Flutamide-induced regression of angiofibroma.
Juvenile nasopharyngeal angiofibroma (JNA) appears to be an endocrine-responsive tumor. This concept was tested in five young men with JNA by treating them with a testosterone receptor blocker (flutamide) for 6 weeks preoperatively. Tumor size was evaluated by axial computed tomography both before and after flutamide therapy. Four of the five patients had an average tumor shrinkage of 44%. The patients tolerated the drug well, and the serum testosterone levels 2 or more years posttherapy were normal. This pilot study demonstrate that preoperative hormonal pharmacoreduction of JNA is a feasible adjunct to surgical therapy that offers the possibility of reduced blood loss. However, the authors believe that a formal clinical trial of this treatment approach is warranted and should be done before widespread adoption of this agent.


Presence, distribution, and pharmacological effects of neuropeptide Y in mammalian gastrointestinal tract.
The quantitative distribution of neuropeptide Y (NPY) immunoreactivity has been determined along the length of the gastrointestinal tract in three mammalian species; rat, pig, and guinea pig. The peptide was shown to be present in all regions studied and in all three species. Exceptionally high concentrations were found in the region of the lower esophageal sphincter. Pretreatment of rats with 6-hydroxydopamine depleted NPY concentrations by 30-40%, indicating that NPY is colocalized in part with adrenergic nerves. Characterization of the NPY immunoreactivity by high-pressure liquid chromatography revealed a single major peak. NPY immunoreactivity derived from rat extracts eluted consistently earlier from the column than synthetic porcine standard, indicating minor species differences. Pharmacological studies using longitudinal muscle from guinea pig terminal ileum demonstrated that NPY caused a dose-dependent inhibition of the electrically stimulated, neurally mediated contraction of longitudinal smooth muscle. This suggested that NPY may act presynaptically to inhibit cholinergic transmission. The effects of various NPY fragments were also tested on the same preparation. The C-terminal fragments were active but were considerably less potent than NPY, while the free acid form of NPY and N-terminal fragment (1-19) were completely inactive. Thus, this study has demonstrated the presence of NPY in the gastrointestinal tract of various species, particularly within the lower esophageal sphincter. The pharmacological actions of the peptide suggest a role in the control of nonvascular smooth muscle tone.


Anterior cruciate ligament tear increases the risk of venous thromboembolism: a population-based cohort study.
Previous studies highlighted an increased risk of venous thromboembolism (VTE) among patients with anterior cruciate ligament reconstruction (ACLR); however, the risk for those with ACL tear but without undergoing ACLR has not been reported yet. The aim of this study was to evaluate the risk of VTE among ACL tear individuals with or without ACLR derived from the general population. A cohort study was conducted using data from the IQVIA Medical Research Database of the United Kingdom. Up to five non-ACL tear individuals (n = 22,235) were matched to each case of ACL tear (n = 4474) by age, sex, body mass index and entry-time. The relation of ACL tear to VTE [pulmonary embolism (PE) and deep vein thrombosis (DVT)] was examined using a multivariable Cox proportional hazard model. A sub-cohort analysis, in which the ACL tear individuals were stratified into those with ACLR and those without ACLR, was also conducted. VTE developed in 13 individuals with ACL tear and nine individuals without ACL tear (incidence rates: 3.1 vs. 0.4/1000 person-years), with multivariable-adjusted hazard ratio (HR) being 6.59 (95% CI 2.28-19.08) in 1-year follow-up. For ACL tear individuals with ACLR, the HR was 11.44 (95% CI 2.71-48.28), and for those without ACLR, the HR was 6.02 (95% CI 1.44-24.25), compared with individuals without ACL tear. This large-sample population-based cohort study provides the first evidence on an increased risk of VTE in ACL tear individuals regardless of subsequent ACLR, which supports the necessity for monitoring venous-thromboembolic complications in the target population, including those without ACLR. III.


Accidental bait: do deceased fish increase freshwater turtle bycatch in commercial fyke nets?
Bycatch of turtles in passive inland fyke net fisheries has been poorly studied, yet bycatch is an important conservation issue given the decline in many freshwater turtle populations. Delayed maturity and low natural adult mortality make turtles particularly susceptible to population declines when faced with additional anthropogenic adult mortality such as bycatch. When turtles are captured in fyke nets, the prolonged submergence can lead to stress and subsequent drowning. Fish die within infrequently checked passive fishing nets and dead fish are a potential food source for many freshwater turtles. Dead fish could thus act as attractants and increase turtle captures in fishing nets. We investigated the attraction of turtles to decomposing fish within fyke nets in eastern Ontario. We set fyke nets with either 1 kg of one-day or five-day decomposed fish, or no decomposed fish in the cod-end of the net. Decomposing fish did not alter the capture rate of turtles or fish, nor did it alter the species composition of the catch. Thus, reducing fish mortality in nets using shorter soak times is unlikely to alter turtle bycatch rates since turtles were not attracted by the dead fish. Interestingly, turtle bycatch rates increased as water temperatures did. Water temperature also influences turtle mortality by affecting the duration turtles can remain submerged. We thus suggest that submerged nets to either not be set or have reduced soak times in warm water conditions (e.g., >20 °C) as turtles tend to be captured more frequently and cannot withstand prolonged submergence.


Von Willebrand factor, its cleaving protease (ADAMTS13), and inflammation in young adults: The African-PREDICT study.
The role of inflammation in the early development of vascular dysfunction remains complex. Interleukin-6 (IL-6) and C-reactive protein (CRP) can cause an acute imbalance in the von Willebrand factor (vWF)-ADAMTS13 interaction, indicating a possible link between markers of haemostasis and low-grade inflammation. To better understand these inter-relationships in the early phases of disease development, we investigated whether vWF and ADAMTS13 associate with the pro-inflammatory markers, IL-6 and CRP in healthy young adults. We considered the role of blood types, sex and race on these relationships. In healthy black and white men and women (n = 1113; 24 ± 5 years; no previous diagnosis or medication use for chronic diseases) we analysed von Willebrand factor antigen (vWFag), ADAMTS13, IL-6 and CRP, and grouped blood types as non-O (A, B and AB) and O. Covariates included socioeconomic status, age, estimated glomerular filtration rate, 24-hour systolic blood pressure, waist circumference, glucose, total cholesterol, platelet count, γ-glutamyl transferase and total energy expenditure. In the total group, vWFag was highest in the third tertile of both IL-6 and CRP (p ≤ 0.014), while ADAMTS13 was lowest in the third compared to the first IL-6 tertile (p = 0.006). In multivariate regression, vWFag associated positively with IL-6 (Adj R2 = 0.169; β = 0.123; p = 0.001) and CRP (Adj R2 = 0.163; β=0.094; p = 0.019) in the total group, in the O blood group (all p ≤ 0.051) and white men (all p ≤ 0.035). ADAMTS13 associated negatively with IL-6 (Adj R2 = 0.053; β = -0.154; p = 0.015) and CRP (Adj R2 = 0.055; β = -0.177; p = 0.009), only in the O blood group. Markers of haemostasis associated independently with low-grade inflammation in the O type blood group and white men. An interplay between the haemostatic and inflammatory systems may already exist in young healthy adults and is dependent on blood groups, sex and race. This extends our understanding on the role of inflammation in the early development of vascular dysfunction prior to cardiovascular compromise.


Arterial thoracic outlet syndrome.
Arterial vascular complications resulting from thoracic outlet compression, although rare, can be substantial and potentially limb threatening. Bony abnormalities such as cervical ribs can lead to chronic trauma to the subclavian artery. Early on, the clinical symptoms can be subtle and confusing, causing potential delay in diagnosis.


12-Lipoxygenase product as an inhibitor of the action of chemoattractant peptide fMet-Leu-Phe in rat neutrophils.
1. 12-Hydroxyeicosatetraenoic acid (12-HETE) has been evaluated for its capacities to modulate neutrophil migration and cytosolic Ca2+ ([Ca2+]i) using compounds prepared by chemical synthesis and tissue extract from dog gingiva. 2. 12-HETE inhibited N-formyl-Met-Leu-Phe (fMLP)-stimulated neutrophil migration in a concentration-dependent fashion. 3. The tissue extract from dog gingiva mimicked the actions of 12-HETE. 4. Although 12-HETE failed to increase [Ca2+]i, preincubation of neutrophils with 12-HETE led to a suppression of [Ca2+]i when the cells were subsequently stimulated by fMLP. 5. Again tissue extract from dog gingiva mimicked the action of 12-HETE on [Ca2+]i. 6. These results suggest the possible correlation of the inhibitory activities of 12-HETE on the regulation of neutrophil migration and Ca2+ mobilization, and this may be important for the role of 12-HETE in pathogenesis in periodontal tissues.


Analysis of enterotoxigenic effect of Staphylococcus aureus and Staphylococcus epidermidis enterotoxins C and L on mice.
Pathogenic properties of orthologues to S. aureus staphylococcal enterotoxin C (SEC) and staphylococcal enterotoxin L (SEL) produced by S. epidermidis are largely unexplored. We assessed the enteropathogenic effects of S. epidermidis SECepi and SELepi and S. aureus SEC3 and SEL after oral administration to Balb/c mice. Intestinal sections from SE-treated mice were analyzed histopathologically. The T cell lineage markers (αβ and γδ TCR CD3, CD4, CD8), T-cell activation marker CD69 and proliferation-related marker CD71 were assessed in intraepithelial lymphocytes (IEL), mesenteric lymph nodes (MLN) and spleens (SPL). Serum concentrations of SEC and SEL were determined. Ortologous S. epidermidis and S. aureus SEs exerted a number of common histopathological changes in the mouse gut. Atrophy, generation of villi gap and edema of the villi were the most prominent effects of SE treatment observed in mouse gut sections. The most marked effect of ortologous S. epidermidis and S. aureus SEs on the number of goblet cells, crypt depth and villi height was noted in the mice duodenum and jejunum. We indicate early changes of TCRαβ CD4-CD8a+ T and TCRαβ CD4+CD8a+ T cells in response to both S. aureus and S. epidermidis SEs. Upon the treatment with SEs, markers of T cell activation and proliferation were upregulated in both αβ and γδ T cell populations derived from IEL and MLN. We demonstrated that S. epidermidis-encoded SEs applied via oral route exert pathological changes in mice gut similarly to S. aureus-encoded SEs. For the first time we indicated that SEL co-produced together with SEC by both S. aureus and S. epidermidis induces some elements of mice gut immune response and contributes to gastrointestinal tract damage. Our results indicate the potential involvement of CoNS-encoded enterotoxins in the pathogenesis of SFP.


High resistance of Pseudomonas aeruginosa to paromomycin, an agent used for selective bowel decontamination (SBD).
Paromomycin is used for selective bowel decontamination (SBD) in patients undergoing bone marrow transplantation in many hospitals, but there are no published resistance data for this compound in the recent medical literature. The aim of this study was to investigate the in vitro activity of paromomycin against the common intestinal bacteria E. coli and P. aeruginosa. 94 E. coli isolates and 77 P. aeruginosa isolates derived from clinical specimens were tested by broth microdilution against paromomycin and amikacin, respectively, following the CLSI recommendations for testing amikacin. 86 of 94 E. coli isolates (91%) and 71 of 77 P. aeruginosa isolates (92%) showed in vitro susceptibility to amikacin (MIC90 for both compounds: 16 µg/ml, range: 1-32 µg/ml for E. coli and 1->128 µg/ml for P. aeruginosa). Paromomycin was active against 83/94 E. coli isolates (88%; MIC90: 32 µg/ml, range: 2->128 µg/ml), but showed poor in vitro activity against P. aeruginosa (3/77 isolates susceptible [4%]; MIC90: >128 µg/ml, range: 2->128 µg/ml). If SBD with inclusion of an aminoglycoside antibiotic is applied, paromomycin should not be used unless local resistance data provide evidence of a sufficient in vitro activity of this compound against P. aeruginosa.


Diverse mutational spectrum in the 13q14 chromosomal region in a Brazilian cohort of retinoblastoma.
Retinoblastoma is a rare childhood tumor caused by the inactivation of both copies of the RB1 gene. Early diagnosis and identification of heritable RB1 mutation carriers can improve the disease outcome and management via genetic counseling. We used the Multiplex Ligation-dependent Probe Amplification (MLPA) method to analyze the RB1 gene and flanking regions in blood samples from 159 retinoblastoma patients previously negative for RB1 point mutations via Sanger sequencing. We detected a wide spectrum of germline chromosomal alterations, ranging from partial loss or duplication of RB1 to large deletions spanning RB1 and adjacent genes. Mutations were validated via karyotyping, fluorescent in situ hybridization (FISH), SNP-arrays (Single Nucleotide Polymorphism-arrays) and/or quantitative relative real-time PCR. Patients with leukocoria as a presenting symptom showed reduced death rate (p = 0.013) and this sign occurred more frequently among carriers of two breakpoints within RB1 (p = 0.05). All unilateral cases presented both breakpoints outside of RB1 (p = 0.0075). Patients with one breakpoint within RB1 were diagnosed at earlier ages (p = 0.017). Our findings characterize the mutational spectrum of a Brazilian cohort of retinoblastoma patients and point to a possible relationship between the mutation breakpoint location and tumor outcome, contributing to a better prospect of the genotype/phenotype correlation and adding to the wide diversity of germline mutations involving RB1 and adjacent regions in retinoblastoma.


Longitudinal evaluation of fentanyl concentrations in equine plasma and synovial fluid following application of transdermal fentanyl patches over one carpal joint.
To determine if transdermally delivered fentanyl can achieve greater concentrations of fentanyl in synovial fluid when applied over a synovial structure. Randomized, experimental study. Six healthy adult horses. Each horse had two 100 μg/h fentanyl matrix patches applied on the dorsal aspect of one, randomly assigned, carpometacarpal joint (CMCJ) for 48 h. Whole blood and bilateral synovial samples from the intercarpal joint were obtained at 0, 2, 6, 12, 24, 36 and 48 h. Fentanyl concentrations were measured with liquid chromatography-mass spectrometry. All subjects achieved detectable concentrations of fentanyl in both plasma and synovial fluid. Time to peak synovial and plasma concentration was 12 h. At 6 h, the synovial concentration in the untreated carpus (0.104 ng/mL ± 0.106) was lower than plasma fentanyl concentrations 0.31 ± 0.27 (p = .036). At 12 h, both treated (0.55 ng/mL ± 0.3) and untreated (0.53 ng/mL ± 0.28) synovial fluid fentanyl concentrations were lower than plasma (0.87 ng/mL ± 0.48) concentrations (p < .001 and p = .001, respectively). Synovial concentrations of fentanyl did not differ between treated and untreated joints (p > 0.608 for all time points). Application of fentanyl matrix patches directly over the CMCJ did not result in increased fentanyl concentrations in the synovial fluid of the treated intercarpal joint in normal horses. There is likely no analgesic advantage to placing fentanyl patches directly over the affected joint, as it did not result in increased synovial concentrations at the tested site.


Effectiveness of Incentive Spirometry on Inspiratory Muscle Strength After Coronary Artery Bypass Graft Surgery.
Although the use of incentive spirometry with a deep breathing exercise (DBE) is widely used in clinical practice in patients who have undergone coronary artery bypass graft (CABG) surgery, the effect of this combination therapy has not been conclusively elucidated. The aim of this study was to investigate the effect of postoperative combined incentive spirometry and DBE versus DBE alone on inspiratory muscle strength following CABG. This randomised clinical trial was conducted in patients scheduled to undergo CABG surgery at Siriraj Hospital, Bangkok Thailand. The study group received incentive spirometry and DBE, and the control group received DBE only. Maximal inspiratory pressure (MIP) before surgery and at day 4 after surgery was assessed by a respiratory pressure meter. Secondary outcomes, including postoperative pulmonary complication and duration of postoperative hospitalisation, were obtained from the medical records. Ninety (90) patients were included, with 47 and 43 patients assigned to the study and control groups, respectively. In both groups, there was a significant reduction in MIP from preoperative baseline to postoperative day 4; however, the MIP in the incentive spirometry group had a significantly smaller reduction in MIP compared with the control group (33.0±23.2% vs 47.2±20.1%, respectively; p=0.006, 95% confidence interval, 3.9-23.3). There was no difference between groups regarding secondary outcomes. Patients in the study group had significantly better recovery of inspiratory muscle strength on day 4 post-CABG than patients in the control group. There was no significant difference between groups for either postoperative pulmonary complications or length of hospital stay.


Polystyrene nanoplastic contamination mixed with polycyclic aromatic hydrocarbons: Alleviation on gas exchange, water management, chlorophyll fluorescence and antioxidant capacity in wheat.
Polycyclic aromatic hydrocarbons (PAHs) constitute a significant environmental pollution group that reaches toxic levels with anthropogenic activities. The adverse effects of nanoplastics accumulating in ecosystems with the degradation of plastic wastes are also a growing concern. Previous studies have generally focused on the impact of single PAH or plastic fragments exposure on plants. However, it is well recognized that these contaminants co-exist at varying rates in agricultural soil and water resources. Therefore, it is critical to elucidate the phytotoxicity and interaction mechanisms of mixed pollutants. The current study was designed to comparatively investigate the single and combined effects of anthracene (ANT, 100 mg L-1), fluorene (FLU, 100 mg L-1) and polystyrene nanoplastics (PS, 100 mg L-1) contaminations in wheat. Plants exposed to single ANT, FLU and PS treatments demonstrated decline in growth, water content, high stomatal limitations and oxidative damage. The effect of ANT + FLU on these parameters was more detrimental. In addition, ANT and/or FLU treatments significantly suppressed photosynthetic capacity as determined by carbon assimilation rate (A) and chlorophyll a fluorescence transient. The antioxidant system was not fully activated (decreased superoxide dismutase, peroxidase and glutathione reductase) under ANT + FLU, then hydrogen peroxide (H2O2) content (by 2.7-fold) and thiobarbituric acid reactive substances (TBARS) (by 2.8-fold) increased. Interestingly, ANT + PS and FLU + PS improved the growth, water relations and gas exchange parameters. The presence of nanoplastics recovered the adverse effects of ANT and FLU on growth by protecting the photosynthetic photochemistry and reducing oxidative stress. PAH plus PS reduced the ANT and FLU accumulation in wheat leaves. In parallel, the increased antioxidant system, regeneration of ascorbate, glutathione and glutathione redox status observed under ANT + PS and FLU + PS. These findings will provide an information about the phytotoxicity mechanisms of mixed pollutants in the environment.


A homozygous insertion-deletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens dystrophic epidermolysis bullosa.
The Hallopeau-Siemens type of recessive dystrophic epidermolysis bullosa (HS-RDEB) is a life-threatening autosomal disease characterized by loss of dermal-epidermal adherence with abnormal anchoring fibrils (AF). We recently linked HS-RDEB to the type VII collagen gene (COL7A1) which encodes the major component of AF. We describe a patient who is homozygous for an insertion-deletion in the FN-4A domain of the COL7A1 gene. This defect causes a frameshift mutation which leads to a premature stop codon in the FN-5A domain, resulting in a marked diminution in mutated mRNA levels, with no detectable type VII collagen polypeptide in the patient. Our data suggest strongly that this null allele prevents normal anchoring fibril formation in homozygotes and is the underlying cause of HS-RDEB in this patient.


Fast calculation of the sensitivity matrix in magnetic induction tomography by tetrahedral edge finite elements and the reciprocity theorem.
Magnetic induction tomography of biological tissue is used to reconstruct the changes in the complex conductivity distribution by measuring the perturbation of an alternating primary magnetic field. To facilitate the sensitivity analysis and the solution of the inverse problem a fast calculation of the sensitivity matrix, i.e. the Jacobian matrix, which maps the changes of the conductivity distribution onto the changes of the voltage induced in a receiver coil, is needed. The use of finite differences to determine the entries of the sensitivity matrix does not represent a feasible solution because of the high computational costs of the basic eddy current problem. Therefore, the reciprocity theorem was exploited. The basic eddy current problem was simulated by the finite element method using symmetric tetrahedral edge elements of second order. To test the method various simulations were carried out and discussed.


Application of capillary zone electrophoresis and reversed-phase high-performance liquid chromatography in the biopharmaceutical industry for the quantitative analysis of the monosaccharides released from a highly glycosylated therapeutic protein.
Two assays for the quantitative determination of the neutral and amino-monosaccharides attached to a therapeutic glycoprotein were developed using capillary zone electrophoresis (CZE) and RP-HPLC. These assays meet the strict batch release requirements of the quality control in biopharmaceutical industry. The monosaccharides were released from the glycoprotein by hydrolysis with 2N trifluoroacetic acid. In the CZE assay the monosaccharides were reacetylated prior to derivatization with 8-aminopyrenesulfonic acid (APTS), reacetylation in the glycoprotein matrix was investigated in detail. The RP-HPLC method used pre-column derivatization with anthranilic acid in methanol-acetate-borate reaction medium; reacetylation was not necessary. However, epimerization of the different monosaccharides was observed and studied in detail. For the quantitative assay, separation of the amino-monosaccharide epimers had to be developed. The HPLC assay was validated.


Anticoccidial derivatives of 6-azauracil. 2. High potency and long plasma life of N1-phenyl structures.
Attachment of substituted phenyl side chains at N1 of 6-azauracil caused striking increases in plasma life and anticoccidial potency. The increases were related in part to the acidity of the imide hydrogen. Maximum effects were shown by phenyl rings substituted in both meta positions by compact, electron-withdrawing, lipophilic substituents, as in 1-(3',5'-dichlorophenyl)-6-azauracil, which had plasma half-life of 160 h and a potency 250-fold greater than that of 6-azauracil.


Identification of sirtuin 5 inhibitors by ultrafast microchip electrophoresis using nanoliter volume samples.
Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that catalyzes removal of post-translational modifications, such as succinyl and malonyl moieties, on lysine residues. In light of SIRT5's roles in regulating metabolism, and its reported oncogenic functions, SIRT5 modulators would be valuable tools for basic biological research and perhaps clinically. Several fluorescence assays for sirtuin modulators have been developed; however, the use of fluorogenic substrates has the potential to cause false positive results due to interactions of engineered substrates with enzyme or test compounds. Therefore, development of high-throughput screening (HTS) assays based on other methods is valuable. In this study, we report the development of a SIRT5 assay using microchip electrophoresis (MCE) for identification of SIRT5 modulators. A novel SIRT5 substrate based on succinate dehydrogenase (SDH) was developed to allow rapid and efficient separation of substrate and product peptide. To achieve high throughput, samples were injected onto the microchip using a droplet-based scheme. By coupling this approach to existing HTS sample preparation workflows, 1408 samples were analyzed at 0.5 Hz in 46 min. Using a 250 ms separation time, eight MCE injections could be made from each sample generating >11,000 electropherograms during analysis. Of the 1280 chemicals tested, eight were identified as inhibiting SIRT5 activity by at least 70% and verified by dose-response analysis.


Aminolysis of Y-substituted phenyl X-substituted benzoates with piperidine: effect of nonleaving group substituent.
The title reaction has been suggested to proceed through a zwitterionic tetrahedral intermediate with a change in the rate determining step on the basis of the curved Brønsted-type plots obtained. The curvature center of the curved Brønsted-type plots is at pKa = 6.4 regardless of the electronic nature of the substituent X in the benzoyl moiety.


Synthesis of 1-substituted 3-pyridinylmethylidenylindolin-2-ones and 1-substituted 3-quinolinylmethylidenylindolin-2-ones as the enhancers of ATRA-induced differentiation in HL-60 cells.
As part of our continuing search for potential differentiation agents, 1-benzyl-3-(4-pyridinylmethylidenyl)indolin-2-one (14) was selected as lead compound, and its new pyridinyl and quinolinyl analogs were synthesized and evaluated for differentiation-inducing activity toward HL-60 cells. Most of the tested compounds enhanced the ATRA-induced differentiation; among them, 1-(1-phenylethyl)-3-(3-quinolinylmethylidenyl)indolin-2-one (25) was the most promising one. The two isomers, 25Z and 25E; consisting 25 were found to have similar differentiation activity. The combination of 25 with all trans retinoic acid (ATRA) was found to induce complete differentiation of HL-60 cells and arrest the cells in the G(0)/G(1) phase of the cell cycle. Beside its excellent differentiation activity, 25 also exhibited relatively low cytotoxicity toward normal cells. Therefore, compound 25 is recommended as a candidate for further development of novel enhancer of ATRA-induced differentiation in HL-60 cells.


Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages.
Investigations on pulmonary macrophages (MΦ) mostly focus on alveolar MΦ (AM) as a well-defined cell population. Characteristics of MΦ in the interstitium, referred to as lung interstitial MΦ (IM), are rather ill-defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue. Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay. IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both MΦ populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6. AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung MΦ in the inflammatory response.


Comparison of left ventricular function by echocardiogram in patients with Wilms' tumor treated with anthracyclines versus those not so treated.
The aim of this report was to evaluate late left ventricular function in survivors of Wilms' tumor and to compare patients treated with anthracyclines with those treated without anthracycline and with normal subjects. Wilms' tumor survivors treated without anthracycline had no myocardial abnormalities. A large percentage of patients treated with anthracycline presented with increased end-systolic wall stress. Results indicate that there is a high incidence of subclinical cardiovascular abnormalities in such patients.


Simulations of pattern dynamics for reaction-diffusion systems via SIMULINK.
Investigation of the nonlinear pattern dynamics of a reaction-diffusion system almost always requires numerical solution of the system's set of defining differential equations. Traditionally, this would be done by selecting an appropriate differential equation solver from a library of such solvers, then writing computer codes (in a programming language such as C or Matlab) to access the selected solver and display the integrated results as a function of space and time. This "code-based" approach is flexible and powerful, but requires a certain level of programming sophistication. A modern alternative is to use a graphical programming interface such as Simulink to construct a data-flow diagram by assembling and linking appropriate code blocks drawn from a library. The result is a visual representation of the inter-relationships between the state variables whose output can be made completely equivalent to the code-based solution. As a tutorial introduction, we first demonstrate application of the Simulink data-flow technique to the classical van der Pol nonlinear oscillator, and compare Matlab and Simulink coding approaches to solving the van der Pol ordinary differential equations. We then show how to introduce space (in one and two dimensions) by solving numerically the partial differential equations for two different reaction-diffusion systems: the well-known Brusselator chemical reactor, and a continuum model for a two-dimensional sheet of human cortex whose neurons are linked by both chemical and electrical (diffusive) synapses. We compare the relative performances of the Matlab and Simulink implementations. The pattern simulations by Simulink are in good agreement with theoretical predictions. Compared with traditional coding approaches, the Simulink block-diagram paradigm reduces the time and programming burden required to implement a solution for reaction-diffusion systems of equations. Construction of the block-diagram does not require high-level programming skills, and the graphical interface lends itself to easy modification and use by non-experts.


Traumatic nerve injuries about the elbow.
Although not common, nerve injuries about the elbow occur because of the proximity of the three upper extremity nerves or because of the relationship of the median, ulnar, and radial nerves to the bony and soft-tissue structures about the elbow joint. Nerve injuries at and about the elbow joint occur more frequently with fractures than with any other kind of trauma. Nerve injuries may be found with periarticular fractures, dislocations, gunshot wounds, lacerations, and other iatrogenic causes.


A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors.
Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors. During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity. Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m(2) irinotecan and 375 mg/m(2) 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G(2)-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD. The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m(2) irinotecan and 300 mg/m(2) 17AAG.


Fertility treatment and oral contraceptive discontinuation for identification of pregnancy planning in routinely collected health data - an application to analgesic and antibiotic utilisation.
Women with unplanned pregnancies use folic acid less frequently, and more often use potentially teratogenic medications in the first trimester. Yet most studies based on routinely collected data lack information on pregnancy planning. Further, only pregnancies proceeding beyond a certain gestational age appear in routinely collected data, creating the possibility for collider-stratification bias. If pregnancy intention could be identified, pregnancies could be ascertained earlier. This study aimed to investigate fertility treatment and discontinuation of oral contraception (OC) as proxies for pregnancy planning by describing variations in patterns of prescription fills for antibiotics and analgesics during the peri-pregnancy period by these proxies of pregnancy intention. Fertility treatment with clomiphene and discontinuation of OC were identified in the Norwegian Prescription Database (NorPD) and linked with data from the Medical Birth Registry of Norway for the years 2006 to 2017. Filled prescriptions for antibiotics and analgesics from NorPD were displayed for women on fertility treatment, women who discontinued OC before pregnancy, and women who discontinued during pregnancy. Of 172,585 included pregnancies, fertility treatment was identified in 19,449, and OC discontinuation before or during pregnancy in 153,136. Women who discontinued OC during pregnancy were less likely to use preconception folic acid (25.4%) than women who discontinued before pregnancy (32.9%), and women on fertility treatment (51.0%). Proportions of first trimester prescription fills were 4.9% (analgesics) and 12.8% (antibiotics) for women who discontinued OC during pregnancy, compared to 4.0 and 11.4% in women who discontinued OC before pregnancy, and 4.7 and 11.0% in women on fertility treatment. There were no substantial differences in patterns of prescription fills for analgesics and antibiotics before or during pregnancy by fertility treatment and OC discontinuation. This suggests that there were few differences in medication use between women with planned and unplanned pregnancies, or that fertility treatment and timing of OC discontinuation from routinely collected health data cannot stand alone in the identification of unplanned pregnancies. A narrower definition of OC discontinuation during pregnancy seemed to be a better proxy, but this should be confirmed in other studies.


The Pareto Analysis for Establishing Content Criteria in Surgical Training.
Current surgical training is still highly dependent on expensive operating room (OR) experience. Although there have been many attempts to transfer more training to the skills laboratory, little research is focused on which technical behaviors can lead to the highest profit when they are trained outside the OR. The Pareto principle states that in any population that contributes to a common effect, a few account for the bulk of the effect. This principle has been widely used in business management to increase company profits. This study uses the Pareto principle for establishing content criteria for more efficient surgical training. A retrospective study was conducted to assess verbal guidance provided by 9 supervising surgeons to 12 trainees performing 64 laparoscopic cholecystectomies in the OR. The verbal corrections were documented, tallied, and clustered according to the aimed change in novice behavior. The corrections were rank ordered, and a cumulative distribution curve was used to calculate which corrections accounted for 80% of the total number of verbal corrections. In total, 253 different verbal corrections were uttered 1587 times and were categorized into 40 different clusters of aimed changes in novice behaviors. The 35 highest-ranking verbal corrections (14%) and the 11 highest-ranking clusters (28%) accounted for 80% of the total number of given verbal corrections. Following the Pareto principle, we were able to identify the aspects of trainee behavior that account for most corrections given by supervisors during a laparoscopic cholecystectomy on humans. This strategy can be used for the development of new training programs to prepare the trainee in advance for the challenges encountered in the clinical setting in an OR.


A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness with all other visual functions, including visual acuity, visual field, and colour vision being usually normal. A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light ('Mizuo phenomenon'; Fig. 1). The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally. The locus for Oguchi disease was recently mapped between D2S172 and D2S345 on distal chromosome 2q by linkage analysis. Interestingly, the gene for arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction, also maps to this region of chromosome 2q (refs 6, 7). Here we report that in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene, predicting a shift in the reading frame and a premature termination of translation which may result in 'functional null alleles.'


Nephrectomy as a cause of chronic kidney disease in the treatment of urolithiasis: a case-control study.
To analyze the clinical course of nephrectomized patients due to complications related to nephrolithiasis and ascertain the prevalence of chronic kidney disease (CKD) in this population. From 2005 to 2010, 658 patients were treated with urolithiasis. Among these, 30 (4.6%) were nephrectomized. For each case, a control was selected and matched to the case by age, sex and disease duration. All data were collected from medical records, which contained the clinical, laboratory evaluation and diagnostic imaging. Age of the study group was 51.5 ± 10.4 years and the control group 47.1 ± 5.2 years. There were 17 (85%) women and three men in each group. Patients from the study group reported 3 (range, 1-5) episodes of acute renal colic before nephrectomy. Urinary tract infection and hematuria was detected in 70% of cases before surgery. In addition, half of the patients had at least one previous urological procedure. The control group showed higher urinary levels of calcium (216.1 ± 114.3 vs. 130.9 ± 72.2), uric acid (530.2 ± 197.4 vs. 424 ± 75.2) and citrate (755 ± 533 vs. 380.2 ± 260.7), p < 0.01, 0.03 and 0.01, respectively. The creatinine clearance was lower in the study group, 52.5 ± 18.8 ml/min vs. 92.9 ± 24.2 ml/min in the control group (p < 0.001). There was a decrease in kidney function in nephrectomized patients compared to a control group of stone-forming patients with both kidneys. Prospective studies are needed to assess the incidence of CKD in patients with nephrolithiasis submitted to nephrectomy.


Intraoperative opioids use for laryngeal squamous cell carcinoma surgery and recurrence: a retrospective study.
To assess whether the use of intraoperative opioids is associated with poor recurrence-free survival (RFS) and overall survival (OS) after lung cancer surgery. Retrospective study. Academic hospital. Patients with laryngeal primary or recurrent laryngeal squamous cell carcinoma who had surgery. Intravenous opioids (remifentanil, fentanyl, sufentanil, and hydromorphone). Univariate and multicovariate Cox proportional hazards models were applied to assess the effects of covariates of interest on OS and RFS. A total of 195 patients were included. All received opioids intraoperatively. The multivariate analysis demonstrated that age (hazard ratio [HR], 1.03; P = .005), negative margin status (HR, 0.163; P = .001], postoperative chemotherapy (HR, 7.38; P < .001), and concurrent chemotherapy and radiation (HR, 3.11; P < .001) treatment and fentanyl equivalent use (HR, 1.001; P = .02) were all predictor factors for 3- and 5-year RFS. The same variables were predictor factors for OS (age: HR, 1.03 [P = .003]; negative margin status: HR, 0.14 [P = .001]; postoperative chemotherapy: HR, 4 [P < .0001]; and fentanyl equivalent use: HR, 1.001 [P = .02]). Our study demonstrates a very weak association between the use of intraoperative opioids and cancer recurrence after laryngeal squamous cell carcinoma surgery.


Continuation of full time employment as an inhibiting factor in Parkinson's disease symptoms.
Parkinson's disease (PD) is a neurodegenerative disease. Due to a constantly growing incidence rate and lowering age of PD patients it is becoming a more serious social problem. The aim of this study was to determine the effectiveness of physiotherapy procedure of patients with PD depending on their working status. The research was carried out on 89 people with diagnosed PD of IInd stage according to the Hoehn and Yahr classification. They were divided into two groups: working professionally and non-working. The Unified Parkinson's Disease Rating Scale (UPDRS) was used to estimate patients' clinical status while the PDQ-39 (Parkinson's Disease Questionnaire) scale evaluated quality of life. Patients took part in rehabilitation activities twice a week for a period of 20 weeks. In both groups an improvement in physical activity and a quality of life were achieved. Better effects were observed in the group of working patients. Statistically significant differences were notice in part II UPDRS (p = 0.001), part I, II and III total of UPDRS (p = 0,001) and in the PDQ-39 test (p = 0.003). Employment and participation in properly planned physiotherapy help reduce the symptoms and improve the quality of life in people with Parkinson's disease.


The G20210A prothrombin variant and the risk of venous thromboembolism or fetal loss in pregnant women: a family study.
The relationship between the G20210A prothrombin variant (PT-G20210A) and adverse pregnancy outcome has been studied by several groups in the last few years. However, because of the different design and sample sizes of these studies the estimated risks have varied. In this retrospective, multi-center, cohort study we assessed the risk of thromboembolic or obstetric complications in women belonging to families of probands with isolated PT-G20210A and that were symptomatic for venous thromboembolism (VTE). Two hundred and eighty-three female family members that had been pregnant at least once were enrolled. The occurrence of VTE and obstetric complications during pregnancy and postpartum were assessed in carriers of PT-G20210A and compared with non- carriers. One thromboembolic event occurred during the postpartum period in the carriers group. In the same group, 48 out of 359 pregnancies resulted in unexplained fetal loss as compared with 50 out of 357 pregnancies in the non-carriers (RR 0.9; 95% CI: 0.7-1.4). After adjustment, carriers of PT-G20210A showed a trend towards a higher risk of late fetal loss as compared with non-carriers (RR 2.2; 95% CI: 0.8-6.2). Furthermore, in pregnancies subsequent to those with previous fetal loss there was not a different risk of adverse outcome regardless of the carrier status. Female family members who are heterozygous carriers of isolated PT-G20210A do not seem to be at significant increased risk for fetal loss as compared with non-carriers. Screening for PT-G20210A of fertile age women belonging to these families is not warranted in this situation.


FPL 62064, a topically active 5-lipoxygenase/cyclooxygenase inhibitor.
FLP 62064 [N-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-amine] is a dual inhibitor of prostaglandin synthetase and 5-lipoxygenase. The compound had anti-inflammatory activity in vivo in a number of models. It inhibited peritoneal inflammation induced by immune-complex when given locally. When applied to the skin, FPL 62064 inhibited UV irradiation-induced erythema and PGE2 formation in the guinea pig and also oedema formation and eicosanoid production in the mouse ear produced by arachidonic acid. Co-injected with arachidonic acid in rabbit skin, FPL 62064 inhibited oedema and eicosanoid formation.


Sociocognitive Functioning and Psychosocial Burden in Patients with Brain Tumors.
Brain tumors may represent devastating diseases and neuro-oncological research in the past solely focused on development of better treatments to achieve disease control. The efficacy of tumor-directed treatment was evaluated by progression-free and overall survival. However, as neuro-oncological treatment became more effective, preservation and improvement of quality of life (QoL) was noticed to represent an important additional outcome measure. The need to balance between aggressive tumor-directed treatment and preservation of QoL was increasingly acknowledged in brain tumor patients. QoL is comprised by many determinants; one of those may have been rather neglected so far: social cognition. Since diagnosis and treatment of brain tumors represent demanding life situations, patients may experience increased psychosocial burden and the negative consequences of illness on well-being may be buffered by intact social relationships. These skills to build and maintain supportive social relationships essentially depend on the ability to empathize with others and to recognize and appropriately address social conflicts, i.e., "sociocognitive functioning". Therefore, sociocognitive functions may influence QoL and treatment outcome. In this article, we review the literature on psychosocial burden and sociocognitive functioning in adult brain tumor patients.


Mechanisms underlying pathological cortical bursts during metabolic depletion.
Cortical activity depends upon a continuous supply of oxygen and other metabolic resources. Perinatal disruption of oxygen availability is a common clinical scenario in neonatal intensive care units, and a leading cause of lifelong disability. Pathological patterns of brain activity including burst suppression and seizures are a hallmark of the recovery period, yet the mechanisms by which these patterns arise remain poorly understood. Here, we use computational modeling of coupled metabolic-neuronal activity to explore the mechanisms by which oxygen depletion generates pathological brain activity. We find that restricting oxygen supply drives transitions from normal activity to several pathological activity patterns (isoelectric, burst suppression, and seizures), depending on the potassium supply. Trajectories through parameter space track key features of clinical electrophysiology recordings and reveal how infants with good recovery outcomes track toward normal parameter values, whereas the parameter values for infants with poor outcomes dwell around the pathological values. These findings open avenues for studying and monitoring the metabolically challenged infant brain, and deepen our understanding of the link between neuronal and metabolic activity.


Effects of low dose perioperative interferon on the surgically induced suppression of antitumour immune responses.
General surgical procedures are followed by a period of generalized immunosuppression that may favour the deposition of metastases seeded at operation in patients with malignant disease. In an attempt to prevent the suppression of host-antitumour immune mechanisms following surgery we have studied the immunological effects of low-dose perioperative interferon-alpha (r-HuIFN alpha). Patients were randomly allocated pre-operatively to the control (n = 15) or treatment group (n = 15). Patients in the treatment arm received a 1-week course of subcutaneous recombinant human interferon-alpha 2a (Roferon-A) at a dose of 2 megaunits daily starting on the evening before surgery. Natural killer cell, lymphokine activated killer cell cytotoxicities and endogenous interleukin 2 production were measured 1 day before surgery and on the first, third, fifth and tenth postoperative days. Treatment with r-HuIFN alpha did not prevent the postoperative impairment of interleukin 2 production or lymphokine activated killer cell cytotoxicity. However it prevented the fall in natural killer cell activity normally observed following surgery. This may have important consequences in controlling metastatic dissemination of tumour in this vulnerable period.


In vivo site-specific integration of transgene in silkworm via PhiC31 integrase-mediated cassette exchange.
Current techniques for genetic engineering of the silkworm Bombyx mori genome utilize transposable elements, which result in positional effects and insertional mutagenesis through random insertion of exogenous DNA. New methods for introducing transgenes at specific positions are therefore needed to overcome the limitations of transposon-based strategies. Although site-specific recombination systems have proven powerful tools for genome manipulation in many organisms, their use has not yet been well established for the integration of transgenes in the silkworm. We describe a method for integrating target genes at pre-defined chromosomal sites in the silkworm via phiC31/att site-specific recombination system-mediated cassette exchange. Successful recombinase-mediated cassette exchange (RMCE) was observed in the two transgenic target strains with an estimated transformation efficiency of 3.84-7.01%. Our results suggest that RMCE events between chromosomal attP/attP target sites and incoming attB/attB sites were more frequent than those in the reciprocal direction. This is the first report of in vivo RMCE via phiC31 integrase in the silkworm, and thus represents a key step toward establishing genome manipulation technologies in silkworms and other lepidopteran species.


Stimulatory effect of ADP, ATP, NAD(P) on pyruvate production from malate by uncoupled human placental mitochondria.
It has been shown that ADP, ATP, NAD(P), and NAD(P)H significantly stimulate pyruvate production from malate by intact uncoupled human term placental mitochondria. No stimulation by ADP was observed when mitochondria were incubated in the presence of NAD(P) or NAD(P)H or when mitochondrial membrane had been disrupted. Atractyloside and oligomycin were without effect on ADP- and ATP-stimulated pyruvate production. Other dinucleotides tested such as GDP, UDP, and CDP, stimulated pyruvate production only slightly when mitochondria were incubated in the absence of phosphate. The rate of pyruvate production by intact mitochondria is commensurate with partly purified NAD(P)-linked malic enzyme activity as measured by NAD(P) reduction as far as the effects of pH of hydroxymalonate on these both processes is concerned. It is concluded that pyruvate production by intact human placental mitochondria is catalyzed by NAD(P)-linked malic enzyme and that this process is stimulated by ADP and ATP.


[Effect of brain extracts from rats subjected to korazol kindling on generalized epileptic activity].
The pharmacological kindling was induced in rats by corazol repeated injections in subthreshold doses. The peptide-containing fraction was emitted from animal brains by the help of hot acetic acid on the stage of generalized clonic-tonic seizures development. Intraperitoneal injection of brain extracts of kindled rats significantly increased corazol and picrotoxin induced seizure severity in mice. The effect was removed by preliminary injection of naloxone or by preventive incubation of extracts with pronase. Intraventricular injection of extracts to intact rats increased the seizure severity which was provoked by corazol and in high doses induced in rats generalized seizure reactions.


Hypoglycemia due to 3β-Hydroxysteroid Dehydrogenase type II Deficiency in a Newborn.
3β-hydroxysteroid dehydrogenase type II deficiency results in decreased production of all three groups of adrenal steroids. Recurrent hypoglycemia as a presenting feature of this disorder has not been reported earlier. A genotypically and phenotypically normal female newborn delivered by in-vitro fertilization presenting with recurrent hypoglycemia. Primary adrenal insufficiency with insignificant mineralocorticoid deficiency and slightly elevated levels of 17-hydro-xyprogesterone, dehydroepian-drosterone sulphate and testosterone. Successfully managed only with corticosteroid replacement. Congenital adrenal hyperplasia can rarely cause recurrent hypoglycemia in newborns.


Paciniolipoma in congenital spinal dysraphism.
The authors describe a case in which an intradural lipoma, causing tethering of the cord, was found on histological examination to exhibit fully differentiated mature pacinian corpuscles throughout. There are only 3 reports in the literature describing this rare tumor, and the authors use the term "paciniolipoma" to refer to it.


Log D analysis using dynamic approach.
Log D the logarithm ( log10 ) of the distribution coefficient ( D ), is one of the important parameters used in Lipinski's rule to assess the druggability of a molecule in pharmaceutical formulations. The distribution of a molecule between a hydrophobic organic phase and an aqueous buffer phase is influenced by the pH of the buffer system. In this work, we used both the conventional algebraic method and the generalized 'dynamic' approach to model the distribution coefficient of amphoteric, diamino-monoprotic molecule and monoprotic acid in the presence of salt or co-solvent. We have shown the equivalence of these methods by analysing the recently reported experimental data of amphoteric molecules such as nalidixic acid, mebendazole, benazepril and telmisartan.


Advances in the development and use of DREB for improved abiotic stress tolerance in transgenic crop plants.
Abiotic stresses negatively influence the survival, biomass production, and yield of crops. Tolerance to diverse abiotic stresses in plants is regulated by multiple genes responding differently to various stress conditions. Genetic engineering approaches have helped develop transgenic crops with improved abiotic stress tolerance including yields. The dehydration-responsive element binding protein (DREB) is a stress-responsive transcription factor that modulates the expression of downstream stress-inducible genes, which confer simultaneous tolerance to multiple stresses. This review focuses on advances in the development of DREB transgenic crops and their characterization under various abiotic stress conditions. It further discusses the mechanistic aspects of abiotic stress tolerance, yield gain, the fate of transgenic plants under controlled and field conditions and future research directions toward commercialization of DREB transgenic crops.


A comparison of adverse events and functional outcomes after restorative proctocolectomy for familial adenomatous polyposis and ulcerative colitis.
Restorative proctocolectomy is the procedure of choice for patients undergoing proctocolectomy for familial adenomatous polyposis or ulcerative colitis. This meta-analysis was designed to identify differences in adverse events and functional outcomes between these two groups. Studies published between 1986 and 2003 that compared outcomes between patients with familial adenomatous polyposis and ulcerative colitis were included. Meta-analytical techniques using random effect models were used to compare short-term and long-term adverse events as well as functional outcomes between the groups. Nineteen studies comprising 5,199 patients (familial adenomatous polyposis, 782; ulcerative colitis, 4,417) were analyzed. There were no significant differences in immediate postoperative adverse events between the two groups. Pouch-related fistulation was significantly increased in the ulcerative colitis group (10.5 percent vs. familial adenomatous polyposis 4.8 percent; odds ratio 2.31; P < 0.001). There was no significant difference in pouch failure between the two groups (ulcerative colitis 5.8 percent vs. familial adenomatous polyposis 4.5 percent; odds ratio 1.22; P = 0.43). The incidence of pouchitis was significantly greater in the ulcerative colitis group (30.1 vs. 5.5 percent; odds ratio 6.44; P < 0.001). Patients with familial adenomatous polyposis had a significant advantage in stool frequency with one less motion per 24 hours (95 percent confidence interval, 0.21-1.76; P = 0.01). In contrast to studies reporting similar outcomes for patients undergoing restorative proctocolectomy for familial adenomatous polyposis or ulcerative colitis, the present meta-analysis suggested that patients with ulcerative colitis are at greater risk of pouch-related fistulation and pouchitis. Although there was an increase in the 24-hour stool frequency in the ulcerative colitis group, this may be accounted for by the younger age at surgery in the familial adenomatous polyposis group.


Effects of etoposide on stage-specific DNA synthesis during rat spermatogenesis.
The stage-specific effect of etoposide on spermatogenic DNA synthesis was measured 1, 3 and 18 days after a single intraperitoneal injection of etoposide. Etoposide inhibited premitotic DNA synthesis most effectively at stages II-III and IV-V of the seminiferous epithelial cycle in which DNA synthesis of late spermatogonia takes place. Compared with control levels, DNA synthesis at stages II-III was maximally inhibited 43% and 57% at doses of 5 and 10 mg/kg, respectively, and at stages IV-V the maximal inhibition was 67% and 62%, at doses of 5 and 10 mg/kg respectively. Premeiotic DNA synthesis was not as vulnerable to the etoposide action as premitotic DNA synthesis, the maximal inhibition of premeiotic DNA synthesis was 39% and 41% compared with control at doses of 5 and 10 mg/kg, respectively. Induction of most probably repair-type DNA synthesis was demonstrated in stages I-III, VIIa-b and XII of the cycle. All the effects of etoposide were most apparent 1 and 3 days after treatment but had not totally disappeared 18 days after the treatment.


The metabolic effects of isotonic amino acid infusion in surgical sepsis.
28 normally nourished adult male and female patients who had undergone major elective surgery were maintained on dextrose-free isotonic amino acid solutions as their sole nutritional support. In the 6 days after surgery, 15 patients had no septic complications, 9 developed superficial sepsis, and 4 developed a deep seated collection of pus or deep sepsis. Patients without infection developed and maintained a fasting metabolic fuel profile within the first 3 days and increasingly spared protein. Superficial sepsis caused a small depression in serum ketone body concentrations but did not otherwise alter the fasting profile. Moreover nitrogen balances and plasma albumin and transferrin concentrations were unaltered by superficial sepsis which is not the response usually recognised with infection. Metabolic adaptation to the fasting state was lost in patients with deep sepsis and nitrogen losses were increased with greater decreases in plasma albumin and transferrin.


Structure and mechanism of MT-ADPRase, a nudix hydrolase from Mycobacterium tuberculosis.
Nudix hydrolases are a family of proteins that contain the characteristic sequence GX(5)EX(7)REUXEEXG(I/L/V), the Nudix box. They catalyze the hydrolysis of a variety of nucleoside diphosphate derivatives such as ADP-ribose, Ap(n)A (3 </= n </= 6), NADH, and dATP. A number of Nudix hydrolases from several species, ranging from bacteria to humans, have been characterized, including, in some cases, the determination of their three-dimensional structures. The product of the Rv1700 gene of M. tuberculosis is a Nudix hydrolase specific for ADP-ribose (ADPR). We have determined the crystal structures of MT-ADPRase alone, and in complex with substrate, with substrate and the nonactivating metal ion Gd(3+), and in complex with a nonhydrolyzable ADPR analog and the activating metal ion Mn(2+). These structures, refined with data extending to resolutions between 2.0 and 2.3 A, showed that there are sequence differences in binding site residues between MT-ADPRase and a human homolog that may be exploited for antituberculosis drug development.


Environmental and kinetic parameters for Cr(VI) bioreduction by a bacterial monoculture purified from Cr(VI)-resistant consortium.
Hexavalent chromium, Cr(VI), is toxic to living systems. Widespread contamination of water and soil by Cr(VI) present a serious public health problem. Chromium-resistant bacteria can reduce and detoxify Cr(VI). Twelve bacteria resistant to high concentrations of Cr(VI) were isolated from soil enrichment cultures. Environmental parameters and kinetic parameters of Cr(VI) bioreduction by one monoculture isolate, identified by 16S rRNA gene sequence as Bacillus sp. PB2, were studied. The optimal temperature for growth and Cr(VI) reduction was 35 degrees C. The isolate grew luxuriantly and substantially reduced Cr(VI) at initial pH 7.5 to 9. Maximal Cr(VI) bioreduction occurred at initial pH 8.0. Substantial Cr(VI) bioreduction was observed in salt media, but removal efficiency was inversely related to salt concentration (1-9%). Michaelis-Menten hyperbolic equation and the Lineweaver-Burk double reciprocal plot were comparatively employed to determine the k (m) and V (max) of Cr(VI) bioreduction. A k (m) of 82.5 microg mL(-1) and V (max) of 7.78 microg mL(-1) h(-1) were calculated by nonlinear regression analysis of the hyperbola curve. Linear regression analysis of the double reciprocal plot revealed k (m) and V (max) of 80.9 microg mL(-1) and 10.6 microg mL(-1) h(-1), respectively. Time course studies displayed about 90% reduction of Cr(VI) at an initial concentration of 8,000 microg L(-1) in 8 h, with an estimated t (1/2) of 4 h. Data from time course analysis of the rate of Cr(VI) bioreduction fitted zero-order model, and the kinetic constant k was calculated to be 840 microg L(-1) h(-1). The monoculture isolate, Bacillus sp. PB2, strongly reduces Cr(VI) and could be used for bioremediation of Cr(VI)-contaminated aquatic and terrestrial environments.


Dual strategies to improve oral bioavailability of oleanolic acid: Enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes.
Oleanolic acid (OA) is a typical BCS IV drug with low water-solubility and poor permeability, metabolized by cytochrome P450 (CYP) isozymes in the intestinal tract, such as CYP3A. These are the reasons for the low oral bioavailability of OA which have restricted its wide application. In this study, a solidified phospholipid complex (OPCH) composed of OA-phospholipid complex (OPC) and hydroxyapatite (HA) was prepared by simple solvent evaporation. OPC was used to improve the liposolubility of OA, and HA was used to improve the flowability of OPC. Ketoconazole (KCZ, inhibitor of CYP3A) was co-administrated with OPCH to inhibit the metabolism of OA by CYP3A in the intestine. DSC, PXRD, SEM and IR analysis confirmed the formation of OPC and OPCH. Compared with the water-solubility and n-octanol solubility of OA, that of OPCH was increased nearly 15.3-fold and 3.19-fold, respectively. An in vitro dissolution study showed that the cumulative dissolution rate of OPCH was nearly 2.23-fold and 4.57-fold higher than that of OA and OPC at 2h. Single-pass intestinal perfusion studies showed that the absorption of OA from OPCH was increased nearly 1.6-2.6-fold compared with that of pure OA and this was mainly due to the improved permeability and was further increased by OPCH with KCZ 1.2-2.4-fold compared with that of OPCH because KCZ inhibited metabolism of OA by CYP3A. A pharmacokinetic study of OPCH in rats following co-administration of KCZ was investigated. The Cmax was increased markedly from 59.5 to 78.7 and 131.3ng/mL in case of OA alone, OPCH alone and OPCH with KCZ. In parallel with the Cmax, the AUC0-24h was increased from 259.6 to 306.6 and 707.7ngh/mL, respectively. All the results obtained demonstrated that formulation of OPCH and co-administration of KCZ significantly improved the bioavailability of OA by increasing the solubility and permeability in combination with inhibiting the metabolism of OA.


The evaluation of cardiac complaints in marathon runners.
In the United States there are now approximately 521 marathons, and in 2005 approximately 432,000 participants completed one. The number of frequent runners (more than 100 days a year) is estimated at over 11 million. When one of these patients presents to the emergency department with cardiac complaints, the risk profile and evaluation may be different than in sedentary subjects. The first and most important step to patient evaluation is the history. An electrocardiogram (ECG) should be obtained in all patients with suspected cardiac complaints. Depending on the study and what is defined as abnormal, 40-80% of athletes' ECGs will show some abnormality. A normal ECG has a 96% negative predictive value for ruling out structural cardiovascular abnormalities, but a positive predictive value for disease of only 7%. The electrocardiogram, cardiac enzymes, and stress testing are useful, but should be interpreted in the context of the sport and the athlete. Echocardiography and cardiac magnetic resonance imaging are indicated for the diagnosis of certain conditions. Cardiology consultation or inpatient evaluation may be indicated when a specific disease process is suspected based on history, physical examination, or ECG. Some patients may require follow-up for further diagnostic testing.


High molecular weight deoxyribonucleic acid polymerase of LF hepatoma. Purification and properties.
A high molecular weight DNA polymerase has been purified from the cytosol of a fast growing hepatoma: LF hepatoma. This enzyme sediments at 11.3 S under polymerization reaction conditions (6 mM KCl) and at 8.3 S in higher salt concentrations (200 mM KCl). In either case, no activity is seen in the 3 to 4 S region where low molecular weight DNA polymerase is found. The purified enzyme has a neutral pH optimum and requires a divalent cation, all four deoxyribonucleoside triphosphates and an initiated DNA template for maximal activity. The synthetic template specificity of LF DNA polymerase has been studied. Although this enzyme cannot copy a polyribonucleotide template, the ribostrand of a synthetic hybrid can be used with low efficiency as an initiator for the synthesis of the complementary deoxyribonucleotide strand. The activity of the purified enzyme is strongly inhibited by thiol-blocking agents. The general properties of LF DNA polymerase are similar to those of high molecular weight mammalian DNA polymerases. In our experimental conditions, the error frequency of this tumoral DNA polymerase was no greater than that made by the purified high molecular weight DNA polymerase of regenerating rat liver.


Early aspects of human cochlea development and tectorial membrane histogenesis.
Several human embryos and foetuses cochlea from the first half of pregnancy were studied by light, transmission and scanning electron microscopy. Cochlea development in man is the result of three coexisting processes: First, coiling and maturation of the cartilaginous otic capsule. Second, resorption of the periodic mesenchymal reticulum with the appearance of the labyrinthine fluids. Third, differentiation of the sensory epithelium. Tectorial membrane morphogenesis is closely related to the apocrine secretory activity of the greater and lesser epithelial ridges in the 50 mm c.r.l. specimen. In the 70, 110 and 120 mm c.r.l. specimens the secretory activity rests on the interdental cells of the spiral limbus, the undifferentiated cells of Corti's primordium and in the most external cells of the lesser epithelial ridge.


Decreased numbers of dendritic spines on cortical pyramidal neurons in dementia. A quantitative Golgi study on biopsy samples.
The number of dendritic spines on the apical dendrites of layer III pyramidal cells was counted in cerebral biopsies, processed in part according to the rapid Golgi method, which had been performed for diagnostic purposes on patients suffering from dementia of different origins. The samples were from cases affected by Alzheimer's disease (3 patients), Parkinson's disease and dementia (1 patient), Creutzfeldt-Jacob disease (4 patients), Pick's disease (1 patient) and dementia paralytica (1 patient). Spines were counted on consecutive segments of the apical dendrite along the 500-microns proximal region from the cell body. A significant decrease in the number of spines was observed in almost every segment of the apical dendrite in demented patients when compared with similar measurements carried out in age-matched controls (p less than 0.01-0.001); Mann-Whitney U-test. Decreased numbers of dendritic spines may result in reduced inputs on cortical neurons and may be a consistent morphological substrate for the impaired mental status in cortical dementia.


Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults.
Glutamate-mediated excitotoxicity might contribute to the pathogenesis of Huntington's disease and other polyglutamine repeat disorders. We used murine neocortical cultures derived from transgenic and knock-in mice to test the effect of expression of expanded polyglutamine-containing huntingtin on neuronal vulnerability to excitotoxins or other insults. Neurons cultured from mice expressing either a normal length (Hdh(Q20)) or expanded (Hdh(Q111)) CAG repeat as a knock-in genetic alteration in exon one of the mouse Hdh gene [Hum Mol Genet 8 (1999) 115] had similar vulnerability to N-methyl-D-aspartate (NMDA) and kainate-mediated excitotoxicity. These neurons also exhibited similar vulnerability to oxidative stress (24 h exposure to 10-100 microM paraquat or 1-10 microM menadione), apoptosis (48 h exposure to 30-100 nM staurosporine or 1 microM dizocilpine maleate (MK-801) and proteasome inhibition (48 h exposure to 0.3-3 microM MG-132). Neocortical neurons cultured from mice transgenic for an expanded CAG repeat-containing exon 1 of the human HD gene (Mangiarini et al., 1996, R6/2 line) and non-transgenic littermate controls also had similar vulnerability to NMDA and kainate-mediated excitotoxicity. These observations suggest that expression of expanded polyglutamine-containing huntingtin does not acutely alter the vulnerability of cortical neurons to excitotoxic, oxidative or apoptotic insults.


Evidence for language-specific influence on the preference of stress patterns in infants learning an Iambic language (Hebrew).
The ability of infants to develop recognition of a common stress pattern that is language specific has been tested mainly in trochaic languages with a strong-weak (SW) stress pattern. The goals of the present study were: (a) to test Hebrew-learning infants on their stress pattern preference in the Hebrew language, for which the weak-strong (WS) stress pattern is the common one, and (b) to test whether the infants would generalize any preference for the common stress pattern in Hebrew to English words, which belong to a different rhythmic class. Fifty-six 9-month-old Hebrew-learning infants were tested on their preference for SW and WS stress patterns using Hebrew and English bisyllabic words with the head-turn preference procedure. The infants showed preference for WS Hebrew words but not for SW English words. Hebrew-learning infants recognize the common stress pattern in their native language, supporting language-specific distributional learning by infants. This recognition, however, is not generalized to a foreign language with different prosodic characteristics.


Prenatal and concurrent blood mercury concentrations and associations with IQ in canadian preschool children.
Prenatal and childhood mercury (Hg) exposures have been associated with negative impacts on child neurodevelopment. It is unclear if associations persist at the low Hg exposures typical in Western countries. To examine associations between prenatal/childhood blood Hg concentrations and child IQ in Canadian male and female children while considering the potential modifying role of prenatal fish consumption. We analyzed data from the Maternal-Infant Research on Environmental Chemicals study. Hg was measured in first trimester (n = 527), cord (n = 430), and child (at 3-4 years of age, n = 355) blood and examined sex-stratified associations between blood Hg and children's Full Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), and General Language Composite (GLC) scores (assessed with WPPSI-III). Prenatal Hg analyses were further stratified by prenatal fish consumption (low: 0-2, moderate: 3-7, or high: ≥8 times/month). Higher cord blood Hg concentrations were associated with lower PIQ (ß = -3.27; 95%CI: 6.44, -0.09) in male children with the lowest prenatal fish consumption. Progressively stronger positive associations were observed with PIQ in male children for moderate (ß = 1.08; 95%CI: 0.10, 2.26) and high (ß = 3.07; 95%CI: 1.95, 4.19) prenatal fish consumption. Cord blood Hg concentrations were positively associated with female children's FSIQ (ß = 1.29; 95% CI: 0.77, 1.81) and PIQ (ß = 2.01; 95% CI: 1.19, 2.83); however, when stratified only in the highest fish consumption subgroup. Among female children, higher child blood Hg concentrations were associated with an approximately 1-point increase in FSIQ, VIQ, and GLC. Prenatal exposure to low levels of Hg was associated with lower PIQ scores in male children with low prenatal fish intake. Positive associations between cord and child blood Hg concentrations and IQ were primarily observed in female children and may be due to beneficial effects of prenatal fish intake.


Rapid and reliable collection of tumor tissue for successful gene panel in a patient with advanced stage lung cancer: A case report.
Rapid and reliable identification of targetable driver mutations in patients with advanced stage lung cancer is essential. Adequate amount of tumor tissue biopsies (i.e., genomic biopsies) are required to successfully analyze the gene panel. In the present case, we performed three pleural fluid investigations, including transbronchial biopsy of the primary tumor, transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of lymph node metastasis, and thoracoscopic biopsy of the pleural seeding sites. Among the three investigations, thoracoscopic biopsy alone successfully obtained a sufficient amount of tissue. Thus, it is important to determine the technique and site of biopsy, as multiple biopsies are not only burdensome to the patient, but also lead to significant delays in therapy induction.


Pressure support ventilation with the I-gel in intensive care unit: case report.
The I-gel supraglottic airway has a non-inflatable cuff made from a gel-like thermoplastic elastomer. The use of the I-gel during anesthesia for spontaneously breathing patients or intermittent positive pressure ventilation has been reported. But there are a few published reports about the use of the I-gel with pressure-controlled ventilation. In this case report we described the use of the I-gel supraglottic airway along 48h in intensive care unit for the management of ventilation in a patient needed mechanic ventilation but in whom tracheal intubation could not be performed.


Treatment and prevention of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is the most common serious, acquired gastrointestinal disorder in the newborn infant. Although many variables are associated with development of NEC, only prematurity has been consistently identified in case-controlled studies. Traditionally, the diving seal reflex has been invoked as the mechanism responsible for ischaemic injury and necrosis. Intestinal ischaemia is likely to be the final common pathway in NEC; however, it is due to the release of vasoconstricting substances, such as platelet activating factor, rather than perinatal asphyxia. Bacteria and/or bacterial toxins are likely to have a key role in the pathogenesis of NEC by fostering production of inflammatory mediators. The role of feeding practices in the pathogenesis of NEC remains controversial. Treatment of infants with NEC generally includes a regimen of bowel rest, gastric decompression, systemic antibiotics and parenteral nutrition. Infants with perforation are generally operated upon; however, there has been recent interest in primary peritoneal drainage as an alternative. Prevention of NEC still remains elusive. Avoidance of preterm birth, use of antenatal steroids and breast-milk feeding are practices that offer the greatest potential benefits. Use of any other strategy should await further trials.


Doxycycline as a potential partner of COVID-19 therapies.
Coronavirus disease 2019 (COVID-19) is a major public health challenge, and the current antiviral arsenal for treatment is limited, with questionable efficacy. Major efforts are under way for discovery of new effective agents, but the validation of new potential treatments for COVID-19 may take a long time. Therefore, the repurposing of existing drugs for new indications is needed. In this article, we argue for the potential benefits of using doxycycline with either hydroxycholoroquine or other putative agents for COVID-19 treatment, as doxycycline has antiviral and anti-inflammatory activities by dampening the cytokine storm and to prevent lung damage.


Biochemical analyses demonstrate that Bt maize has no adverse effects on Eisenia fetida.
The potential effects of Bt (Bacillus thuringiensis) maize on non-target organisms should be evaluated before such maize is commercially planted. Earthworms play an indispensable role in the soil ecosystem; act as important bio-indicators of soil quality and environmental pollution. Therefore, earthworms are often used as the object to evaluate the non-target effect of Bt maize. To accelerate the commercialization of transgenic maize in China, a 90-day Eisenia fetida feeding experiment was conducted to evaluate the potential effects of Bt maize line, BT799-which was developed by China Agricultural University and contains the Cry1Ac gene-and its non-Bt conventional isoline-Zheng 58-on E. fetida. Our results showed that the Bt maize line had no significant effects on the growth, reproduction, or enzymatic activities of these earthworms. In summary, Bt maize had no toxic effects on E. fetida.


Efficacy of perineural hypertonic saline injection versus acupoints of foot in the management of diabetic neuropathy: a multicenter, double-blinded randomized controlled trial.
Aim: Painful diabetic polyneuropathy is one of the most common disabling problems worldwide. We aimed to determine if a perineural injection of hypertonic saline compared with foot acupoints decreased the neuropathic pain score in patients with diabetes. Patients & methods/materials: Patients were assigned to receive either perineural or acupoints injection of hypertonic saline 5% in their feet for three weekly sessions. Douleur Neuropathique 4 (DN4) questionnaire for neuropathic pain was assessed. Results: Both groups observed a significant reduction of the DN4 score throughout 8 weeks of follow-up. Conclusion: Both perineural and acupoints hypertonic saline injections of the foot could improve neuropathic pain in patients with diabetes.


Skin test reactions to a phenol-soluble antigen of Brucella abortus among veterinary students, Lyon, France, 1984.
In December 1984, 424 students at the National Veterinary College, Lyon, France, were skin-tested with a phenol-soluble antigen of Brucella abortus B19. Of all students, 2.6% had a positive intradermal reaction indicating previous contact with Brucella. Prevalence of positive reactions was significantly lower among students from the three first school years (less than 2%) compared with students in their last school year (5.9%). These results are discussed and compared to the prevalence of brucellosis among cattle. Specificity (94%) of the intradermal testing resembles that of serological testing but its sensitivity (75%) seems to be better.


Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern.
Alanine aminotransferase (ALT) activity is the most widely used laboratory test for the recognition of liver disease. Normality limits for values of serum ALT activity have been questioned lately. One reason for this recent uncertainty may be an unrecognized decline in aminotransferase levels in the aging population. Cross-sectional evaluation of the association between age and ALT activity. Laboratory data of residents in single home for the aged and of adult subjects in three general practice clinics in Jerusalem, Israel were reviewed, excluding subjects with known liver disease. A single laboratory performed all the tests. We examined the associations of serum aminotransferase levels with age, sex, body-mass-index (BMI), and estimated glomerular filtration rate (GFR). Polynomial regression and analysis of variance (ANOVA) with corrections for multiple comparisons were utilized for the statistical analyses. One hundred and twenty-eight individuals from the home for the aged and 207 individuals from three family practices were included. ALT activity linearly regressed with age (r = 0.22, p < 0.0001). However, polynomial regression revealed a better fit (r = 0.33, p < 0.0001), creating an inverted U curve with a peak at 40-55 yr. According to age groups, serum ALT level was 19 +/- 13 U/L in those under 40 yr, 25 +/- 19 U/L in 40-55 yr olds, 22 +/- 10 U/L in 56-72 yr olds, 17 +/- 9 U/L in 73-83 yr olds, and 13 +/- 5 U/L in 83-100 yr olds (p < 0.0001). GFR (r = 0.1, p < 0.05) and BMI (r = 0.14, p < 0.01) weakly correlated with ALT. Gender also associated with ALT; 22 +/- 15 U/L in men, and 17 +/- 11 U/L in women (p < 0.005). Multiple regression analysis including age, gender, GFR, and BMI revealed that age (p= 0.01) and gender (p= 0.04) retained association with ALT activity. No such associations were noted for aspartate aminotransferase (AST) activity. Our data suggest a significant association between age and serum ALT activity. This association is not a simple linear correlation, but rather an inverted-U-like relation. Thus, when interpreting the laboratory results of a subject suspected of liver disease, age should probably be taken into account. Larger-scale studies are needed to better characterize this issue.


Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study.
Psoriasis, Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders with overlapping genetic architecture. However, data on the frequency and risk of CD and UC in psoriasis are scarce and poorly understood. To investigate the association between CD and UC in patients with psoriasis. All Danish individuals aged ≥ 18 years between 1 January 1997 and 31 December 2012 were linked in nationwide registers. Psoriasis severity was defined in two models: hospital visits and medication. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) were estimated by Poisson regression. In the total cohort (n = 5 554 100) there were 75 209 incident cases of psoriasis, 11 309 incident cases of CD and 30 310 incident cases of UC, during follow-up. The adjusted IRRs (95% confidence intervals) of CD were 1·28 (1·03-1·59), 2·56 (1·87-3·50), 2·85 (1·72-4·73) and 3·42 (2·36-4·95) in patients with mild psoriasis, severe psoriasis (hospital), severe psoriasis (medication) and psoriatic arthritis, respectively. Similarly, the adjusted IRRs of UC were 1·49 (1·32-1·68), 1·56 (1·22-2·00), 1·96 (1·36-2·83) and 2·43 (1·86-3·17), respectively. The 10-year incidence of CD was 2-5 per 1000 patients and of UC 7-11 per 1000 patients, depending on psoriasis severity and the presence of psoriatic arthritis. Additionally, an increased risk of incident psoriasis was found following CD or UC. We observed a psoriasis-associated increased risk of CD and UC, which was higher in severe psoriasis, and an increased risk of psoriasis in patients with inflammatory bowel disease. Increased focus on gastrointestinal symptoms in patients with psoriasis may be warranted.


Synthesis and structure-activity relationships of antifungal crassinervic acid analogs.
A series of analogs of the natural antifungal compound crassinervic acid, a constituent of Piper crassinervium, were synthesized to gain insight into the most relevant structural features affecting the activity of the parent molecule. Most compounds were prepared by aldol reaction of methyl 3-acetyl-4-hydroxybenzoate with a series of ketones, followed by reduction, hydrolysis, and oxidation. The antifungal activities of crassinervic acid and its analogs was assessed against Cladosporium cladosporioides by using the method of bioautography. The bioassay results allowed us to depict structureactivity relationships for this class of compounds.


Role of non-coding RNAs in cardiotoxicity of chemotherapy.
The long-time paradoxical situation of non-coding RNAs (ncRNAs) has been terminated for they emerge as executive at full spectrum of gene expression and translation. More recently, it has been demonstrated that some ncRNAs apparently are associated with chemotherapy, causing cardiotoxicity, which taint long-term recovery of patients in growing body of evidence. The current review focused on up-to-date knowledge on regulation change and molecular signaling of ncRNAs, at mean time evaluate their potentials as diagnostic biomarkers or therapeutic targets to monitor and protect cardio function.


Determination of whole-body metabolic burden as a quantitative measure of disease activity in lymphoma: a novel approach with fluorodeoxyglucose-PET.
Currently, there is no definite consensus regarding the best index to assess disease activity with fluorodeoxyglucose-PET imaging. Maximum standardized uptake value (SUVmax) is most frequently used in day-to-day practice for this purpose. This approach very often reflects the metabolic activity of only a small sample of the total ongoing process in the entire body. Here we introduce a new concept called metabolic burden (MB) to measure disease activity in cancer patients. MB was calculated by measuring the volume (VCT) around a lesion that appeared on computed tomography (CT), the mean SUV that appeared on PET of the CT volume (SUVmean CT), and the recovery coefficient (RC) using the following formula: (Equation is included in full-text article.) If CT was unavailable, a region of interest (ROI) around the lesion was defined by a 40% SUVmax threshold and the volume and SUVmean were determined for that ROI. The whole-body metabolic burden (WBMB) was calculated as the sum of the individual MBs of all the lesions identified. We retrospectively reviewed 19 patients with non-Hodgkin's lymphoma who were treated with commercially available anti-CD20 radioimmunotherapy agents or conventional chemotherapy. All had a pretreatment and posttreatment fluorodeoxyglucose-PET and CT scan within 1-3 months of receiving systemic therapy. Either abnormal areas appearing on PET alone or corresponding lesions on CT were used to calculate the tumor volume (TV). Nodes of less than 2 cm occurring in clusters were grouped together into a single ROI. Thirty-eight regional collections in 14 patients were found in combined pretreatment and posttreatment studies and were assessed. The TVs varied in pretreatment size from 5.8 to 857 cm and posttreatment from 0 to 81 cm. Pretreatment WBMB varied from 27 to 10 218 cm and posttreatment from 0 to 279 cm. We then compared the standard indices of SUVmean and SUVmax with those of WBMB to determine which of the indices would have the best sensitivity as a predictor of therapeutic response. Five of the 19 patients had a complete response. In 14 patients with partial response, the average change in WBMB was 80%, the TV decreased by 76%, the SUVmax decreased by 42%, and the SUVmean decreased by 38.5%. The results of this analysis demonstrate that measurement of WBMB may prove to be superior to the existing methods in assessing and managing patients with non-Hodgkin's lymphoma. This index may be the best way to monitor the changes in WBMB as a patient is undergoing treatment.


Zn2+ regulation of ornithine transcarbamoylase. I. Mechanism of action.
Ornithine transcarbamoylase catalyzes the formation of L-citrulline from carbamoyl phosphate and L-ornithine. The anabolic enzyme from Escherichia coli is composed of three identical subunits and resembles, in both primary and quaternary structures, the catalytic unit of aspartate transcarbamoylase. However, ornithine transcarbamoylase has no regulatory subunits. Although this enzyme does not bind its substrates co-operatively, fluorescence spectroscopic experiments show that zinc adds allosterically to the free enzyme. The metal binding process is dictated by deprotonation of an enzymic group with a pKa less than 7. The saturation binding curve of the metal ion is sigmoidal and yields a Hill coefficient of 1.6 at pH 8.5 and 25 degrees C. In the absence of substrates, zinc further promotes a slow enzyme isomerization, which occurs with a first-order rate constant of 7 min-1; thus, the metal is a slow, tight-binding inhibitor. The isomerized enzyme is inactive and contains three zinc ions. When the enzyme is first bound with carbamoyl phosphate, steady-state kinetic assays reveal that zinc again binds co-operatively to the binary enzyme complex, with a Hill coefficient of 1.5, but the metal ion now behaves simply as a classical, reversible inhibitor; it is competitive against L-ornithine, non-competitive against carbamoyl phosphate, and induces no enzyme isomerization. However, as a result of the competition between zinc and L-ornithine for the same site on the enzyme, the L-ornithine saturation curve becomes sigmoidal. Displacement of the allosteric zinc from the enzyme by L-ornithine is the cause of co-operative addition of this substrate. The combined results suggest that zinc regulates ornithine transcarbamoylase via two routes: (1) as an allosteric cofactor of the substrate-bound enzyme in mediating site-site interactions; and (2) as a slow, tight-binding inhibitor of the free enzyme in inducing inactivation. The concentration of zinc that is effective for action is in the micromolar range. The finding that E. coli ornithine transcarbamoylase can be induced to express co-operativity in binding its substrates has recently been confirmed by site-directed mutagenesis experiments. When the active site residue Arg106 is altered to a glycine, the resultant mutant enzyme exhibits both homotropic and heterotropic interactions towards its substrates. In view of the quaternary structure of holoenzyme aspartate transcarbamoylase, the "silent" co-operativity of ornithine transcarbamoylase is of particular interest in the study of evolution of complex, regulatory proteins.


Components of skin impedance level.
Eighty students were trained on a maze-like ballboard over a series of 24 trials, while the skin impedance level was recorded from the palmar and dorsal sides of their fingers. A principal component analysis of the cross-products for the palmar and dorsal data treated separately resulted in two components for the palmar data (55% and 25% of variance) and one component for the dorsal data (80% of variance) and thus supported Edelberg's findings.


[Maintaining opioid abstinence long after inpatient treatment with opioid substitution in an addictology hospital unit].
Assess the effectiveness of hospital detoxification of opiate substitution treatment (OST) in patients who failed to withdraw as outpatients. Retrospective study, conducted among patients admitted for withdrawal of OST in an addiction unit between 2005 and 2011. Referent physicians were interviewed about outcomes at M2, M3, M6 and M12. 47 patients were hospitalized for OST withdrawal. The opioid abstinence rates at 2, 6 and 12 months were 60, 28 and 21 %. No death occurred within 12 months after withdrawal. The only variables significantly associated with the M3 opioids abstinence were : age at admission and among the patients admitted for buprenorphine withdrawal, a low dose of buprenorphine at admission. OST withdrawal in a specialized inpatient unit among patients with failure of outpatient withdrawal appears as an option, with an efficacy at least comparable to other methods of detoxification. It allows a comprehensive care and to prevent the risk of overdose.


Etoposide stimulates 1,25-dihydroxyvitamin D3 differentiation activity, hormone binding and hormone receptor expression in HL-60 human promyelocytic cells.
The simultaneous administration of the DNA topoisomerase II inhibitor etoposide (0.15 mM) and 1,25-dihydroxyvitamin D3 (VD3) (10 nM) synergistically induced the differentiation of HL-60 human promyelocytic leukemia cells. Similar results were obtained using U-937 human promonocytic cells, or the topoisomerase II inhibitors doxorubicin (15 nM) and mitoxantrone (2.5 nM). When sequential treatments were used, pre-incubation with VD3 had little effect on the subsequent action of etoposide, while pre-incubation with etoposide greatly potentiated the subsequent action of VD3. In addition, etoposide treatment stimulated VD3 binding activity and increased VD3 receptor mRNA and protein levels. The increase in hormone receptor expression may explain, at least in part, the capacity of topoisomerase inhibitors to potentiate the differentiation inducing activity of VD3.


Integrative transcriptome and metabolome analysis reveals the mechanism of exogenous melatonin alleviating drought stress in maize roots.
Melatonin (MT) is essential for plant development and drought adaptation. However, the molecular and metabolic mechanisms underlying MT-induced drought tolerance in maize roots remain largely unclear. Herein, we investigated the effects of MT on drought tolerance in maize roots using integrated transcriptomic and metabolomic analyses, and identified MT-induced genes and metabolites associated with drought resistance. Compared with the untreated control plants, MT application alleviated the deleterious effects of drought on roots, by decreasing the malondialdehyde level and increasing the solute potential, eventually promoting root growth. Transcriptome and metabolome analysis demonstrated that MT significantly upregulates the expression of genes related to flavonoid biosynthesis (PAL, C4H, 4CL, HCT, CHS, CHI, F3'5'H, and DFR), activates drought-responsive transcription factors (ERFs, NACs, MYBs, and bHLHs), and regulates hormone signaling-related genes, especially ethylene response factors (ERF4, ERF81, and ERF110). Moreover, MT increased the accumulation of flavonoid metabolites, particularly apigenin, luteolin, and quercetin, under drought-stress conditions. These findings were further supported by quantitative real-time polymerase chain reaction analysis and total flavonoid measurements. Altogether, our findings suggest that MT promotes maize root growth during drought by regulating flavonoid synthesis pathways, transcription factors, and plant hormone signals. This study provides new insights into the complex mechanisms by which MT enhances crop resistance to drought damage.


Multiple Chronic Conditions, Spouse's Depressive Symptoms, and Gender within Marriage.
Multiple chronic conditions (i.e., multimorbidity) increase a person's depressive symptoms more than having one chronic condition. Little is known regarding whether multimorbidity similarly increases the depressive symptoms of one's spouse and whether this depends on type of condition, gender, or both spouses' health status. Analysis of multiple waves of the Health and Retirement Study reveals husband's number of chronic conditions is positively related to wife's depressive symptoms when both spouses are chronically ill. The association between wife's chronic conditions and husband's depressive symptoms is weaker and less robust. Type of chronic condition also matters but which type depends on the gender and health status of both spouses. By highlighting key contexts where chronic conditions are connected to spousal depressive symptoms, this study identifies areas of vulnerability and urges researchers and clinicians to consider multimorbidity when designing and implementing interventions, along with gender, both spouses' chronic conditions, and condition type.