Pain and itch are closely related sensations, yet qualitatively quite distinct. Despite recent advances in brain imaging techniques, identifying the differences between pain and itch signals in the brain cortex is difficult due to continuous temporal and spatial changes in the signals. The high spatial resolution of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) has substantially advanced research of pain and itch, but these are uncomfortable because of expensiveness, importability and the limited operation in the shielded room. Here, we used near infrared spectroscopy (NIRS), which has more conventional usability. NIRS can be used to visualize dynamic changes in oxygenated hemoglobin and deoxyhemoglobin concentrations in the capillary networks near activated neural circuits in real-time as well as fMRI. We observed distinct activation patterns in the frontal cortex for acute pain and histamine-induced itch. The prefrontal cortex exhibited a pain-related and itch-related activation pattern of blood flow in each subject. Although it looked as though that activation pattern for pain and itching was different in each subject, further cross correlation analysis of NIRS signals between each channels showed an overall agreement with regard to prefrontal area involvement. As a result, pain-related and itch-related blood flow responses (delayed responses in prefrontal area) were found to be clearly different between pain (τ = +18.7 sec) and itch (τ = +0.63 sec) stimulation. This is the first pilot study to demonstrate the temporal and spatial separation of a pain-induced blood flow and an itch-induced blood flow in human cortex during information processing.
Supercritical fluid carbon dioxide extraction technology was developed to gain the active components from a Taiwan native plant, Zingiber officinale (ginger). We studied the biological effects of ginger extracts via multiple assays and demonstrated the biofunctions in each platform. Investigations of ginger extracts indicated antioxidative properties in dose-dependant manners on radical scavenging activities, reducing powers and metal chelating powers. We found that ginger extracts processed moderate scavenging values, middle metal chelating levels, and slight ferric reducing powers. The antibacterial susceptibility of ginger extracts on Staphylococcus aureus, Streptococcus sobrinus, S. mutans, and Escherichia coli was determined with the broth microdilution method technique. The ginger extracts had operative antimicroorganism potentials against both Gram-positive and Gram-negative bacteria. We further discovered the strong inhibitions of ginger extracts on lethal carcinogenic melanoma through in vivo xenograft model. To sum up, the data confirmed the possible applications as medical cosmetology agents, pharmaceutical antibiotics, and food supplements.
This study is to investigate the significance and risk factors of fecal toxigenic (tCdC) or non-toxigenic Clostridium difficile colonization (ntCdC) among hospitalized patients.
Adults admitted to medical wards in a district hospital between January 2011 and June 2012 were enrolled, and those with a history of colectomy, C. difficile fecal colonization or infection or receipt of either metronidazole or oral vancomycin within 3 months, were excluded. Stools collected within 48 hours after admission and every week during hospitalization were cultured for C. difficile.
Among the 441 enrolled patients, 84 (20.0%) had CdC at initial screening, including 58 (13.2%) with tCdC and 26 (6.8%) with ntCdC. Among patients with initial negative fecal screening for CdC, it took an average of 70.6 days or 66.5 days to develop tCdC or ntCdC during the study period. Finally 78 (17.7%) had tCdC and 34 (7.7%) had ntCdC. During the follow-up period, the patients with tCdC had a higher risk of CDAD (11/79, 14.1%) than those without CdC (3/328, 0.9%) and those with ntCdC (0/34, 0%) (P<0.001). In multivariate analysis, the TLR4 rs1927914 polymorphism (GG genotype) (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.6–11.8, P = 0.003) and recent cefepime therapy (OR 5.3, 95% CI 2.1–13.2, P<0.001) were independently associated with tCdC, whereas recent cefuroxime (OR 11.7, 95% CI 2.3–60.2, P = 0.003) and glycopeptide therapy (OR 10.9, CI: 2.1–57.2, P = 0.005) associated with ntCdC.
The incidence of CDAD is highest in patients with tCdC and lowest in patients with ntCdC, and the TLR4 rs1927914 polymorphism GG genotype and recent cefepime therapy were independently associated with tCdC.
Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active tuberculosis (TB). Evidence of the long-term risk and outcome of active TB after acute kidney injury (AKI) is limited.
This population-based-cohort study used claim records retrieved from the Taiwan National Health Insurance database. We retrieved records of all hospitalized patients, more than 18 years, who underwent dialysis for acute kidney injury (AKI) during 1999–2008 and validated using the NSARF data. Time-dependent Cox proportional hazards model to adjust for the ongoing effect of end-stage renal disease (ESRD) was conducted to predict long-term de novo active TB after discharge from index hospitalization.
Out of 2,909 AKI dialysis patients surviving 90 days after index discharge, 686 did not require dialysis after hospital discharge. The control group included 11,636 hospital patients without AKI, dialysis, or history of TB. The relative risk of active TB in AKI dialysis patients, relative to the general population, after a mean follow-up period of 3.6 years was 7.71. Patients who did (hazard ratio [HR], 3.84; p<0.001) and did not (HR, 6.39; p<0.001) recover from AKI requiring dialysis had significantly higher incidence of TB than patients without AKI. The external validated data also showed nonrecovery subgroup (HR = 4.37; p = 0.049) had high risk of developing active TB compared with non-AKI. Additionally, active TB was associated with long-term all-cause mortality after AKI requiring dialysis (HR, 1.34; p = 0.032).
AKI requiring dialysis seems to independently increase the long-term risk of active TB, even among those who weaned from dialysis at discharge. These results raise concerns that the increasing global burden of AKI will in turn increase the incidence of active TB.
This research focuses on creating a standardized nasal cavity model of adult Malaysian females. The methodology implemented in this research is a new approach compared to other methods used by previous researchers. This study involves 26 females who represent the test subjects for this preliminary study. Computational fluid dynamic (CFD) analysis was carried out to better understand the characteristics of the standardized model and to compare it to the available standardized Caucasian model. This comparison includes cross-sectional areas for both half-models as well as velocity contours along the nasal cavities. The Malaysian female standardized model is larger in cross-sectional area compared to the standardized Caucasian model thus leading to lower average velocity magnitudes. The standardized model was further evaluated with four more Malaysian female test subjects based on its cross-sectional areas and average velocity magnitudes along the nasal cavities. This evaluation shows that the generated model represents an averaged and standardized model of adult Malaysian females.
Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.
Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling metabolic dysfunction associated with chronic inflammation remains unexplored. We demonstrate here that administration of Lacto-N-fucopentaose III (LNFPIII), a LewisX containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased Il-10 production by LNFPIII activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment up-regulates nuclear receptor Fxr-α (or Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-Ap1 pathway appears to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide novel therapeutic approaches to treat metabolic diseases.
An association between chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) has been described, mainly due to smoking and corticosteroid use. Whether inhaled corticosteroid (ICS) therapy is associated with an increased risk of TB remains unclear.
We selected COPD cases by using six diagnostic scenarios and control subjects from a nationwide health insurance database, and applied time-dependent Cox regression analysis to identify the risk factors for TB.
Among 1,000,000 beneficiaries, 23,594 COPD cases and 47,188 non-COPD control subjects were selected. Cox regression analysis revealed that age, male gender, diabetes mellitus, end-stage renal disease, and cirrhosis, as well as COPD (hazard ratio = 2.468 [2.205–2.762]) were independent risk factors for TB. Among the COPD cases, those who developed TB received more oral corticosteroids and oral β-agonists. Time-dependent Cox regression analysis revealed that age, male gender, diabetes mellitus, low income, oral corticosteroid dose, and oral β-agonist dose, but not ICS dose, were independent risk factors for TB. The identified risk factors and their hazard ratios were similar among the COPD cases selected using different scenarios.
Keeping a high suspicion and regularly monitoring for the development of pulmonary TB in COPD patients are necessary, especially for those receiving higher doses of oral corticosteroids and other COPD medications. Although ICS therapy has been shown to predispose COPD patients to pneumonia in large randomized clinical trials, it does not increase the risk of TB in real world practice.
Chronic obstructive pulmonary disease; Tuberculosis; Inhaled corticosteroid; Oral corticosteroid; Time-dependent cox regression
Scientists routinely scan DNA sequences for transcription factor (TF) binding
sites (TFBSs). Most of the available tools rely on position-specific scoring
matrices (PSSMs) constructed from aligned binding sites. Because of the
resolutions of assays used to obtain TFBSs, databases such as TRANSFAC,
ORegAnno and PAZAR store unaligned variable-length DNA segments containing
binding sites of a TF. These DNA segments need to be aligned to build a
PSSM. While the TRANSFAC database provides scoring matrices for TFs, nearly
78% of the TFs in the public release do not have matrices available. As work
on TFBS alignment algorithms has been limited, it is highly desirable to
have an alignment algorithm tailored to TFBSs.
We designed a novel algorithm named LASAGNA, which is aware of the lengths of
input TFBSs and utilizes position dependence. Results on 189 TFs of 5
species in the TRANSFAC database showed that our method significantly
outperformed ClustalW2 and MEME. We further compared a PSSM method dependent
on LASAGNA to an alignment-free TFBS search method. Results on 89 TFs whose
binding sites can be located in genomes showed that our method is
significantly more precise at fixed recall rates. Finally, we described
LASAGNA-ChIP, a more sophisticated version for ChIP (Chromatin
immunoprecipitation) experiments. Under the one-per-sequence model, it
showed comparable performance with MEME in discovering motifs in ChIP-seq
We conclude that the LASAGNA algorithm is simple and effective in aligning
variable-length binding sites. It has been integrated into a user-friendly
webtool for TFBS search and visualization called LASAGNA-Search. The tool
currently stores precomputed PSSM models for 189 TFs and 133 TFs built from
TFBSs in the TRANSFAC Public database (release 7.0) and the ORegAnno
database (08Nov10 dump), respectively. The webtool is available at
The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.
UVR; apoptosis; oxidative stress; keratinocyte; langerhans cells; immunosuppression; phototherapy
Stem cell function is an exquisitely regulated process. To date, however, the contribution of metabolic cues to stem cell function is poorly understood. Here we identify a novel PML - Peroxisome-proliferator activated receptor delta (PPARδ) - fatty acid oxidation (FAO) pathway for haematopoietic stem cell (HSC) maintenance. We have found that loss of Ppard profoundly affects the maintenance of HSCs. Moreover, treatment with PPARδ agonists improves these HSC functions, whereas, conversely, inhibition of mitochondrial FAO induces loss of the HSC compartment. Importantly, we demonstrate that PML exerts its essential role in HSC maintenance through regulation of PPAR signalling and FAO. Mechanistically, the PML-PPARδ-FAO pathway controls HSC asymmetric division. Depletion of Ppard or Pml, as well as FAO inhibition, results in symmetric commitment of HSC daughter cells while, conversely, PPARδ activation increases asymmetric division. Thus, our findings identify a new metabolic switch for the control of HSC cell fate with important therapeutic implications.
Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13–/–) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13–/– mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.
The prolyl hydroxylase Ofd1 enables yeast cells to adapt to hypoxia by regulating the DNA binding and degradation of the hypoxic transcription factor Sre1N. These two regulatory functions are inseparable in vivo. A mathematical model of the Ofd1 system is used to show that both functions are necessary for Ofd1 to work as observed.
Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element–binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present, the prolyl hydroxylase Ofd1 down-regulates Sre1N activity in two ways: first, by inhibiting its binding to DNA, and second, by accelerating its degradation. Here we use a mathematical model to assess what each of these two regulatory functions contributes to the hypoxic response of the cell. By disabling individual regulatory functions in the model, which would be difficult in vivo, we found that the Ofd1 function of inhibiting Sre1N binding to DNA is essential for oxygen-dependent Sre1N regulation. The other Ofd1 function of accelerating Sre1N degradation is necessary for the yeast to quickly turn off its hypoxic response when oxygen is restored. In addition, the model predicts that increased Ofd1 production at low oxygen plays an important role in the hypoxic response, and the model indicates that the Ofd1 binding partner Nro1 tunes the response to oxygen. This model quantifies our understanding of a novel oxygen-sensing mechanism that is widely conserved.
Xenobiotic-mediated induction of cytochrome P450 (CYP) drug metabolizing enzymes (DMEs) is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance. However, autoinduction via CYP1A is encountered less frequently. In this report, an experimental compound, A-998679 [3-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl) benzonitrile], was shown to enhance its own clearance via induction of Cyp1a1 and Cyp1a2. Rats were dosed for 5 days with 30, 100, and 200 mg/kg/day A-998679. During the dosing period, the compound's plasma AUC decreased at 30 mg/kg (95%) and 100 mg/kg (80%). Gene expression analysis and immunohistochemistry of the livers showed a large increase in the mRNA and protein levels of Cyp1a, which was involved in the biotransformation of A-998679. Induction of CYP1A was confirmed in primary rat, human, and dog hepatocytes. The compound also weakly inhibited CYP1A2 in human liver microsomes. A-998679 activated the aryl hydrocarbon receptor (AhR) in a luciferase gene reporter assay in HepG2 cells, upregulated expression of genes associated with AhR activation in rat liver and enhanced nuclear migration of AhR in HepG2 cells. Collectively these results demonstrate that A-998679 is an AhR activator that induces Cyp1a1 and Cyp1a2 expression, resulting in an autoinduction phenomenon. The unique properties of A-998679, along with its novel structure distinct from classical polycyclic aromatic hydrocarbons (PAHs), may warrant its further evaluation as a tool compound for use in studies involving AhR biology and CYP1A-related mechanisms of drug metabolism and toxicity.
aryl hydrocarbon receptor; cytochrome P450; autoinduction
Regulation of gene expression plays an integral role in adaptation of cells to hypoxic stress. In mammals, prolyl hydroxylases control levels of the central transcription factor hypoxia inducible factor (HIF) through regulation of HIFα subunit stability. Here, we report that the hydroxylase Ofd1 regulates the Sre1 hypoxic transcription factor in fission yeast by controlling DNA binding. Prolyl hydroxylases require oxygen as a substrate and the activity of Ofd1 regulates Sre1-dependent transcription. In the presence of oxygen, Ofd1 binds the Sre1 N-terminal transcription factor domain (Sre1N) and inhibits Sre1-dependent transcription by blocking DNA binding. In the absence of oxygen, the inhibitor Nro1 binds Ofd1, thereby releasing Sre1N and leading to activation of genes required for hypoxic growth. In contrast to the HIF system where proline hydroxylation is essential for regulation, Ofd1 inhibition of Sre1N does not require hydroxylation, and thus defines a new mechanism for hypoxic gene regulation.
Hemodialysis (HD) patients are susceptible to extended spectrum beta-lactamase (ESBL)-producing bacterial infections. Because the optimal treatment and clinical significance of ESBL-producing Klebsiella pneumoniae (ESBL-Kp) HD access-related bacteremia remain unclear, we conducted this retrospective study to determine the clinical outcomes of patients treated with either flomoxef or a carbapenem.
The eligibility criterion was fistula or graft- or catheter- related ESBL-Kp bacteremia in patients on maintenance HD. The clinical characteristics and antibiotic management were analyzed. Outcome was determined by mortality resulting from bacteremia during the 14‐day period after the first positive blood culture for flomoxef-susceptible ESBL-Kp.
The 57 patients studied were predominantly elderly, malnourished, with a history of severe illnesses and broad-spectrum antibiotic use before the onset of bacteremia, and with severe septicemia as determined by the Pitt bacteremia score (PBS). The study population comprised 7 fistula, 8 graft, and 42 HD catheter-related bacteremia (CRB) cases, and the mortality rate was high (36/57, 63.2%) in these 57 patients. Of 42 patients with CRB, those in the deceased group (27/42, 64.3%) had significantly lower levels of serum albumin, longer prior hospital stay and duration of catheter-dependent HD, and higher PBS than patients in the survived group. Failure to receive effective antibiotics (flomoxef or a carbapenem) within 5 days after onset of bacteremia and treatment with flomoxef both significantly contributed to higher mortality. Multivariate analyses revealed that flomoxef use, PBS, and catheter-dependent HD >30 days were independently associated with increased mortality (OR, 3.52; 95% CI, 1.19–58.17, OR, 2.92; 95% CI, 1.36–6.26 and OR, 5.73; 95% CI, 1.21–63.2, respectively).
Considering the high mortality rate, ESBL-Kp should be recognized as a possible pathogen in patients on maintenance HD at high risk of acquiring HD access infections associated with ESBL-producing bacteria. Carbapenems rather than flomoxef should be the therapy of choice in these critically vulnerable patients.
Bacteremia; Carbapenems; Extended spectrum beta-lactamase; Flomoxef; Hemodialysis access; Klebsiella pneumoniae
Computational approaches to transcription factor binding site identification have been actively researched in the past decade. Learning from known binding sites, new binding sites of a transcription factor in unannotated sequences can be identified. A number of search methods have been introduced over the years. However, one can rarely find one single method that performs the best on all the transcription factors. Instead, to identify the best method for a particular transcription factor, one usually has to compare a handful of methods. Hence, it is highly desirable for a method to perform automatic optimization for individual transcription factors.
We proposed to search for transcription factor binding sites in vector spaces. This framework allows us to identify the best method for each individual transcription factor. We further introduced two novel methods, the negative-to-positive vector (NPV) and optimal discriminating vector (ODV) methods, to construct query vectors to search for binding sites in vector spaces. Extensive cross-validation experiments showed that the proposed methods significantly outperformed the ungapped likelihood under positional background method, a state-of-the-art method, and the widely-used position-specific scoring matrix method. We further demonstrated that motif subtypes of a TF can be readily identified in this framework and two variants called the k NPV and k ODV methods benefited significantly from motif subtype identification. Finally, independent validation on ChIP-seq data showed that the ODV and NPV methods significantly outperformed the other compared methods.
We conclude that the proposed framework is highly flexible. It enables the two novel methods to automatically identify a TF-specific subspace to search for binding sites. Implementations are available as source code at:
In recent years white adipose tissue inflammation has been recognized to be associated with obesity. Adipocytes and adipose tissue associated macrophages (ATMs) secrete bioactive molecules, including adipokines, chemokines/cytokines and free fatty acids that modulate the development of low-grade inflammation and insulin resistance responsible for obesity-related metabolic and cardiovascular diseases. Nuclear receptors, notably peroxisome-proliferator-activated receptors, are sensors of dietary lipids and control transcriptional programs of key metabolic and inflammatory pathways in adipocytes and macrophages. This review focuses on mechanisms by which nuclear receptors maintain white adipose tissue homeostasis. The identification of ATMs as active players in the initiation of chronic inflammation and the links between inflammatory signaling and metabolic dysfunction will be presented, followed by discussion of recent evidence for nuclear receptors in ATM function, with an emphasis on the paracrine interaction between adipocytes and ATMs.
nuclear receptors; metabolic syndrome; insulin resistance; obesity; adipocyte; adipokines; macrophage; inflammation; PPAR
The impact of toxigenic Clostridium difficile colonization (tCDC) in hospitalized patients is not clear.
To study the significance of tCDC in hospitalized patients.
A prospective study in the medical wards of a regional hospital was performed from January to June 2011. Fecal samples collected from patients at the time of admission were tested for tcdB by real-time polymerase chain reaction (PCR) and cultured for C. difficile. The patients were followed up weekly or when they developed diarrhea during hospitalization. If C. difficile was isolated, tcdA and tcdB would be tested by multiplex PCR. The primary outcome was the development of C. difficile-associated diarrhea (CDAD).
Of 168 patients enrolled, females predominated (87, 51.8%), and the mean patient age was 75.4 years old. Approximately 70% of the patients were nursing home residents, and one third had a recent hospitalization within the prior three months. Twenty-eight (16.7%) patients had tCDC, including 16 (9.5%) patients with tCDC at the time of admission and 12 (7.2%) with tCDC during the follow-up period. With regard to the medications taken during hospitalization, the patients were more likely to have tCDC if they had received more than one class of antibiotics than if they had received monotherapy (odds ratio [OR] 6.67, 95% confidence interval [CI] 1.41–31.56, P = 0.01), particularly if they received a glycopeptide in combination with a cephalosporin or penicillin or a cephalosporin and a carbapenem. More patients with tCDC developed CDAD than those without tCDC (17.9%, 5/28 vs. 1.4%, 2/140, P = 0.002). Overall 7 (4.2%) of the 168 patients developed CDAD, and crude mortality rate of those with and without tCDC was similar (21.4%, 6/28 vs. 19.4%, 27/140, P = 0.79).
Recent use of glycopeptides and β-lactam antibiotics is associated with toxigenic C. difficile colonization, which is a risk factor for developing C. difficile-associated diarrhea.
Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. It has been suggested as an important risk factor of chronic obstructive pulmonary disease (COPD), which is also a major cause of morbidity and mortality. This study investigated the impact of pulmonary TB and anti-TB treatment on the risk of developing COPD.
Design, Setting, and Participants
This cohort study used the National Health Insurance Database of Taiwan, particularly the Longitudinal Health Insurance Database 2005 to obtain 3,176 pulmonary TB cases and 15,880 control subjects matched in age, sex, and timing of entering the database.
Main Outcome Measures
Hazard ratios of potential risk factors of COPD, especially pulmonary TB and anti-TB treatment.
The mean age of pulmonary TB cases was 51.9±19.2. The interval between the initial study date and commencement of anti-TB treatment (delay in anti-TB treatment) was 75.8±65.4 days. Independent risk factors for developing COPD were age, male, low income, and history of pulmonary TB (hazard ratio 2.054 [1.768–2.387]), while diabetes mellitus was protective. The impact of TB persisted for six years after TB diagnosis and was significant in women and subjects aged >70 years. Among TB patients, delay in anti-TB treatment had a dose-response relationship with the risk of developing COPD.
Some cases of COPD may be preventable by controlling the TB epidemic, early TB diagnosis, and prompt initiation of appropriate anti-TB treatment. Follow-up care and early intervention for COPD may be necessary for treated TB patients.
Chromosome pairing in meiotic prophase is a prerequisite for the high fidelity of chromosome segregation that haploidizes the genome prior to gamete formation. In the budding yeast Saccharomyces cerevisiae, as in most multicellular eukaryotes, homologous pairing at the cytological level reflects the contemporaneous search for homology at the molecular level, where DNA double-strand broken ends find and interact with templates for repair on homologous chromosomes. Synapsis (synaptonemal complex formation) stabilizes pairing and supports DNA repair. The bouquet stage, where telomeres have formed a transient single cluster early in meiotic prophase, and telomere-promoted rapid meiotic prophase chromosome movements (RPMs) are prominent temporal correlates of pairing and synapsis. The bouquet has long been thought to contribute to the kinetics of pairing, but the individual roles of bouquet and RPMs are difficult to assess because of common dependencies. For example, in budding yeast RPMs and bouquet both require the broadly conserved SUN protein Mps3 as well as Ndj1 and Csm4, which link telomeres to the cytoskeleton through the intact nuclear envelope. We find that mutants in these genes provide a graded series of RPM activity: wild-type>mps3-dCC>mps3-dAR>ndj1Δ>mps3-dNT = csm4Δ. Pairing rates are directly correlated with RPM activity even though only wild-type forms a bouquet, suggesting that RPMs promote homologous pairing directly while the bouquet plays at most a minor role in Saccharomyces cerevisiae. A new collision trap assay demonstrates that RPMs generate homologous and heterologous chromosome collisions in or before the earliest stages of prophase, suggesting that RPMs contribute to pairing by stirring the nuclear contents to aid the recombination-mediated homology search.
Sexual reproduction involves the fusion of gametes, as of a sperm and an egg, to produce the next generation. Each gamete must carry half the number of chromosomes of each parent so that the correct number is restored at fertilization. In order to orient chromosomes properly so that the two chromosomes of each pair (“homologs”) separate to opposite poles in the first meiotic division, the chromosomes first must find one another and align in close proximity (“pairing”) and then be fastened together along their lengths (“synapsis”) in meiotic prophase. Pairing is a poorly understood process that involves movement coupled with a mechanism for recognizing homology. We examine the role played by telomere-promoted chromosome movements (rapid prophase movements, or “RPMs”) and find a correlation between movement and pairing rates, suggesting that RPMs contribute directly to pairing. RPMs cause collisions between nonhomologous as well as between homologous chromosomes, suggesting that RPMs stir the nuclear contents to stimulate recombination-dependent pairing.
Fission yeast protein Sre1, the homolog of the mammalian sterol regulatory element binding protein (SREBP), is a hypoxic transcription factor required for sterol homeostasis and low oxygen growth. Nro1 regulates the stability of the N-terminal transcription factor domain of Sre1 (Sre1N) by inhibiting the action of the prolyl 4-hydroxylase-like Ofd1 in an oxygen-dependent manner. The crystal structure of Nro1 determined at 2.2 Å resolution shows an all-α-helical fold that can be divided into two domains: a small N-terminal domain and a larger C-terminal HEAT-repeat domain. Follow-up studies showed that Nro1 defines a new class of nuclear import adaptor that functions both in Ofd1 nuclear localization and in the oxygen-dependent inhibition of Ofd1 to control the hypoxic response.
Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.
Classification of mitochondrial DNA (mtDNA) into their respective haplogroups allows the addressing of various anthropologic and forensic issues. Unique to mtDNA is its abundance and non-recombining uni-parental mode of inheritance; consequently, mutations are the only changes observed in the genetic material. These individual mutations are classified into their cladistic haplogroups allowing the tracing of different genetic branch points in human (and other organisms) evolution. Due to the large number of samples, it becomes necessary to automate the classification process. Using 5-fold cross-validation, we investigated two classification techniques on the consented database of 21 141 samples published by the Genographic project. The support vector machines (SVM) algorithm achieved a macro-accuracy of 88.06% and micro-accuracy of 96.59%, while the random forest (RF) algorithm achieved a macro-accuracy of 87.35% and micro-accuracy of 96.19%. In addition to being faster and more memory-economic in making predictions, SVM and RF are better than or comparable to the nearest-neighbor method employed by the Genographic project in terms of prediction accuracy.
mitochondrial DNA; ensemble learning; classification algorithms; support vector machines; random forest; genographic project