafting were extensively absorbed and replaced by newly formed bone 6 years and 7 months after the implantation. Therefore, we conclude that HA is biodegradable. Sintering temperature, porosity, and pore diameter seem to influence the biodegradability of HA.


Investigation of potent anticarcinogenic activity of 1, 3-diarylpyrazole acrylamide derivatives in vitro.
Pyrazole derivatives are pharmacologically powerful agents pointing at new horizons in the development of anticancer therapies. In this study, anticarcinogenic potential of a series of pyrazole-acrylamide derivatives has been investigated in mesothelial, malignant mesothelioma and lung cancer cell lines. The effect of compounds on the viability of cells and the distribution of cell cycle were examined through MTS assay and PI staining, respectively. Apoptosis was evaluated via caspase-3 enzymatic assay and AO/EB staining. Proteins involved in proliferation, survival and apoptosis were analysed by immunoblotting. Twelve compounds of 21 (4a-4v) reduced the viability of cells but, only the subset of five (4f, 4i, 4j, 4k and 4v) induced the caspase-3 activity. Among five, only one compound (4k) significantly suppressed phosphorylation and expression of ERK1/2 and AKT proteins in 24 h. Exposing cancer cells to successive concentrations of 4k gave rise to dose- and time-dependent G2/M phase arrest and apoptosis. 4k has revealed its potent antiproliferative activity by decreasing viability and inhibiting proliferation and survival signals of cancer cells. Moreover, 4k has exposed cytostatic and apoptotic effect especially, on cancer cells. Therefore, it may be necessary to examine the biological actions of 4k in vivo as well.


Optimal ossicular site for maximal vibration transmissions to coupled transducers.
Totally implantable middle-ear prosthetic devices, such as the Esteem system (Envoy Medical Corporation), detect vibrational motion of the middle-ear ossicles rather than acoustic stimulation to the eardrum. This eliminates the need for a subcutaneous microphone, which is susceptible to interference by ambient noises. Study of the vibrational characteristics of the human ossicles provides valuable information for determining the site of maximum ossicular motion that would be optimal for attachment of the sensor portion of the prosthesis. In this study, vibrational responses at seven locations on the middle-ear ossicles (i.e., the malleus head, 4 different points on the incus body, middle of the incus long process, tip of the incus long process) in human temporal bones (n = 6) were measured using a laser Doppler vibrometer. The measurements were repeated after separating the incudostapedial joint (ISJ). Measured displacement at each location was normalized with the sound pressure level near the tympanic membrane (TM) for representation in the form of a displacement transfer function (DTF). The normalized squared sum of the DTFs (NSSDTF) was then calculated as a measure of vibration motion through a specific frequency range at the considered sites. The relatively large NSSDTF was observed at the sites on the superior part of the malleus head (MH), on the lateral part of the incus body (IBL), and on the superior part of the incus body near the incudomalleal joint (IBS1) for the frequency ranges of 1-4 kHz and 1-9 kHz, regardless of the condition of the ISJ. This indicates that maximum vibrational motion of the middle-ear is deliverable to the piezoelectric transducer of totally implantable devices through these sites. This article is part of a special issue entitled "MEMRO 2012".


Association between wind-up ratio and central serotonergic function in healthy subjects and depressed patients.
Temporal summation of C-fiber evoked responses generates an increase in action potential discharge in second-order neurons and in perceived pain intensity (wind-up). This may be related to the central serotonergic system which modulates and partly inhibits sensory input. Aim of the study was to investigate the relationship between wind-up and serotonergic activity using loudness dependence of auditory evoked potentials (LDAEP). 18 healthy subjects were compared to 18 patients with major depression, a disease with a putative serotonin deficit. They were examined with quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain (DFNS), including the wind-up ratio (WUR), LDAEP, and psychometric measurements. We found a slight positive correlation between WUR and LDAEP both in healthy controls and depressed patients combined (r=0.340, p=0.043), indicating that WUR may be modulated by serotonergic activity. It can be concluded that inhibitory control to noxious stimuli is partly associated with the central serotonergic function as indicated by LDAEP.


Comparison of navigated laser and conventional single-spot laser system for induced pain during panretinal photocoagulation.
To compare the panretinal photocoagulation (PRP)-induced pain response between novel navigated laser (Navilas) and conventional single-spot laser. The eyes were randomly assigned to Navilas or conventional laser. Contralateral eyes underwent PRP with the other system with 30 min resting interval. Pulse duration was 100 ms in conventional laser and 30 ms or 100 ms in Navilas and power setting was enough to create gray-white light burn on both devices. Pain response was evaluated by verbal scale (VS) (0-4) and visual analog scale (VAS) (0-10) after each PRP application. The mean age of 70 patients (140 eyes) was 62.52 ± 9.49 years. Mean power and spot numbers for Navilas and conventional laser were 291.9 ± 85.3 mW vs 368.4 ± 72.0 mW, and 375.4 ± 108.4 vs 374.2 ± 105.0 (p < 0.001 and p = 0.53, respectively). Pain scores for Navilas and conventional laser were 1.19 ± 0.73 and 1.99 ± 0.84 for VS and 2.41 ± 1.65 and 4.74 ± 2.17 for VAS (p < 0.001 and p < 0.001). More comfortable PRP is achieved with Navilas system in comparison with conventional single-spot laser system. However, small number of patients treated with same pulse duration and different contact lenses used for two systems should be taken into consideration. Besides, we did not report comparative clinical efficiency of either laser system.


[Biosynthesis of renal prostaglandins in spontaneously hypertensive rats].
Biosynthesis of prostaglandins E2 and F2alpha from the exogenously added 14C-arachidonic acid in the renal medulla of spontaneously hypertensive (SHR) and normotensive Wistar rats (1 1/2- and 3 1/2-months-old) was studied. Investigations carried out showed that the formation of PgE2 from the arachidonic acid by the kidneys of SHR was significantly lower than in Wistar rats, whereas biosynthesis of PgF2alpha was practically normal. No difference in the prostaglandin-synthetase activity was noted in the kidneys of SHR of different age, whereas Wistar rats displayed a reduction of the PgE2 synthesis by the age of 3 1/2 months.


Shape, connectedness and dynamics in neuronal networks.
The morphology of neurons is directly related to several aspects of the nervous system, including its connectedness, health, development, evolution, dynamics and, ultimately, behavior. Such interplays of the neuronal morphology can be understood within the more general shape-function paradigm. The current article reviews, in an introductory way, some key issues regarding the role of neuronal morphology in the nervous system, with emphasis on works developed in the authors' group. The following topics are addressed: (a) characterization of neuronal shape; (b) stochastic synthesis of neurons and neuronal systems; (c) characterization of the connectivity of neuronal networks by using complex networks concepts; and (d) investigations of influences of neuronal shape on network dynamics. The presented concepts and methods are useful also for several other multiple object systems, such as protein-protein interaction, tissues, aggregates and polymers.


Markers of Epstein-Barr Virus Infection in Association with the Onset and Poor Control of Rheumatoid Arthritis: A Prospective Cohort Study.
Although the connection between Epstein-Barr virus (EBV) and rheumatoid arthritis (RA) has been studied for over 40 years, many questions still need clarification. The study aimed to analyze the possible association between anti-EBV antibody titers, EBV DNA viremia, EBV infection status and EBNA1 (Epstein-Barr nuclear antigen 1-EBNA1) variants and clinical parameters of RA patients. This prospective cohort study included 133 RA patients and 50 healthy controls. Active/recent EBV infection was more prevalent in RA patients than in controls (42% vs. 16%, p < 0.001). RA patients had higher titers of anti-EBV-CA-IgM (capsid antigen-CA) and anti-EBV-EA(D)-IgG (early antigen-EA) antibodies than controls (p = 0.003 and p = 0.023, respectively). Lower levels of anti-EBNA1-IgG and anti-EBV-CA-IgG were observed in RA patients who received methotrexate (anti-EBNA1 IgG p < 0.001; anti-EBV-CA IgG p < 0.001). Based on amino acid residue on position 487, two EBNA1 prototypes were detected: P-Thr and P-Ala. Patients with active/recent EBV infection had a five times more chance of having RA and a nearly six times more chance of getting RA. Also, EBV active/recent infection is twice more likely in newly diagnosed than in methotrexate-treated patients. Further studies are needed to clarify "who is the chicken and who is the egg" in this EBV-RA relationship.


Resveratrol protects Lactobacillus reuteri against H2O2- induced oxidative stress and stimulates antioxidant defenses through upregulation of the dhaT gene.
Understanding of the mechanisms implicated in the protective role of probiotic bacteria is of the utmost scientific interest. This study provides original insight into the genetic and molecular basis of the responses of Lactobacillus reuteri PL503 against hydrogen peroxide (H2O2)-induced oxidative stress. Six experimental groups were considered depending on the addition and concentration of H2O2 and resveratrol: 1. CONTROL (L. reuteri in MRS broth); 2. H2O2 (L. reuteri in MRS broth + 0.5 mM H2O2); 3. LRES (L. reuteri in MRS broth + 20 μM resveratrol); 4. HRES (L. reuteri in MRS broth + 100 μM resveratrol); 5. H2O2-LRES (L. reuteri in MRS broth + 0.5 mM H2O2 + 20 μM resveratrol); 6. H2O2-HRES (L. reuteri in MRS broth + 0.5 mM H2O2 + 100 μM resveratrol). Three replicates were incubated at 37 °C for 24 h in microaerophilic conditions sampled at 12, 16, 20 and 24 h. The NADH-dependent-oxidoreductase encoded by the dhaT gene is a plausible candidate to be strongly implicated in the antioxidant response of L. reuteri. Resveratrol (100 μM) is found to protect L. reuteri against protein carbonylation plausibly through various mechanisms including direct scavenging of reactive oxygen species (ROS), upregulation of the dhaT gene and promoting the synthesis of sulfur containing compounds. The hypothesis formulated on the ability of L. reuteri to detoxify H2O2 and its underlying mechanism needs to be clarified. Furthermore, the consequences of protein carbonylation as a reflection of oxidative damage to bacteria and its role in the responses of bacteria to oxidative stress need to be further investigated.


Administration of nintedanib after discontinuation for acute exacerbation of idiopathic pulmonary fibrosis: a case report.
Nintedanib is a multi-target receptor tyrosine kinase inhibitor. In two recent randomized phase 3 trials (INPULSIS™-1 and -2), it has been shown to slow the disease progression of idiopathic pulmonary fibrosis (IPF) by reducing the decline in the forced vital capacity (FVC). Although the INPULSIS™ trials indicate that nintedanib may serve to prevent acute exacerbations or delay the time to the first acute exacerbation, a certain number of IPF patients develop acute exacerbations while receiving nintedanib. However, there has been no report on the readministration of nintedanib in IPF patients who develop acute exacerbations during initial treatment with nintedanib. A 64-year-old man with IPF had nintedanib added to his ongoing pirfenidone therapy. He developed dyspnea after 65 days and presented with hypoxemia after 68 days. At presentation, chest computed tomography showed newly developed diffuse ground glass opacities with the pre-existing subpleural reticular shadows. Because of the absence of infection or other potential causative factors, we diagnosed an acute exacerbation of IPF. Nintedanib was temporarily discontinued and the acute exacerbation was successfully managed with intensive treatment. We re-initiated nintedanib 30 days after cessation, which helped stabilize his FVC for 8 months. Nintedanib was safely continued for 28 months until he died of a bacterial infection. To the best of our our knowledge, this is the first reported case of an acute exacerbation of IPF during nintedanib treatment, wherein nintedanib was safely and successfully restarted after treatment of the acute exacerbation. Our case indicates that nintedanib can be safely resumed and a desired effect on FVC can be obtained, even in IPF patients who develop acute exacerbations. However, we recommend close monitoring and appropriate measures until the long-term safety profile is clarified.


[Preliminary study on the relation between serum growth hormone and 1,25-dihydroxyvitamin D3 in acromegalic patients].
Eight acromegalic patients were treated with SMS 201-995 for 12 months. At the 3rd, 6th and 12th month from the beginning of treatment, blood samples of these patients were taken for determination of growth hormone (GH), 1,25-(OH)2D3, SMC, calcium and phosphorus. The serum levels of GH decreased significantly at the 3rd, 6th and 12th months compared with the basal levels before treatment (P less than 0.01, P less than 0.05 and P less than 0.05 respectively). The concentrations of serum 1,25-(OH)2D3 and SMC also decreased significantly. Mean serum GH, 1,25-(OH)2D3 and SMC levels were reduced from 34.8 +/- 10.7 to 15.5 +/- 5.9 ng/ml (P less than 0.05), 76.2 +/- 2.7 to 45.9 +/- 8.3 pg/ml (P less than 0.05) and 8.5 +/- 1.2 to 4.4 +/- 1.0 U (P less than 0.05) respectively at the 12th month after treatment. Serum phosphorus levels reduced from 4.7 +/- 0.4 to 4.1 +/- 0.2 mg% (P less than 0.05) at the 6th month after treatment, but there was no change in the serum levels of total calcium. The treatment with SMS 201-995 directly evoked a reduction of serum GH in acromegalic patients and at the same time, the levels of serum SMC and 1,25-(OH)2D3 were decreased. The results suggest that GH may stimulate indirectly the production of 1,25-(OH)2D3 through the mediation of SMC.


Prognostic value of normal adenosine-stress cardiac magnetic resonance imaging.
We investigated the prognostic value of normal adenosine stress cardiac magnetic resonance (CMR) in suspected coronary artery disease (CAD). Prospectively enrolled in the study were 218 patients with suspected CAD, no stress hypoperfusion, and no delayed enhancement in CMR, and consecutively deferred coronary angiography. The primary end point was a 12-month rate of major adverse cardiac events (MACE; cardiovascular mortality, myocardial infarction, revascularization, hospitalization due to cardiovascular event). CMR indication was symptomatic angina (Canadian Cardiovascular Society II in 42% and III in 7%) or evaluation of myocardial ischemia in patients with arrhythmia, syncope, and/or equivocal stress tests and cardiovascular risk factors (51%). As the main result, the 12-month MACE rate was 2/218 (1 stent implantation, 1 bypass surgery) and CMR negative predictive value 99.1%. There was no cardiac death or myocardial infarction. In conclusion, normal adenosine stress CMR predicts a very low MACE rate and an excellent 1-year prognosis in patients with suspected CAD. Our results provide clinical reassurance that patients at risk for CAD-associated MACE were not missed by CMR. Hence, CMR may serve as a reliable noninvasive gatekeeper to reduce the number of redundant coronary angiographies.


Levels of autoantibodies against beta-adrenergic receptors and mitochondrial antigens in sera of cardiomyopathic patients estimated by ELISA method.
Levels of autoantibodies against beta-adrenergic receptors and mitochondrial antigens were estimated by the ELISA method in a group of 41 cardiomyopathic children. These results were compared with results obtained from 26 sera of a control group. In the group of cardiomyopathic patients 11 sera with significantly increased levels of autoantibodies against beta-adrenergic receptors and seven sera with increased levels of autoantibodies against mitochondrial antigens were found. In no sample of the control group did we observe sera with increased levels of autoantibodies. Statistical significance of this data was evaluated by chi 2-test (p less than 0.005 or p less than 0.05, resp.).


Efficacy of tyrosine kinase inhibitors for the treatment of patients with HER2-positive breast cancer with brain metastases: a systematic review and meta-analysis.
Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2 tyrosine kinase inhibitors (TKIs) are promising agents for the treatment of BM. In this study, we assess the clinical outcomes of patients with HER2-positive MBC and BM treated with TKI-containing regimens compared with those treated with non-TKI-containing regimens. PubMed, Embase, Cochrane Library, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) were searched up to June 2021. The primary endpoint was progression-free survival (PFS) in patients with BM. Secondary endpoints included PFS in patients without BM and overall survival (OS). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models. This systematic review and meta-analysis included data from 2437 patients (490 with and 1947 without BM at baseline) enrolled in five trials assessing tucatinib-, lapatinib-, pyrotinib-, or afatinib-based combinations. A nonstatistically significant PFS benefit favoring TKI-containing regimens was observed in both patients with BM [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.41-1.12; P = 0.13] and without BM (HR 0.55, 95% CI 0.24-1.26; P = 0.16). Sensitivity analysis, excluding each study singly, demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM after the exclusion of afatinib from the analysis (HR 0.56, 95% CI 0.35-0.90; P = 0.016). No statistically significant differences in OS were observed between the comparison groups. A trend in PFS favoring TKI-containing regimens was observed in patients with BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib, or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM.


Suppressing progress of pancreatitis through selective inhibition of NF-KappaB activation by using NAC.
To explore the characteristics of NF-KappaB activation in the progress of pancreatitis, the relationship with expression of TNF-alpha in the inflammatory reaction, and prevent the exacerbation of pancreatitis by using NAC. Forty-eight rats were divided into three groups: therapy (group C), pancreatitis (group B) and control (group A). NAC served as the inhibitor of NF-KappaB activation. In the time intervals of 1.5, 3.0, 6.0, 12.0 hour, NF-KappaB activation was detected with flow cytometry (FCM) and the expression of TNF-alpha mRNA and protein with in situ hybridization (ISH) and enzyme-linked immuno-sorbent assay (ELISA) respectively. Meanwhile, the level of lipase and amylase in the serum was assayed and the pathological change was evaluated. NF-KappaB activation in the pancreatitis group was higher than that in the control group (P<0.01), peaked at 3 hours, and was depressed by the inhibitor of NF-KappaB, NAC. The expression of TNF-alpha as well as the level of lipase and amylase in the serum also rose synchronously with activation of NF-KappaB. In contrast to group A, it was significantly different (P<0.01) in group B. After using NAC in group C, all of these values were decreased and the inflammatory reaction in the pancreas abated evidently. The pathology changes of the pancreas were shown to be alleviated in group C. First, NF-KappaB activity is intensively initiated in the course of pancreatitis and shown to have closely relationship with the release of cytokines. Second, use of NAC markedly depressed NF-KappaB activation. TNF-alpha expression is down regulated by cytokines. It is suggested that NAC probably acts as a useful agent for treatment of pancreatitis by indirectly inhibiting activation of NF-KappaB.


Diagnosis of follicular carcinoma of the thyroid: role of sonography in preoperative diagnosis of follicular nodules.
The purpose of this study was to evaluate sonographic examination, as well as other clinical tests, for clarifying the parameters for predicting follicular carcinoma in follicular nodules of the thyroid. Nine hundred and ten consecutive patients with follicular nodules were pathologically classified as having follicular carcinoma (109 patients) or benign tumor (811 patients). Benign tumors included follicular adenoma (237 patients) and adenomatous thyroid nodules (574 patients). A case-control study was performed for follicular carcinomas and benign tumors. "Thyroglobulin 1000 ng/ml≦", "cytology class 3≦", and a "solid pattern", "low-echoic level of internal echo", and "jagged borders" of follicular carcinomas were found to be significantly higher than those of benign tumors. The sensitivities of a solid pattern (79.8%) and a low-echoic level (75.2%) were found to be relatively higher than those of other features and findings. The specificities of thyroglobulin 1000 ng/ml≦(84.0%), cytology class 3≦, and jagged borders (86.2%) were found to be relatively higher than those of other features and findings. We concluded that thyroglobulin 1000 ng/ml≦ and cytology class 3≦ in clinical features, and a solid pattern, low-echoic level, and jagged borders on sonography, indicated an increased risk of follicular carcinoma of the thyroid in follicular nodules.


A Mg(2+)-dependent endonuclease is responsible for internucleosomal DNA fragmentation in human B lymphoblastic IM9 cells.
We have identified a Mg(2+)-dependent endonuclease activity from human B lymphoblastic IM9 cell lysates and nuclei using autodigestion method and DNA-native-polyacrylamide gel electrophoresis (DNA-native-PAGE) nuclease assay system. The level of the endonuclease activity in cell lysates was significantly decreased at certain stage by treatment of the cells with cycloheximide. However, the enzyme activity consistently remained for over 12 hours in the isolated nuclei of the apoptotic IM9 cells. The Mg(2+)-dependent endonuclease isolated from the nuclei by native-PAGE elution was able to catalyze the conversion of supercoiled plasmid DNA into linear form. This particular endonuclease activity was not detected in cycloheximide treated-U937 cells. Several lines of experimental evidence suggest that the Mg(2+)-dependent endonuclease localized in the nucleus may be responsible for the DNA fragmentation of apoptotic IM9 cells.