TNF inhibitors associated with cardiovascular diseases and cardiometabolic risk factors: a Mendelian randomization study.

OBJECTIVE: There is still disagreement about whether anti-tumor necrosis factor (TNF) therapy is beneficial or detrimental to cardiovascular conditions. This two-sample Mendelian randomization (MR) study aimed to evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on cardiovascular diseases (CVDs) and cardiometabolic risk factors via genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) and TNF. MATERIALS AND METHODS: Two genetic instruments were examined to mimic the long-term effect of TNF inhibitors. The first were single-nucleotide polymorphisms (SNPs) within or nearby drug-target genes TNFRSF1A and TNF (encoding TNFR1 and TNF) associated with circulating CRP levels. The other instruments were the expression quantitative trait loci (eQTLs) near the genes. Inverse variance-weighted MR (IVW-MR) and summary-based MR (SMR) methods were employed to estimate causal effects. RESULTS: In IVW-MR analysis, TNF-mediated circulating CRP levels were significantly associated with 4 out of 12 CVDs, including hypertension [odds ratio (OR) = 1.13; 95% CI, 1.09-1.18], coronary artery disease (OR = 3.18; 95% CI, 1.77-5.71), coronary atherosclerosis (OR = 1.05; 95% CI, 1.02-1.08) and type 2 diabetes (OR = 3.48; 95% CI, 1.98-6.10). These findings were also validated in the FinnGen study. Moreover, TNF inhibition was also associated with total cholesterol, triglycerides, apolipoprotein B, systolic blood pressure, serum cystatin C, height, weight, and body mass index. CONCLUSIONS: In this study, the decrease in several CVDs and cardiometabolic risk factors has been found to be causally associated with genetically proxied TNF inhibitors.

Effects of water-sodium balance and regulation of electrolytes associated with antidiabetic drugs.

As the prevalence of diabetes rises, the use of antidiabetic drugs becomes more frequent. Thus, focusing on the effects of these drugs on water-sodium balance and electrolyte regulation is necessary. This review discusses the effects and the mechanisms behind them. Several sulfonylureas, such as chlorpropamide, methanesulfonamide, and tolbutamide, exhibit water-retaining properties. Other sulfonylureas, such as glipizide, glibenclamide, acetohexamide, and tolazamide, are not antidiuretic or even diuretic. Numerous clinical studies showed that metformin can reduce serum magnesium concentrations and may have an effect on the cardiovascular system, but the specific mechanism remains to be discussed. Different opinions exist about the mechanisms of thiazolidinedione-induced fluid retention. Sodium-glucose cotransporter 2 inhibitors can cause osmotic diuresis and natriuresis and elevated serum potassium and magnesium concentrations. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors can enhance urine sodium excretion. At the same time, increased urinary sodium caused by sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors reduce blood pressure and plasma volume, thereby protecting the heart. Insulin has a sodium-retaining effect and is also associated with hypokalemia, hypomagnesemia, and hypophosphatemia. Several of the aforementioned pathophysiological changes and mechanisms have been discussed, and conclusions have been drawn. However, further investigation and discussion are still warranted.

Residence times of groundwater along a flow path in the Great Artesian Basin determined by 81Kr, 36Cl and 4He: Implications for palaeo hydrogeology.

Understanding the age distribution of groundwater can provide information on both the recharge history as well as the geochemical evolution of groundwater flow systems. Of the few candidates available that can be used to date old groundwater, 81Kr shows the most promise because its input function is constant through time and there are less sources and sinks to complicate the dating procedure in comparison to traditional tracers such as 36Cl and 4He. In this paper we use 81Kr in a large groundwater basin to obtain a better understanding of the residence time distribution of an unconfined-confined aquifer system. A suite of environmental tracers along a groundwater flow path in the south-west Great Artesian Basin of Australia have been sampled. All age tracers (85Kr, 39Ar 14C, 81Kr, 36Cl and 4He) display a consistent increase in groundwater age with distance from the recharge area indicating the presence of a connected flow path. Assuming that 81Kr is the most accurate dating technique the 36Cl/Cl systematics was unravelled to reveal information on recharge mechanism and chloride concentration at the time of recharge. Current-day recharge occurs via ephemeral river recharge beneath the Finke River, while diffuse recharge is minor in the young groundwaters. Towards the end of the transect the influence of ephemeral recharge is less while diffuse recharge and the initial chloride concentration at recharge were higher.

[Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development].

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

Optical Excitation and Trapping of

We have realized optical excitation, trapping, and detection of the radioisotope ^{81}Kr with an isotopic abundance of 0.9 ppt. The 124 nm light needed for the production of metastable atoms is generated by a resonant discharge lamp. Photon transport through the optically thick krypton gas inside the lamp is simulated and optimized to enhance both brightness and resonance. We achieve a state-of-the-art ^{81}Kr loading rate of 1800 atoms/h, which can be further scaled up by adding more lamps. The all-optical approach overcomes the limitations on precision and sample size of radiokrypton dating, enabling new applications in the earth sciences, particularly for dating of polar ice cores.

Therapeutic efficacy of dexmedetomidine on chronic obstructive pulmonary disease via downregulating lncRNA PACER.

OBJECTIVE: The aim of the study was to clarify the therapeutic mechanism of Dexmedetomidine (DEX) on the chronic obstructive pulmonary disease (COPD) and its regulatory effect on long non-coding RNA (lncRNA) PACER. PATIENTS AND METHODS: Serum level of PACER in COPD patients was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic potential of PACER in COPD was assessed by plotting ROC curves. The in vivo COPD model was generated in rats by cigarette smoking exposure. Primary rat alveolar epithelial cells were isolated, purified and cultured. After overexpression of PACER in primary rat alveolar epithelial cells, proliferative and migratory abilities were assessed by cell counting kit-8 (CCK-8) and transwell assay, respectively. Subsequently, we detected changes in PACER expression, viability and migratory potentials in primary rat alveolar epithelial cells harvested from control rats, and those harvested from COPD rats and induced with either DEX or not. Rescue experiments were conducted to uncover the involvement of PP2A in PACER-regulated cell phenotypes. RESULTS: PACER was upregulated in serum of COPD patients, which was a potential biomarker for diagnosing COPD. Overexpression of PACER in primary rat alveolar epithelial cells enhanced proliferative and migratory abilities. Compared with primary rat alveolar epithelial cells harvested from control rats, proliferative and migratory abilities were stronger in those harvested from COPD rats and induced with either DEX or not. Notably, DEX induction decreased PACER expression, and proliferative and migratory abilities in primary rat alveolar epithelial cells harvested from COPD rats. Overexpression of PP2A could partially abolish the promotive effects of PACER on proliferative and migratory abilities in DEX-induced primary rat alveolar epithelial cells harvested from COPD rats. CONCLUSIONS: PACER drives the proliferative and migratory abilities of alveolar epithelial cells through activating PP2A. Dexmedetomidine is conducive to COPD treatment by downregulating PACER.

An electromagnetic separation system for the enrichment of 39Ar.

An isotope enrichment system for 39Ar has been developed at the Institute of Modern Physics, which is designed to increase the abundance of 39Ar in the incident sample gas. With intense Ar+ beams produced by a 2.45 GHz electron cyclotron resonance ion source and a high mass resolution spectrometer system, Ar isotopes are evidently separated on the target plane and selectively collected by an Al target. The separated Ar isotopes have been identified on the target plane, which is consistent with the simulations. According to the recent cross-checked results with atom trap trace analysis, a high enrichment factor of 39Ar has been successfully achieved. This paper will present the design and test results of this system.

Neuroprotective effect of gastrodin in methamphetamine-induced apoptosis through regulating cAMP/PKA/CREB pathway in cortical neuron.

OBJECTIVE: Methamphetamine (MA) abuse induces neurotoxicity and causes neuronal cell apoptosis. Gastrodin is a traditional Chinese herbal medicine used for the treatment of nerve injuries, spinal cord injuries, and some central nervous system diseases as well. The present study investigated the neuroprotective effects of gastrodin against MA-induced neurotoxicity in neuronal cells and its potential protective mechanism. METHODS: The primary cortex neuronal culture was divided into four groups (control group, MA group, MA + gastrodin group, and MA + gastrodin + small interfering RNA group). The neurotoxicity of MA was assessed by detecting apoptotic cells by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay and cell viability by cell counting kit 8 (CCK-8) method, the Tuj1-positive cells and the average axonal length were detected by immunofluorescence, and the expressions of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element-binding (CREB), and brain-derived neurotrophic factor (BDNF) proteins were detected by Western blot. RESULTS: The results of CCK-8 assay showed that 0.5 mM MA was an optimal concentration that induced neurotoxicity (p < 0.01). Pretreatment with 25 mg/L gastrodin exerted maximum protective effects on neuronal cells. The expression levels of cAMP, PKA, phosphorylated PKA, CREB, phosphorylated CREB, and BDNF proteins were decreased in the MA group, and pretreatment with gastrodin upregulated the expression levels of these proteins (p < 0.01). The expressions of PKA and CREB proteins showed no significant changes in the control group, MA group, and gastrodin group. Compared the MA + gastrodin + small interfering RNA group with MA + gastrodin group, the Tuj1-positive cells and the average axonal length were decreased significantly, while the number of apoptotic cells was increased (p < 0.05). CONCLUSION: Gastrodin has neuroprotective effects against MA-induced neurotoxicity, which exerts neuroprotective effects via regulation of cAMP/PKA/CREB signaling pathway and upregulates the expression of BDNF.

Adsorption of metal atoms on silicene: stability and quantum capacitance of silicene-based electrode materials.

We explore the adsorption stability and quantum capacitance of transition metal atoms on silicene based on first-principles calculations. Silicene with a buckled atomic layer has a high surface/volume ratio and silicene-based materials are expected to have potential applications for supercapacitors. We find that the most favorable adsorption sites on pristine silicene are valley sites for Al and Ti, and hollow sites for Ag, Cu and Au, respectively. Among all these systems with the doping of metal atoms, silicene is modulated to possess a quasi-metallic characteristic, accompanied by an appreciable electron transfer and the formation of defect states near the Fermi level. Due to the low density of states near the Fermi level, the quantum capacitance of pristine silicene has been limited. By the doping of metal atoms, especially Ti atoms, with the introduction of localized defect states near the Fermi level, quantum capacitance is found to be enhanced significantly. In addition, the quantum capacitance is found to increase monotonically following the increase of doping concentrations.

The international phase 4 validation study of the EORTC QLQ-SWB32: A stand-alone measure of spiritual well-being for people receiving palliative care for cancer.

The EORTC Quality of Life Group has just completed the final phase (field-testing and validation) of an international project to develop a stand-alone measure of spiritual well-being (SWB) for palliative cancer patients. Participants (n = 451)-from 14 countries on four continents; 54% female; 188 Christian; 50 Muslim; 156 with no religion-completed a provisional 36-item measure of SWB plus the EORTC QLQ-C15-PAL (PAL), then took part in a structured debriefing interview. All items showed good score distribution across response categories. We assessed scale structure using principal component analysis and Rasch analysis, and explored construct validity, and convergent/divergent validity with the PAL. Twenty-two items in four scoring scales (Relationship with Self, Relationships with Others, Relationship with Someone or Something Greater, and Existential) explained 53% of the variance. The measure also includes a global SWB item and nine other items. Scores on the PAL global quality-of-life item and Emotional Functioning scale weakly-moderately correlated with scores on the global SWB item and two of the four SWB scales. This new validated 32-item SWB measure addresses a distinct aspect of quality-of-life, and is now available for use in research and clinical practice, with a role as both a measurement and an intervention tool.

KRT19 directly interacts with ß-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties.

Studies have reported that interactions between keratins (KRTs) and other proteins initiate signaling cascades that regulate cell migration, invasion, and metastasis. In the current study, we found that expression of KRT19 was specifically high in breast cancers and significantly correlated with their invasiveness. Moreover, knockdown of KRT19 led to increased proliferation, migration, invasion, drug resistance, and sphere formation in breast cancer cells via an upregulated NOTCH signaling pathway. This was owing to reduced expression of NUMB, an inhibitory protein of the NOTCH signaling pathway. In addition, we found that KRT19 interacts with ß-catenin/RAC1 complex and enhances the nuclear translocation of ß-catenin. Concordantly, knockdown of KRT19 suppressed the nuclear translocation of ß-catenin as well as ß-catenin-mediated NUMB expression. Furthermore, modulation of KRT19-mediated regulation of NUMB and NOTCH1 expression led to the repression of the cancer stem cell properties of breast cancer patient-derived CD133high/CXCR4high/ALDH1high cancer stem-like cells (CSLCs), which showed very low KRT19 and high NOTCH1 expression. Taken together, our study suggests a novel function for KRT19 in the regulation of nuclear import of the ß-catenin/RAC1 complex, thus modulating the NUMB-dependent NOTCH signaling pathway in breast cancers and CSLCs, which might bear potential clinical implications for cancer or CSLC treatment.

Imaging findings of solitary fibrous tumor in the abdomen and pelvis.

PURPOSE: The purpose of this study was to investigate the imaging characteristics of solitary fibrous tumor (SFT) in the abdomen and pelvis. METHODS: Nine cases of SFT confirmed by surgery and pathology were retrospectively analyzed in terms of computed tomography (CT, eight cases) and magnetic resonance imaging (MRI, one case). RESULTS: SFT were located in the retroperitoneum (4/9), abdominal cavity (1/9), pelvis (4/9). Eight cases were single (8/9) and one case (1/9) with three tumors. The average tumor size of 11 lesions was 9.7 cm (4.7-20 cm). Nine tumors were round or ovoid, and two lesions were irregular. The CT value of the plain scans ranged from 33 to 43 Hounsfield units (HU, mean 37.6 HU) in five cases. Arterial-phase CT found solid parts demonstrate avid enhancement (eight cases) and five of them presented with multiple circuitous vessels along the periphery with a CT value of 68-89 HU (mean 76.6 HU). In the venous and delayed phases, enhancement was strengthened progressively. The CT values at venous (eight cases) and delayed phases (five cases) were 108-115 and 112-123 HU respectively, with averages of 109.8 and 114.8 HU. Patch or nodular no-enhanced areas were observed in eight cases during the enhanced phases. One case showed isointensity on T1-weighted images and high signal intensity on T2-weighted images accompanied by linear or curvilinear hypointense lines. Intense enhancements along with linear no-enhancement areas are seen in the arterial and venous phases. CONCLUSION: The possibility of SFT should be considered when a single or multiple masses with sharp border, inhomogeneous density or signal are detected, especially, with inhomogeneous intense enhancement in the arterial phase being maintained in the venous and delayed phases.

Analysis of 85Kr: a comparison at the 10 -14 level using micro-liter samples.

The isotopic abundance of (85)Kr in the atmosphere, currently at the level of 10(-11), has increased by orders of magnitude since the dawn of nuclear age. With a half-life of 10.76 years, (85)Kr is of great interest as tracers for environmental samples such as air, groundwater and ice. Atom Trap Trace Analysis (ATTA) is an emerging method for the analysis of rare krypton isotopes at isotopic abundance levels as low as 10(-14) using krypton gas samples of a few micro-liters. Both the reliability and reproducibility of the method are examined in the present study by an inter-comparison among different instruments. The (85)Kr/Kr ratios of 12 samples, in the range of 10(-13) to 10(-10), are measured independently in three laboratories: a low-level counting laboratory in Bern, Switzerland, and two ATTA laboratories, one in Hefei, China, and another in Argonne, USA. The results are in agreement at the precision level of 5%.

Normalization of the single atom counting rate in an atom trap.

The single atom counting rate of a rare isotope and the loading rate of another stable isotope with an abundance over 10 orders of magnitude larger are measured in one atom trap. The linear correlation between the measured counting/loading rates is examined to determine the (84)Kr/(82)Kr and (85)Kr/(83)Kr ratios of a Kr gas sample. Experiments show that the relative uncertainty is reduced to 1.3% when the single atom counting rate of (85)Kr is normalized by the measured (83)Kr loading rate. The measurement of the normalized single atom counting rate can be used to determine extremely low (10(-16)-10(-11)) isotope abundance. This normalization method is robust and can also be applied in other atomic systems.

Analysis of prognosis-related factors in patients with invasive cervical adenocarcinoma.

OBJECTIVE: To explore the prognostic related factors in patients with cervical adenocarcinoma. METHODS: Clinical and pathological data were retrospectively analyzed in 144 patients with cervical adenocarcinoma between 1995 and 2004. RESULTS: Five-year survival rates were 80.1%, 59.7%, 6.3 % and 0.0%, respectively, in patients with Stage I, II, III and IV cervical adenocarcinoma, and the overall 5-year survival rate was 59.0%. Univariate analysis indicated poor prognosis in non-exophytic tumor, tumor diameter > 4 cm, advanced clinical stage, mucinous adenocarcinoma and clear cell carcinoma, or poorly differentiated tumor. The prognosis was related to lymph node metastasis and deep myometrial invasion. Multivariate analysis indicated that besides clinical stage, myometrial invasion and lymph node metastasis, tumor shape was also an independent prognostic related factor. CONCLUSION: The prognosis is associated with tumor shape besides pre-confirmed clinical stage, myometrial invasion and lymph node metastasis. Ovarian preservation in young women remains to be further explored.

An efficient magneto-optical trap of metastable krypton atoms.

We report a magneto-optical trap of metastable krypton atoms with a trap loading rate of 3×10(11) atoms/s and a trap capture efficiency of 3×10(-5). The system starts with an atomic beam of metastable krypton produced in a liquid-nitrogen cooled, radio-frequency driven discharge. The metastable beam flux emerging from the discharge is 1.5×10(14) atoms/s/sr. The flux in the forward direction is enhanced by a factor of 156 with transverse laser cooling. The atoms are then slowed inside a Zeeman slower before captured by a magneto-optic trap. The trap efficiency can be further improved, possibly to the 10(-2) level, by gas recirculation. Such an atom trap is useful in trace analysis applications where available sample size is limited.

Synthesis and field electron emission properties of hybrid carbon nanotubes and nanoparticles.

Hybrid ZnO-carbon nanotubes as well as nanodiamond-carbon nanotubes were synthesized via a straightforward process of plasma enhanced chemical vapor deposition. For the former, ZnO nanoparticles were instantly coated on the tube surface in the final growing process of carbon nanotubes, while for the latter diamond nanoparticles were grown using pretreatment of a silicon substrate with Ni(NO(3))(2)·6H(2)O/Mg(NO(3))(2)·6H(2)O alcohol solution prior to deposition and a high H(2)/CH(4) gas flow ratio in the deposition process. The morphology and microstructure of the obtained hybrid materials were characterized by transmission electron microscopy. Both hybrid ZnO-carbon nanotubes and nanodiamond-carbon nanotubes exhibited excellent field emission properties.

Bifemelane hydrochloride enhances 'ischemic tolerance' phenomenon in gerbil hippocampal CA1 neurons.

Neurons are so vulnerable to ischemic insults that transient forebrain ischemia for 5 min killed most CA1 neurons in the gerbil hippocampus (surviving neurons: 4%). In contrast, 2 days after a nonlethal challenge of 2-min ischemia, 51% of CA1 neurons became resistant to subsequent, otherwise lethal ischemia for 5 min. Bifemelane hydrochloride (20 mg/kg, i.p.), which helps ischemic brain recover from oxidative stress and inhibition of protein synthesis, significantly enhanced the 'ischemic tolerance' phenomenon if injected 1 day after 2-min ischemia: 94% of neurons survived after 5-min ischemia. This finding carries implications for possible preventive treatment following warning signs of transient ischemic attack.

[Effects of desensitization and immunologic changes in patients with allergic asthma].

The allergic dermal tests were carried out in 122 patients who were treated from June 1987 to August 1988. The positive rates for mycomutacapitis, myco-root-black, dust mite and artemisia pollemo were 37.5%, 34.5%, 34.2% and 21.88% respectively in inhaled antigens used for skin test. The positive rates for sesame, peanut, allium and garlic were rather high in food antigens used for skin test. The serum IgE and the total IgE tested by BA-ELISA and human basophil degranulation test (HBDT) were observed in 68 patients with allergic asthma and 52 healthy persons. It was found that the positive rate of BA-ELISA (82.35%) and HBDT (84.70%) coincided well with the dermal test. There was significant changes in serum level of the specific IgE and the total IgE before and after desensitizing therapy with the dust mite dermotaphagoides for 6 months (P less than 0.001).

Isoenzymes of phenol oxidase in adult female Schistosoma japonicum.

Isoelectric focusing was used to study the phenol oxidase isozymes in adult female worms of Schistosoma japonicum. More than one form of phenol oxidase has been demonstrated in extracts of female worms when incubated with 3,4-dihydroxyphenylalanine (DOPA), catechol or cresol as substrates. DOPA is the best substrate among all of them. The 5-6 bands of phenol oxidase exhibit pI values in the range of 6.0-7.5, the major band is at pI 6.0.