Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese.
HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively.
From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33–0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97–9.59) in multivariate analysis.
Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.
Syntrophorhabdus aromaticivorans strain UI is a mesophilic bacterium capable of degrading aromatic substrates in syntrophic cooperation with a partner methanogen. The draft genome sequence is 3.7 Mb, with a G+C content of 52.0%.
Brace treatment has served as a vital non-surgical procedure for immature adolescent idiopathic scoliosis (AIS) patients with a mild or moderate curve. For the patients who fail in bracing and resort to surgery, it is unclear whether prior full-time brace treatment significantly influences outcomes. This study aims to investigate whether prior brace treatment has a negative impact upon the flexibility and correctability of the main curve in patients with AIS.
The participants were collected from female AIS patients who underwent posterior correction surgery with pedicle screw instrumentation from August 2006 to December 2010, with or without prior brace treatment. Patients included in Group A had prior brace treatment over a 1-year period, and underwent surgery within 6 months after cessation of bracing; those in Group B received no prior treatment and were randomly selected from our database. Curve flexibility pre-surgery and curve correctability post-surgery were computed and compared between both groups and subgroups according to the curve location.
Each group consisted of 35 patients. Age, curve magnitude and location were comparable between the two groups. Before surgery, patients in Group A had a slightly lower curve flexibility than those in Group B (52 vs. 60 %, P = 0.036). After surgery, satisfactory correction results were observed in both groups, but the average post-operative main curve magnitude of patients in Group B was 4° less than that of Group A (10° vs. 14°, P = 0.010). The curve correctability in Group B was significantly higher than that in Group A (80 vs. 74 %, P = 0.002). No matter what curve pattern the patient had, having a prior history of brace treatment resulted in a trend of lower flexibility and correctability of their scoliosis.
Good surgical correction can be achieved in AIS patients who have been unsuccessful with prior brace treatment. However, a history of prior brace treatment leads to a trend of lowering the curve flexibility, and in turn, negatively impacts upon the curve correctability.
Adolescent idiopathic scoliosis; Bracing; Surgery; Flexibility; Correction
T follicular helper (TFH) cells provide critical help to B cells during humoral immune responses. Here we report that mice with T cell-specific deletion of miR-17~92 family miRNAs (tKO mice) exhibited severely compromised TFH differentiation, germinal center formation, antibody responses, and failed to control chronic virus infection. Conversely, T cell-specific miR-17~92 transgenic mice spontaneously accumulated TFH cells and developed fatal immunopathology. Mechanistically, miR-17~92 family miRNAs control CD4+ T cell migration into B cell follicles by regulating ICOS-PI3K signaling intensity through suppressing the expression of the Akt phosphatase Phlpp2. These findings demonstrate that miR-17~92 family microRNAs play an essential role in TFH differentiation and establish Phlpp2 as an important mediator of their function in this process.
Objectives: The objectives of this study were to compare the serologic responses at week 48 to primary vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV) vs. 7-valent pneumococcal conjugate vaccine (PCV); and to identify factors associated with serologic response in HIV-infected adult patients with access to combination antiretroviral therapy (cART).
Methods: One hundred and four CD4-matched pairs of HIV-infected patients who underwent primary pneumococcal vaccination with 23-valent PPV or 7-valent PCV were enrolled for determinations of anti-capsular antibody responses against four serotypes (6B, 14, 19F and 23F) at baseline, 24 weeks and 48 weeks following vaccination. Significant antibody responses were defined as 2-fold or greater increase of antibody levels at week 48 compared with baseline. The logistic regression model was used to determine the factors associated with serologic response to at least one and two serotypes.
Results: At week 48, patients who received PCV demonstrated a statistically significantly higher response rate to at least 2 serotypes than those who received PPV (37.5% vs. 20.2%, p = 0.006). In multivariate analysis, factors associated with significant antibody responses to at least one or two serotypes included receipt of PCV (adjusted odds ratio [AOR], 2.42 [95% CI, 1.23–4.78] and 3.58 [95% CI. 1.76–7.28], respectively), and undetectable plasma HIV RNA load (< 400 copies/ml) at vaccination (AOR, 1.47 [95% CI, 0.60–3.64] and 3.62 [95% CI, 1.11–11.81], respectively).
Conclusions: Primary vaccination with 7-valent PCV achieved a significantly better serologic responses to one or two out of the four serotypes studied at week 48 than with 23-valent PPV in HIV-infected patients in the cART era. Suppression of HIV replication when primary vaccination was administered was associated with better serologic responses.
Streptococcus pneumoniae; pneumococcal conjugate vaccine; pneumococcal polysaccharide vaccine; HIV infection; immunogenicity; combination antiretroviral therapy
Nodal, a TGF-β-related embryonic morphogen, is involved in multiple biologic processes. However, the expression of Nodal in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis, epithelial-mesenchymal transition, and prognosis is unclear.
We used real-time PCR and Western blotting to investigate Nodal expression in 6 HCC cell lines and 1 normal liver cell line, 16 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine Nodal expression in HCC and corresponding paracarcinomatous tissues from 96 patients. CD34 and Vimentin were only examined in HCC tissues of patients mentioned above. Nodal gene was silenced by shRNA in MHCC97H and HCCLM3 cell lines, and cell migration and invasion were detected. Statistical analyses were applied to evaluate the prognostic value and associations of Nodal expression with clinical parameters.
Nodal expression was detected in HCC cell lines with high metastatic potential alone. Nodal expression is up-regulated in HCC tissues compared with paracarcinomatous and normal liver tissues. Nodal protein was expressed in 70 of the 96 (72.9%) HCC tumors, and was associated with vascular invasion (P = 0.000), status of metastasis (P = 0.004), AFP (P = 0.049), ICGR15 (indocyanine green retention rate at 15 min) (P = 0.010) and tumor size (P = 0.000). High Nodal expression was positively correlated with high MVD (microvessal density) (P = 0.006), but not with Vimentin expression (P = 0.053). Significantly fewer migrated and invaded cells were seen in shRNA group compared with blank group and negative control group (P<0.05). High Nodal expression was found to be an independent factor for predicting overall survival of HCC.
Our study demonstrated that Nodal expression is associated with aggressive characteristics of HCC. Its aberrant expression may be a predictive factor of unfavorable prognosis for HCC after surgery.
The purpose of this study was to analyze age, geographical and seasonal variations in medical service utilization by patients with inguinal hernia in Taiwan, and the influence of herniorrhaphy on development of ipsilateral varicocele in male patients.
Between 2001 and 2008, comprehensive data on the characteristics of medical service utilization by patients with inguinal hernia was evaluated via a retrospective nationwide population-based study. Data were obtained from the National Health Insurance Research Database in Taiwan. Parameters for comparison included newly diagnosed inguinal hernia cases, number of herniorrhaphies, and incidence rates every year, number of outpatient visits for inguinal hernia, and herniorrhaphy by age, season, and area of Taiwan.
There was an average of 1,466 newly diagnosed inguinal hernia cases and 871.9 herniorrhaphies performed per year per million population during the study period. The male ratio for both newly diagnosed inguinal hernia cases and number of herniorrhaphies increased significantly by age. The number of newly diagnosed inguinal hernia cases and outpatient visits for inguinal hernia was highest during summer, followed by spring, autumn, and winter, and in the north of Taiwan, followed by the center, south, and east. Additionally, the incidence of developing ipsilateral varicocele after herniorrhaphy was low in male patients.
The number of newly diagnosed inguinal hernia cases and outpatient visits for inguinal hernia is highest during summer and lowest in eastern Taiwan. In addition, the incidence of developing ipsilateral varicocele after herniorrhaphy is higher in patients aged 10–19 years.
age; herniorrhaphy; inguinal hernia; season; varicocele
Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects.
A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50–65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3–5 times/week and 30–60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview.
Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases.
Current Controlled Trials: ISRCTN42622771.
Liver fat content; Glucose metabolism; Lipid metabolism; Gut microbiota; Metabonomics; Human; Clinical setting
Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.
Being unable to move away from their places of germination, in order to avoid excess metal-induced damages, plants have to evolve different strategies and complex regulatory mechanisms to survive harsh conditions. While both ROS and auxin are documented to be important in plant response to metal stress, the mechanisms underlying the crosstalk between ROS and auxin in metal stress are poorly understood. In this review, we provide an update on the regulation of plant responses to metal-stress by ROS and auxin signaling pathways, primarily, with a focus on the copper, aluminum and cadmium stress. We aim at surveying the mechanisms underlying how metal stress modulates the changes in auxin distribution and the network of ROS and auxin in plant response to metal stress based on recent studies.
abiotic stress; aluminium; auxin; cadmium; metal stress; copper; heavy metal stress; ROS
Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have a high risk of bone fracture because of low bone mineral density and poor bone quality. Osteoporosis also features low bone mass, disarranged microarchitecture, and skeletal fragility, and differentiating between osteoporosis and CKD-MBD in low bone mineral density is a challenge and usually achieved by bone biopsy. Bisphosphonates can be safe and beneficial for patients with a glomerular filtration rate of 30 mL/min or higher, but prescribing bisphosphonates in advanced CKD requires caution because of the increased possibility of low bone turnover disorders such as osteomalacia, mixed uremic osteodystrophy, and adynamic bone, even aggravating hyperparathyroidism. Therefore, bone biopsy in advanced CKD is an important consideration before prescribing bisphosphonates. Treatment also may induce hypocalcemia in CKD patients with secondary hyperparathyroidism, but vitamin D supplementation may ameliorate this effect. Bisphosphonate treatment can improve both bone mineral density and vascular calcification, but the latter becomes more unlikely in patients with stage 3-4 CKD with vascular calcification but no decreased bone mineral density. Using bisphosphonates requires considerable caution in advanced CKD, and the lack of adequate clinical investigation necessitates more studies regarding its effects on these patients.
Pain in masticatory muscles is among the most prominent symptoms of temperomandibular disorders (TMDs) that have diverse and complex etiology. A common complaint of TMD is that unilateral pain of craniofacial muscle can cause a widespread of bilateral pain sensation, although the underlying mechanism remains unknown. To investigate whether unilateral inflammation of masseter muscle can cause a bilateral allodynia, we generated masseter muscle inflammation induced by unilateral injection of complete Freund’s adjuvant (CFA) in rats, and measured the bilateral head withdrawal threshold at different time points using a von Frey anesthesiometer. After behavioral assessment, both right and left trigeminal ganglia (TRG) were dissected and examined for histopathology and transient receptor potential vanilloid 1 (TRPV1) mRNA expression using quantitative real-time PCR analysis. A significant increase in TRPV1 mRNA expression occurred in TRG ipsilateral to CFA injected masseter muscle, whereas no significant alteration in TRPV1 occurred in the contralateral TRG. Interestingly, central injection of TRPV1 antagonist 5-iodoresiniferatoxin into the hippocampus significantly attenuated the head withdrawal response of both CFA injected and non-CFA injected contralateral masseter muscle. Our findings show that unilateral inflammation of masseter muscle is capable of inducing bilateral allodynia in rats. Upregulation of TRPV1 at the TRG level is due to nociception caused by inflammation, whereas contralateral nocifensive behavior in masticatory muscle nociception is likely mediated by central TRPV1, pointing to the involvement of altered information processing in higher centers.
Hippocampus; Masseter muscle; TMD; TRG; TRPV1
Nasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.
A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.
Univariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×109/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×109/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR = 0.558, 95% confidence interval or 95% CI = 0.417–0.748; P<0.001), DFS (HR = 0.669, 95% CI = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).
The elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.
The process of store-operated calcium entry (SOCE), whereby the release of intracellular Ca2+ from endoplasmic reticulum (ER) activates Ca2+ influx channels in the plasma membrane, has been demonstrated to impact a diverse range of cell functions. In the present study, we investigated the potential protective effect of SOCE inhibition against 1-methyl-4-phenylpyridinium (MPP+) injury by using pharmacological antagonists or specific small interfering RNA (siRNA) in PC12 cells. The results showed that both antagonists (15 μM MRS-1845 and 50 μM ML-9) and stromal interacting molecule-1 (STIM1) targeted siRNA (Si-STIM1) significantly increased cell viability, decreased apoptotic cell death and reduced intracellular reactive oxygen species (ROS) production and lipid peroxidation in MPP+ injured PC12 cells. SOCE inhibition also prevented MPP+ induced mitochondrial dysfunction and activation of mitochondrial related apoptotic factors, while had no effect on mitochondrial biogenesis. Moreover, inhibition of SOCE by antagonists and siRNA increased the expression levels of Homer1a mRNA and protein, and knockdown of Homer1a expression by specific siRNA partly reversed the protective effects induced by SOCE inhibition in PC12 cells. All these results indicated that SOCE inhibition protected PC12 cells against MPP+ insult through upregulation of Homer1a expression, and SOCE might be an ideal target for investigating therapeutic strategy against neuronal injury in PD patients.
Cisplatin is used as a treatment for various types of solid tumors. Renal injury severely limits the use of cisplatin. Renal cell apoptosis, oxidative stress, and inflammation contribute to cisplatin-induced nephrotoxicity. Previously, we found that an extract of Rhodobacter sphaeroides (Lycogen™) inhibited proinflammatory cytokines and the production of nitric oxide in activated macrophages in a dextran sodium sulfate (DSS)-induced colitis model. Here, we evaluated the effect of Lycogen™, a potent anti-inflammatory agent, in mice with cisplatin-induced renal injury. We found that attenuated renal injury correlated with decreased apoptosis due to a reduction in caspase-3 expression in renal cells. Oral administration of Lycogen™ significantly reduced the expression of tumor necrosis factor-α and interleukin-1β in mice with renal injury. Lycogen™ reduces renal dysfunction in mice with cisplatin-induced renal injury. The protective effects of the treatment included blockage of the cisplatin-induced elevation in serum urea nitrogen and creatinine. Meanwhile, Lycogen™ attenuated body weight loss and significantly prolonged the survival of mice with renal injury. We propose that Lycogen™ exerts anti-inflammatory activities that represent a promising strategy for the treatment of cisplatin-induced renal injury.
Rhodobacter sphaeroides; Lycogen™; cisplatin; nephrotoxicity
Human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF) 07_BC has caused serious HIV-1 epidemics among injecting drug users (IDUs) in East Asia. Little is known about the characteristics of the virus and its impact on disease progression among the infected individuals. In this study, we compared immunological progression between 423 IDUs infected with CRF07_BC and 194 men who have sex with men (MSM) with primary subtype B infection, and a representative full-length CRF07_BC molecular clone, pCRF07_BC, was constructed to characterize the virus. We found that IDUs infected with CRF07_BC had significantly slower immunological progression in the Cox proportional hazards model (hazard ratio: 0.30; 95% confidence interval: 0.13–0.69; P=0.004). The constructed recombinant CRF07_BC viruses had a reduced processing of the Gag/Gag-Pol polyproteins, a decreased incorporation of Vpr in the virus particle, tethering of virus particles on the plasma membrane and decreased virus growth kinetics. These phenotypes are related to the unique 7-amino acid deletion in the p6 of CRF07_BC, since complementation of the 7-amino acid in pCRF07_BC could improve the defective phenotypes. In summary, compared with MSM infected with HIV-1 subtype B, IDUs infected with CRF07_BC had slower immunological progression, which is likely correlated with interference of virus particle maturation by the 7-amino acid deletion in p6.
disease progression; growth kinetics; HIV subtype; injecting drug use; men who have sex with men; primary HIV infection
To evaluate the long-term effects of thrombolysis on patients with submassive pulmonary embolism (PE).
Data of 136 patients with acute submassive PE and low risk of bleeding were prospectively collected from January 2005 to October 2011 in a single medical center. Patients received recombinant tissue plasminogen activator (r-tPA) plus low molecular weight heparin (LMWH, TT group, n = 79) or LMWH alone (AT group, n = 57), depending on treating physician's recommendation and patient's preference. Echocardiography was performed at admission, 24 h, 6 and 12 months to evaluate right ventricular function. Computed tomography pulmonary angiography (CTPA) and lung perfusion scan were performed on admission, at 7 days, 6 and 12 months to evaluate clot burden.
Seventy-nine patients received r-tPA plus LMWH (TT group) while 57 received LMWH alone (AT group). The baseline characteristics and risk factors did not differ between the two groups. Respiratory rate, heart rate, and systolic blood pressure improved within two hours in both groups. Systolic pulmonary arterial pressure and tricuspid regurgitation improved to a greater extent in the TT group at 24 h, and at 12 months (P < 0.001), as compared to those in the AT group. At one week, and 12 months, clot burden decreased more in AT group, as compared to that in AT group (P < 0.001). There was no death due to bleeding in both groups. Recurrent PE were similar in both groups (2.5% in TT vs. 1.8% in AT). The rates of minor hemorrhages were 6.3% in TT group and 1.8% in AT group (P < 0.05).
In submassive PE patient who has low risk of bleeding, thrombolysis plus anticoagulation can lead to greater improvement of right ventricular dysfunction and clot burden reduction as compared to anticoagulation therapy alone.
Pulmonary embolism; Right ventricle dysfunction; Thrombolysis; Anticoagulation; Bleeding
Reduced root meristem length in tic mutant is due to the repressed expression of PIN genes for decreased acropetal auxin transport, leading to low auxin accumulation. MYC2-mediated JA-signaling pathway may not be involved in this process
Roots play important roles in plant survival and productivity as they not only anchor the plants in the soil but are also the primary organ for the uptake of nutrients from the outside. The growth and development of roots depend on the specification and maintenance of the root meristem. Here, we report a previously unknown role of TIME FOR COFFEE (TIC) in controlling root meristem size in Arabidopsis. The results showed that loss of function of TIC reduced root meristem length and cell number by decreasing the competence of meristematic cells to divide. This was due to the repressed expression of PIN genes for decreased acropetal auxin transport in tic-2, leading to low auxin accumulation in the roots responsible for reduced root meristem, which was verified by exogenous application of indole-3-acetic acid. Downregulated expression of PLETHORA1 (PLT1) and PLT2, key transcription factors in mediating the patterning of the root stem cell niche, was also assayed in tic-2. Similar results were obtained with tic-2 and wild-type plants at either dawn or dusk. We also suggested that the MYC2-mediated jasmonic acid signalling pathway may not be involved in the regulation of TIC in controlling the root meristem. Taken together, these results suggest that TIC functions in an auxin–PLTs loop for maintenance of post-embryonic root meristem.
Arabidopsis thaliana; auxin; circadian clock; jasmonic acid; MYC2; PIN; root meristem; TIME FOR COFFEE.
Few studies have examined relationships among neurophysiological, psychological, and behavioral factors with regard to their effects on sleep quality. We used a structure equation model to investigate behavioral and psychological factors that influence neurophysiological regulation of sleep in shift workers. Using a cross-sectional study design, we tested the model with a sample of 338 female nurses working rotating shifts at an urban regional hospital. The Morningness-Eveningness Questionnaire (MEQ) and short-form Menstrual Distress Questionnaire (MDQ) were used to measure neurophysiological factors involved in morningness-eveningness and menstrual distress. The Sleep Hygiene Awareness and Practice Scale (SHAPS) and Profile of Mood States Short Form (POMS-SF) were completed to measure behavioral factors of sleep hygiene practices and psychological factors of mood states. In addition, the Pittsburgh Sleep Quality Index (PSQI) measured participant's self-reported sleep quality. The results revealed that sleep hygiene practices and mood states mediated the effects of morningness-eveningness and menstrual distress on sleep quality. Our findings provide support for developing interventions to enhance sleep hygiene and maintain positive mood states to reduce the influence of neurophysiological factors on sleep quality among shift workers.
Chronic kidney disease (CKD) is a major global public health burden, but there is limited understanding of the relationship of alcohol consumption with CKD.
In this cross-sectional multivariable study, all participants of a health check-up program in Ditmanson Medical Foundation Chia-Yi Christian Hospital in Taiwan from 2003 to 2009 (15 353 women and 11 900 men) were included for analysis. Estimated glomerular filtration rate was used to define CKD stage and history of alcohol consumption was obtained by self-reporting. Multivariable logistic regression analyses of gender-specific association of alcohol drinking with stage 3 CKD were conducted. A trend tests was conducted to check the dose–response relationship of alcohol consumption with renal disease. A sensitivity test was conducted to rule out the likelihood of reverse causality.
The prevalence of stage 3 CKD was lower in drinkers than non-drinkers (p < 0.001) and the percentage of drinkers with stage 3 CKD was less than that of non-drinkers. Multivariable analysis indicated that alcohol consumption was negatively associated with the presence of stage 3 CKD in men (adjusted odds ratio [aOR] for occasional drinking: 0.68, 95% CI: 0.59 ~ 0.78, p < 0.001; aOR for frequent drinking: 0.47, 95% CI: 0.35 ~ 0.63, p < 0.001). Advanced age, hypertension, anemia, BMI of at least 24, hyperuricemia, and proteinuria were also associated with stage 3 CKD in men. Trend tests indicated lower odds of having stage 3 CKD with increased alcohol consumption in both genders. Subgroup analyses and sensitivity tests also indicated the reverse association between alcohol consumption and stage 3 CKD in men regardless of age, diabetes status, and other risky behaviors.
Alcohol consumption was inversely associated with stage 3 CKD in Taiwanese men. However, considering the potential of other health damage with alcohol consumption, the current results should be interpreted cautiously.
Alcohol consumption; Chronic kidney disease; Gender; Proteinuria; Taiwan
Stomata play significant roles in plant evolution. A trio of closely related basic Helix-Loop-Helix (bHLH) subgroup Ia genes, SPCH, MUTE and FAMA, mediate sequential steps of stomatal development, and their functions may be conserved in land plants. However, the evolutionary history of the putative SPCH/MUTE/FAMA genes is still greatly controversial, especially the phylogenetic positions of the bHLH Ia members from basal land plants. To better understand the evolutionary pattern and functional diversity of the bHLH genes involved in stomatal development, we made a comprehensive evolutionary analysis of the homologous genes from 54 species representing the major lineages of green plants. The phylogenetic analysis indicated: (1) All bHLH Ia genes from the two basal land plants Physcomitrella and Selaginella were closely related to the FAMA genes of seed plants; and (2) the gymnosperm ‘SPCH’ genes were sister to a clade comprising the angiosperm SPCH and MUTE genes, while the FAMA genes of gymnosperms and angiosperms had a sister relationship. The revealed phylogenetic relationships are also supported by the distribution of gene structures and previous functional studies. Therefore, we deduce that the function of FAMA might be ancestral in the bHLH Ia subgroup. In addition, the gymnosperm “SPCH” genes may represent an ancestral state and have a dual function of SPCH and MUTE, two genes that could have originated from a duplication event in the common ancestor of angiosperms. Moreover, in angiosperms, SPCHs have experienced more duplications and harbor more copies than MUTEs and FAMAs, which, together with variation of the stomatal development in the entry division, implies that SPCH might have contributed greatly to the diversity of stomatal development. Based on the above, we proposed a model for the correlation between the evolution of stomatal development and the genes involved in this developmental process in land plants.
FK506, structurally similar to FK520 and rapamycin, is an α-keto amide bonding-containing, macrolide natural product that exhibits potent immunosuppressive activity and moderate antifungal activity. FK506 biosynthesis requires a hybrid polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) system to construct the skeleton of the macrolide. The mechanism for tailoring this macrolide to furnish FK506 remains poorly understood. In this study, we report a maturation paradigm common for FK506, FK520, and rapamycin, by characterizing two conserved regiospecific, post-PKS-NRPS modifications in an FK506-producing Streptomyces tsukubaensis strain. A cytochrome P450 protein, FkbD, catalyzes a less common, four-electron oxidation at C-9 to give a rarely found α-keto amide group, whereas a methyltransferase, FkbM, is responsible for O-methylation at C-31 to afford a methoxy group. Both FkbD and FkbM are highly tolerant in their substrate choice; therefore, the order of FkbD- and FkbM-catalyzed reactions is interchangeable in the FK506 biosynthetic pathway. Inactivation of fkbD produced a new intermediate, 9-deoxo-FK506, which displayed antifungal activity lower than that of FK506. Taking previously reported bioassay results regarding the intermediates 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 into account, it is clear that the modifications catalyzed by FkbD and FkbM are of importance to reach the full biological activity of FK506 by forming a key structure motif that is necessary for interaction of the molecule with the receptor and, subsequently, the downstream intracellular responses.
Paraganglioma is a rare neuroendocrine neoplasm observed in patients of all ages, with an estimated incidence of 3/1,000,000 population. It has long been recognized that some cases are familial. The majority of these tumors are benign, and the only absolute criterion for malignancy is the presence of metastases at sites where chromaffin tissue is not usually found. Some tumors show gross local invasion and recurrence, which may indeed kill the patient, but this does not necessarily associate with metastatic potential. Here, we report a case of vertebral metastatic paraganglioma that occurred 19 months after the patient had undergone partial cystectomy for urinary bladder paraganglioma. We believe this to be a rarely reported bone metastasis of paraganglioma arising originally within the urinary bladder. In this report, we also provide a summary of the general characteristics of this disease, together with progress in diagnosis, treatment, and prognosis.
Bone neoplasms; malignant paraganglioma; neuroendocrine peptide; neuroendocrine tumors; surgery; carcinoma
This study aimed to compare the efficacy and safety of thrombolytic and anticoagulant therapy for acute submassive pulmonary embolism (PE). A retrospective evaluation was performed on 25 consecutive inpatients with acute submassive PE treated by thrombolytic therapy and 25 earlier consecutive inpatients with acute submassive PE treated by anticoagulant therapy. No statistically significant difference in clinical curative effect was identified between the thrombolysis and anticoagulation groups (P>0.05). Following 24 h of therapy, the improvement rates of dyspnea and revascularization in the thrombolysis group achieved statistical significance compared with those of the anticoagulation group (P<0.01 for each). The PO2 level of the thrombolysis group (81.18±5.66 mmHg) was notably higher than that of the anticoagulation group and the difference was statistically significant (P<0.01). The pulmonary arterial pressures of the thrombolysis group (51.21±6.86 mmHg) were significantly lower than those of the anticoagulation group (60.64±5.17 mmHg) (P<0.01). Furthermore, the difference between the hemorrhage rates of the two groups was statistically significant (P<0.05). Thrombolysis was shown to rapidly relieve dyspnea, reduce pulmonary arterial pressure and revascularize the embolized blood vessels. However, the hemorrhage rate of the thrombolysis group was higher than that of the anticoagulation group. The overall efficacies and fatality rates of the thrombolysis and anticoagulation groups were similar.
submassive; pulmonary embolism; anticoagulation; thrombolysis
Regulation of genes that initiate and amplify inflammatory programs of gene expression is achieved by signal-dependent exchange of co-regulator complexes that function to read, write and erase specific histone modifications linked to transcriptional activation or repression. Here, we provide evidence for the role of trimethylated histone H4 lysine 20 (H4K20me3) as a repression checkpoint that restricts expression of toll like receptor 4 (TLR4) target genes in macrophages. H4K20me3 is deposited at the promoters of a subset of these genes by the SMYD5 histone methyltransferase through its association with NCoR corepressor complexes. Signal-dependent erasure of H4K20me3 is required for effective gene activation and is achieved by NF-κB-dependent delivery of the histone demethylase PHF2. Liver X receptors antagonize TLR4-dependent gene activation by maintaining NCoR/SMYD5-mediated repression. These findings reveal a histone H4K20 tri-methylation/de-methylation strategy that integrates positive and negative signaling inputs that control immunity and homeostasis.