The role of tramadol in pain management in Latin America: a report by the Change Pain Latin America Advisory Panel.
Change Pain Latin America (CPLA) was created to enhance chronic pain understanding and develop pain management improving strategies in this region. During its seventh meeting (August 2016), the main objective was to discuss tramadol's role in treating pain in Latin America. Furthermore, potential pain management consequences were considered, if tramadol was to become more stringently controlled. Key topics discussed were: main indications for prescribing tramadol, its pharmacological characteristics, safety and tolerability, effects of restrictions on its availability and use, and consequent impact on pain care quality. The experts agreed that tramadol is used to treat a wide spectrum of non-oncological pain conditions (e.g. post-surgical, musculoskeletal, post-traumatic, neuropathic, fibromyalgia), as well as cancer pain. Its relevance when treating special patient groups (e.g. the elderly) is recognized. The main reasons for tramadol's high significance as a treatment option are: its broad efficacy, an inconspicuous safety profile and its availability, considering that access to strong analgesics - mainly controlled drugs (classical opioids) - is highly restricted in some countries. The CPLA also agreed that tramadol is well tolerated, without the safety issues associated with long-term nonsteroidal anti-inflammatory drug (NSAID) use, with fewer opioid-like side effects than classical opioids and lower abuse risk. In Latin America, tramadol is a valuable and frequently used medication for treating moderate to severe pain. More stringent regulations would have significant impact on its availability, especially for outpatients. This could cause regression to older and frequently inadequate pain management methods, resulting in unnecessary suffering for many Latin American patients.


Secondary central nervous system lymphoma: spectrum of morphological MRI appearances.
Secondary central nervous system lymphoma (SCNSL) is a rare and aggressive disease, which is defined as secondary central nervous system (CNS) involvement in patients with systemic lymphoma. According to previous reports, SCNSL presents mostly with leptomeningeal spread; however, our experience differs. In the present study, we demonstrate the diversity of magnetic resonance imaging (MRI) patterns in SCNSL. Initial morphological MRI findings in 21 patients (10 women and 11 men with mean age 62.3±16.2 years) with SCNSL were retrospectively evaluated. All patients suffered from neurological symptoms and underwent MRI, and all cases were histologically verified. Twelve patients were treated by corticosteroids at the time of the initial MRI. Parenchymal lesions were present in 18 of 21 cases (85.7%), solitary meningeal infiltration was present in 1 patient (4.8%), leptomeningeal infiltration in combination with hypophyseal involvement in 1 patient (4.8%), and solitary involvement of the sixth cranial nerve (CN) was found in 1 patient (4.8%). Multiple lesions were present in 11 of 21 cases (52.4%). Diffusion restriction in all or part of the lesion was detected in 14 of 18 cases (77.8%). All parenchymal lesions had an infiltrative appearance and most enhanced homogenously (11 of 17 cases; 64.7%). A combination of parenchymal and meningeal involvement was found in 10 of 21 cases (47.6%). Infiltration of the CNs, basal ganglia, corpus callosum, and ependyma was present in 8 of 21 cases (38.1%) for each of the abovementioned structures; hypothalamic-hypophyseal axis was affected in 7 of 21 cases (33.3%). In contrast to previous reports, SCNSL presented as parenchymal disease. MRI is not sufficient for differentiation between primary and secondary CNS lymphoma.


Combined Transcriptome and Proteome Analysis Provides Insights into Petaloidy in Pomegranate.
Petaloidy leads to a plump floral pattern and increases the landscape value of ornamental pomegranates; however, research on the mechanism of petaloidy in ornamental pomegranates is limited. In this study, we aimed to screen candidate genes related to petaloidy. We performed transcriptomic and proteomic sequencing of the stamens and petals of single-petal and double-petal flowers of ornamental pomegranates. Briefly, 24,567 genes and 5865 proteins were identified, of which 5721 genes were quantified at both transcriptional and translational levels. In the petal and stamen comparison groups, the association between differentially abundant proteins (DAPs) and differentially expressed genes (DEGs) was higher than that between all genes and all proteins, indicating that petaloidy impacts the correlation between genes and proteins. The enrichment results of transcriptome, proteome, and correlation analyses showed that cell wall metabolism, jasmonic acid signal transduction, redox balance, and transmembrane transport affected petaloidy. Nine hormone-related DEGs/DAPs were selected, among which ARF, ILR1, LAX2, and JAR1 may promote petal doubling. Sixteen transcription factor DEGs/DAPs were selected, among which EREBP, LOB, MEF2, MYB, C3H, and trihelix may promote petal doubling. Our results provide transcriptomic and proteomic data on the formation mechanism of petaloidy and a theoretical basis for breeding new ornamental pomegranate varieties.


Effects of two commercial diets and two supplements on urinary pH in dogs.
Urinary pH manipulation by therapeutic foods or supplements is part of the treatment for urolithiasis. The effectiveness of these diets and supplements should be studied to determine which of these strategies is most effective. To assess the effect of the oral supplementation of potassium citrate, an ammonium chloride solution (Urical) and two dry therapeutic foods-Hill's® Prescription Diet® u/d® Canine (u/d diet) and Royal Canin® Urinary S/O dog (S/O diet)-on a dog's urinary pH at different time points over 8 h. Seven healthy adult male research beagle dogs. A prospective interventional study lasting 31 days. The dogs either received a supplement (potassium citrate or rical) with a dry adult maintenance diet (control diet) or the therapeutic diet (u/d diet or S/O diet). Each treatment had a duration of 2-5 days, with 2- to 4-day washout periods in between. Urinary pH measurements were performed every 2 h between 07h00 and 15h00, with the food being given at 07h00 and 15h00, right after urine collection. The pH measurements obtained in each of the four treatments were compared to control (same dogs fed the control diet exclusively). When compared to the control diet at the same time points, biologically relevant changes in urinary pH (defined as ≥0.5) were: increase with potassium citrate at 7h00 and 13h00; increase with u/d diet at 9h00, 13h00, and 15h00; decrease with S/O diet at 9h00 and 11h00; Urical did not have a detectable effect on urinary pH. The present study confirms that therapeutic foods S/O and u/d, and potassium citrate supplement affected acid-base balance in healthy adult male beagle dogs, with the tested diets being more effective than the administered doses of the tested supplements at influencing urinary pH.


Aerosol climate change effects on land ecosystem services.
A coupled global aerosol-carbon-climate model is applied to assess the impacts of aerosol physical climate change on the land ecosystem services gross primary productivity (GPP) and net primary productivity (NPP) in the 1996-2005 period. Aerosol impacts are quantified on an annual mean basis relative to the hypothetical aerosol-free world in 1996-2005, the global climate state in the absence of the historical rise in aerosol pollution. We examine the separate and combined roles of fast feedbacks associated with the land and slow feedbacks associated with the ocean. We consider all fossil fuel, biofuel and biomass burning aerosol emission sources as anthropogenic. The effective radiative forcing for aerosol-radiation interactions is -0.44 W m-2 and aerosol-cloud interactions is -1.64 W m-2. Aerosols cool and dry the global climate system by -0.8 °C and -0.08 mm per day relative to the aerosol-free world. Without aerosol pollution, human-induced global warming since the preindustrial would have already exceeded the 1.5 °C aspirational limit set in the Paris Agreement by the 1996-2005 decade. Aerosol climate impacts on the global average land ecosystem services are small due to large opposite sign effects in the tropical and boreal biomes. Aerosol slow feedbacks associated with the ocean strongly dominate impacts in the Amazon and North American Boreal. Aerosol cooling of the Amazon by -1.2 °C drives NPP increases of 8% or +0.76 ± 0.61 PgC per year, a 5-10 times larger impact than estimates of diffuse radiation fertilization by biomass burning aerosol in this region. The North American Boreal suffers GPP and NPP decreases of 35% due to aerosol-induced cooling and drying (-1.6 °C, -0.14 mm per day). Aerosol-land feedbacks play a larger role in the eastern US and Central Africa. Our study identifies an eco-climate teleconnection in the polluted earth system: the rise of the northern hemisphere mid-latitude reflective aerosol pollution layer causes long range cooling that protects Amazon NPP by 8% and suppresses boreal NPP by 35%.


Total 18F-FDG PET/CT Metabolic Tumor Volume Is Associated With Postoperative Biochemical Response in Patients With Metastatic Pheochromocytomas and Paragangliomas.
The aim of this pilot study was to determine if metabolic tumor volume (MTV) and total lesion glycolysis (TLG) could serve as predictors of biochemical remission and pharmacotherapy-free interval in patients with metastatic pheochromocytomas (PCCs) and paragangliomas (PGLs). Patients with metastatic PCCs/PGLs have a high rate of biochemical recurrence, which can be associated with increased cardiovascular morbidity. Predictors of biochemical response are needed to guide and select patients who may benefit from therapy. Whole body MTV and TLG was calculated from preoperative 18F-FDG PET/CT scans and analyzed as marker of biochemical response and pharmacotherapy-free interval. Seventeen patients underwent a total of 19 procedures, with a median follow-up time of 26.4 months. Whole body MTV of patients with biochemical recurrence (n = 13, mean 73.8 mL) was higher than those who had a biochemical response (n = 6, mean 14.7 mL, P = 0.05). Patients with low MTV (<37.2 mL) had an improved durable partial biochemical response (P < 0.05), and a statistical trend for complete biochemical remission (P = 0.07) and pharmacotherapy-free interval (P = 0.06). In 8 patients with metastatic disease outside the abdomen, 4 patients had less than 35% of their disease burden outside the abdomen and these patients had a more durable partial biochemical response compared to patients with greater than 35% of their disease burden outside the abdomen (P < 0.05). Whole body MTV and TLG represents novel and valuable predictors of biochemical response for patients with metastatic PCCs and PGLs. A larger prospective study should be performed to validate these findings.


Use of hepatobiliary scintigraphy in clinically normal cats.
Hepatobiliary scintigraphy provides a noninvasive assessment of hepatobiliary structure and function, and has been used extensively in people. Hepatocellular measurements determined in the cats of this study include cardiac washout (< or = 2 minutes) and time of maximal hepatic activity (< or = 5 minutes) and hepatic washout (< or = 30 minutes). The gallbladder response to synthetic cholecystokinin was determined to be < or = 3 minutes. Additional measurements also were identified. Potential use of hepatobiliary scintigraphy in feline medicine is discussed.


Vegetative storage protein in Litchi chinensis, a subtropical evergreen fruit tree, possesses trypsin inhibitor activity.
Vegetative storage proteins (VSPs) are commonly bioactive in herbaceous plants but few VSPs with bioactivity have been identified in trees. In addition, information on the characterization of VSPs in evergreen trees is limited. The objective of this study was to characterize the VSPs with bioactivity in evergreen trees. Methods The VSP in lychee (Litchi chinensis), an evergreen fruit tree, was characterized by a combination of cytological, biochemical and molecular biological techniques. The VSP in lychee was a 22-kDa protein. It accumulated in the large central vacuoles of protein-storing cells (PSCs) in two distinguishable forms, granular and floccular. The PSCs were of a novel type. The 22-kDa protein is distributed in mature leaves, bark tissues of branches, trunk and large roots, paralleling the distribution of PSCs. Its homologues were present in mature seed. During young shoot development and fruiting, the 22-kDa protein decreased apparently, suggesting a nitrogen-storage function. The 22-kDa protein had several isoforms encoded by a small multigene family. One gene member, LcVSP1, was cloned. The LcVSP1 had no intron and contained a 675 bp open reading frame encoding a putative protein of 225 amino acids. LcVSP1 was homologous to Kunitz trypsin inhibitors. The 22-kDa protein inhibited trypsin and chymotrypsin, but had no inhibitory effect on subtilisin. Lychee is rich in a 22-kDa VSP with trypsin inhibitor activity. The VSP plays an important role in nitrogen storage while its possible defensive function remains to be elucidated.


Nuclear import of adenovirus DNA involves direct interaction of hexon with an N-terminal domain of the nucleoporin Nup214.
In this study, we characterized the molecular basis for binding of adenovirus (AdV) to the cytoplasmic face of the nuclear pore complex (NPC), a key step during delivery of the viral genome into the nucleus. We used RNA interference (RNAi) to deplete cells of either Nup214 or Nup358, the two major Phe-Gly (FG) repeat nucleoporins localized on the cytoplasmic side of the NPC, and evaluated the impact on hexon binding and AdV infection. The accumulation of purified hexon trimers or partially disassembled AdV at the nuclear envelope (NE) was observed in digitonin-permeabilized cells in the absence of cytosolic factors. Both in vitro hexon binding and in vivo nuclear import of the AdV genome were strongly reduced in Nup214-depleted cells but still occurred in Nup358-depleted cells, suggesting that Nup214 is a major binding site of AdV during infection. The expression of an NPC-targeted N-terminal domain of Nup214 in Nup214-depleted cells restored the binding of hexon at the NE and the nuclear import of protein VII (pVII), indicating that this region is sufficient to allow AdV binding. We further narrowed the binding site to a 137-amino-acid segment in the N-terminal domain of Nup214. Together, our results have identified a specific region within the N terminus of Nup214 that acts as a direct NPC binding site for AdV. AdVs, which have the largest genome of nonenveloped DNA viruses, are being extensively explored for use in gene therapy, especially in alternative treatments for cancers that are refractory to traditional therapies. In this study, we characterized the molecular basis for binding of AdV to the cytoplasmic face of the NPC, a key step for delivery of the viral genome into the nucleus. Our data indicate that a 137-amino-acid region of the nucleoporin Nup214 is a binding site for the major AdV capsid protein, hexon, and that this interaction is required for viral DNA import. These findings provide additional insight on how AdV exploits the nuclear transport machinery for infection. The results could promote the development of new strategies for gene transfer and enhance understanding of the nuclear import of other viral DNA genomes, such as those of papillomavirus or hepatitis B virus that induce specific cancers.


Effects of C-reactive protein on the expression of matrix metalloproteinases and their inhibitors via Fcγ receptors on 3T3-L1 adipocytes.
The association between obesity and inflammation is well documented in epidemiological studies. Proteolysis of extracellular matrix (ECM) proteins is involved in adipose tissue enlargement, and matrix metalloproteinases (MMPs) collectively cleave all ECM proteins. Here, we examined the effects of C-reactive protein (CRP), an inflammatory biomarker, on the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs), which are natural inhibitors of MMPs, in adipocyte-differentiated 3T3-L1 cells. We analyzed the expression of Fcγ receptor (FcγR) IIb and FcγRIII, which are candidates for CRP receptors, and the effects of anti-CD16/CD32 antibodies, which can act as FcγRII and FcγRIII blockers on CRP-induced alteration of MMP and TIMP expression. Moreover, we examined the effects of CRP on the activation of mitogen-activated protein kinase (MAPK) signaling, which is involved in MMP and TIMP expression, in the presence or absence of anti-CD16/CD32 antibodies. Stimulation with CRP increased MMP-1, MMP-3, MMP-9, MMP-11, MMP-14, and TIMP-1 expression but did not affect MMP-2, TIMP-2, and TIMP-4 expression; TIMP-3 expression was not detected. Adipocyte-differentiated 3T3-L1cells expressed FcγRIIb and FcγRIII; this expression was upregulated on stimulation with CRP. Anti-CD16/CD32 antibodies inhibited CRP-induced expression of MMPs, except MMP-11, and TIMP-1. CRP induced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK but did not affect SAPK/JNK phosphorylation, and Anti-CD16/CD32 attenuated the CRP-induced phosphorylation of p38 MAPK, but not that of ERK1/2. These results suggest that CRP facilitates ECM turnover in adipose tissue by increasing the production of multiple MMPs and TIMP-1 in adipocytes. Moreover, FcγRIIb and FcγRIII are involved in the CRP-induced expression of MMPs and TIMP-1 and the CRP-induced phosphorylation of p38, whereas the FcγR-independent pathway may regulate the CRP-induced MMP-11 expression and the CRP-induced ERK1/2 phosphorylation.


Sequential compression pump effect on hypotension due to spinal anesthesia for cesarean section: A double blind clinical trial.
Spinal anesthesia (SA) is a standard technique for cesarean section. Hypotension presents an incident of 80-85% after SA in pregnant women. To determine the effect of intermittent pneumatic compression of lower limbs on declining spinal anesthesia induced hypotension during cesarean section. This double-blind clinical prospective study was conducted on 76 non-laboring parturient patients, aged 18-45 years, with the American Society of Anesthesiologist physical status I or II who were scheduled for elective cesarean section at Razi Hospital, Ahvaz, Iran from December 21, 2015 to January 20, 2016. Patients were divided into treatment mechanical pump (Group M) or control group (Group C) with simple random sampling. Fetal presentation, birth weight, Apgar at 1 and 5 min, time taken for pre-hydration (min), pre-hydration to the administration of spinal anesthesia (min), initiation of spinal to the delivery (min) and total volume of intravenous fluids, total dose of ephedrine and metoclopramide were recorded. Data were analyzed by SPSS version 19, using repeated measures of ANOVA and Chi square test. Heart rate, MPA, DAP and SAP changes were significantly higher in off-pump group in the baseline and 1st-minute (p<0.05), and in the other times, this change was significantly different with control groups. This research showed the suitability of the use of Sequential Compression Device (SCD) in reducing hypotension after spinal anesthesia for cesarean section, also this method can cause reducing vasopressor dosage for increased blood pressure, but the approval of its effectiveness requires repetition of the study with a larger sample size. The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT2015011217742N3. The authors received no financial support for the research, authorship, and/or publication of this article.


Changes in Free-Living Glycemic Profiles after 12 Months of Lifestyle Intervention in Children with Overweight and with Obesity.
Previous studies demonstrated that hyperglycemic glucose concentrations are observed in children that are overweight or have obesity. The aim of this study was to evaluate the effect of a 12 month lifestyle intervention on free-living glycemic profiles in children that were overweight or had obesity, and the association of the alterations with changes in cardiovascular risk parameters. BMI z-score, free-living glycemic profiles, continuous overlapping net glycemic action (CONGA), and cardiovascular parameters were evaluated before and after a multidisciplinary lifestyle intervention, in 33 non-diabetic children that were overweight or had obesity. In children with a decrease in BMI z-score, the duration which glucose concentrations were above the high-normal threshold (6.7 mmol/L) and the glycemic variability decreased significantly. In these children, a decrease in median sensor glucose was associated with decreases in LDL-cholesterol, and systolic and diastolic blood pressure z-score. A decrease in BMI z-score was associated with a decrease in CONGA1, 2, and 4. In conclusion, the glycemic profiles in free-living conditions in children that were overweight improved in children with a decrease in BMI z-score after lifestyle intervention. In those children, changes in median sensor glucose concentrations were associated with changes in LDL-cholesterol and blood pressure z-scores. These results suggest that glucose homeostasis can improve after one year of lifestyle intervention and that these improvements are associated with improvements in cardiovascular health parameters.


Representation of the molecular topology of cyclical structures by means of cycle graphs. 3. Hierarchical model of screening of chemical databases.
The increase in the size and complexity of chemical databases necessitates the proposal and development of efficient methods of classification and recovery of information, which supposes proposal of a model of classification of database records and the use of a compatible model of screening for inspection of clusters and recovery of the molecules that satisfy the search criterion. The cycle graphs model based on consideration of all the cycles and chains (and equivalent cycles and chains) present in the molecular structure has been proven appropriate for classification of chemical databases, giving rise to a generation of different classification levels depending on the structural elements (cycles and chains) that are considered. In this paper we propose a screening model, compatible with the cycle graphs model, based on a hierarchy of levels of abstraction. The set of molecules that satisfies a screening model (or selection criterion) diminishes as we advance in the hierarchy of levels of the model, which allows filtering of records and, therefore, an increase in the efficiency of the screening process. In the following work of this series we describe and validate the screening tool developed.


Cloning of cold-active alkaline phosphatase gene of a psychrophile, Shewanella sp., and expression of the recombinant enzyme.
A psychrophilic alkaline phosphatase (EC 18.104.22.168) from Shewanella sp. is a cold-active enzyme that has high catalytic activity at low temperature [Ishida et al. (1998) Biosci. Biotechnol. Biochem., 62, 2246-2250]. Here, we identified the nucleotide sequence of a gene encoding the enzyme after cloning with the polymerase chain reaction (PCR) and inverted PCR techniques. The deduced amino acid sequence of the enzyme contained conserved amino acids found among mesophilic alkaline phosphatases and showed some structural characteristics including a high content of hydrophobic amino acid residues and the lack of single alpha-helix compared with the alkaline phosphatase of Escherichia coli, which were possibly efficient for catalytic reaction at low temperatures. The recombinant enzyme expressed in E. coli was purified to homogeneity with the molecular mass of 41 kDa. The recombinant enzyme had a specific activity of 1,500 units/mg and had high catalytic activity at low temperatures.


Medium-grade tubular proteinuria is common in HIV-positive patients and specifically associated with exposure to tenofovir disoproxil Fumarate.
The aim of this cross-sectional study was to evaluate the prevalence and risk factors of medium-grade proteinuria (100-500 mg/g creatinine) among HIV-positive adults. Spot urine samples of HIV-positive adults without known renal disease were analyzed quantitatively between January 2009 and February 2011. Demographic and medical data were collected. Multivariate regression models for different patterns of proteinuria were constructed. Among 411 patients, 18 (4.4 %) presented albuminuria >300 mg/g creatinine and/or proteinuria >500 mg/g creatinine and were excluded from further analyses. Among the study population of 393 patients, 181 (46.1 %) had no significant proteinuria or albuminuria (<100 and <30 mg/g creatinine, respectively), 60 (15.3 %) had moderate albuminuria, while 152 (38.7 %) had proteinuria without albuminuria, suggesting tubular proteinuria. Independent predictors for medium-grade tubular proteinuria in multivariate analysis were exposure to tenofovir (DF), a CD4 nadir <500/µl, older age, and anti-HCV-antibodies. There was no association with classic renal risk factors like diabetes mellitus and arterial hypertension, or with estimated glomerular filtration rate (eGFR). We detected significant proteinuria in 230 (56.0 %) of 411 HIV-positive patients. Among this group, 152 (66.1 %) had medium-grade proteinuria without albuminuria, which was significantly associated with exposure to tenofovir, older age, a lower CD4 nadir and Hepatitis C. Nephrologic or HIV treatment guidelines fail to detect most of these patients but rather identify patients with high cardiovascular risk. In the absence of an association with eGFR the role of medium-grade tubular proteinuria as a potential early marker of chronic kidney disease remains unclear. Prospective studies are needed.


Associations between physical fitness and activity patterns during adolescence and cardiovascular risk factors in young adulthood: the Northern Ireland Young Hearts Project.
The aim of the present study was to examine relationships between cardiovascular disease (CVD) risk factor status in young adulthood (mean age = 22.5 yrs) and antecedent physical fitness and physical activity at ages 12 and 15 years. The data were obtained from the Young Hearts Project, a longitudinal observational study of CVD risk factors in a representative sample of young people from Northern Ireland. Physical fitness was measured by the 20-metre endurance shuttle run, and physical activity and sports participation by a self-report recall questionnaire. CVD risk factors examined included serum total cholesterol (TC) and HDL cholesterol concentrations, the TC:HDL ratio, systolic and diastolic blood pressure and body fatness (sum of four skinfolds). Linear regression analyses showed modest relationships between physical fitness in adolescence and both TC:HDL ratio and body fatness in young adulthood. No such relationships were apparent for adolescent physical activity. The promotion of physical fitness during adolescence may reduce exposure to other risk factors lasting into early adulthood.


Tocilizumab therapy in SARS-CoV-2 pneumonia: A matched retrospective cohort analysis.
The effect of immunomodulatory therapy with tocilizumab for coronavirus disease 2019 (COVID-19) in real-life clinical practice remains controversial. Single-center retrospective matched cohort analysis including 47 consecutive patients treated with intravenous tocilizumab for severe COVID-19 pneumonia ("TCZ group"), matched by age, comorbidities, time from symptoms onset and baseline SpO2/FiO2 ratio with 47 patients receiving standard of care alone ("SoC group"). There were no significant differences between the TCZ and SoC groups in the rate of clinical improvement (hospital discharge and/or a decrease of ≥2 points on a six-point ordinal scale) by day 7 (51.1% [24/47] versus 48.9% [23/47]; P-value=1.000). No differences were observed at day 14 in terms of clinical improvement (72.3% versus 76.6%; P-value=0.791), all-cause mortality (10.6% versus 12.8%; P-value=1.000), and the composite of invasive mechanical ventilation and/or death (25.5% versus 23.4%; P-value=1.000) either. Patients in the TCZ group had a more rapid normalization of C-reactive protein levels. No apparent benefit was observed in patients with severe COVID-19 treated with tocilizumab as compared to a matched retrospective cohort.


High-frequency oscillatory ventilation for infants and children with adult respiratory distress syndrome.
Two infants and two children suffered from severe hypoxemia, presenting as a ratio of arterial to alveolar PaO2 < 0.1, persisting for more than 3 hours in spite of high settings on conventional mechanical ventilator. Adult respiratory distress syndrome was diagnosed with the support of bilateral diffuse haziness on chest radiographs. High-frequency oscillatory ventilation with high-lung-volume strategy resulted in prompt decrease in oxygenation index and increase in ratio of arterial to alveolar P O2 in three (75%) of the 4 patients within 6 hours. After a mean duration of 96 hours, high-frequency oscillatory ventilation could be weaned off and conventional ventilation could be resumed at lower mean airway pressure in 3 patients. They continued to improve and finally recovered. The other one showed initially steady improvement on high-frequency oscillatory ventilation for 20 hours, but ultimately died of unresolved cytomegalovirus pneumonitis and intractable pulmonary hemorrhage. There were 2 episodes of pneumothorax developing during high-frequency oscillatory ventilation. After decreasing mean airway pressure and amplitude, the airleak resolved with chest tube insertion. We conclude that high-frequency oscillatory ventilation with high-lung-volume strategy may be an effective rescue therapy to relieve profound hypoxemia in infants and children with adult respiratory distress syndrome.


A 30-day follow-up study on the prevalence of SARS-COV-2 genetic markers in wastewater from the residence of COVID-19 patient and comparison with clinical positivity.
Wastewater based epidemiology (WBE) is an important tool to fight against COVID-19 as it provides insights into the health status of the targeted population from a small single house to a large municipality in a cost-effective, rapid, and non-invasive way. The implementation of wastewater based surveillance (WBS) could reduce the burden on the public health system, management of pandemics, help to make informed decisions, and protect public health. In this study, a house with COVID-19 patients was targeted for monitoring the prevalence of SARS-CoV-2 genetic markers in wastewater samples (WS) with clinical specimens (CS) for a period of 30 days. RT-qPCR technique was employed to target nonstructural (ORF1ab) and structural-nucleocapsid (N) protein genes of SARS-CoV-2, according to a validated experimental protocol. Physiological, environmental, and biological parameters were also measured following the American Public Health Association (APHA) standard protocols. SARS-CoV-2 viral shedding in wastewater peaked when the highest number of COVID-19 cases were clinically diagnosed. Throughout the study period, 7450 to 23,000 gene copies/1000 mL were detected, where we identified 47 % (57/120) positive samples from WS and 35 % (128/360) from CS. When the COVID-19 patient number was the lowest (2), the highest CT value (39.4; i.e., lowest copy number) was identified from WS. On the other hand, when the COVID-19 patients were the highest (6), the lowest CT value (25.2 i.e., highest copy numbers) was obtained from WS. An advance signal of increased SARS-CoV-2 viral load from the COVID-19 patient was found in WS earlier than in the CS. Using customized primer sets in a traditional PCR approach, we confirmed that all SARS-CoV-2 variants identified in both CS and WS were Delta variants (B.1.617.2). To our knowledge, this is the first follow-up study to determine a temporal relationship between COVID-19 patients and their discharge of SARS-CoV-2 RNA genetic markers in wastewater from a single house including all family members for clinical sampling from a developing country (Bangladesh), where a proper sewage system is lacking. The salient findings of the study indicate that monitoring the genetic markers of the SARS-CoV-2 virus in wastewater could identify COVID-19 cases, which reduces the burden on the public health system during COVID-19 pandemics.


A unified approach to symptomatic juxtasternal arthritis and enthesitis.
Symptomatic arthritic and enthesopathic conditions of the sternum and its articulations have not been studied well as a group, despite previous reports of individual diseases and radiographic abnormalities that affect these structures. The lack of a unified clinical approach has been partly due to the absence of a name for the clinical condition, which we propose to call juxtasternal arthro-osteitis. Although juxtasternal arthro-osteitis may be caused by septic arthritis, this study was based on 24 adult patients with noninfectious juxtasternal arthro-osteitis, collected retrospectively from records of patients who had sternal tomography and from rheumatology clinic populations. Twelve of the patients had an underlying systemic arthropathy that met standard diagnostic criteria; three patients had an unclassifiable systemic arthropathy; and nine patients had the idiopathic localized disease, which has been termed sternocostoclavicular hyperostosis. Radiographic findings in the various diseases followed definite trends, but were not sufficiently distinct to provide the sole basis for diagnosis. Initial failure to correlate dermatologic, rheumatologic, radiographic, and laboratory findings led to prolonged delays in diagnosis in many cases. When juxtasternal arthro-osteitis is encountered, a thorough evaluation should be made for systemic disease. Idiopathic sternocostoclavicular hyperostosis can be diagnosed only after systemic arthropathy or enthesopathy has been excluded.


An indirect treatment comparison (ITC) and matching-adjusted indirect comparison (MAIC) between a 15-valent (V114) and a 20-valent (PCV20) pneumococcal conjugate vaccine among healthy infants.
Immunogenicity between 15-valent V114 (PCV15) and 20-valent PCV20 pneumococcal conjugate vaccines in healthy infants is compared in an indirect treatment comparison and matching-adjusted indirect comparison. Hypotheses: immunogenicity of V114 is non-inferior to PCV20 for all PCV13 serotypes, and superior to PCV20 for serotype 3 based on lower bound margins. Two phase 3 pivotal studies on 3 + 1 pediatric vaccination schedule at age 2, 4, 6, and 12-15 months compared V114 (N = 858) to PCV13 (N = 856) and PCV20 (N = 1001) to PCV13 (N = 987). Infant's age and race in V114 study were matched to those in PCV20 study. Primary endpoints were serotype-specific Immunoglobulin G (IgG) response rate difference (RRD) 30 days post-dose (PD)3; IgG geometric mean concentration (GMC) ratios 30 days PD3 and PD4. V114 was non-inferior (marginRRD>-10%-point; marginGMCratio >0.5) to PCV20 (p-value <0.001) for all endpoints. V114 was superior (marginRRD >0%-point; marginGMCratio >1.2) to PCV20 (p-value <0.001) for serotype 3: RRD was 34.5% (95%CI 27.9%-41.1%) PD3, and IgG GMC ratios were 2.39 (95%CI 2.12-2.68) PD3 and 2.15 (95%CI 1.90-2.41) PD4. Immune response to V114 administered in a 3 + 1 schedule in healthy infants was considered non-inferior to PCV20 for all 13 PCV13 serotypes and superior for serotype 3 PD3 and PD4. www.clinicaltrials.gov identifiers NCT03893448, NCT04382326.


Addressing Needs of Women Radiologists: Opportunities for Practice Leaders to Facilitate Change.
Women are, and have always been, underrepresented in radiology. This gender disparity must be addressed. Women bring a different perspective to the workplace; and their collaborative, empathetic, and compassionate approach to patient care and education is an asset that the radiology community should embrace and leverage. Radiologic organizations should focus on removing barriers to the entry of women physicians into radiology as a specialty and to their career advancement. Organizations should address bias, promote physician well-being, and cultivate a safe and positive work environment. Radiology leaders committed to increasing gender diversity and fostering an inclusive workplace have the opportunity to strengthen their organizations. This article outlines the key steps that practice leaders can take to address the needs of women in radiology: (a) marketing radiology to talented women medical students, (b) addressing recruitment and bias, (c) understanding and accommodating the provisions of the Family and Medical Leave Act of 1993 and the Fair Labor Standards Act for both trainees and radiologists in practice, (d) preventing burnout and promoting well-being, (e) offering flexible work opportunities, (f) providing mentorship and career advancement opportunities, and (g) ensuring equity. ©RSNA, 2018.


Diminishing returns from increased percent Bt cotton: the case of pink bollworm.
Regional suppression of pests by transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) has been reported in several cropping systems, but little is known about the functional relationship between the ultimate pest population density and the pervasiveness of Bt crops. Here we address this issue by analyzing 16 years of field data on pink bollworm (Pectinophora gossypiella) population density and percentage of Bt cotton in the Yangtze River Valley of China. In this region, the percentage of cotton hectares planted with Bt cotton increased from 9% in 2000 to 94% in 2009 and 2010. We find that as the percent Bt cotton increased over the years, the cross-year growth rate of pink bollworm from the last generation of one year to the first generation of the next year decreased. However, as the percent Bt cotton increased, the within-year growth rate of pink bollworm from the first to last generation of the same year increased, with a slope approximately opposite to that of the cross-year rates. As a result, we did not find a statistically significant decline in the annual growth rate of pink bollworm as the percent Bt cotton increased over time. Consistent with the data, our modeling analyses predict that the regional average density of pink bollworm declines as the percent Bt cotton increases, but the higher the percent Bt cotton, the slower the decline in pest density. Specifically, we find that 95% Bt cotton is predicted to cause only 3% more reduction in larval density than 80% Bt cotton. The results here suggest that density dependence can act against the decline in pest density and diminish the net effects of Bt cotton on suppression of pink bollworm in the study region. The findings call for more studies of the interactions between pest density-dependence and Bt crops.


Prostate-specific antigen nadir after high-dose-rate brachytherapy predicts long-term survival outcomes in high-risk prostate cancer.
To evaluate the prognostic value of prostate-specific antigen nadir (nPSA) after high-dose-rate (HDR) brachytherapy in clinically non-metastatic high-risk prostate cancer patients. Data from 216 patients with high-risk or locally advanced prostate cancer who underwent HDR brachytherapy and external beam radiation therapy with long-term androgen deprivation therapy (ADT) between 2003 and 2008 were analyzed. The median prostate-specific antigen (PSA) level at diagnosis was 24 ng/ml (range: 3-338 ng/ml). The clinical stage was T1c-2a in 55 cases (26%), T2b-2c in 48 (22%), T3a in 75 (35%), and T3b-4 in 38 (17%). The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After 5 fractions, external beam radiation therapy with 10 fractions of 3 Gy was administered. All patients initially underwent neoadjuvant ADT for at least 6 months, and adjuvant ADT was continued for 36 months. The median follow-up was 7 years from the start of radiotherapy. The 7-year PSA relapse-free rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 94%, compared with 23% for patients with higher nPSA values (HR = 28.57; 95% CI: 12.04-66.66; p < 0.001). Multivariate analysis revealed that the nPSA value after radiotherapy was a significant independent predictor of biochemical failure, whereas pretreatment predictive values for worse biochemical control including higher level of initial PSA, Gleason score ≥ 8, positive biopsy core rate ≥ 67%, and T3b-T4, failed to reach independent predictor status. The 7-year cancer-specific survival rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 99%, compared with 82% for patients with higher nPSA values (HR = 32.25; 95% CI: 3.401-333.3; p = 0.002). A post-radiotherapy nPSA value of ≤ 0.02 ng/ml was associated with better long-term biochemical tumor control even if patients had pretreatment predictive values for worse control.


The use of non-standard CT conversion ramps for Monte Carlo verification of 6 MV prostate IMRT plans.
Monte Carlo (MC) dose calculation algorithms have been widely used to verify the accuracy of intensity-modulated radiotherapy (IMRT) dose distributions computed by conventional algorithms due to the ability to precisely account for the effects of tissue inhomogeneities and multileaf collimator characteristics. Both algorithms present, however, a particular difference in terms of dose calculation and report. Whereas dose from conventional methods is traditionally computed and reported as the water-equivalent dose (Dw), MC dose algorithms calculate and report dose to medium (Dm). In order to compare consistently both methods, the conversion of MC Dm into Dw is therefore necessary. This study aims to assess the effect of applying the conversion of MC-based Dm distributions to Dw for prostate IMRT plans generated for 6 MV photon beams. MC phantoms were created from the patient CT images using three different ramps to convert CT numbers into material and mass density: a conventional four material ramp (CTCREATE) and two simplified CT conversion ramps: (1) air and water with variable densities and (2) air and water with unit density. MC simulations were performed using the BEAMnrc code for the treatment head simulation and the DOSXYZnrc code for the patient dose calculation. The conversion of Dm to Dw by scaling with the stopping power ratios of water to medium was also performed in a post-MC calculation process. The comparison of MC dose distributions calculated in conventional and simplified (water with variable densities) phantoms showed that the effect of material composition on dose-volume histograms (DVH) was less than 1% for soft tissue and about 2.5% near and inside bone structures. The effect of material density on DVH was less than 1% for all tissues through the comparison of MC distributions performed in the two simplified phantoms considering water. Additionally, MC dose distributions were compared with the predictions from an Eclipse treatment planning system (TPS), which employed a pencil beam convolution (PBC) algorithm with Modified Batho Power Law heterogeneity correction. Eclipse PBC and MC calculations (conventional and simplified phantoms) agreed well (<1%) for soft tissues. For femoral heads, differences up to 3% were observed between the DVH for Eclipse PBC and MC calculated in conventional phantoms. The use of the CT conversion ramp of water with variable densities for MC simulations showed no dose discrepancies (0.5%) with the PBC algorithm. Moreover, converting Dm to Dw using mass stopping power ratios resulted in a significant shift (up to 6%) in the DVH for the femoral heads compared to the Eclipse PBC one. Our results show that, for prostate IMRT plans delivered with 6 MV photon beams, no conversion of MC dose from medium to water using stopping power ratio is needed. In contrast, MC dose calculations using water with variable density may be a simple way to solve the problem found using the dose conversion method based on the stopping power ratio.


Development of an index to evaluate symptoms in men with androgen deficiency.
Healthier lifestyles and better medical care are contributing to greater life expectancy in U.S. males. Couple this with the great emphasis our society places on youth, and it is not surprising that older men want to look, feel, and act younger. Androgen replacement may have a role in this setting, but it is not clear exactly what symptoms signal a problem or warrant therapy. A valid and reproducible index that sufficiently defines the problems experienced by androgen-deficient men will go a long way toward helping both researchers and clinicians better understand and manage these men.


The value of qualitative data in Quality Improvement Projects in the care of older adults: the case of frailty scores in the emergency department.
This commentary discusses the role and value of qualitative data when undertaking quality improvement (QI) focussing on the care of older adults. To illustrate this, we reflect on our own experiences of planning a QI project to improve the documentation of Clinical Frailty Scale (CFS) scores in the emergency department (ED) during the coronavirus disease of 2019 (COVID-19) pandemic. National clinical guidance for COVID-19 states that all adults over the age of 65 should be given a CFS at the first point of contact during hospital admission. Therefore, there is a need to improve CFS documentation, specifically in acute care settings. We describe how qualitative methods facilitated an understanding of the barriers to CFS documentation in ED. Staff see the CFS as a useful tool for inter-professional communication, though there are tensions between clinical guidance and their beliefs. Staff had moral concerns about how an ED-allocated CFS might limit available treatment options for older adults. Our findings demonstrate how qualitative methods can illuminate the important social and moral dimensions of why improvement does or does not occur.


Imatinib mesylate in the treatment of hematologic malignancies.
The treatment of hematologic malignancies has been based for many years on chemotherapy and possibly, for the more aggressive forms, stem cell transplantation. In 2001, the signal transduction inhibitor 571 (STI571, imatinib mesylate) was reported to have striking effects in chronic myeloid leukaemia patients. Since then, imatinib became the first molecular-targeted agent approved for the treatment of human cancer and was later on demonstrated to be effective in other malignancies, such as Philadelphia positive acute lymphoid leukemia, hypereosinophilic syndromes, gastrointestinal stromal tumours and more recently, systemic mastocytosis and other myeloprolipherative disease-carrying platelet-derived growth factor receptor abnormalities. In this article, the authors review the evidence which led to imatinib approval in the treatment of several of the above mentioned diseases.


Healthcare provider training in tobacco treatment: building competency.
One of the most effective disease prevention and health promotion strategies available is the treatment of tobacco dependence. The Agency for Healthcare Research and Quality (AHRQ) clinical practice guideline for treating tobacco use and dependence provides a number of recommendations for interventions by health care systems and providers, including that treatment be reimbursed, identification of tobacco users be institutionalized, and all patients be offered brief treatment and have more intensive treatment available to them. Unfortunately, these recommended interventions have not been routinely implemented. As part of a comprehensive approach to improving implementation, provider training is needed. Three models for training healthcare providers in brief tobacco treatment intervention (medical education, professional education, and community-based education) are described, a model for training providers in intensive tobacco treatment interventions is presented, and a rationale for a national training and certification program is made.


Weight gain in women diagnosed with breast cancer.
This review of the literature indicates that weight gain is a common observation among women after the diagnosis of breast cancer. Gains in weight range from 0 to 50 lb and are influenced by menopausal status; nodal status; and the type, duration, and intensity of treatment. Weight gain appears to be greater among premenopausal women; among those who are node positive; and among those receiving higher dose, longer duration, and multiagent regimens. Psychosocial research suggests that weight gain has a profoundly negative impact on quality of life in patients with breast cancer. Recent findings also suggest that weight gain during therapy may increase the risk of recurrence and decrease survival. Although weight gain in patients with breast cancer is clinically well appreciated, little research has been conducted to investigate the underlying mechanisms of energy imbalance. Changes in rates of metabolism, physical activity, and dietary intake are all plausible mechanisms and call for more research. Further study will provide valuable insight into the problem of weight gain and encourage effective interventions to improve the quality and quantity of life for the woman with breast cancer. Until more is known, however, dietetics practitioners will have to monitor and work individually with patients with breast cancer and use empirical approaches to achieve the important goal of weight management.


Development of intraarterial contrast-enhanced 2D MRDSA with a 0.3 tesla open MRI system.
The purpose of this study was to develop a new technique for a high temporal resolution two-dimensional MR digital subtraction angiography (2D MRDSA) sequence under intraarterial injection of contrast material to permit the visualization of vascular anatomy and hemodynamics. 2D MRDSA was imaged on a 0.3T open MR scanner with a T(1)-weighted fast gradient echo sequence. The phantom study examined vials containing gadolinium (Gd) solutions ranging in concentration from 0.5 mmol/L to 100 mmol/L. Repetition time and echo time were fixed at minimal values in order to achieve high temporal resolution, and only the flip angle was changed in 10-degree increments between 10 and 90 degrees. The in vivo study examined a brachial artery of a human volunteer. MRDSA images were acquired continuously during intraarterial injections of Gd solutions ranging in concentration from 0.5 mmol/L to 100 mmol/L. The subtracted images were displayed on the monitor in real time at a frame rate of one frame per second and evaluated to determine the optimal concentration of contrast material. In the phantom study, a 10-mmol/L Gd concentration with a flip angle of 50 degrees -90 degrees and a 25-mmol/L Gd concentration with a flip angle of 60 degrees -90 degrees showed high signal-to-noise ratios. In the human brachial artery experiment, the forearm arteries were well visualized when solutions of 5-50 mmol/L Gd concentration were used. The 10- and 25-mmol/L Gd concentrations were considered optimal. The palmar digital arteries were also visualized. Higher Gd concentrations showed a paradoxical signal increase when diluted by blood. We successfully developed an intraarterial contrast-enhanced 2D MRDSA sequence. With appropriate settings of imaging parameters and Gd concentrations, we obtained acceptable vessel visualization in the human study. The low Gd concentration for optimal visualization permits repeated intraarterial injections. This technique can be a useful tool for investigating the vascular anatomy and hemodynamics required for MR-guided vascular interventions.


Killing of human malaria parasites by macrophage secretory products.
The susceptibility of the human malaria parasite, Plasmodium falciparum, to killing in vitro by macrophage secretory products was investigated. The effect of O2 radicals and tumor necrosis factor on parasite viability was assessed both morphologically and by following the uptake of [3H]hypoxanthine. H2O2 produced by the interaction of glucose and glucose oxidase was found to reduce viability; this effect was reversed by the addition of exogenous catalase. Further studies indicated that the catalase level within the erythrocyte was not altered upon parasite invasion. O2 radicals produced during the xanthine-xanthine oxidase interaction also killed P. falciparum. The addition of various O2 radical scavengers (including catalase) did not reverse this effect; therefore, it was not possible to determine which of the O2 radicals were involved in the killing process. Samples from three different sources containing tumor necrosis factor, a nonspecific soluble mediator derived from Mycobacterium bovis BCG-activated macrophages treated with endotoxin, also killed the parasite. There was no evidence that tumor necrosis factor or the products of the xanthine-xanthine oxidase interaction caused damage to the erythrocyte membrane that could be implicated as an important aspect of the killing process. These findings all strongly suggest that such macrophage products play an important role in immunity to malaria.


Prophylaxis with ranitidine against peptic ulcer disease after liver transplantation.
Upper gastrointestinal bleeding resulting from peptic ulcer disease is a potentially life-threatening situation. There are several reports on the association of ulcer disease and corticosteroid treatment, especially when high doses (greater than 40 mg/day) are used. Some categories of patients are prone to ulcer disease under steroid treatment. Prophylaxis in this situation therefore seems reasonable. We compared 23 consecutive liver transplant patients who received ranitidine prophylaxis with 33 previously transplanted patients who had no prophylaxis. In the control group there were 13 patients who had an ulcer, seven of whom bled. In the treated group two ulcers without upper GI bleeding were found. The results indicate that ranitidine can effectively reduce peptic ulcer disease in liver transplantation patients, despite the use of very high doses of corticosteroids.


Physiological functions of glucocorticoids in stress and their relation to pharmacological actions.
Almost any kind of threat to homeostasis or stress will cause plasma glucocorticoid levels to rise. The increased levels have traditionally been ascribed the physiological function of enhancing the organism's resistance to stress, a role well recognized in glucocorticoid therapy. How the known physiological and pharmacological effects of glucocorticoids might accomplish this function, however, remains a mystery. A generalization that is beginning to emerge is that many of these effects may be secondary to modulation by glucocorticoids of the actions of numerous intercellular mediators, including established hormones, prostaglandins and other arachidonic acid metabolites, certain secreted neutral proteinases, lymphokines, and a variety of bioactive peptides. These mediators participate in physiological mechanisms--endocrine, renal, immune, neural, etc.--that mount a first line of defense against such challenges to homeostasis as hemorrhage, metabolic disturbances, infection, anxiety, and others. Contrary to the traditional view that glucocorticoids enhance these defense mechanisms, however, it has become increasingly clear that glucocorticoids at moderate to high levels generally suppress them. This paradox, which first emerged when glucocorticoids were discovered to be antiinflammatory agents, remains a major obstacle to a unified picture of glucocorticoid function. We propose that stress-induced increases in glucocorticoid levels protect not against the source of stress itself but rather against the body's normal reactions to stress, preventing those reactions from overshooting and themselves threatening homeostasis. This hypothesis, the seeds of which are to be found in many discussions of particular glucocorticoid effects, immediately accounts for the paradox noted above. Furthermore, it provides glucocorticoid physiology with a unified conceptual framework that can accommodate such apparently unrelated physiological and pharmacological effects as those on carbohydrate metabolism, inflammatory processes, shock, and water balance. It also leads us to suggest that some of the enzymes rapidly induced by glucocorticoids, such as glutamine synthetase, detoxify mediators released during stress-induced activation of primary defense mechanisms. These mediators would themselves lead to tissue damage if left unchecked.


Far-infrared radiation promotes angiogenesis in human microvascular endothelial cells via extracellular signal-regulated kinase activation.
This study was designed to determine the in vitro angiogenic ability of far-infrared (FIR) radiation in the skin-derived cultured human microvascular endothelial cells and to elucidate the role of mitogen-activated protein kinases (MAPKs) in this process. The results revealed that FIR radiation from a WS(TM) TY301 FIR emitter activated p38 and extracellular signal-regulated kinase (ERK), but not Akt or c-Jun N-terminal protein kinases (JNK), and significantly promoted angiogenesis by increasing tube formation in Matrigel and the migration of cells across an eight micron polyester filter. The addition of 50 μM PD98059, a MEK inhibitor, significantly inhibited the activation of ERK and the enhanced angiogenesis; in contrast, the inhibition of p38 phosphorylation did not inhibit the enhanced angiogenesis. After FIR radiation, there was no increase in vascular endothelial growth factor (VEGF) isoforms (VEGF-A, -B, -C and -D) mRNA and VEGF protein, no increase phosphorylation of endothelial nitric oxide synthase (eNOS) detected using Western blotting, and no increase in NO production detected using flow cytometry in cells pre-incubated with the cell-permeable NO-binding dye diluted 4-amino-5-methylamino-2', 7'-difluorofluorescein diacetate (DAF-FM DA). This study revealed that FIR radiation possesses in vitro angiogenic activity via the activation of the MEK/ERK but not the VEGF/Akt/eNOS-dependent signaling pathways.


Modulation of the peripheral immune system after low-dose radon spa therapy: Detailed longitudinal immune monitoring of patients within the RAD-ON01 study.
The pain-relieving effects of low-dose radon therapies on patients suffering from chronic painful inflammatory diseases have been described for centuries. Even though it has been suggested that low doses of radiation may attenuate chronic inflammation, the underlying mechanisms remain elusive. Thus, the RAD-ON01 study was initiated to examine the effects of radon spa therapy and its low doses of alpha radiation on the human immune system. In addition to an evaluation of pain parameters, blood was drawn from 100 patients suffering from chronic painful degenerative musculoskeletal diseases before as well as 6, 12, 18, and 30 weeks after the start of therapy. We verified significant long-term pain reduction for the majority of patients which was accompanied by modulations of the peripheral immune cells. Detailed immune monitoring was performed using a multicolor flow cytometry-based whole blood assay. After therapy, the major immune cells were only marginally affected. Nevertheless, a small but long-lasting increase in T cells and monocytes was observed. Moreover, neutrophils, eosinophils and, in particular, dendritic cells were temporarily modulated after therapy. Regarding the immune cell subsets, cytotoxic T and NK cells, in particular, were altered. However, the most prominent effects were identified in a strong reduction of the activation marker CD69 on T, B, and NK cells. Simultaneously, the percentage of HLA-DR+ T cells was elevated after therapy. The RAD-ON01 study showed for the first time a modulation of the peripheral immune cells following standard radon spa therapy. These modulations are in line with attenuation of inflammation.


Gonadotropin-releasing hormone and pituitary adenylate cyclase-activating polypeptide affect levels of cyclic adenosine 3',5'-monophosphate-dependent protein kinase A (PKA) subunits in the clonal gonadotrope alphaT3-1 cells: evidence for cross-talk between PKA and protein kinase C pathways.
We have shown previously that protein kinase A (PKA) subunit levels are regulated by activation of PKA or protein kinase C (PKC) in anterior pituitary cells. GnRH also influenced PKA subunit levels, suggesting that hormonal regulation occurs in gonadotrophs, and therefore, we have reexamined this question using the clonal gonadotrope-derived cell line (alphaT3-1 cells). Western blot analysis, using specific immunoaffinity purified immunoglobulins, revealed expression of catalytic (Cat) and regulatory type I (RI) and type II (RII) subunits of PKA in these cells. Activation of adenylyl cyclase (AC) with forskolin, or of PKC with tetradecanoyl phorbol acetate (TPA), caused a rapid (detectable at 0.5-1 h) and concentration-dependent loss of all PKA subunits. Forskolin (10-100 microM) reduced Cat and RI by 60% and RII by 30%, whereas TPA (0.1-1 microM) reduced Cat and RII by 50% and RI by 40%. Simultaneous activation of PKA and PKC caused the expected dose-dependent reductions in Cat, and the effects of forskolin or TPA were nearly additive. RI and RII were reduced similarly by 10 nM TPA, whereas 100 nM TPA tended to prevent the reduction of RI or RII caused by forskolin. GnRH, which activates phosphoinositidase C and not AC in these cells, caused a clear loss of Cat or RII at all concentrations tested and of RI at 0.1 nM. Pituitary adenylate cyclase-activating polypeptide 38, which acts via PVR-1 receptors to stimulate both phosphoinositidase C and AC in these cells, also caused a clear dose-dependent decrease in Cat, RI, and RII, although higher concentrations were needed for the latter effects. Together, the data demonstrate that catalytic and regulatory subunits of PKA are subject to both hormonal and receptor-independent regulation in alphaT3-1 cells, reinforcing the possibility that such effects occur in nonimmortalized gonadotropes. Whereas the effects of PKA activators very likely involve proteolytic degradation of the dissociated PKA holoenzyme, the effects of TPA and GnRH occur in the absence of cAMP elevation by unknown mechanisms. Whatever the mechanisms involved, the data reveal a mechanism for cross-talk between phosphoinositidase C and AC-mediated hormonal signals, in which PKC activation seems to play a pivotal role.


Appetite influences the responses to meal ingestion.
We have previously shown that the postprandial experience includes cognitive sensations, such as satiety and fullness, with a hedonic dimension involving digestive well-being and mood. Preload conditioning has been shown to modulate appetite and food consumption under certain conditions, but its effects on the responses to meal ingestion are not clear. We hypothesized that appetite modulation by preload conditioning has differential effects on the cognitive and the emotive responses to meal ingestion. The effects of preload conditioning (ingestion of a low- vs a high-calorie breakfast) on appetite and on the cognitive and emotive responses to a comfort probe meal ingested 2 hours later (ham and cheese sandwich with orange juice; 300 mL, 425 Kcal) was tested in healthy subjects (n=12) in a cross-over design. Sensations were measured at regular intervals 15 minutes before and 60 minutes after the probe meal. As compared to the low-calorie breakfast, the high-calorie breakfast reduced basal hunger sensation and influenced the responses to the subsequent probe meal: it increased satiety (4.3±0.2 score vs 2.7±0.2 score; P<.001) and fullness (5.4±0.5 score vs 3.1±0.5; P<.001), but reduced the expected postprandial experience of digestive well-being after a palatable meal (1.3±0.7 score vs 3.0±0.3; P=.045). Appetite modulation by preload conditioning has differential effects on the cognitive and emotive responses to a meal. Preload conditioning of the postprandial experience may be applicable to dietary planning and prevention of postprandial symptoms.


Risk Factors for All-Cause Early Reoperation Following Tumor Resection and Endoprosthetic Reconstruction: A Secondary Analysis from the PARITY Trial.
Oncologic resection and endoprosthetic reconstruction of lower-extremity musculoskeletal tumors are complex procedures fraught with multiple modes of failure. A robust assessment of factors contributing to early reoperation in this population has not been performed in a large prospective cohort. The aim of the present study was to assess risk factors for early reoperation in patients who underwent tumor excision and endoprosthetic reconstruction, with use of data from the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial. Baseline characteristics were assessed, including age, sex, tumor type, tumor location, presence of a soft-tissue mass, diabetes, smoking status, chemotherapy use, and neutropenia. Operative factors were recorded, including operative time, topical antibiotics, silver-coated prosthetics, endoprosthetic fixation, extra-articular resection, length of bone resected, margins, tranexamic acid, postoperative antibiotics, negative-pressure wound therapy, and length of stay. Univariate analysis was utilized to explore the differences between patients who did and did not undergo reoperation within 1 year postoperatively, and a multivariate Cox proportional hazards regression model was utilized to explore the predictors of reoperation within 1 year. A total of 155 (25.7%) of 604 patients underwent ≥1 reoperation. In univariate analysis, tumor type (p < 0.001), presence of a soft-tissue mass (p = 0.045), operative time (p < 0.001), use of negative-pressure wound therapy (p = 0.010), and hospital length of stay (p < 0.001) were all significantly associated with reoperation. On multivariate assessment, tumor type (benign aggressive bone tumor versus primary bone malignancy; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 to 0.63; p = 0.01), operative time (HR per hour, 1.15; 95% CI, 1.10 to 1.23; p < 0.001), and use of negative-pressure wound therapy (HR, 1.93; 95% CI, 1.30 to 2.90; p = 0.002) remained significant predictors of reoperation within 1 year. Independent variables associated with reoperation within 1 year in patients who underwent tumor resection and endoprosthetic reconstruction included tumor type (benign aggressive bone tumor versus primary bone malignancy), operative time, and use of negative-pressure wound therapy. These results will help to inform patients and surgeons regarding the risk of reoperation by diagnosis and reinforce operative time as a factor influencing reoperation. These results also support further investigation into the use of negative-pressure wound therapy at the time of surgery in this patient population. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Transcriptome profiling of the antiviral immune response in Atlantic cod macrophages.
A study was conducted to determine the transcriptome response of Atlantic cod (Gadus morhua) macrophages to the viral mimic, polyriboinosinic polyribocytidylic acid (pIC), using a 20K Atlantic cod microarray platform and qPCR. We identified 285 significantly up-regulated and 161 significantly down-regulated probes in cod macrophages 24 h after pIC stimulation. A subset of 26 microarray-identified transcripts was subjected to qPCR validation using samples treated with pIC or phosphate-buffered saline (control) over time (3, 6, 12, 24, 48 h), and 77% of them showed a significant response to pIC. The microarray and qPCR analyses in this study showed that pIC induced the expression of cod macrophage transcripts involved in RLR- and TLR-dependent pathogen recognition (e.g. tlr3, tlr7, mda5 and lgp2), as well as signal transducers (e.g. stat1 and nfkbia) and transcription activators (e.g. irf7 and irf10) in the MyD88-independent and dependent signalling pathways. Several immune effectors (e.g. isg15s, viperin, herc4, mip2 and ccl13) were significantly up-regulated in pIC-stimulated cod macrophages. The expression of some transcripts (e.g. irf7, irf10, viperin) was significantly up-regulated by pIC as early as 12 h. All pIC-induced transcripts had peak expression at either 24 h (e.g. tlr7, irf7, mip2) or 48 h (e.g. tlr3, lgp2, stat1). This study suggests possible roles of both vertebrate-conserved (e.g. tlr3 as an up-regulated gene) and fish-specific (tlr22g as a down-regulated gene) receptors in dsRNA recognition, and the importance of conserved and potentially fish-specific interferon stimulated genes in cod macrophages.


Finding sequins in the rubble: The journeys of two Latina migrant lesbians in Los Angeles.
Mainstream research on lesbian, gay, bisexual, transgender Los Angeles (LA) has ignored Latinx queer communities until recently, and lesbian Latinas, particularly those who are migrants and/or refugees, have been especially marginalized. Building on scholarship and creative work by Chicana, Latina, women of color feminist, queer of color, and queer migration activists and scholars, this essay contributes to research on Mexican, Central American, and Latina lesbians in LA. In her research on sexually non-conforming Latinas, Katie L. Acosta argues that to better understand Latinas' sexualities in all their complexities, future scholarly work should address the pleasures and desires of Latina lesbians, as well as the quality and stability of the relationships they nurture in the borderlands. Building on queer migration research and using what Nan Alamilla Boyd and Horacio Roque Ramírez call "queer oral history," this article focuses on two everyday lesbians in LA whose stories add depth to our understandings of LA queer history and to the lives of queer migrants in the city. The narratives of Luna and Dulce, migrant lesbians from Mexico and Guatemala, respectively, provide a context for better understanding diverse experiences of migrant Latina lesbians in LA. Situating their lives within ongoing research on lesbian Latinas, this essay focuses on three themes-migration, leisure spaces, and family-to explore how these inform the women's everyday choices and shape their practices of freedom. Their stories and perspectives have been instrumental in enabling me to develop an interdisciplinary theoretical framework that I call "finding sequins in the rubble," through which we can recognize and understand how queer Latinx communities engage in processes of queer-world making and radical possibility through everyday acts of resilience and self-care in the midst of familial, institutional, and state violence.


Current issues in the prevention of mother-to-child transmission of HIV-1 infection.
Worldwide every year approximately 750,000 children become infected with HIV, mostly through mother-to-child transmission (MTCT). Without specific interventions, the rate of MTCT is approximately 15-20%, with prolonged breastfeeding doubling the rate to 35-40%. Current approaches to intervention to reduce the risk of MTCT focus mainly on antiretroviral prophylaxis during pregnancy, labour and in the early neonatal period, but in some settings also on delivery procedures and avoidance of breastfeeding. To reduce the risk of breastfeeding transmission, shortening the breastfeeding period and/or encouraging exclusive breastfeeding has been suggested. MTCT rates of less than 2% are now reported from countries where antiretroviral prophylaxis, elective Caesarean section and refraining from breastfeeding can be applied, whilst in settings where refraining from breastfeeding is not feasible or safe and where elective Caesarean section is also not a safe option, peripartum antiretroviral therapy can halve the risk to levels of approximately 10% at 6 weeks, although further acquisition of infection through breastfeeding substantially increases the overall rate to 20% or more. In light of the high mortality in all children of HIV-infected women, programmes for prevention of MTCT should be monitored not only in terms of HIV transmission avoided but also in terms of child survival.


Strangulated obturator hernia: can mortality be reduced?
We describe two patients with strangulated obturator hernia to enhance clinical awareness of the varied presentations of this uncommon hernia, which occurs especially in elderly women with either recurrent abdominal pain or partial intestinal obstruction, a positive Howship-Romberg sign, and an absent thigh adductor reflex. Early laparotomy for unexplained bowel obstruction is essential to avoid the complications associated with strangulated obturator hernia.


Efficacy and Safety of Nivolumab for Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.
To assess the efficacy and safety of nivolumab for advanced renal cell carcinoma (RCC) via meta-analysis. In this systematic review and meta-analysis, we searched PubMed, Embase, Science Citation Index Expanded, The Cochrane Library, and Web of Science for randomized controlled trials (RCTs) using nivolumab for patients with advanced RCC published before 30 December 2021. Quality assessments and meta-analyses were performed on all the literature assessed for eligibility. Of 203 studies identified as potentially eligible from 3214 studies in a preliminary search, three RCTs including 2550 RCC cases met the inclusion criteria and were of high quality. Meta-analysis showed benefits of nivolumab in the progression-free survival (PFS) (HR = 0.73, 95% CI: 0.54 to 0.99, P=0.04) and overall survival (OS) (HR = 0.70, 95% CI: 0.63 to 0.78, P < 0.001) of patients with advanced RCC, and no increase in documented adverse events was recorded. Nivolumab plus ipilimumab has significant benefits versus sunitinib in the treatment of advanced RCC in terms of tumor progression control and prolongation of OS and PFS, with a manageable safety profile.


Bulk COFs and COF nanosheets for electrochemical energy storage and conversion.
Covalent organic frameworks (COFs) as an emerging class of crystalline porous materials have received much attention due to their tunable porosity, modifiable skeletons, and atomically precise structures. Besides, COFs can provide multiple high-rate charge carrier transport (electron, hole, and ion) pathways, including conjugated skeletons, overlapped π electron clouds among the stacked layers, and open channels with a variable chemical environment. Therefore, they have shown great potential in electrochemical energy storage (EES) and conversion (EEC). However, in bulk COFs, the defects always impede charge carrier conduction, and the difficulties in reaching deep-buried active sites by either electrons or ions lead to limited performance. To overcome these obstacles, numerous research studies have been carried out to obtain COF nanosheets (NSs). This review first describes the preparation strategies of COF NSs via bottom-up and top-down approaches. Then, the applications of bulk COFs and COF NSs in EES and EEC are summarized, such as in batteries, supercapacitors, and fuel cells. Finally, key challenges and future directions in these areas are discussed.


Preventing Indigenous youth homelessness in Canada: A qualitative study on structural challenges and upstream prevention in education.
Drawing on a partnership with a group of Indigenous youth experiencing homelessness in Vancouver, Canada, this study identifies four structural challenges that have impacted them and four actionable upstream strategies to further prevent youth housing precarity. As a secondary analysis of a community-engaged study with youth experiencing homelessness, we conducted a thematic analysis with qualitative data, which included qualitative interviews with five young people and researcher observations. The results reflect the racial, colonial, and economic concerns that impact Indigenous youth experiencing homelessness. The four actionable upstream solutions highlight human rights-based approaches to homelessness, ranging from advancing and strengthening public services, transitional justice processes, and cultural and socioeconomic safety. This study provides strategies to promote Indigenous youth wellbeing and decrease risk of housing precarity, while centering and drawing from youth knowledge production. Strengths and limitations of the study are also discussed.


Evidence for nitrogen catabolite repression during citric acid production by Aspergillus niger under phosphate-limited growth conditions.
Experiments performed in batch fermentation under phosphate-limited growth conditions showed that the citric acid yield was inversely related to the excess nitrogen concentration in the medium. Results from chemostat culture confirmed a negative relationship between the citric acid yield and both the specific growth rate and the nitrogen consumption rate. This is evidence for nitrogen catabolite repression. A fed-batch fermentation performed under dual phosphate/nitrogen limitation produced results very similar to those from a culture limited by nitrogen alone. There is no advantage in maintaining an excess of phosphate during citric acid production and the process will therefore be more economic when operated under dual limitation conditions.


The Impact of Virtual Reality Hypnosis on Pain and Anxiety Caused by Trauma: Lessons Learned from a Clinical Trial.
This randomized, controlled trial tested the impact that hypnosis delivered through immersive virtual reality technology on background pain, anxiety, opioid use, and hospital length of stay in a sample of patients hospitalized for trauma. Participants were randomly assigned to receive either virtual-reality-induced hypnosis, virtual reality for distraction, or usual care during the course of their hospitalization. Mean number of treatment sessions was 3. A total of 153 patients participated in the study. Results indicated no significant differences between the experimental and control conditions on any outcome measures. This study used an early version of virtual reality technology to induce hypnosis and highlighted several important lessons about the challenges of implementation of this technology and how to improve its use in clinical settings.


Characterization and differentiation of sheep's milk from Greek breeds based on physicochemical parameters, fatty acid composition and volatile profile.
There are only limited studies in the literature attempting to differentiate sheep's milk originating from different sheep breeds. In the present study the physicochemical parameters (pH, percent fat, percent protein, percent lactose and percent total solids), fatty acid composition and volatile profile of raw milk from four autochthonous Greek breeds (Karagouniko, Mpoutsiko, Artas and Chios) were determined. The objective of the present study was to characterize and differentiate the sheep breeds based on the above analytical parameters in combination with chemometrics. The overall correct classification rate was 79.7%%, 84.4% and 100% based on physicochemical parameters, fatty acid composition and volatile profile, respectively. Volatiles proved to be the most effective of parameters analyzed for the differentiation of sheep breed. Furthermore, the combination of physicochemical parameters and fatty acid composition gave a correct classification rate equal to 96.9%. Either volatile profile or the combination of physicochemical parameters and fatty acid composition may be easily determined and used for the differentiation of sheep's milk from four different Greek breeds, this being the novelty of the present work. This may be very important in terms of PDO (Protected Designation of Origin) and PGI (Protected Geographical Indication) products related to specific geographical origin and sensory characteristics. © 2018 Society of Chemical Industry.


Cytocompatibility of Wood-Derived Cellulose Nanofibril Hydrogels with Different Surface Chemistry.
The current study aims to demonstrate the influence of the surface chemistry of wood-derived cellulose nanofibril (CNF) hydrogels on fibroblasts for tissue engineering applications. TEMPO-mediated oxidation or carboxymethylation pretreatments were employed to produce hydrogels with different surface chemistry. This study demonstrates the following: first, the gelation of CNF with cell culture medium and formation of stable hydrogels with improved rheological properties; second, the response of mouse fibroblasts cultured on the surface of the hydrogels or sandwiched within the materials with respect to cytotoxicity, cell attachment, proliferation, morphology, and migration. Indirect cytotoxicity tests showed no toxic effect of either hydrogel. The direct contact with the carboxymethylated hydrogel adversely influenced the morphology of the cells and limited their spreading, while typical morphology and spreading of cells were observed with the TEMPO-oxidized hydrogel. The porous fibrous structure may be a key to cell proliferation and migration in the hydrogels.


E-scribing: more realistic than ever.
Electronic medication administration and prescription offer caregivers one strategy to reduce medication errors. Advances in bar coding, robotics, and wireless technology, and sophisticated clinical decision support systems are paving the way.


Chronic ringworm infestation and Marjolin's ulcer, an association unknown in the literature.
We report here a case of Marjolin's ulcer developing in a long-standing, inadequately treated, chronic ringworm infestation of the lower limb. A 35-year-old female patient with a ten-year history of a chronic ringworm infestation had developed a nonhealing ulcer in an area of infestation on the right leg. A biopsy revealed well-differentiated squamous cell carcinoma associated with the ringworm infection. A below-knee amputation by an inguinal block dissection was performed. We conclude that proper and timely treatment of fungal infections of the skin is needed to allow for healing of dermal infections and thus the prevention of the disastrous consequences that recurrent mechanical trauma from scratching of the affected area, leading to occult malignancy, which may occur in a small number of patients.


[Cognitive impairment in multiple sclerosis].
The various lesions affecting the central nervous system in multiple sclerosis (MS) lead to a wide range of symptoms. Until now, physical disabilities have been the main focus of studies on the symptoms of MS; however, cognitive impairment that prominently affects sustained attention and information processing speed has been found by neuropsychological studies to affect over half of all MS patients. Because this cognitive impairment typically involves domain-specific deficits rather than global cognitive decline, it is usually difficult to detect. Cognitive dysfunction in MS patients could influence social activities, such as employment status. Therefore, we must pay greater attention to cognitive function in the milieu of clinical neurology.


Dynamic head-neck stabilization and modulation with perturbation bandwidth investigated using a multisegment neuromuscular model.
The human head-neck system requires continuous stabilization in the presence of gravity and trunk motion. We investigated contributions of the vestibulocollic reflex (VCR), the cervicocollic reflex (CCR), and neck muscle co-contraction to head-in-space and head-on-trunk stabilization, and investigated modulation of the stabilization strategy with the frequency content of trunk perturbations and the presence of visual feedback. We developed a multisegment cervical spine model where reflex gains (VCR and CCR) and neck muscle co-contraction were estimated by fitting the model to the response of young healthy subjects, seated and exposed to anterior-posterior trunk motion, with frequency content from 0.3 up to 1, 2, 4 and 8Hz, with and without visual feedback. The VCR contributed to head-in-space stabilization with a strong reduction of head rotation (<8Hz) and a moderate reduction of head translation (>1Hz). The CCR contributed to head-on-trunk stabilization with a reduction of head rotation and head translation relative to the trunk (<2Hz). The CCR also proved essential to stabilize the individual intervertebral joints and prevent neck buckling. Co-contraction was estimated to be of minor relevance. Control strategies employed during low bandwidth perturbations most effectively reduced head rotation and head relative displacement up to 3Hz while control strategies employed during high bandwidth perturbations reduced head global translation between 1 and 4Hz. This indicates a shift from minimizing head-on-trunk rotation and translation during low bandwidth perturbations to minimizing head-in-space translation during high bandwidth perturbations. Presence of visual feedback had limited effects suggesting increased usage of vestibular feedback.


Vitamin D and psoriasis pathology in the Mediterranean region, Valencia (Spain).
Vitamin D has important immunomodulatory effects on psoriasis in the Mediterranean region. To measure vitamin D intake in subjects with and without psoriasis, and to find an association with relevant clinical features, a case-control study was performed using cases (n = 50, 50% participation rate) clinically diagnosed with psoriasis and 200 healthy subjects (39.5% participation rate), leaving a final sample of 104 people. A survey was conducted using a food frequency questionnaire and clinical histories. Cases and controls were compared using univariate and multivariate analyses. We observed insufficient intake of cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) for both cases and controls. Patients with psoriasis were at greater risk of associated pathologies: dyslipidaemia (OR: 3.6, 95% CI: 0.8-15.2); metabolic syndrome (OR: 3.3, 95% CI: 0.2-53.9); hypertension (OR: 1.7, 95% CI: 0.4-7.2). Insufficient vitamin D intake in both psoriasis patients and controls in the Mediterranean population, and cardiovascular comorbility is more frequent in patients with psoriasis.


Benign cardiac tumours associated with sudden death.
Sudden cardiac death (SCD) accounts for 50% of cardiovascular mortality with an estimated annual toll of 300 000 deaths in the USA and 60 000 deaths in the UK. Benign primary cardiac tumours are extremely rare, and although many of these entities are clinically silent, a few can cause significant morbidity or even sudden death. The objective of the study is to raise awareness of benign primary cardiac tumours as a possible cause of SCD so that more cases are identified by pathologists during life. Between 1994 and 2012, the hearts of more than 1600 people who had SCD were referred for pathological assessment to ascertain the precise aetiology of SCD. Eleven cases of SCD associated with benign cardiac tumours were identified; four were cystic tumours of the atrioventricular (AV) node, three lipomas, two rhabdomyomas, one haemangioma, and one myxoma. This study highlights that benign cardiac tumours are exceptionally uncommon yet potentially lethal. Careful examination of the heart will identify most of these lesions. A major exception, however, is cystic tumour of the AV node, the most common primary cardiac tumour causing sudden death. Since the gross findings of this lesion may be minimal, we recommend taking a routine section of the conducting system, including the AV node, in all cases of sudden death.


Upregulating KTN1 promotes Hepatocellular Carcinoma progression.
Background: Hepatocellular carcinoma (HCC) presents a common malignant tumor worldwide. Although kinectin 1 (KTN1) is the most frequently identified antigen in HCC tissues, the detailed roles of KTN1 in HCC remain unknown. This study seeks to clarify the expression status and clinical value of KTN1 in HCC and to explore the complicated biological functions of KTN1 and its underlying mechanisms. Methods: In-house reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of KTN1 in HCC tissues. External gene microarrays and RNA-sequencing datasets were downloaded to confirm the expression patterns of KTN1. The prognostic ability of KTN1 in HCC was assessed by a Kaplan-Meier curve and a hazard ratio forest plot. The CRISPR/Cas9 gene-editing system was used to knock out KTN1 in Huh7 cells, which was verified by PCR-Sanger sequencing and western blotting. Assays of cell migration, invasion, viability, cell cycle, and apoptosis were conducted to explore the biological functions. RNA sequencing was performed to quantitatively analyze the functional deregulation in KTN1-knockout cells compared to Huh7-wild-type cells. Upregulated genes that co-expressed with KTN1 were identified from HCC tissues and were functionally annotated. Results: KTN1 expression was increased in HCC tissues (standardized mean difference [SMD] = 0.20 [0.04, 0.37]). High KTN1 expression was significantly correlated with poorer prognosis of HCC patients, and KTN1 may be an independent risk factor for HCC (pooled HRs = 1.31 [1.05, 1.64]). After KTN1-knockout, the viability, migration, and invasion ability of HCC cells were inhibited. The proportion of HCC cells in the G0-G1 phases increased after KTN1 knockout, which also elevated the apoptosis rates in HCC cells. Several cascades, including innate immune response, chemical carcinogenesis, and positive regulation of transcription by RNA polymerase II, were dramatically changed after KTN1 knockout. KTN1 primarily participated in the cell cycle, DNA replication, and microRNAs in cancer pathways in HCC tissues. Conclusion: Upregulation of KTN1 served as a promising prognosticator in HCC patients. KTN1 promotes the occurrence and deterioration of HCC by mediating cell survival, migration, invasion, cell cycle activation, and apoptotic inhibition. KTN1 may be a therapeutic target in HCC patients.


p53--a natural cancer killer: structural insights and therapeutic concepts.
Every single day, the DNA of each cell in the human body is mutated thousands of times, even in absence of oncogenes or extreme radiation. Many of these mutations could lead to cancer and, finally, death. To fight this, multicellular organisms have evolved an efficient control system with the tumor-suppressor protein p53 as the central element. An intact p53 network ensures that DNA damage is detected early on. The importance of p53 for preventing cancer is highlighted by the fact that p53 is inactivated in more than 50 % of all human tumors. Thus, for good reason, p53 is one of the most intensively studied proteins. Despite the great effort that has been made to characterize this protein, the complex function and the structural properties of p53 are still only partially known. This review highlights basic concepts and recent progress in understanding the structure and regulation of p53, focusing on emerging new mechanistic and therapeutic concepts.


Hybrid vigor between native and introduced salamanders raises new challenges for conservation.
Hybridization between differentiated lineages can have many different consequences depending on fitness variation among hybrid offspring. When introduced organisms hybridize with natives, the ensuing evolutionary dynamics may substantially complicate conservation decisions. Understanding the fitness consequences of hybridization is an important first step in predicting its evolutionary outcome and conservation impact. Here, we measured natural selection caused by differential viability of hybrid larvae in wild populations where native California Tiger Salamanders (Ambystoma californiense) and introduced Barred Tiger Salamanders (Ambystoma tigrinum mavortium) have been hybridizing for 50-60 years. We found strong evidence of hybrid vigor; mixed-ancestry genotypes had higher survival rates than genotypes containing mostly native or mostly introduced alleles. Hybrid vigor may be caused by heterozygote advantage (overdominance) or recombinant hybrid vigor (due to epistasis or complementation). These genetic mechanisms are not mutually exclusive, and we find statistical support for both overdominant and recombinant contributions to hybrid vigor in larval tiger salamanders. Because recombinant homozygous genotypes can breed true, a single highly fit genotype with a mosaic of native and introduced alleles may eventually replace the historically pure California Tiger Salamander (listed as Threatened under the U.S. Endangered Species Act). The management implications of this outcome are complex: Genetically pure populations may not persist into the future, but average fitness and population viability of admixed California Tiger Salamanders may be enhanced. The ecological consequences for other native species are unknown.


Anisotropic growth and formation mechanism investigation of 1D ZnO nanorods in spin-coating sol-gel process.
ZnO nanorods are fabricated on glass substrate by spin-coating sol-gel process using non-basic aged solution and annealing. Sample solutions reserved in room temperature for different time (one day, one month, two months and four months) are prepared for the experiment. The morphology study indicates that the aging time has direct influence on the final products. This is verified by the Transmission Electron Microscopy and Photon Correlation Spectroscopy study. Small crystalline nanoparticles would gradually nucleate and aggregate in the sol during the aging process. They act as nucleation site for the secondary crystal growth into nanorods during anneal. Both the size of crystalline particles in the sol and the size of nanorods will grow bigger as the aging time increases. The products' structure and optical property are further studied by X-ray diffraction spectroscopy, Photoluminescence and Raman spectroscopy. This work also helps to further clarify the formation mechanism of ZnO nanorods by solution-based method.


Reversible renal failure following bilateral renal artery occlusive disease. Clinical features, pathology, and the role of surgical revascularization.
Three patients with severe hypertension and rapidly progressive oliguric renal failure who required dialysis were found by aortography to have bilateral renal artery occlusion or stenosis. Each had peripheral arteriosclerosis or an abdominal bruit. Following renal artery reconstructive surgery, all three patients recovered nearly normal renal function in 3 to 12 weeks, though mild hypertension persisted in two patients. The common findings of a normal-sized kidney with collateral blood flow and nearly normal histological features were predictive of recovery of renal function. Prolonged postoperative oliguria in two patients may have been due to increased preglomerular vascular resistance mediated by the renin-angiotensin system.


Intracellular signaling via ERK/MAPK completes the pathway for tubulogenic fibronectin in MDCK cells.
A classic in vitro model of branching morphogenesis utilizes the Madin-Darby canine kidney (MDCK) cell line. MDCK Strain II cells form hollow monoclonal cysts in a three-dimensional collagen matrix over the course of 10 days and tubulate in response to hepatocyte growth factor (HGF). We and our colleagues previously showed that activation of the extracellular-signal regulated kinase (ERK, aka MAPK) pathway is necessary and sufficient to induce tubulogenesis in MDCK cells. We also showed in a microarray study that one of the genes upregulated by HGF was the known tubulogene fibronectin. Given that HGF activates a multitude of signaling pathways, including ERK/MAPK, to test the intracellular regulatory pathway, we used two distinct inhibitors of ERK activation (U0126 and PD098059). Following induction of MDCK Type II cells with HGF, tubulogenic fibronectin mRNA was upregulated fourfold by real-time PCR, and minimal or no change in fibronectin expression was seen when HGF was added with either U0126 or PD098059. We confirmed these results using an MDCK cell line inducible for Raf, which is upstream of ERK. Following activation of Raf, fibronectin mRNA and protein expression were increased to a similar degree as was seen following HGF induction. Furthermore, MDCK Strain I cells, which originate from collecting ducts and have constitutively active ERK, spontaneously initiate tubulogenesis. We show here that MDCK Strain I cells have high levels of fibronectin mRNA and protein compared to MDCK Strain II cells. When U0126 and PD098059 were added to MDCK Strain I cells, fibronectin mRNA, and protein levels were decreased to levels seen in MDCK Strain II cells. These data allow us to complete what we believe is the first description of a tubulogenic pathway from receptor/ligand (HGF/CMET), through an intracellular signaling pathway (ERK/MAPK), to transcription and, finally, secretion of a critical tubuloprotein (fibronectin).


Concise and Versatile Synthesis of Sulfoquinovosyl Acyl Glycerol Derivatives for Biological Applications.
Sulfoquinovosyl acylpropanediol (SQAP), a chemically modified analogue of sulfoquinovosyl acylglycerol (SQAG) that occurs in sea algae, has been reported to show a variety of biological activities, including accumulation in tumor cells and the inhibition of tumor cell growth. We report herein on a new concise and versatile synthesis of SQAP itself and derivatives bearing iodoaryl groups and boronclusters. This method should be useful for the design and synthesis of SQAG/SQAP derivatives for diagnosis and the treatment of cancer and related diseases.