Combined exposure to multiple air pollutants and incident ischemic heart disease in individuals with and without type 2 diabetes: A cohort study from the UK Biobank.

BACKGROUND: Air pollution and type 2 diabetes (T2D) are both associated with an increased risk of ischemic heart disease (IHD). Little is known about the combined effects of multiple air pollutants on IHD risk, especially among individuals with T2D. We sought to assess the association of combined exposure to multiple air pollutants with incident IHD and examine the modification effect of T2D. METHODS: This study included 388780 individuals (20036 individuals with T2D) free of cardiovascular disease and cancer from the UK Biobank. The combined exposure to multiple air pollutants, including particulate matter (PM) with diameters ≤ 2.5 µm (PM2.5), PM with diameters between 2.5 and 10 µm (PMcoarse), PM with diameters ≤ 10 µm (PM10), nitrogen dioxide (NO2), and nitrogen dioxides (NOx), was assessed by creating a weighted air pollution score (APS), with a higher APS representing a higher level of air pollution exposure. Hazard ratios (HR) and 95 % confidence intervals (CI) for incident IHD were assessed by multivariable-adjusted Cox proportional hazard models. RESULTS: During a median of 12.9 years of follow-up, 27333 incident IHD cases were observed. Compared with the lowest tertile of the APS, the multivariable-adjusted HR (95 % CI) of IHD risk for the highest tertile was 1.13 (1.03-1.23) among individuals with T2D, while the HR was 1.06 (1.03-1.10) among individuals without T2D. Additionally, the associations between APS and IHD incidence showed a linear relationship among individuals with T2D (nonlinearity: P = 0.37), whereas a non-linear relationship was observed among individuals without T2D (nonlinearity: P = 0.02). For the joint analysis, individuals in the highest tertile of APS and with T2D had a 54 % higher risk of IHD compared to individuals in the lowest tertile of APS and without T2D, with a significant additive interaction (Pinteraction < 0.01). The proportion of relative excess risk was 17 % due to the interaction in categorical analyses. CONCLUSIONS: The combined exposure to multiple air pollutants has been associated with an elevated risk of incident IHD, and the association is more pronounced among individuals with T2D.

Tenofovir alafenamide significantly increased serum lipid levels compared with entecavir therapy in chronic hepatitis B virus patients.

BACKGROUND: Tenofovir alafenamide (TAF) has a serum lipid-raising effect in patients with HIV; however, its effect on serum lipids and nonalcoholic fatty liver disease (NAFLD) risk in patients with chronic hepatitis B (CHB) is unclear. AIM: To compare the effects of TAF and entecavir (ETV) on serum lipid levels in patients with CHB. METHODS: In this retrospective cohort study, the data including the clinical features, serum lipids, and metabolic factors of patients with CHB at baseline and approximately 1 year after TAF or ETV treatment were collected and analyzed. We used propensity score-matched models to assess the effects on high-density lipoprotein, low-density lipoprotein, triglycerides, and total cholesterol (TCHO). RESULTS: A total of 336 patients (75.60% male) were included; 63.69% received TAF and 36.31% received ETV. Compared with the ETV group, the TAF group had significantly higher TCHO levels after treatment (4.67 ± 0.90 vs 4.36 ± 1.05, P = 0.006). In a propensity score-matched model for body mass index, age, sex, smoking, drinking, presence of comorbidities such as NAFLD, cirrhosis, diabetes mellitus, and hypertension, TAF-treated patients had significantly increased TCHO levels compared to that at baseline (P = 0.019). There was no difference for the ETV group. Body mass index, sex, hypertension, baseline TCHO, and creatine kinase-MB isoenzyme levels were significantly associated with elevated TCHO levels in logistic regression analysis. However, 1-year TAF treatment did not increase the incidence of NAFLD. CONCLUSION: A greater increase in TCHO was observed in patients with CHB receiving TAF compared to those receiving ETV. However, TAF-induced dyslipidemia did not increase the incidence of NAFLD.

Evolution characteristic of atmospheric black carbon particles at a coastal site in the Pearl River Delta, China.

The mixing of black carbon (BC) with secondary materials is a major uncertainty source in assessing its radiative forcing. However, current understanding of the formation and evolution of various BC components is limited, particularly in the Pearl River Delta, China. This study measured submicron BC-associated nonrefractory materials and the total submicron nonrefractory materials using a soot particle aerosol mass spectrometer and a high-resolution time-of-flight aerosol mass spectrometer, respectively, at a coastal site in Shenzhen, China. Two distinct atmospheric conditions were also identified to further explore the distinctive evolution of BC-associated components: polluted period (PP) and clean period (CP). Comparing the components of two particles, we found that more-oxidized organic factor (MO-OOA) prefers to form on BC during PP rather CP. The formation of MO-OOA on BC (MO-OOABC) was affected by both enhanced photochemical processes and nocturnal heterogeneous processes. Enhanced photo-reactivity of BC, photochemistry during the daytime, and heterogeneous reaction at nighttime were potential pathways for MO-OOABC formation during PP. The fresh BC surface was favorable for the formation of MO-OOABC. Our study shows the evolution of BC-associated components under different atmospheric conditions, which should be considered in regional climate models to improve the assessment of the climate effects of BC.

Design and synthesis of novel anti-multidrug-resistant staphylococcus aureus derivatives of glycyrrhetinic acid by blocking arginine biosynthesis, metabolic and H2S biogenesis.

With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.

[Material basis of Rhei Radix et Rhizoma-Coptidis Rhizoma combination in alleviating "bitter-cold" properties based on supramolecular chemistry of Chinese medicine].

The present study aimed to explore the material basis of Rhei Radix et Rhizoma-Coptidis Rhizoma combination in alleviating "bitter-cold" properties based on the supramolecular chemistry of Chinese medicine.Dynamic light scattering and scanning/transmission electron microscopy were used to characterize the morphological characteristics of supramolecules in the decoction of Rhei Radix et Rhizoma and Coptidis Rhizoma.The chemical composition of supramolecules, as well as the dissolution and release processes of supramolecules and the medicinal components of Coptidis Rhizoma decoction, was determined by the high-performance liquid chromatography-mass spectrometry.The differences in "bitter-cold" medicinal properties between Rhei Radix et Rhizoma decoction, Coptidis Rhizoma decoction, and co-decoction were analyzed by sensory evaluation, electronic tongue, mouse diarrhea model, and pathological indicators.The anthraquinones/tannins and alkaloids interacted to form supramolecules with a scale of about 400 nm when Rhei Radix et Rhizoma and Coptidis Rhizoma were decocted together, which delayed the dissolution and release of the active components represented by berberine. Compared with the consequence of single drug administration at 4 g·kg~(-1), the combination of the two drugs at 8 g·kg~(-1) significantly alleviated the "bitter-cold" properties.The effective components interacted to form supramolecules in the co-decoction of Rhei Radix et Rhizoma and Coptidis Rhizoma, which affected the dissolution and release of the effective components of Chinese medicinal decoction, thereby alleviating the "bitter-cold" properties.The findings of this study provide a new idea for revealing the scientific compatibility of Rhei Radix et Rhizoma and Coptidis Rhizoma.

Clinical value of predictive models based on liver stiffness measurement in predicting liver reserve function of compensated chronic liver disease.

BACKGROUND: Assessment of liver reserve function (LRF) is essential for predicting the prognosis of patients with chronic liver disease (CLD) and determines the extent of liver resection in patients with hepatocellular carcinoma. AIM: To establish noninvasive models for LRF assessment based on liver stiffness measurement (LSM) and to evaluate their clinical performance. METHODS: A total of 360 patients with compensated CLD were retrospectively analyzed as the training cohort. The new predictive models were established through logistic regression analysis and were validated internally in a prospective cohort (132 patients). RESULTS: Our study defined indocyanine green retention rate at 15 min (ICGR15) ≥ 10% as mildly impaired LRF and ICGR15 ≥ 20% as severely impaired LRF. We constructed predictive models of LRF, named the mLPaM and sLPaM, which involved only LSM, prothrombin time international normalized ratio to albumin ratio (PTAR), age and model for end-stage liver disease (MELD). The area under the curve of the mLPaM model (0.855, 0.872, respectively) and sLPaM model (0.869, 0.876, respectively) were higher than that of the methods for MELD, albumin-bilirubin grade and PTAR in the two cohorts, and their sensitivity and negative predictive value were the highest among these methods in the training cohort. In addition, the new models showed good sensitivity and accuracy for the diagnosis of LRF impairment in the validation cohort. CONCLUSION: The new models had a good predictive performance for LRF and could replace the indocyanine green (ICG) clearance test, especially in patients who are unable to undergo ICG testing.

Loss and Natural Variations of Blast Fungal Avirulence Genes Breakdown Rice Resistance Genes in the Sichuan Basin of China.

Magnaporthe oryzae is the causative agent of rice blast, a devastating disease in rice worldwide. Based on the gene-for-gene paradigm, resistance (R) proteins can recognize their cognate avirulence (AVR) effectors to activate effector-triggered immunity. AVR genes have been demonstrated to evolve rapidly, leading to breakdown of the cognate resistance genes. Therefore, understanding the variation of AVR genes is essential to the deployment of resistant cultivars harboring the cognate R genes. In this study, we analyzed the nucleotide sequence polymorphisms of eight known AVR genes, namely, AVR-Pita1, AVR-Pii, AVR-Pia, AVR-Pik, AVR-Pizt, AVR-Pi9, AVR-Pib, and AVR-Pi54 in a total of 383 isolates from 13 prefectures in the Sichuan Basin. We detected the presence of AVR-Pik, AVR-Pi54, AVR-Pizt, AVR-Pi9, and AVR-Pib in the isolates of all the prefectures, but not AVR-Pita1, AVR-Pii, and AVR-Pia in at least seven prefectures, indicating loss of the three AVRs. We also detected insertions of Pot3, Mg-SINE, and indels in AVR-Pib, solo-LTR of Inago2 in AVR-Pizt, and gene duplications in AVR-Pik. Consistently, the isolates that did not harboring AVR-Pia were virulent to IRBLa-A, the monogenic line containing Pia, and the isolates with variants of AVR-Pib and AVR-Pizt were virulent to IRBLb-B and IRBLzt-t, the monogenic lines harboring Pib and Piz-t, respectively, indicating breakdown of resistance by the loss and variations of the avirulence genes. Therefore, the use of blast resistance genes should be alarmed by the loss and nature variations of avirulence genes in the blast fungal population in the Sichuan Basin.

Ultrasonic spleen thickness-based indexes surpass Baveno VI criteria in high-risk gastroesophageal varices detection.

AIMS: To evaluate the efficiency of ultrasonic spleen thickness (UST), routine variables and (expanded) Baveno VI criteria for high-risk gastroesophageal varices (HRGOV) detection in cirrhotic patients. METHODS: In total, 305 cirrhotic patients were retrospectively enrolled in the deriving cohort and 328 cirrhotic patients with hepatitis B sustained viral response were prospectively enrolled in the validation cohort. HRGOV was defined as medium and severe gastroesophageal varices (GOV), mild GOV with red signs or Child-Pugh C. The cut-offs for HRGOV were determined by likelihood ratio indicating strong evidences. Algorithms of Spleen thickness-Age-Liver stiffness measurement (LSM, by Fibroscan®)-Albumin (SALA) and Spleen thickness-Platelet-Albumin (SPA) were derived by multivariate analyses. RESULTS: The area under receiver operating characteristics curve of SALA, SPA, UST, platelet, and LSM were 0.849, 0.835, 0.808, 0.746, and 0.655 in the deriving cohort, and improved to 0.901, 0.904, 0.858, 0.876, and 0.811 in the validation cohort, respectively. While SALA, SPA, UST, platelet, Baveno VI criteria (BVI), and expanded BVI spared 46.6%, 38.0%, 29.2%, 21.0%, 12.1%, and 23.6% esophagogastroduodenoscopy in the deriving cohort, these numbers were improved to 68.1%, 66.8%, 27.1%, 37.8%, 36.0%, and 61.0% in the validating cohort, respectively; however, the negative likelihood ratio of expanded BVI was up to 0.16. SPA spared less esophagogastroduodenoscopy than SALA, which can be supplemented by stepwise applying UST and SPA. Sequentially combining UST and SALA, BVI and SALA exempted additional 10-5% endoscopies. CONCLUSIONS: SPA, without LSM, improves HRGOV detection comparing with BVI. UST based algorithms combination can achieve the best efficiency especially in sustained virus response hepatitis B.

Decisive role of ozone formation control in winter PM2.5 mitigation in Shenzhen, China.

During the COVID-19 lockdown, atmospheric PM2.5 in the Pearl River Delta (PRD) showed the highest reduction in China, but the reasons, being a critical question for future air quality policy design, are not yet clear. In this study, we analyzed the relationships among gaseous precursors, secondary aerosols and atmospheric oxidation capacity in Shenzhen, a megacity in the PRD, during the lockdown period in 2020 and the same period in 2021. The comprehensive observational datasets showed large lockdown declines in all primary and secondary pollutants (including O3). We found that, however, the daytime concentrations of secondary aerosols during the lockdown period and normal period were rather similar when the corresponding odd oxygen (Ox≡O3+NO2, an indicator of photochemical processing avoiding the titration effect of O3 by freshly emitted NO) were at similar levels. Therefore, reduced Ox, rather than the large reduction in precursors, was a direct driver to achieve the decline in secondary aerosols. Moreover, Ox was also found to determine the spatial distribution of intercity PM2.5 levels in winter PRD. Thus, an effective strategy for winter PM2.5 mitigation should emphasize on control of winter O3 formation in the PRD and other regions with similar conditions.

Blocking miR530 Improves Rice Resistance, Yield, and Maturity.

MicroRNAs fine-tune plant growth and resistance against multiple biotic and abiotic stresses. The trade-off between biomass and resistance can penalize crop yield. In this study, we have shown that rice miR530 regulates blast disease resistance, yield, and growth period. While the overexpression of miR530 results in compromised blast disease resistance, reduced grain yield, and late maturity, blocking miR530 using a target mimic (MIM530) leads to enhanced resistance, increased grain yield, and early maturity. Further study revealed that the accumulation of miR530 was decreased in both leaves and panicles along with the increase of age. Such expression patterns were accordant with the enhanced resistance from seedlings to adult plants, and the grain development from panicle formation to fully-filled seeds. Divergence analysis of miR530 precursor with upstream 1,000-bp promoter sequence in 11 rice species revealed that miR530 was diverse in Oryza sativa japonica and O. sativa indica group, which was consistent with the different accumulation of miR530 in japonica accessions and indica accessions. Altogether, our results indicate that miR530 coordinates rice resistance, yield, and maturity, thus providing a potential regulatory module for breeding programs aiming to improve yield and disease resistance.

[Fetal malnutrition assessment program].

OBJECTIVE: To study the application of ponderal index (PI), body mass index (BMI), mid-arm circumference/head circumference (MAC/HC), and Clinical Assessment of Nutritional Status (CANS) score in assessing the nutritional status of neonates at birth, and to find a simple and reliable scheme for the assessment of fetal nutritional status. METHODS: PI, BMI, MAC/HC, and CANS were used to assess the nutritional status of full-term infants and preterm infants shortly after birth. The assessment results of these methods were analyzed. RESULTS: Among the 678 full-term infants, 61, 102, 47, and 131 were diagnosed with malnutrition by PI, BMI, MAC/HC, and CANS respectively. Among the 140 preterm infants, 30, 87, 9, and 112 were diagnosed with malnutrition by PI, BMI, MAC/HC, and CANS respectively. The combination of BMI and CANS had a detection rate of 99.3% in full-term infants and 100% in preterm infants. Compared with the single method, the combination significantly improved the detection rate of malnutrition (P < 0.05), while there was no significant difference between the combination of BMI+CANS and the combination of PI+BMI+CANS (P > 0.05). CONCLUSIONS: The combination of BMI+CANS can reduce the rate of missed diagnosis of fetal malnutrition. It is therefore a simple and reliable method for the assessment of fetal malnutrition.

The complete chloroplast genome sequence of Firmina danxiaensis.

The complete chloroplast genome of Firmina danxiaensis, an important deciduous tree, was identified and sequenced in this study. The genome size is 161,205 bp, the GC content is 36.88%. A total of 129 genes were identified, including 84 protein-coding genes, 8 rRNA genes, and 37 tRNA genes. 10 plastome accessions from Sterculiaceae were selected to assess the phylogenetic placement of genus and the result showed that F. danxiaensis is most closely related to F. simplex.

Alanine aminotransferase influencing performances of routine available tests detecting hepatitis B-related cirrhosis.

The performances of routine tests such as FIB-4 and APRI in detecting cirrhosis and significant fibrosis in chronic hepatitis B (CHB) have been shown to be discrepant between studies. Novel tests such as red cell distribution width-platelet ratio (RPR), γ-glutamyl transpeptidase to platelet ratio (GPR) and easy liver fibrosis test (eLIFT) are introduced recently. To evaluate the aminotransferase influence on the performance of these routine tests, a total of 1005 CHB patients who underwent liver biopsies and routine tests were retrospectively analysed. The diagnostic cut-offs referring to likelihood ratio were determined for excluding or including cirrhosis diagnosis and also for ruling in significant fibrosis diagnosis. The performances of RPR, FIB-4, eLIFT and APRI in detecting cirrhosis seemed improved at higher ALT levels, while GPR was conversely impaired. The likelihood ratio was âˆ for APRI cut-off 2 diagnosing cirrhosis in ALT < 2 upper limit of normal (ULN), 14.6 for APRI cut-off 1.5 determining significant fibrosis in ALT ≤ 5ULN and 20.6 for FIB-4 cut-off 3.2 diagnosing ≥ F3 in the total cohort, respectively. The optimal cut-offs for cirrhosis diagnosis were increased with higher ALTs by tests which included aminotransferase, but not for RPR. The proportions of patients classified as having cirrhosis or no cirrhosis stratified by ALT level cut-offs were superior. Stepwise applying RPR, GPR and eLIFT would determine 60% of patients as having cirrhosis or no cirrhosis with an accuracy of 93.0%. In conclusion, the performance of aminotransferase comprising tests in detecting cirrhosis in CHB were influenced by ALT levels. Thus, ALT stratified cut-offs may be a preferred alternative. In resource-limited settings, stepwise applying routine tests could be recommended as a preferred measurement for cirrhosis detection.

A 3-year clinical evaluation of endodontically treated posterior teeth restored with two different materials using the CEREC AC chair-side system.

STATEMENT OF PROBLEM: The introduction of polymer-infiltrated ceramic network (PICN) materials may provide more options for dentists in restoring short clinical crowns and extensively damaged posterior teeth, but clinical data for their performance are lacking. PURPOSE: The purpose of this clinical study was to compare the 3-year performance and survival rates of PICN material with those of conservative ceramic onlay restorations for endodontically treated posterior teeth using the CEREC AC chair-side system. MATERIAL AND METHODS: A total of 101 onlay restorations of endodontically treated posterior teeth using the CEREC AC chair-side system were provided in 93 participants. The 101 teeth were divided into 2 groups: Vita Enamic group and Vitablocs Mark II group. Using the modified US Public Health Service quality evaluation system, 2 calibrated evaluators examined the performance of the onlay restorations over 3 years. The Kaplan-Meier method was adopted to analyze the survival rate of restorations (α=.05). The log rank test was used to compare the survival rates of the 2 groups. The Fisher exact test was performed to detect differences in the success rates for extensively damaged teeth and short clinical crown restorations between the 2 groups. The Silness and Löe gingival index was also recorded. RESULTS: The restoration survival rates in the 2 groups were 97.0% (Vita Enamic) and 90.7% (Vitablocs Mark II) (P>.05). Five failures were recorded (4.95%). These failures were caused by restoration debonding (60%), ceramic fractures (20%), and tooth fractures (20%). There were no significant differences between the success rates of restoring extensively damaged teeth and short clinical crowns between the 2 groups (P>.05). The periodontal condition of 25% of participants was improved 3 years after the onlay restorations. CONCLUSIONS: Onlay restorations of endodontically treated posterior teeth with Vita Enamic using the CEREC AC chair-side system are clinically promising prosthodontic alternatives, with a survival rate of 97.0% after 3 years. More research is needed to verify the results of this study.

Enrichment of denitratating bacteria from a methylotrophic denitrifying culture.

Denitratation (nitrite produced from nitrate), has the potential applications in wastewater treatment by combining with ANAMMOX process. The occurrence of denitratation has been shown to be effected qualitatively by various parameters in the environment. A more quantitative understanding can be obtained using enrichment cultures in lab-scale experiments, yet information on the enrichment of functional microorganisms responsible for denitratation is lacking. In this study, a stable denitratation-dominated culture was obtained from methylotrophic denitrifying culture. The results showed that, besides the substitution of acetate for methanol, the lasting starvation following saturation of electron donor was another pivotal selection pressure that favored the growth of denitratating bacteria, which was supported by the distinctive physiological strategy involving the higher growth rate combining with larger poly-hydroxybutyrate (PHB) accumulation at sufficient electron donor situation and then manage the stress of electron donor starvation by consumpiton of the PHB. High-throughput 16S rRNA gene sequencing analysis indicated that non-methylotrophic Halomonas campisalis (48.1 %) and Halomonas campaniensis (30.4 %) dominated in the denitratating community. Moreover the denitratation was driven by the nitrate inhibiting the nirS transcription in the Halomonas species.

Effect of self-alkalization on nitrite accumulation in a high-rate denitrification system: Performance, microflora and enzymatic activities.

The self-alkalization of denitrifying automatic circulation (DAC) reactor resulted in a large increase of pH up to 9.20 and caused a tremendous accumulation of nitrite up to 451.1 ± 49.0 mgN L(-1) at nitrate loading rate (NLR) from 35 kgN m(-3) d(-1) to 55 kgN m(-3) d(-1). The nitrite accumulation was greatly relieved even at the same NLR once the pH was maintained at 7.6 ± 0.2 in the system. Enzymatic assays indicated that the long-term bacterial exposure to high pH significantly inhibited the activity of copper type nitrite reductase (NirK) rather than the cytochrome cd1 type nitrite reductase (NirS). The terminal restriction fragment length polymorphism (T-RFLP) analysis revealed that the dominant denitrifying bacteria shifted from the NirS-containing Thauear sp. 27 to the NirK-containing Hyphomicrobium nitrativorans strain NL23 during the self-alkalization. The significant nitrite accumulation in the high-rate denitrification system could be therefore, due to the inhibition of Cu-containing NirK by high pH from the self-alkalization. The results suggest that the NirK-containing H. nitrativorans strain NL23 could be an ideal functional bacterium for the conversion of nitrate to nitrite, i.e. denitritation, which could be combined with anaerobic ammonium oxidation (Anammox) to develop a new process for nitrogen removal from wastewater.

NF-κB regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis.

Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-κB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-κB activation in Fas killing and the effect of NF-κB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-κB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-κB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of IκBα (DN-IκBα) or an IκB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-κB signaling, we found that DN-IκBα only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-κB activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-κB. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-κB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-κB pro-apoptotic pathway in neuroblastoma cells.

The relationship between growth spurts and myopia in Singapore children.

PURPOSE: We aimed to determine the relationship between puberty and growth spurts with peak spherical equivalent (SE) or axial length (AL) velocity in Singapore schoolchildren. METHODS: In the Singapore Cohort Study of the Risk Factors for Myopia of 1779 schoolchildren, the longitudinal refractive and pubertal status of 892 boys and 887 girls from ages 6 to 14 years were assessed. The study sample included 1329 Chinese, 316 Malays, 114 Indians, and 20 children of other races. Information regarding puberty parameters, age of peak height velocity, age of menarche, and break of voice (BOV) was obtained. Peak velocity was defined as the greatest change in measurements over a period of 1 year. Tanner stage 1 for pubic hair or breast development, in boys and girls, respectively, at age 12 was categorized as "later puberty," whereas stages 2 to 5 corresponded to "earlier puberty." Refractive error was determined by cycloplegic autorefraction using the Canon RK-F5, and AL was measured using the A-scan biometry machine. RESULTS: The children were examined annually, and the mean number of visits was 5.7 ± 1.3. Age of peak height velocity occurred earlier in girls than in boys (11.0 ± 1.2 vs. 12.0 ± 1.7 years, P < 0.001). Girls with earlier peak height velocity experienced peak AL velocity and peak SE velocity approximately half a year earlier than those with later puberty (mean age of 10.3 ± 1.6 vs. 10.8 ± 1.7 years, P < 0.001; and 10.0 ± 1.5 vs. 10.6 ± 1.25 years, P < 0.001, respectively). Similarly, boys who had earlier peak height velocity also achieved peak AL and peak SE velocity earlier than those who experienced later peak height velocity (mean age of 10.4 ± 1.6 vs. 11.1 ± 1.8 years, P < 0.001; and 10.1 ± 1.5 vs. 10.6 ± 1.7 years, P = 0.01). Both girls and boys who had early peak height velocity had earlier age of onset of myopia than those with later peak height velocity (9.7 ± 1.4 vs. 10.1 ± 1.5 years for girls, P = 0.04; and 9.9 ± 1.5 vs. 10.4 ± 1.6 years for boys, P = 0.03). Myopia progression, in terms of AL velocity, also occurred earlier in boys and girls with earlier peak height velocity (10.2 ± 1.5 vs. 11.0 ± 1.9 for boys, P < 0.001; and 10.2 ± 1.5 vs. 10.7 ± 1.7 for girls, P = 0.004, respectively). The associations were not significant when Tanner staging, age of menarche, or BOV was used to determine stage of puberty. CONCLUSIONS: Boys and girls with earlier peak height velocity experienced earlier peak SE and AL velocity, and age of myopia onset. Thus, variations in the onset and peak progression of myopia may be associated with height spurts.

Dorsal root ganglion compression as an animal model of sciatica and low back pain.

As sciatica and low back pain are among the most common medical complaints, many studies have duplicated these conditions in animals. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The surgery is simple: after exposing the L4/L5 intervertebral foramina, stainless steel rods are implanted unilaterally, one rod for each vertebra, to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia - evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.