Ethnicity and breast cancer in Hawaii: increased survival but continued disparity.
To examine ethnic variation in survival among 7722 women diagnosed with invasive breast cancer in Hawaii between 1990 and 2002 and to extend previous multivariate analyses by adding a new prognostic variable: estrogen receptor/progesterone receptor (ER/PR) status. Cox regression analysis of retrospective data. Population-based data from the Hawaii Tumor Registry, which is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. 7722 women in 5 ethnic groups--Caucasian, Chinese, Japanese, Filipino, and Native Hawaiian--diagnosed with invasive breast cancer between 1990 and 2002. Survival, examining death from breast cancer and death from a cause other than breast cancer. Compared to Caucasians, significantly smaller proportions of Japanese and Chinese women and larger proportions of Native Hawaiian and Filipino women were diagnosed in later stages of disease and at earlier ages. The four minority ethnic groups had higher rates of ER+PR+ tumors than Caucasians. For both causes of death, ethnic disparities in survival were reduced, but still existed, after controlling for age, stage, and ER/PR status. Japanese had the highest rates of survival for either cause of death. Native Hawaiians and Filipinos had the lowest rates of survival for breast cancer, and Native Hawaiians and Caucasians had the lowest rates of survival for other causes of death. Future studies should examine other reasons for continued ethnic differences in breast cancer survival in Hawaii, including socioeconomic status, access to insurance, adequacy of recommended screening frequency, comorbid conditions, treatment appropriateness and compliance, and genetic markers of tumor aggressiveness.


[Therapy with opioids in liver or renal failure].
In patients with renal or hepatic failure, the pharmacokinetics of opioids may be affected in several ways, leading to the necessity to correct the dose. The liver is the major site for biotransformation of most opioids. The major metabolic pathway is oxidation. Exceptions to this are morphine and buprenorphine, which undergo primarily glucuronidation, and remifentanil which is cleared by esther hydrolysis. The hydrophilic metabolites are predominantly excreted by the kidneys and may accumulate in patients with renal insufficiency. Some metabolites such as morphine-6-glucuronide (M6G) or normeperidine are active opioid agonists. With high concentrations they may cause narcotic effects or respiratory depression. In addition, special risks are known for normepridine that has been shown to exert neurotoxic effects with the risk of seizures. Few cases of respiratory depression following the administration of codeine, dihydrocodeine and tramdol have been reported. The elimination half-life of these drugs was prolonged. Lastly, the disposition of methadone, buprenorphine, fentanyl, sufentanyl and remifentanil appears to be unaffected in renal failure. In patients with hepatic cirrhosis it has been shown that oxidation of opioids is reduced, resulting in a decreased drug clearance (meperidine, propoxyphene, pentazocine, tramadol and alfentanil) and increased oral bioavailability due to reduced first-pass metabolism (meperidine, propoxyphene, pentazocine, dihydrocodeine). Although glucuronidation is thought to be less affected in liver cirrhosis, the clearance of morphine was found to be decreased and its oral bioavailability increased. The consequence of reduced drug metabolism is the risk of accumulation in the body, especially with repeated administrations. As for patients with renal failure, special risks are known for meperidine with potential accumulation of normeperidine, which can cause seizures, and for propoxyphene for which several cases of hepatotoxicity have been reported. On the other hand, the analgesic activity of codeine and tilidine depends on transformation into the active metabolites, morphine and nortilidine. In the case of reduced metabolism in chronic liver disease, the analgesic action of these drugs may be compromised. Lastly, the disposition of a few opioids, such as fentanyl, sufentanil, and remifentanil, appears to be unaffected in liver disease.


Hematopoietic cell kinase enhances osteosarcoma development via the MEK/ERK pathway.
Osteosarcoma (OS) is a sarcoma with high rates of pulmonary metastases and mortality. The mechanisms underlying tumour generation and development in OS are not well-understood. Haematopoietic cell kinase (HCK), a vital member of the Src family of kinase proteins, plays crucial roles in cancer progression and may act as an anticancer target; however, the mechanism by which HCK enhances OS development remains unexplored. Therefore, we investigated the role of HCK in OS development in vitro and in vivo. Downregulation of HCK attenuated OS cell proliferation, migration and invasion and increased OS cell apoptosis, whereas overexpression of HCK enhanced these processes. Mechanistically, HCK expression enhanced OS tumorigenesis via the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway; HCK upregulation increased the phosphorylation of MEK and ERK and promoted epithelial-mesenchymal transition, with a reduction in E-cadherin in vitro. Furthermore, HCK downregulation decreased the tumour volume and weight in mice transplanted with OS cells. In conclusion, HCK plays a crucial role in OS tumorigenesis, progression and metastasis via the MEK/ERK pathway, suggesting that HCK is a potential target for developing treatments for OS.


[Azlocillin and mezlocillin: two new semisynthetic acylureido-penicillins (author's transl)].
The pharmacokinetic parameters of two new ureido-penicillins (azlocillin and mezlocillin) were determined in 12 healthy subjects after a half-hour continuous infusion of 5,000 mg. The agar diffusion test (test strain Bacillus subtilis ATCC 6633) was used for the microbiological assays. The mean azlocillin serum concentration after the half-hour infusion was 431.0 +/- 75.0 microgram/ml; after eight hours it had fallen to a mean value of 4.7 +/- 2.6 microngram/ml. The mean elimination half-life was 77.5 +/- 10.4 minutes, and the relative distribution volume was 19.4 +/- 1.9% of the bodyweight. At the end of the infusion, mezlocillin showed a mean serum concentration of 426.0 +/- 61.0 microgram/ml and after eight hours an average of 1.1 +/-0.9 microgram/ml; the half-life was shorter (56.9 +/- 9.9 minutes) and the distribution volume lower (14.8 +/- 3.1%) than that of azlocillin. The renal clearance values measured in three subjects during a four-hour continuous infusion were: azlocillin 111.6 ml/min/1.73 m2, mezlocillin 121.5 ml/min/1.73 m2. The kinetic behaviour of the two ureido-penicillins was essentially very similar to that of ampicillin and carbenicillin, 38 patients with bronchopneumonia, cholangitis or urinary tract infections, which in some instances were severe, were treated for an average of 10 days with an average daily dosage of 3X4.0 g azlocillin or 3X5.0 g mezlocillin. 30 patients showed clinical improvement, and in 17 of these the pathogen was eliminated. These therapeutic results appear more favourable than those obtained with the newer aminoglycoside antibiotics (amikacin, sisomicin); in particular the drug was well tolerated.


An enzyme-linked immunosorbent assay suitable for the routine estimation of specific immunoglobulin G responses to polyvalent pneumococcal polysaccharide vaccine in humans.
Antibodies to pneumococcal antigens have routinely been measured by radioimmunoassay (RIA). An enzyme-linked immunosorbent assay (ELISA) is proposed which is simpler and less expensive than RIA. The ELISA was used in a study involving a group of splenectomised patients and controls, to estimate the immunoglobulin G (IgG) response to 5 serotypic antigens (2, 7F, 9N, 14 and 23F) after immunisation with polyvalent pneumococcal polysaccharide vaccine. The 5 serotypic antigens were selected for their low optimum binding concentration and because they represented a range of clinical isolation rates in Western Australia (frequent, medium and rare). No significant difference could be found between the mean-fold increases of the 2 groups using Student's t-test. However, 6 out of 34 splenectomised patients failed to respond to any of the 5 serotypes, whereas no individual in the control group failed to yield a significant response to at least one serotype.


Colonization of Aspergillus japonicus on synthetic materials and application to the production of fructooligosaccharides.
The ability of Aspergillus japonicus ATCC 20236 to colonize different synthetic materials (polyurethane foam, stainless steel sponge, vegetal fiber, pumice stones, zeolites, and foam glass) and to produce fructooligosaccharides (FOS) from sucrose (165 g/L) is described. Cells were immobilized in situ by absorption, through direct contact with the carrier particles at the beginning of fermentation. Vegetal fiber was the best immobilization carrier as A. japonicus grew well on it (1.25 g/g carrier), producing 116.3g/L FOS (56.3g/L 1-kestose, 46.9 g/L 1-nystose, and 13.1g/L 1-beta-fructofuranosyl nystose) with 69% yield (78% based only in the consumed sucrose amount), giving also elevated activity of the beta-fructofuranosidase enzyme (42.9 U/mL). In addition, no loss of material integrity, over a 2 day-period, was found. The fungus also immobilized well on stainless steel sponge (1.13 g/g carrier), but in lesser extents on polyurethane foam, zeolites, and pumice stones (0.48, 0.19, and 0.13 g/g carrier, respectively), while on foam glass no cell adhesion was observed. When compared with the FOS and beta-fructofuranosidase production by free A. japonicus, the results achieved using cells immobilized on vegetal fiber were closely similar. It was thus concluded that A. japonicus immobilized on vegetal fiber is a potential alternative for high production of FOS at industrial scale.


Dried blood spots combined to an UPLC-MS/MS method for the simultaneous determination of drugs of abuse in forensic toxicology.
A method for the simultaneous determination of 11 illicit drugs, using the dried blood spot (DBS) sampling technique combined with the UPLC-MS/MS technology was developed to study its applicability within the forensic toxicology. The DBS samples, prepared from a blood volume of 50μL and using the Whatman® BFC 180 bloodstain cards, were extracted with a methanol/acetonitrile mixture. The chromatographic separation was performed using an Acquity UPLC® HSS T3 column (100mm×2.1mm, 1.8μm) and an acetonitrile/2mM ammonium formate (0.1% formic acid) gradient. The detection was accomplished with a TQ Detector, operating in the ESI+ and MRM modes. The method was validated in terms of selectivity, matrix effect, extraction recovery (42%-91%), carryover, LOD and LOQ (0.5-1ng/mL and 1-5ng/mL, respectively), linearity (LOQ to 500ng/mL), intraday and interday precision (3.8-14% and 5.3-13%, respectively), accuracy (-9.3% to 7.9%) and dilution integrity. An eight months stability study at room temperature, 2-8°C and -10°C, was also performed, with the best results obtained at -10°C. The procedure was applied to 64 real samples (92 positive results for substances included in this study). The results were compared with the methodologies routinely applied in the laboratory and the statistical analysis allowed to establish an acceptable correlation. This study permitted to determine that the DBS can represent an alternative or a complement to conventional analytical and sampling techniques, responding to some of the present issues concerning the different forensic toxicology applications.


Ophthalmology in the United States at the time of the revolution.
At the time of the American Revolution, understanding of diseases of the eye was rudimentary, treatment of ocular problems was largely ineffective, and American physicians were highly dependent on their European colleagues for training and development. Knowledge of optics, light and color was somewhat more advanced. The author reviews the state of eye care during the Revolutionary period, historically and anecdotally, with references to the literature of that time.


Cytoarchitectonic study of the brain of a dwarf snakehead, Channa gachua (Ham.). I. The telencephalon.
Cytoarchitectonic pattern of the telencephalon of a dwarf snakehead, Channa gachua, is studied by serial transverse sections of the brain (Kluver and Barrera staining). On the anteriormost extremity of the telencephalon, olfactory bulbs terminate that are sessile. The olfactory bulbs comprise four concentric layers, which from outside toward the center are olfactory nerve layer, a glomerular layer, mitral cell layer, and internal cell layer. Large terminal nerve ganglion cells are prominently visible in the dorsomedial position where the bulbs terminate on the telencephalon. In all, 24 nuclei are identified in the telencephalon on ventral and dorsal areas and are named according to their position. Ventral telencephalon exhibits 11 nuclei. On the dorsal telencephalon, there are 13 nuclei. These again are named according to their position on dorsal, ventral, median, lateral, or posterior part. This study reported for the first time in this fish will be useful in tracing the neuronal system of Channa gachua and subsequent studies of the functional aspects of these nuclei in the regulation of reproductive cycle of this species.


Development of a monoclonal antibody specific to granulocytes and its application for variation of granulocytes in scallop Chlamys farreri after acute viral necrobiotic virus (AVNV) infection.
A monoclonal antibody (MAb 6H7) specific to granulocytes of scallop Chlamys farreri was produced by immunising mice with separated granulocytes as an antigen. Characterised using a flow cytometric immunofluorescence assay, MAb 6H7 reacted to granulocytes by 87.1% of total positive haemocytes. At the ultrastructural level, MAb 6H7 demonstrated epitope in cytoplasmic granules of granulocytes. Western blotting analysis indicated that a peptide of 155 kDa was recognised by MAb 6H7. It was therefore used to investigate granulocyte variation in C. farreri after acute viral necrobiotic virus (AVNV) infection using an enzyme-linked immunosorbent assay. The result illustrated that granulocytes varied greatly by AVNV infection, and their amount significantly increased on day 1 post-injection, then decreased on days 2, 3 and 4, thereafter, rebounded and approached to a second peak on day 6, finally went down gradually to the control level on day 8.


Intraobserver variability in fibroid size measurements: estimated effects on assessing fibroid growth.
To evaluate intraobserver variability of fibroid sonographic measurements and apply this factor to fibroid growth assessment. Study participants were African American women aged 23 to 34 years who had never had a diagnosis of uterine fibroids. All participants underwent transvaginal sonography to screen for the presence of previously undiagnosed fibroids (≥0.5 cm in diameter). The diameters of up to 6 fibroids were measured in 3 perpendicular planes at 3 separate times during the examinations by experienced sonographers. Intraobserver variability as measured by the coefficient of variation (CV) for fibroid diameter and volume was calculated for each fibroid, and factors associated with the CV were assessed by regression models. The impact of variability on growth assessment was determined. Ninety-six of 300 women screened were found to have at least 1 fibroid, yielding a total of 174 fibroids for this analysis. The mean CV for the 3 measurements of fibroid maximum diameter was 5.9%. The mean CV for fibroid volume was 12.7%. Fibroid size contributed significantly to intraobserver variability (P = .04), with greater variability for smaller fibroids. Fibroid type (submucosal, intramural, or subserosal) was not important. Fibroids from the same woman tended to have similar measurement variability when assessed for volume but not for maximum diameter. Calculations showed that when following up fibroids, as much as a 20% increase in diameter could be due to measurement error, not "true growth." A small fibroid must have a greater change in size than a large fibroid to conclude that it is growing, but even for small fibroids an increase in diameter of greater than 20% is likely to indicate true growth, not measurement variability.


Rubus suavissimus S. Lee extract increases early adipogenesis in 3T3-L1 preadipocytes.
Leaves of Rubus suavissimus S. Lee (Rosaceae) are used to prepare tiencha or sweet tea, which is helpful for body weight control by restricting calorie intake in obese patients. Obesity is a risk factor for metabolic syndrome, and a possible approach to treatment is to promote early adipogenesis in adipose tissue, thereby leading to replacement of enlarged adipocytes that secrete inflammatory factors with small adipocytes.We therefore investigated the effect of extract of tiencha leaves on early adipogenesis by using 3T3-L1 preadipocytes as a model. Tiencha extract significantly and concentration-dependently increased adipogenesis measured in terms of lipid accumulation by means of Oil Red O assay and increased the expression of adiponectin and leptin. In the early phase of adipogenesis, tiencha extract increased the mRNA expression of adipogenic transcription factors CCAAT/enhancer binding protein α (C/EBPα) and proliferator-activated receptor γ (PPARγ). In contrast, mRNA expression of other adipogenic transcription factors, C/EBPδ and C/EBPβ, was unaffected. The mRNA expression levels of adipocyte-specific genes encoding adipocyte protein 2 (aP2), lipoprotein lipase (LPL), and glucose transporter 4 (Glut4), which are regulated by C/EBPα and PPARγ, were also increased. A PPARγ inhibitor, GW9662, partially inhibited the enhancing effect of tiencha extract on lipogenesis. These results suggest that tiencha extract enhances early adipogenesis by increasing the expression of adipogenic transcription factors C/EBPα and PPARγ.


Co-transfection of GK and mhPINS genes into HepG2 cells confers glucose-stimulated insulin secretion.
The purpose of this study was to construct an 'artificial beta cell' that can exhibit physiologic glucose-stimulated insulin secretion for the treatment of type 1 diabetes. Retroviral vector containing the glucokinase (GK) gene and mutated human proinsulin (mhPINS) gene was constructed. HepG2 cells were first infected with recombinant retrovirus carrying the GK and mhPINS genes, then selectively cultured with G418 to obtain the positive clones. GK and mhPINS gene transcription and expression were identified by radioimmunity, Western blot and RT-PCR techniques. Finally, the dose-response effect of glucose on insulin secretion from those HepG2 cells that expressed both GK and mhPINS genes was tested with HepG2 cells that only expressed the mhPINS gene as a control. HepG2 cells with transferred GK and mhPINS genes were selectively cultured with G418 and the positive clones were obtained in 3 weeks. Four clones with GK and mhPINS gene expression were selected from 20 positive clones by radioimmunity and Western blot. We picked up one clone with a strong GK and mhPINS gene expression and named it clone Beta. In clone Beta, differences in insulin secretion at 0.5 and 0.75 mmol/L glucose concentrations were not significant (P>0.05) and differences in insulin secretion at 2.0, 3.0, 4.0, 5.0 and 6.0 mmol/L glucose concentrations were not significant (P>0.05), while there were significant differences in insulin secretion at other glucose concentrations(P<0.05). The artificial beta cell, clone Beta, obtained a glucose-stimulated insulin secretion with maximal insulin secretion at 1.75-2.00 mmol/L glucose concentrations. An artificial beta cell that exhibits glucose-stimulated insulin secretion can be constructed successfully.


Low absolute lymphocyte count is a poor prognostic factor for untreated advanced follicular lymphoma treated with rituximab plus bendamustine: results of the prospective phase 2 CONVERT trial.
The aim of this trial is to evaluate the utility of rituximab-bendamustine (R-B) for untreated advanced follicular lymphoma (FL) showing non-optimal response (nOR) to R-CHOP, and to identify clinical prognostic factors for FL patients receiving R-B. Patients who failed to achieve complete response/complete response unconfirmed (CR/CRu) [nOR-group] after 2 cycles of R-CHOP subsequently received 6 cycles of R-B. The primary endpoint was the 3-year progression-free survival (PFS) rate. Secondary endpoints included determination of prognostic factors. Fifty-six patients initially received R-CHOP, 43/56 patients (76.8%) were judged as nOR, and 33/43 patients (76.7%) completed 6 cycles of R-B. At a median follow-up of 50.6 months in the nOR-group, the 3-year PFS rate was 69.0%, and the 3-year overall survival (OS) rate was 92.7%. The most common toxicities associated with R-B were grade 3-4 lymphopenia (93.0%) and neutropenia (74.4%), both of which were manageable. A multivariate analysis including dose intensity, serum soluble interleukin-2 receptor, and FL international prognostic index-2 revealed low absolute lymphocyte count (< 869/μL) at diagnosis was an independent poor prognostic factor for both PFS and OS in the R-B-treated nOR-group. This result was further confirmed in validation cohorts including R-B-treated de novo (n = 40) and relapsed (n = 49) FL patients.


Conformation of liquid N-alkanes.
The conformations of liquid n-alkanes have been studied using neutron scattering techniques to better understand the conformational forces present in membrane lipid interiors. We have studied hydrocarbon chains having lengths comparable to those found for esterified membrane lipid fatty acids, and find that the steric constraints of packing in the liquid state do not change the conformational distributions of hydrocarbon chains from those imposed by the intrachain forces present in the gas phase. It follows that the central region of membranes containing lipids in the disordered state should contain hydrocarbon chain conformations determined primarily by intrachain forces.


An assessment of vertical banded gastroplasty-Roux-en-Y gastric bypass for the treatment of morbid obesity.
To analyze retrospectively the mortality, morbidity, and weight loss of a specific form of gastric bypass for the treatment of morbid obesity. The technique incorporates a small pouch along the lesser curvature of the stomach, an outlet restricted by a nondistensible band and a Roux-en-Y gastric bypass. We analyzed 652 consecutive patients with no previous bariatric surgery who underwent our present form of gastric bypass. Parameters used to evaluate the technique included mortality, weight loss at 5 years and complications. The operation is a combination of vertical banded gastroplasty and Roux-en-Y gastric bypass (VBG-RGB). The patients followed up to 5 years had an initial weight of 140 kg [range, 94 to 288] and a BMI of 50 [range, 38 to 86]. Superobese individuals (BMI of 60 [range, 48 to 86]) made up 42% of the group. There was an early reoperation rate of 0.5%. The incidence of late complications that required reoperation was 0.5%. There were 2 deaths in the study from pulmonary embolism for a mortality of 0.3%. At 5 years, the patients had lost an average of 58kg [range, 14 to 143] and had a percentage excess weight loss of 77 [range, 32 to 108]. Their BMI was reduced to 29 kg/m(2) [range, 20 to 43] and 93% lost more than 50% of the excess weight. VBG-RGB is effective in producing superior weight loss in morbid and superobese patients and has a low mortality and morbidity. We recommend this procedure without reservations.


Separation of the tremorous and muscular rigidity components of the ethanol withdrawal syndrome in the rat.
The alcohol withdrawal syndrome consists of a kinetic tremor, the tremorous component, and a peculiar abnormality of tone called asterixis, the muscular rigidity component. The severity of the ethanol withdrawal syndrome in the rat is generally assessed by the severity of the tremors. 3-Hydroxybutyrate suppresses the tremorous component but not the muscular rigidity component of the ethanol withdrawal syndrome, thus effectively differentiating the two components in the rat.


Echocardiographic recognition of ventricular septal aneurysm--a case report.
The noninvasive detection of an aneurysm of the interventricular septum may be predictive of spontaneous closure of a ventricular septal defect. Moreover, in patients with audible systolic clicks the distinction must be made between septal aneurysm and mitral valve prolapse. The current report describes the echocardiographic visualization and pattern of motion of an aneurysm of the membranous ventricular septum. The diagnosis was made by both single crystal and real-time cross-sectional, multiple crystal ultrasound techniques prior to catheterization. These findings from the basis of the present study.


Tricolor photography for assessment of spermatozoa motility.
A rapid and accurate technique for assessment of spermatozoa motility has been developed. With the use of tricolor photography with sequential exposures in green, red, and blue light, spermatozoa were photographed in Makler chambers with a depth of 10 mu. Exposure in green light had a 1-second duration and was immediately followed by the red light from an electronic flash, and 0.05 second later by the blue light from a second flash. With this system, spermatozoa with motility would leave a green track, at the end of which they would appear first red and then blue. The colors and their intensity were chosen so that, when superimposed on nonmotile spermatozoa, the latter would appear white. By projection of the transparent film onto white paper, spermatozoa, motile and nonmotile, were easily counted and the percentage and motility was determined. Also, concentration could be calculated because the photograph represented a semen volume of 0.001 mu. Measurement of the green track and conversion to true length in micrometers gave the velocity in micrometers per second.


Impact of Concomitant Prostate Cancer Medications on Efficacy and Safety of Relugolix Versus Leuprolide in Men With Advanced Prostate Cancer.
To characterize the impact of concomitant prostate cancer treatments with the use of relugolix, the oral GnRH receptor antagonist, in advanced prostate cancer, a subgroup and pharmacokinetic/pharmacodynamic analyses of the HERO study was undertaken. Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide or docetaxel 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant enzalutamide or docetaxel. A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Pharmacokinetic/pharmacodynamic analyses of 20 participants in the relugolix treatment group assessed the net effect of enzalutamide on exposure to relugolix. Overall, 125 patients (13.4%) took concomitant therapies that could impact testosterone levels. Enzalutamide (n = 23) was the most frequently used therapy in the relugolix (2.7%) and leuprolide groups (1.9%). Docetaxel (n = 13) was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. Sensitivity analysis showed concomitant therapy did not impact the testosterone levels. Castration rates were similar with and without concomitant use of enzalutamide or docetaxel. No clinically relevant differences in adverse events were observed between subgroups in either treatment group. No differences in relugolix Ctrough or testosterone concentrations were observed, suggesting that any induction or inhibition properties of enzalutamide on relugolix metabolism result in a neutral net effect on relugolix exposure and testosterone suppression. Treatment with relugolix was associated with similar efficacy and safety profiles with and without concomitant enzalutamide or docetaxel. Standard-of-care use of relugolix in combination with these agents is supported by these data.


Method for the isolation and liquid chromatographic determination of eight sulfonamides in milk.
A method for the isolation and liquid chromatographic determination of eight sulfonamides in milk is presented. Fortified or blank milk samples (0.5 ml) were blended with octadecylsilyl (C18T) derivatized silica (2 g). A column made from the sample C18T matrix was first washed with hexane (8 ml) following which the sulfonamides were eluted with methylene chloride (8 ml). The eluate contained sulfonamide analytes which were free from interferences when analyzed by high-performance liquid chromatography (HPLC) utilizing UV detection (270 nm, photodiode array). Standard curve correlation coefficients (range, 0.998 +/- 0.002 to 0.999 +/- 0.001), average percentage recoveries (73.1 +/- 7.4 to 93.7 +/- 2.7%), and the inter-(3.9-9.6%) and intra-assay (2.2-6.7%) variabilities, were determined for the concentration range examined (62.5-2000 ng/ml) and resulted in a minimal detectable limit of 1.25 ng on column (62.5 ng/ml, 20 microliters injection from a final sample volume of 0.5 ml). Savings in terms of time and solvent make this procedure attractive when compared to classical isolation techniques for sulfonamides.


Spectral turbulence analysis of the signal-averaged electrocardiogram and its predictive accuracy for inducible sustained monomorphic ventricular tachycardia.
This study was designed to assess the accuracy of a new noninvasive frequency analysis method for predicting patients with inducible sustained monomorphic ventricular tachycardia (VT) at electrophysiologic study and hence the risk of spontaneous ventricular tachyarrhythmias. Signal-averaged electrocardiograms from 3 orthogonal bipolar surface leads were evaluated using a microcomputer-based frequency analysis system that performs analysis of conventional time-domain late potentials as well as incorporating a new technique for spectral analysis of relatively short, overlapping signal segments spanning the whole QRS complex. The spectral analysis technique measured abnormalities anywhere in the entire QRS complex and did so without dependence on any arbitrarily defined frequency, duration or amplitude cutoffs. The hallmark of arrhythmogenic abnormality was hypothesized to be frequent and abrupt changes in the frequency signature of the QRS wave front velocity as it propagates throughout the ventricle around areas of abnormal conduction, resulting in a high degree of spectral turbulence. One-hundred forty-two subjects were studied, including 71 totally normal control subjects ("true negatives"), 33 with both late potentials by time-domain analysis and inducible sustained monomorphic VT ("true positives"), 28 with late potentials but no evidence of spontaneous or inducible sustained monomorphic VT ("false positives") and 10 with inducible sustained monomorphic VT but absence of time-domain late potentials ("false negatives"). The frequency analysis technique correctly classified 100% of the true negatives, 97% of the true positives, 86% of the late potentials false positives and 60% of the late potentials false negatives. The total predictive accuracy of frequency analysis for all groups was 94%, compared with 73% for time-domain late potential analysis. The results suggest that a high degree of spectral turbulence of the overall QRS signal during sinus rhythm may provide a more accurate marker for the anatomic-electrophysiologic substrate of reentrant tachyarrhythmias than detection of late potentials in the terminal QRS region by either time- or frequency-domain analysis. Spectral turbulence analysis is applicable to patients irrespective of the QRS duration and the presence or absence of bundle branch block.


Effects of copper exposure on lipid metabolism and SREBP pathway in the Chinese mitten crab Eriocheir sinensis.
Copper (Cu) is not only a common metal pollutant in the aquatic environment but also an essential trace element for aquatic organisms such as the Chinese mitten crab (Eriocheir sinensis). Cu is known to regulate lipid metabolism yet exert toxic effects if ingested in excess. However, the molecular regulatory roles of Cu in the lipid metabolism of crabs remains unclear. Thus, this study investigated the potential regulatory mechanism of Cu onto lipid metabolism of E. sinensis following acute Cu exposure. Crabs were exposed to environmental concentration of Cu (50 μg/L) for 96 h, and the expression of sterol regulatory element binding protein (SREBP) was knocked down by RNA interference (RNAi) to test its effect on Cu exposure. The results showed that RNAi significantly attenuated the Cu exposure-induced increase in lipid synthesis and triglycerides (TG) hydrolysis, while significantly inhibited the Cu exposure-induced decrease in fatty acid β-oxidation, suggesting that SREBP is involved in Cu-induced lipid metabolism. Subsequent analyses of the transcriptome results further revealed potential responsive genes of SREBP that were linked to lipid metabolism and immune regulation. Moreover, Cu may affect lipid metabolism through the TOR-SREBP pathway in E. sinensis. This work provides a reference for exploring the effects of Cu on lipid metabolism disorders in crustaceans.


Impact of flumioxazin herbicide on growth and carbohydrate physiology in Vitis vinifera L.
The impact of flumioxazin herbicide on in vitro-grown grapevine ( Vitis vinifera L. cv. Chardonnay) was investigated. The herbicide treatments (1, 10 or 100 micro M flumioxazin in MM medium) had a negative impact on photosynthesis, as revealed by a reduction in foliar chlorophyll and carotenoid contents, gas exchanges and alteration in plastid structure and, consequently, resulted in a strong inhibition of plantlet growth. Surprisingly, soluble sugars and starch accumulated in all organs, suggesting a stimulation of sugar uptake from the medium. Moreover, photosynthetic activity and starch content partially recovered within 3 weeks of treatment at the weakest herbicide concentration. These results provide new insights into the physiological responses of non-target crops to flumioxazin, showing that flumioxazin is active in photosynthetic tissues of the non-target grapevine via root uptake, which is contrary to what is mentioned in the literature, and that the in vitro-grown plantlet is a good model for investigating the physiological effects of pesticides on crop species.


A resting state EEG study on depressed persons with suicidal ideation.
Major Depressive Disorder (MDD) is a psychiatric illness that is often associated with potentially life-threatening physiological changes and increased risk for suicidal behavior. Electroencephalography (EEG) research suggests an association between depression and specific frequency imbalances in the frontal brain region. Further, while recently developed technology has been proposed to simplify EEG data acquisition, more research is still needed to support its use in patients with MDD. Using the 14-channel EMOTIV EPOC cap, we recorded resting state EEG from 15 MDD patients with and MDD persons with suicidal ideation (SI) vs. 12 healthy controls (HC) to investigate putative power spectral density (PSD) between-group differences at the F3 and F4 electrode sites. Specifically, we explored 1) between-group alpha power asymmetries (AA), 2) between-group differences in delta, theta, alpha and beta power, 3) between PSD data and the scores in the Beck's Depression Inventory-II (BDI-II), Beck's Anxiety Inventory (BAI), Reasons for Living Inventory (RFL), and Self-Disgust Questionnaire (SDS). When compared to HC, patients had higher scores on the BAI (p = 0.0018), BDI-II (p = 0.0001) or SDS (p = 0.0142) scale and lower scores in the RFL (p = 0.0006) scale. The PSD analysis revealed no between-group difference or correlation with questionnaire scores for any of the measures considered. The present study could not confirm previous research suggesting frequency-specific anomalies in depressed persons with SI but might suggest that frontal EEG imbalances reflect greater anxiety and negative self-referencing. Future studies should confirm these findings in a larger population sample.


The interaction between ICOS and B7RP-1 is not required for the development of experimental murine allergic conjunctivitis.
It is still unclear whether the interaction between inducible costimulator (ICOS) and its ligand, B7 related protein (B7RP)-1, is important for the development of allergic diseases. We investigated whether blocking the ICOS/B7RP-1 interaction affects the development of murine experimental allergic conjunctivitis (EC). EC was induced in Balb/c mice either by active immunization of ragweed (RW) or by transferring RW-primed splenocytes, followed by challenge with RW-containing eye drops. The mice were treated with anti-B7RP-1 antibody (Ab) or normal rat immunoglobulin G (IgG) during either the induction or effector phase. Regardless of the induction method or when the animals were treated, eosinophil infiltration into the conjunctiva was not affected by the anti-B7RP-1 Ab treatment. Splenocyte responses were not largely affected by this treatment. However, serum Ig levels were significantly reduced. These data suggest that blocking the ICOS/B7RP-1 in allergic diseases may not always be therapeutic.


Escherichia coli ribosomal protein S1 recognizes two sites in bacteriophage Qbeta RNA.
As a component of bacteriophage Qbeta replicase, S1 is required both for initiation of Qbeta minus strand RNA synthesis and for translational repression, which has been traced to the ability of the enzyme to bind to an internal site in the Qbeta RNA molecule. Previously, Senear and Steitz (Senear, A. W., and Steitz, J. A. (1976) J. Biol. Chem. 251, 1902-1912) found that isolated S1 protein binds specifically to an oligonucleotide spanning residues -38 to -63 from the 3' terminus of Qbeta RNA. Here we report that S1 also interacts strongly with a second oligonucleotide in Qbeta RNA, which is derived from the region recognized by replicase just 5' to the Qbeta coat protein cistron. Both sequences exhibit pyrimidine-rich regions.


Validation of the Spanish Healthy Lifestyle Questionnaire.
Background/Objective: It is essential to carry out a diagnosis of people's healthy lifestyles, in order to apply strategies to improve them. The aim of the study was to validate the Healthy Lifestyles Questionnaire (CEVS-II), collecting all factors that make up the concept of a healthy lifestyle, such as a balanced diet, respect for mealtimes, tobacco consumption, rest habits, alcohol consumption, other drug use and physical activity. Method: The questionnaire was completed by 1,132 people between 18 and 89 (M = 42.43; SD = 18.69) years from different parts of Spain. Results: The seven-factor model proposed by the Confirmatory Factor Analysis, according to the goodness indices, presented an acceptable fit (SRMR = .059; CFI = .973; RMSEA = .049; 90% CI [.046, .052]; χ 2/df = 3.76), also presented good reliability indices and was endowed with concurrent validity. Conclusions: The results of the present study proved the validity and reliability of the Healthy Lifestyles Questionnaire in a Spanish population, which is an adequate instrument for the diagnosis of a healthy lifestyles in the Spanish population.


BLIMP-1 Plays Important Role in the Regulation of Macrophage Pyroptosis for the Growth and Multiplication of Leishmania donovani.
Visceral leishmaniasis, one of the fatal forms of the disease, is caused by Leishmania donovani and presents morbid clinical manifestations. The parasite evades pro-inflammatory immune responses by several reported mechanisms and modulates the host immune system to cause fatal symptoms. A plethora of reports related to the role of BLIMP-1 and its involvement in suppressing the immune response in various infectious diseases have been documented. Higher parasitic burden due to increased BLIMP-1 production has been reported earlier for malaria and leishmaniasis with no detailed information. We report for the first time the role of BLIMP-1 in suppressing macrophage pyroptosis during L. donovani infection and thereby tweaking the tight regulation of the NFκβ-NLRP3 signaling pathway. Expression analyses of BLIMP-1 and NFκβ have been measured using real-time PCR and Western blotting. The importance of BLIMP-1 has been validated using a siRNA-mediated experiment along with caspase 1 activity, LDH release assay, and infectivity index analyses. An inverse relationship between BLIMP-1 and NFκβ expression has been highlighted during L. donovani infection, which is reversed in blimp-1 deficient cells infected with promastigotes. The above fact has been further validated with caspase 1 activity assay, and LDH release along with IFNγ and TNF-α release assay. Finally, resumption of pyroptosis has been concluded in infected blimp-1 deficient cells in contrast to wild type infected cells. We conjecture that parasites modulate the NFκβ-NLRP3 signaling pathway by taking advantage of BLIMP-1 dependent IL-10 production and finally disrupting an inflammation-mediated pyroptosis cell death pathway in infected cells.


Oncological outcomes of high-grade T1 non-muscle-invasive bladder cancer treatment in octogenarians.
To evaluate the outcomes of high-grade T1 non-muscle-invasive bladder cancer treatment (NMIBC) in elderly patients over 80 years of age. This is a retrospective single tertiary-centre study. Medical records of patients with T1 high-grade NMIBC treated with transurethral resection of the bladder tumour (TURBT) were reviewed. Among 269 patients with high-grade T1 NMIBC, 74 individuals were over 80 years of age at the time of surgery. Finally, 67 patients met the inclusion criteria. Only 47.8% of patients (N = 32) received at least five of the six instillations of the BCG immunotherapy induction course. Oncological outcomes were compared between patients who received at least the induction course of BCG and non-BCG-treated patients matched to each other based on age and Charlson comorbidity index. Thirty case-control pairs were included in the final analysis. Rates of disease recurrence (80% vs. 53%) and cancer-specific mortality (40% vs. 10%) were significantly higher in the group of patients who did not receive BCG. BCG therapy, Charlson comorbidity index, haemoglobin concentration and the number of tumours > 3 in TURBT constituted independent prognostic factors for cancer-specific survival (CSS). BCG should be strongly recommended to patients with T1HG NMIBC despite advanced age and comorbidities. Already BCG induction improves CSS and reduces the recurrence rate in octogenarians with T1HG bladder cancer.


Secretin activates brown fat and induces satiation.
Brown adipose tissue (BAT) thermogenesis is activated by feeding. Recently, we revealed a secretin-mediated gut-BAT-brain axis, which stimulates satiation in mice, but the purpose of meal-induced BAT activation in humans has been unclear. In this placebo-controlled, randomized crossover study, we investigated the effects of intravenous secretin on BAT metabolism (measured with [18F]FDG and [15O]H2O positron emission tomography) and appetite (measured with functional magnetic resonance imaging) in healthy, normal weight men (GUTBAT trial no. NCT03290846). Participants were blinded to the intervention. Secretin increased BAT glucose uptake (primary endpoint) compared to placebo by 57% (median (interquartile range, IQR), 0.82 (0.77) versus 0.59 (0.53) μmol per 100 g per min, 95% confidence interval (CI) (0.09, 0.89), P = 0.002, effect size r = 0.570), while BAT perfusion remained unchanged (mean (s.d.) 4.73 (1.82) versus 6.14 (3.05) ml per 100 g per min, 95%CI (-2.91, 0.07), P = 0.063, effect size d = -0.549) (n = 15). Whole body energy expenditure increased by 2% (P = 0.011) (n = 15). Secretin attenuated blood-oxygen level-dependent activity (primary endpoint) in brain reward circuits during food cue tasks (significance level false discovery rate corrected at P = 0.05) (n = 14). Caloric intake did not significantly change, but motivation to refeed after a meal was delayed by 39 min (P = 0.039) (n = 14). No adverse effects were detected. Here we show in humans that secretin activates BAT, reduces central responses to appetizing food and delays the motivation to refeed after a meal. This suggests that meal-induced, secretin-mediated BAT activation is relevant in the control of food intake in humans. As obesity is increasing worldwide, this appetite regulating axis offers new possibilities for clinical research in treating obesity.


Glucagon and insulin secretion during acid-base alterations.
Previously, we reported that change from the normal pH of 7.4 surrounding the islet cells to 7.8 results in a decreased B-cell response to 16.6 mM glucose, 10 mM arginine or 400 micrograms/ml tolbutamide. In the present report we studied the effect of modifications in the extracellular pH on glucose- and arginine-induced glucagon and insulin secretion by the perfused rat pancreas. It was found that at pH 7.8, arginine-induced glucagon secretion was significantly greater than at pH 7.4. On the other hand, the switch from pH 7.4 to 7.8 in a pancreas already stimulated by either low glucose or arginine, produced fast and transient glucagon release. Sequential extracellular pH changes from 7.4 to 7.8 and back to 7.4 in the presence of 8.3 mM glucose and a 5 mM arginine stimulus demonstrated that A- and B-cells rapidly modify their secretion in response to extracellular alkalosis in opposite directions. While glucagon output was enhanced (mean secretory rates at pH 7.4, 0.692 +/- 0.042 ng/min and 0.948 +/- 0.57 at pH 7.8), insulin secretion was clearly reduced (72.6 +/- 6.2 ng/min and 35.7 +/- 2.8 ng/min at pH 7.4 and 7.8, respectively). The above observations, together with our previously reported data, indicate that extracellular pH plays an important role in the regulation of glucagon and insulin release. Particularly, extracellular alkalosis enhances A-cell response to 2.3 mM glucose and 5 mM arginine while partially inhibiting B-cell secretion in the perfused rat pancreas.


Bullying in nursing: How has it changed over 4 decades?
This study sought to explore how bullying in the nursing profession in Australia has changed over four decades, and why it continues to persist. Bullying in nursing is recognized as a pervasive problem. While much attention has been given to demonstrating the existence and impact of bullying in the nursing profession, little is understood about the evolution of this phenomenon and factors that contribute to its persistence. This study employed an historical methodology using the testimony method of data collection. Testimonies were collected online and via interview from seventy registered nurses across Australia. Data were analysed using a three-dimensional analysis to produce a chronological historiography. This study found that the antecedents, manifestations, responses to and impacts of bullying in the nursing profession changed according to context and over time. The findings shed light on the role of nurse managers in the prevention and appropriate management of bullying in the workplace. Prevention and intervention approaches must be developed to combat the complex and changing factors that allow bullying to persist. This study shows the role that management plays in tackling the problem of bullying in nursing. It can no longer be acceptable for culture to be used as an excuse for unacceptable behaviour, nor for power to be abused to protect perpetrators of workplace bullying. The findings discussed in this paper reveal that inexperienced nurse managers are often ill-equipped to identify and manage bullying. Nurses in management positions must recognize and acknowledge this deficit if the problem of bullying is to be effectively tackled.


Regulation of the sensitivity of hepatocarcinoma cells by ORMDL3, to sorafenib by autophagy.
Serum orosomucoid1-like protein 3 (ORMDL3) is a membrane protein in the endoplasmic reticulum, known to regulate many important signal transduction processes and autophagy regulation, but it is unclear whether it is involved in the intratumoral microenvironment and cancer drug resistance. Our present study found that silencing ORMDL3 increases the inhibitory effect of sorafenib on the viability and proliferation in HCC cells, and increases the sensitivity of HCC cells to sorafenib. In addition, silencing ORMDL3 can increase ROS levels by inhibiting autophagy, thereby increasing sorafenib-induced apoptosis of HCC cells. Further, our study also found that ORMDL3 silencing inhibits autophagy through the PERK-ATF4-Beclin1 pathway, thus affecting sorafenib sensitivity. The in vivo effects of sorafenib were tested by xenografting using nude mice. It showed that silencing ORMDL3 in HCC cells could increase the inhibitory effect of sorafenib on the growth of tumors. This is the first report to describe the relationships among ORMDL3, autophagy, and sorafenib resistance. This study provides available targets that might have a synergetic effect with sorafenib.


Effects of adrenalectomy and replacement therapy of corticosterone on cell proliferation and neuroblast differentiation in the rat dentate gyrus.
Newly generated neurons in the dentate gyrus differentiate into mature granule cells. In the present study, we observed the effects of adrenalectomy (ADX) and corticosterone replacement therapy (CRT) on cell death, cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus (SZDG). For this, the animals received vehicle or CRT after ADX, and were sacrificed 5 or 42 days later. Plasma corticosterone levels were very low in the adrenalectomized groups, whereas CRT after ADX significant increased serum corticosterone levels at 42 days, not 5 days, after ADX. ADX induced some neuronal damage in the dentate gyrus at 5 days post-ADX. CRT did not significantly reduce the neuronal damage at 5 days post-ADX; however, neuronal damage was not shown at 42 post-ADX with CRT. Ki67 (a marker for cell proliferation) and doublecortin (DCX, a marker for neuronal differentiation) immunoreaction was detected in the SZDG. ADX transiently increased cell proliferation and neuroblast differentiation 5 days after ADX, not 42 days, after ADX, and the CRT 42 days after ADX prominently decreased cell proliferation and neuroblast differentiation in the dentate gyrus. These results suggest that adrenal corticosteroid hormone is not essential for cell proliferation and neuroblast differentiation in long-term period after ADX.


Dexmedetomidine attenuates neuropathic pain in chronic constriction injury by suppressing NR2B, NF-κB, and iNOS activation.
The effective treatment of patients suffering from neuropathic pain remains challenging. Dexmedetomidine (DEX) possesses anti-inflammatory activity. However, the role of DEX in neuropathic pain is still unclear. The aim of the present study was to examine DEX an α2-adrenoceptor agonist could improve pain hypersensitivity and reduce inflammatory in a chronic constriction injury (CCI) model of the sciatic nerve in Sprague-Dawley rats. Dex was intrathecally administrated 1-h after operation. The paw mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were measured on day 1 before operation and on days 1, 7, 14 and 21 after operation, respectively. On day 21, all the rats were decapitated to collect the L4-6 segments of the spinal cord to examine IL-1, TNF-α, IL-6, NR2B, NF-κB, and iNOS mRNA levels using RT-PCR. The postoperative MWT and PWTL were significantly decreased in CCI, and DEX groups as compared to those before surgery and Sham group (P < 0.05). And DEX reversed this trend (P < 0.05). Interleukin 1 (IL-1), tumor necrosis factor α (TNF-α), IL-6 mRNA expression significantly increased postsurgery in CCI group as compared to that of Sham group (P < 0.05); DEX blocked increased IL-1, TNF-α, IL-6, N-methyl-D-aspartate (NMDA) receptor 2B (NR2B), nuclear factor κB (NF-κB), and inducible isoform of nitric oxide synthase (iNOS) mRNA levels (P < 0.05). DEX may alleviate neuropathic hypersensitivity and inflammation partially by inhibiting NR2B, NF-κB, and iNOS expression in the spinal cord of rats with neuropathic pain resulting from CCI of the sciatic nerve.


Improving everyday memory performance after acquired brain injury: An RCT on recollection and working memory training.
To show the effectiveness of a combined recognition and working memory training on everyday memory performance in patients suffering from organic memory disorders. In this double-blind, randomized controlled Study 36 patients with organic memory impairments, mainly attributable to stroke, were assigned to either the experimental or the active control group. In the experimental group a working memory training was combined with a recollection training based on the repetition-lag procedure. Patients in the active control group received the memory therapy usually provided in the rehabilitation center. Both groups received nine hours of therapy. Prior (T0) and subsequent (T1) to the therapy, patients were evaluated on an everyday memory test (EMT) as well as on a neuropsychological test battery. Based on factor analysis of the neuropsychological test scores at T0 we calculated composite scores for working memory, verbal learning and word fluency. After treatment, the intervention group showed a significantly greater improvement for WM performance compared with the active control group. More importantly, performance on the EMT also improved significantly in patients receiving the recollection and working memory training compared with patients with standard memory training. Our results show that combining working memory and recollection training significantly improves performance on everyday memory tasks, demonstrating far transfer effects. The present study argues in favor of a process-based approach for treating memory impairments. (PsycINFO Database Record


Attentional disturbances in patients with unipolar psychotic depression: a selective and sustained attention study.
Psychotic depression is a clinical subtype of major depressive disorder in the recent editions of the psychiatric diagnostic systems ICD-10 (1992) and DSM-IV (1994). Recent evidence suggests that psychotic depressed patients are more impaired on neuropsychologic tests measuring attention as compared to nonpsychotic depressed patients. However, information on this issue between psychotic and nonpsychotic depression is limited. It has become clear that attention is not a single concept; thus we studied both selective and sustained attention using the theoretic model of automatic and controlled information processing. Thirty-two patients with major depressive disorder, 16 psychotics and 16 nonpsychotics, were investigated and compared with 20 patients with schizophrenic disorder and 20 healthy volunteers who comprised the control groups, using Ruff's 2 and 7 selective attention tests. Compared to the healthy controls, both depressed groups were impaired; however, the psychotic depressed group was more severely impaired on both measures. Attentional performance speed and accuracy scores, on both effortless and effortful conditions, were significantly lower in the psychotic depressed group than in the nonpsychotic depressed group. No significant differences were found on attentional performance between the psychotic depressed patients and those with schizophrenic disorder. Attention deficits are thus more prominent in psychotic than in nonpsychotic depression. Furthermore, taking attention as a criterion, psychotic depression, although of mood congruent subtype, lies closer to schizophrenia than to nonpsychotic depression.


High-performance liquid affinity chromatography and in situ fluorescent labeling on thin-layer chromatography of glycosphingolipids.
A method combining high-performance liquid affinity chromatography and in situ fluorescent labeling on thin-layer chromatography is introduced for determination of glycosphingolipids. Glycolipids in crude extract from rat liver were separated quantitatively from neutral lipids and phospholipids with a phenylboronic acid-derivatized silica gel column. Glycolipids were eluted quantitatively with approximately 98% of crude extract recovered. This column is useful for selective cleanup of glycosphingolipids in crude extract from tissue. Simultaneously, a fluorometric determination of glycosphingolipids with 7-amino-4-methylcoumarin after NaIO4 oxidation on a TLC plate was introduced and its condition was optimized. Glycolipids in amounts ranging from 1 to 100 pmol are easily detectable and give linear responses over the respective ranges. The method is fast and useful for the determination of glycolipids from small amounts of biological samples and requires a minimum amount of about 1 mg of biological specimen for determination of glycolipids.


5-LO-derived LTB4 plays a key role in MCP-1 expression in HMGB1-exposed VSMCs via a BLTR1 signaling axis.
Monocyte chemoattractant protein-1 (MCP-1) plays an important role in initiating vascular inflammation; however, its cellular source in the injured vasculatures is unclear. Given the importance of high mobility group box 1 (HMGB1) in tissue injury, we investigated the role of vascular smooth muscle cells (VSMCs) in MCP-1 production in response to HMGB1. In primary cultured rat aortic VSMCs stimulated with HMGB1, the expression of MCP-1 and 5-lipoxygenase (LO) was increased. The increased MCP-1 expression in HMGB1 (30 ng/ml)-stimulated cells was significantly attenuated in 5-LO-deficient cells as well as in cells treated with zileuton, a 5-LO inhibitor. Likewise, MCP-1 expression and production were also increased in cells stimulated with exogenous leukotriene B4 (LTB4), but not exogenous LTC4. LTB4-induced MCP-1 expression was attenuated in cells treated with U75302, a LTB4 receptor 1 (BLTR1) inhibitor as well as in BLTR1-deficient cells, but not in 5-LO-deficient cells. Moreover, HMGB1-induced MCP-1 expression was attenuated in BLTR1-deficient cells or by treatment with a BLTR1 inhibitor, but not other leukotriene receptor inhibitors. In contrast to MCP-1 expression in response to LTB4, the increased MCP-1 production in HMGB1-stimulated VSMC was markedly attenuated in 5-LO-deficient cells, indicating a pivotal role of LTB4-BLTR1 signaling in MCP-1 expression in VSMCs. Taken together, 5-LO-derived LTB4 plays a key role in MCP-1 expression in HMGB1-exposed VSMCs via BLTR1 signaling, suggesting the LTB4-BLTR1 signaling axis as a potential therapeutic target for vascular inflammation in the injured vasculatures.


Differences in Survival between Black and White Patients with Head and Neck Squamous Cell Carcinoma: Comparison of Data from the DoD Central Cancer Registry and SEER.
Barriers to health care access may contribute to the poorer survival of Black patients with head and neck squamous cell carcinoma (HNSCC) than their White counterparts in the U.S. general population. The Department of Defense's (DoD) Military Health System (MHS) provides universal health care access to all beneficiaries with various racial backgrounds. We compared overall survival of HNSCC patients by race in the MHS and the general population, respectively, to assess whether there were differences in racial disparity between the two populations. The MHS patients were identified from the DoD's Central Cancer Registry (CCR) and the patients from the U.S. general population were identified from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program. For each cohort, a retrospective study was conducted comparing survival by race. Black and White patients in the CCR cohort had similar survival in multivariable Cox regression models with a hazard ratio (HR) of 1.04 and 95% confidence interval (95% CI) of 0.81-1.33 after adjustment for the potential confounders. In contrast, Black patients in the SEER cohort exhibited significantly worse survival than White patients with an adjusted HR of 1.47 (95% CI= 1.43-1.51).These results remained similar in the subgroup analyses for oropharyngeal and non-oropharyngeal sites, respectively. There was no racial difference in survival among HNSCC patients in the MHS system, while Black patients had significantly poorer survival than White patients in the general population. Equal access to health care could reduce racial disparity in overall survival among HNSCC patients.


Protein kinase C in focal ischemic rat brain: dual autoradiographic analysis of [14C]iodoantipyrine (IAP) and [3H]phorbol-12,13-dibutyrate (PDBu).
Protein kinase C (PKC) activity was measured in rat brain with 2 h of middle cerebral artery (MCA) and common carotid artery (CCA) occlusion, using dual autoradiography of [14C]iodoantipyrine (IAP) and [3H]phorbol-12,13-dibutyrate (PDBu). In the ischemic brain, it required more than 120 min of incubation to obtain a plateau in PDBu binding. In contrast, the binding of PDBu in non-ischemic brain reached a plateau with incubation for 60 min. This delay of PDBu binding in the ischemic brain suggests that the affinity of this ligand is reduced due to a change in structure of the cell membrane caused by ischemia. PDBu binding in the ischemic brain increased significantly compared to the non-ischemic brain. This finding provides further evidence that excessive activation of PKC in the ischemic brain may play an important role in ischemic neuronal damage.


Patient-Reported Outcomes of Video-Assisted Thoracoscopic Surgery Versus Thoracotomy for Locally Advanced Lung Cancer: A Longitudinal Cohort Study.
The effects of video-assisted thoracoscopic surgery (VATS) and traditional thoracotomy with respect to patient-reported outcomes (PROs) have only been assessed for early-stage lung cancer. This study was a longitudinal PRO assessment to compare the effects of these surgeries for locally advanced (stage II and III) lung cancer from the patients' perspective. We investigated lung cancer patients from a previous prospective, multicentre study. Longitudinal data of clinical characteristics and PROs were collected. PROs were obtained preoperatively, daily in the hospital postoperatively, and weekly up to 4 weeks after discharge or the beginning of postoperative adjuvant therapy. Symptoms and impact on daily functioning and quality of life (QOL) were assessed by using the MD Anderson Symptom Inventory for lung cancer and a single-item QOL scale. Trajectories of PROs over the investigation period were compared. Overall, 117 primary lung cancer patients (stage II or III), including 63 and 54 patients who underwent VATS and traditional thoracotomy, respectively, were included. During postoperative hospitalization, VATS patients reported milder disturbed sleep (p = 0.048), drowsiness (p = 0.008), and interference with activity (p = 0.001), as well as better work ability (p < 0.0001), walking ability (p < 0.0001), and life enjoyment (p = 0.004). Post-discharge, VATS patients had less distress (p = 0.039), milder pain (p = 0.006), better work ability (p = 0.001), and better QOL (p = 0.047). Locally advanced lung cancer patients who underwent VATS had lower postoperative symptom burden, less daily function interference, and better QOL than those who underwent thoracotomy.


Lumbar fetiform teratoma; a case report.
Fetiform teratoma is a rare highly developed mature teratoma with organoid differentiation although it is not as developed as fetus in fetus which is the only differential diagnosis of this entity. It should be distinguished from the fetus in fetu by absence of the axial skeleton. A 6-month-old baby girl with a lumbar lump underwent ultrasonography, CT-scan and surgery. On imaging, a sac-like structure was noted in the lumbar region containing bowel segments, mesentery-like structure and few lymph nodes. The patient underwent surgery. The entire sac with its content were completely excised. Very few cases of fetiform teratoma have been reported in English literature however to the best of our knowledge lumbar fetiform teratoma has not been reported up to now. Highly developed teratoma is a diagnostic dilemma as it resembles fetus in fetu. The absence of a spinal axis differentiates this entity from the fetus in fetu.


Presence of human papillomavirus in genital tumors.
Human papillomavirus (HPV) types 16 and 18 have been identified in two different human cervical carcinomas. The viral DNAs were molecularly cloned and used as probes to screen a large number of genital tumors by Southern blot analysis. HPV-16 or HPV-18 sequences, respectively, were found in a high percentage of cervical carcinomas, but only in a small number of condylomata acuminata or flat condylomas. The majority of the latter lesions, however, contained HPV-6 or HPV-11 sequences, respectively, which in contrast were detected only rarely in carcinomas in situ or invasively growing carcinomas. A similar distribution of the different papillomaviruses was observed when cell swabs taken from the cervix were tested by in situ hybridization.


Turnover of myelin proteins of rat brain, determined in fractions separated by sedimentation in a continuous sucrose gradient.
Rats that received intracranial injections of [3H]leucine at 14 days of age were killed on days 17, 24, 38, 55, and 89 post-injection. Brains were homogenized and the myelin membranes separated in a sucrose density gradient. At day 17 sodium dodecylsulfate polyacrylamide gels of water-shocked, delipidated membrane fractions showed a difference in the specific activity of myelin proteins across the gradient. A decrease in specific activity was found in all of the proteins in the denser fractions, compared with the lighter fractions. As time after injection progressed, the difference became more pronounced; a two- to threefold decrease in specific activity was seen across the gradient in the various myelin proteins. The proteins of the lightest membrane fractions retained their high specific activity throughout the experiment in spite of extensive new myelin synthesis. Taking this new myelin into account, the decrease in specific activity in the denser myelin fractions could be explained by isotope dilution. Therefore, proteins present in at least some of the myelin are essentially stable.


Causes of Death in COVID-19 Patients with Cardiac Injury.
The causes of death in COVID-19 patients with cardiac injury are uncertain. We conducted a case-control study and reviewed the electronic medical record of 109 deceased COVID-19 patients with cardiac injury on admission and 32 deceased COVID-19 patients without cardiac injury at two hospitals in Rhode Island. Among the 109 deceased COVID-19 patients who had cardiac injury on admission, 79 patients (72.5%) died of hypoxic respiratory failure, 21 patients (19.2%) of multi-organ failure and septic shock, 6 patients (5.5%) of cardiac arrhythmia, 3 patients (2.8%) of severe kidney failure as the immediate causes of death. We observed a similar pattern of distribution when compared to deceased patients without cardiac injury on admission (n=32). The main causes of death of COVID-19 patients with cardiac injury were non-cardiac, mostly hypoxic respiratory failure. Cardiac-related arrhythmia only accounted for a small proportion of cases.


Price and revenue projections under alternative policy shocks due to the coronavirus: Canadian lobster and snow crab.
The coronavirus will have serious consequences for the fishing industry. The purpose here is to simulate price and revenue outcomes for Canadian lobster and snow crab markets under alternative policy shocks due to the coronavirus. Predictions are based on three policy scenarios representing upper and lower bounds on the range of possible landings and economic outcomes for the period 2019-2021. Based on past research, demand equations for both the lobster and snow crab markets are used to empirically simulate price projections. The results for snow crab are startling with predicted serious declines in price and generated revenue, particularly for Québec and Newfoundland and Labrador (NL). Compared to 2018, projections suggest a decline in average revenue for 2021 of - 18% Gulf, - 32% Maritimes, - 53% Québec, and - 57% NL. The outcome for lobster is not as bleak, projections showing a 21% decline in revenue for 2020 but with recovery in 2021.


Butyrylcholinesterase level as an independent prognostic factor for overall survival in patients on maintenance hemodialysis: a single-center retrospective study.
We investigated whether butyrylcholinesterase (BChE) was independently related to the overall survival (OS) of patients on maintenance hemodialysis (MHD). Baseline information, serum BChE level, and other laboratory data were collected from 295 patients on MHD in a single HD hospital in 2018. We retrospectively investigated the mortality of these patients after 38 months. We assessed the prognostic markers such as the Geriatric Nutritional Risk Index (GNRI), Erythropoiesis Resistance Index (ERI), and Simplified Creatinine Index (SCI) of each patient. The primary objective was to examine the impact of BChE on OS. The secondary objective included the designation of a risk score in predicting the OS. We evaluated 284 patients. The median value of the serum BChE level was 206 IU/L. Of 284 patients evaluated, eighty-six patients died; all had a higher ERI and a lower serum BChE level, SCI, and GNRI than the surviving patients. The optimal cutoff values of the BChE level, GNRI, ERI, and SCI for OS were 166 IU/L, 90.0, 8.00, and 20.6, respectively. The multivariate Cox regression analysis showed that the age, HD vintage, dialysis dose, GNRI of < 90.0, and serum BChE level of < 166 IU/L (hazard ratio, 2.03; P = 0.003) were the independent prognostic factors. We designed a risk score consisting of the GNRI and serum BChE level. The predictive value of our risk score was superior to that of GNRI alone. The serum BChE level could be an independent prognostic factor for patients on MHD.


[Psychological impacts of follow up for occupational asbestos exposure. Consequences after compensation for occupational disease in the SPP-A cohort].
In France, long-term follow-up after occupational exposure to asbestos is recommended. This study looked at the psychological consequences in the longer term following a CT-scan, in particular the impact of having received compensation for an occupational disease. As part of an asbestos post-exposure survey study (APExS), volunteers from Normandy were asked to complete self-assessment questionnaires about their psychological condition at different points during follow-up, including a psychological questionnaire before, then 6 months, and finally 18 to 24 months after their chest CT-scan. Information collected from 622 individuals were analyzed based on information provided as to the result of the screening and whether they had received compensation for having an occupational disease. The identification of an occupational disease eligible for compensation is associated with a long term increase in psychological distress. The impact of psychological state during follow-up is greater in men who reported receiving occupational disease compensation. The discovery of an asbestos-related disease during the screening is associated with a negative perception of general health and an increase in psychological distress. The receipt of compensation of an occupational disease does not seem to compensate for the negative psychological impact related to the discovery of a disease during the asbestos post-exposure follow-up.


Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings.
Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). To report integrated long-term safety data from phase 2/3 fingolimod studies. Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received fingolimod 0.5mg (n=1640) or 1.25-0.5mg (n=1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with fingolimod and placebo in FREEDOMS. In the All Studies group, fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with fingolimod 0.5mg and placebo. The safety profile of fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo.


Attitudes to cuts in expenditure and increased fees in health care.
The aim of this postal questionnaire study was to measure attitudes to cuts and increased fees in health care in various Finnish population groups. Four groups were identified; a population sample of 2000 subjects, aged 18-70 y; a random sample of 1500 medical doctors of working age; a random sample of 1000 nurses of working age; and a sample of 2200 politicians involved in health and social care administration, mostly at the municipal level (altogether 6700 subjects). The main questionnaire included, among other things, the following questions: (1) Which of 18 specified medical activities at the primary health care level could be cut without causing severe harm to the population? (2) For which of 13 specified medical activities should clients pay at least 50% of the real cost? All the groups indicated the greatest willingness to cut expenditure on health education, occupational health services, hygiene inspection, substance abuse care, rehabilitation services for war veterans, and family planning. All the groups were least willing to make cuts in home care for disabled and elderly people, maternity services and clinics for under-fives. Most respondents in all groups felt that the activities for which clients should pay at least 50% of the cost were visits to physicians, occupational health services and dental services, whereas clinics for under-five and home care for disabled and elderly persons should be kept free of charge. As a conclusion, primary health care and prevention of diseases for small children, mothers, the elderly and disabled persons, were prioritised by all the groups.


Effects of the pyrethroid insecticide, deltamethrin, on respiratory modulated hypoglossal motoneurons in a brain stem slice from newborn mice.
We have studied the action of deltamethrin on respiratory modulated hypoglossal motoneurons in a brain stem slice from newborn mice. Deltamethrin depolarized the hypoglossal motoneurons, increased the background synaptic noise and reduced the frequency and amplitude of current elicited action potentials. Deltamethrin transiently increased the frequency of the respiratory rhythm. Inspiratory potentials in hypoglossal motoneurons were decreased in amplitude and increased in duration. In conclusion, deltamethrin perturbs the respiratory output from the hypoglossal nucleus through postsynaptic actions on hypoglossal motoneurons and by affecting the inspiratory synaptic drive.


A Method for Organoid Transplantation and Whole-Mount Visualization of Post-Engraftment Vascularization.
As the field of organoid development matures, the need to transplant organoids to evaluate and characterize their functionality grows. Decades of research developing islet organoid transplantation for the treatment of type 1 diabetes can contribute substantially to accelerating diverse tissue organoid transplantation. Biomaterials-based organoid delivery methods offer the potential to maximize organoid survival and engraftment. In this protocol, we describe a vasculogenic degradable hydrogel vehicle and a method to deliver organoids to intraperitoneal tissue. Further, we describe a method to fluorescently label and image functional vasculature within the graft as a tool to investigate organoid engraftment.


Screening of Probiotic Lactic Acid Bacteria Isolated from Fermented Pak-Sian for Use as a Starter Culture.
The objective of this research was to evaluate the probiotic properties of lactic acid bacteria (LAB) isolated from fermented Pak-Sian, a traditional Thai food in the northeastern region of Thailand (Kalasin, Sakon Nakhon, Maha Sarakham, and Khon Kaen Provinces). A total of 61 LAB isolates isolated from selective MRS agar were screened by SDS-PAGE and identified by 16S rDNA analysis. Seventeen bacterial strains were found consisting of Pediococcus pentosaceus (6 strains) Lactiplantibacillus plantarum (5 strains), Levilactobacillus brevis (1 strain), Lactobacillus fermentum (3 strains), and Weissella cibaria (2 strains). A PH tree grouped 17 LAB strains into 5 clusters with three clusters only recorded from Sakon Nakhon Province. All strains were tested for probiotic properties. Results showed that 14 strains had the ability to resist pH 2.5 as resistant to bile salts and survive in gastric juices and the intestinal tract. LAB demonstrated antimicrobial activity against 4 pathogens: Staphylococcus aureus TISTR746, Salmonella typhimurium TISTR1472, Escherichia coli ATCC25922, and Bacillus cereus TISTR1449. Most LAB strains were resistant to all antibiotics tested, while some Lactobacillus strains were moderately susceptible to chloramphenicol, rifampicin, and ampicillin. None of the 14 strains produced biogenic amine and eight showed no hemolysis activity, indicating the safety of these strains. These 8 strains were selected to determine mucin adhesion capacity. Lactobacillus fermentum SK324 and Levilactobacillus brevis SK335 showed the highest adhesion capacity of 2.39 and 2.34%, respectively. These two strains showed promise as alternative starter cultures to improve probiotic health benefits of local fermented Pak-Sian products as a functional food.


Molecular Characterization and Response of Prolyl Hydroxylase Domain (PHD) Genes to Hypoxia Stress in Hypophthalmichthys molitrix.
As an economically and ecologically important freshwater fish, silver carp (Hypophthalmichthys molitrix) is sensitive to low oxygen tension. Prolyl hydroxylase domain (PHD) proteins are critical regulators of adaptive responses to hypoxia for their function of regulating the hypoxia inducible factor-1 alpha subunit (HIF-1α) stability via hydroxylation reaction. In the present study, three PHD genes were cloned from H. molitrix by rapid amplification of cDNA ends (RACE). The total length of HmPHD1, HmPHD2, and HmPHD3 were 2981, 1954, and 1847 base pair (bp), and contained 1449, 1080, and 738 bp open reading frames (ORFs) that encoded 482, 359, and 245 amino acids (aa), respectively. Amino acid sequence analysis showed that HmPHD1, HmPHD2, and HmPHD3 had the conserved prolyl 4-hydroxylase alpha subunit homolog domains at their C-termini. Meanwhile, the evaluation of phylogeny revealed PHD2 and PHD3 of H. molitrix were more closely related as they belonged to sister clades, whereas the clade of PHD1 was relatively distant from these two. The transcripts of PHD genes are ubiquitously distributed in H. molitrix tissues, with the highest expressional level of HmPHD1 and HmPHD3 in liver, and HmPHD2 in muscle. After acute hypoxic treatment for 0.5 h, PHD genes of H. molitrix were induced mainly in liver and brain, and different from HmPHD1 and HmPHD2, the expression of HmPHD3 showed no overt tissue specificity. Furthermore, under continued hypoxic condition, PHD genes exhibited an obviously rapid but gradually attenuated response from 3 h to 24 h, and upon reoxygenation, the transcriptional expression of PHD genes showed a decreasing trend in most of the tissues. These results indicate that the PHD genes of H. molitrix are involved in the early response to hypoxic stress, and they show tissue-specific transcript expression when performing physiological regulation functions. This study is of great relevance for advancing our understanding of how PHD genes are regulated when addressing the hypoxic challenge and provides a reference for the subsequent research of the molecular mechanisms underlying hypoxia adaptation in silver carp.


The p75 neurotrophin receptor in human development and disease.
The functional effects of nerve growth factor (NGF) and its precursor, pro-NGF, are thought to be mediated through binding of these ligands to one or both of their receptors, TrkA and p75NTR. While the signaling pathways and downstream effects of NGF binding to TrkA are reasonably well known, those related to the binding of NGF and pro-NGF to p75NTR are less well understood. Furthermore, p75NTR appears to play functional roles that are unrelated to its ability to bind NGF and pro-NGF, some of which are ligand-independent and others of which are dependent upon binding to other neurotrophins. As these functional roles and their biochemical mechanisms become better known, the importance of p75NTR, related receptors, and both extracellular ligands and intracellular interactors and effectors for human development and health has become increasingly apparent. A complete understanding of p75NTR and its cellular partners is best served by approaching the remaining questions from both sides, with studies of function in normal states and studies of dysfunction in aberrant states mutually informing one another.


A double-blind cross-over evaluation of ketoprofen (Orudis) and ibuprofen in the management of rheumatoid arthritis.
In a multi-centre double-blind cross-over trial using the double-placebo technique, 55 patients with rheumatoid arthritis were treated for 10 days for each trial drug with ketoprofen (200 mg/day) and ibuprofen (1200 mg/day). Both drugs induced a clinically and statistically significant improvement of all the symptoms studied, except for pain at night during ibuprofen administration. Ketoprofen displayed a therapeutic efficacy significantly superior to ibuprofen in five of the eight symptoms studied. Side-effects were recorded in 10 patients receiving ketoprofen (one patient withdrew because of heartburn) and in nine patients receiving ibuprofen.


The effect of enzyme digestions on the activity of eosinophil chemotactic factor of anaphylaxis (EFC-A).
Preparations of ECF-A derived from anaphylactic guinea-pig lung diffusates were subjected to a variety of enzymatic degradations. The enzymes employed had specificityonly for their appropiate subtstates. No effect was found following treatmentwith relatively high doses of trypsin, alpha-chymotrypsin, pronase, alkaline phosphataseand sialidase. In contrast a loss of activity was demonstated in a dose-dependent fashion following incubation with tyrosinase, aryl sulphatase and leucine aminopeptidase, suggesting that ECF-A contains a phenolic hydroxyl group, a sulphate ester anda peptide linkage with a free alpha-amino group.


Sacred oak woods increase bird diversity and specialization: Links with the European Biodiversity Strategy for 2030.
Sacred groves in Greece are usually forest remnants with large trees around chapels, protected through centuries by Orthodox religion. We examined the comparative ecological value of 20 oak-dominated sacred groves vs managed oakwoods, in terms of their habitat characteristics and avian communities (passerines and woodpeckers). Sacred groves have maintained a more pronounced old-growth character than managed oakwoods in terms of average Diameter at Breast Height (DBH) and tree height. Besides holding significantly greater bird species richness and abundance, they supported greater functional richness, phylogenetic diversity, and phylogenetic bird species variability. Bird communities in sacred groves were more heterogeneous and showed greater avian specialization levels than in managed woods. Generalized Linear Models showed that the main factor positively affecting all aspects of bird diversity was DBH, while the abundance of dead trees increased bird abundance. Our results underline the importance of maintaining large-sized trees in forest management practices to support bird diversity and decrease biotic homogenization. Since the new European Biodiversity Strategy explicitly requires all remaining European primary and old-growth forests to be strictly protected by 2030, we argue that sacred groves, despite their small size, meet the criteria to be considered in the strict protection and restoration targets of the strategy, as primary old growth woods of high biodiversity value.


Effects of andrographolide on the activation of mitogen activated protein kinases and nuclear factor-κB in mouse peritoneal macrophage-derived foam cells.
To observe the effect of andrographolide on the activation of mitogen-activated protein kinases (MAPKs) and expression of nuclear factor-κB (NF-κB) in macrophage foam cells. The mouse peritoneal macrophages were cultured in the media in the presence of oxidized low-density lipoprotein (ox-LDL), ox-LDL+andrographolide, or neither (control). The phosphorylation of MAPK molecules (p38MAPK, JNK, ERK1/2) and the expressions of NK-κB p65 were examined by Western blot. As compared with cells in the control group, the expressions of phospho-p38 and NF-κB p65 were increased in the cells cultured with either ox-LDL or ox-LDL+andrographolide (P<0.01), but attenuated significantly in the presence of ox-LDL+ andrographolide when compared with ox-LDL (P<0.05). The phospho-JNK increased in the presence of either ox-LDL or ox-LDL+andrographolide when compared with control cells (P<0.01), but no significant difference existed between ox-LDL and ox-LDL+andrographolide (P>0.05). The expression of phospho-ERK1/2 was increased in the presence of ox-LDL compared with the control cells (P<0.01), but no significant differences existed between the cells cultured in the presence of ox-LDL+andrographolide and the control medium (P>0.05). Andrographolide could inhibit the activation of ERK1/2, p38MAPK and NK-κB induced by ox-LDL in macrophage foam cells, which might be one of its mechanisms in preventing atherosclerosis.


[Risk factors for Abacavir-induced hypersensibility syndrome in the "real world"].
Abacavir (ABC) is a generally well-tolerated NRTI. However, up to 5% of patients may develop hypersensitivity syndrome (HSS) within the first weeks of treatment. The objectives of this study were to describe the side effects of ABC, to evaluate the incidence of the ABC-HSS, and to identify the risk factors of HSS after first exposure to ABC in a cohort of patients followed up in a university HIV clinic. The charts of all HIV-infected patients who started ABC between February 1998 and May 2002 were reviewed. HSS was defined as the onset, within 8 weeks of ABC initiation, of either a skin rash associated with at least one of the following symptoms (fever, gastrointestinal symptoms, respiratory symptoms, myalgia, malaise) or at least three of the above symptoms in the absence of rash. A multivariate logistic regression analysis was performed to identify risk factors of HSS. Of the 191 patients studied (134 M, 57 F, mean age 39 years), 53 (27.8%) presented with manifestations that were regarded as potential side-effects of ABC. Ten (5.2%) developed HSS, none of whom died. Two factors were independently associated with an increased risk of HSS: history of allergy to nevirapine (OR 8.1, 95% CI 1.6-40.5, p = 0.02), and being naïve to ART (OR 5.8, 95% CI 1.2-28.5, p = 0.04). This study "in the real world" confirms that the incidence of ABC-induced HSS is of about 5%. It also confirms that HSS occurs more frequently in patients with a history of allergy to nevirapine and in ART-naïve patients.


A dose-response study of the effect of levobunolol on ocular hypertension.
We conducted a randomized, double-masked, dose-response study of the ocular hypotensive effect of the beta-adrenergic blocker, levobunolol. A single drop of placebo or levobunolol (at concentrations of 0.03%, 0.3%, 0.6%, 1%, and 2%) was administered to one eye of each of 48 patients with ocular hypertension. The 0.3% and 0.6% concentrations decreased intraocular pressure significantly from baseline levels compared to placebo at one, two, and four hours after treatment. The 1% and 2% concentrations decreased intraocular pressure significantly from baseline compared to placebo at one, two, four, six, eight, and 12 hours after administration. No objective or subjective side effects were noted, and no substantial changes in visual acuity, pupil diameter, pulse rate, or blood pressure were recorded during the study. These results appear to justify long-term studies of levobunolol for the treatment of increased intraocular pressure.


[Treatment of lateral humeral condyle fractures in children].
Surgical treatment of lateral humeral condyle fractures with reduction and retention in order to prevent lasting malalignment, pseudarthrosis, and joint instability. Absolute: fractures with a complete dislocation or those in which plaster-free control X-ray on day 4 shows a gap of > 2 mm. Relative: complete fractures of the lateral humeral condyle which demonstrate a dislocation < or = 2 mm on follow-up. Incomplete, so-called hanging fractures of the lateral humeral condyle without notable secondary dislocation on follow-up. Open reduction of the lateral humeral condyle via a lateral approach to the elbow joint. In smaller children (< 5 years of age) fixation with Kirschner wires. In older children (> or = 5 years of age) or in cases requiring compression radial screw fixation is recommended. In all cases, suture repair of the periosteum is advisable. Long upper-arm plaster cast until wound healing is achieved. Subsequently, upper-arm plaster cast for 3-4 weeks postoperatively. Implants are removed following consolidation (confirmed by X-ray) after approximately 2-3 months. Routine physiotherapy is normally not required. From January 1, 1999 to December 31, 2006, 85 children with a median age of 6.1 years had lateral condyle fracture of the humerus treated. 47 patients underwent surgery. Of these, 31 were treated with a combination of screw and Kirschner wire fixation, 13 with a single screw, and in three cases, the fracture was fixed with Kirschner wires only. After a median of 8.6 weeks (range, 5.0-17.1 weeks), implants were removed. Median follow-up time was 6 months (range, 2-50 months). There were no late complications in this series (e.g., lack of consolidation, pseudarthrosis). In five cases, hyposensitivity of the skin above the proximal aspect of the radial bone was noted postoperatively. This problem was solved in all instances within the following 6 months. A telephone survey with a response rate of 87% (74 patients) was undertaken in September 2007. Three children noted a minimal deficiency in strength of the injured arm in comparison to the contralateral extremity. One of these children additionally stated a minor flexion deficit of the elbow already present at the last follow-up in the outpatient clinic, which showed no progress. None of the patients had to be referred back to the outpatient clinic because of persistent problems and/or unacceptable results.


What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population?
The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of β-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. With increasing sophistication in genetic experimental techniques, additional mechanisms associated with excessive amyloid deposits were postulated and tested in brains of people with Down syndrome and Alzheimer's disease and in those with early-onset Alzheimer's disease. This in turn led to the proposal and testing for particular genetic defects associated with familial early-onset Alzheimer's disease. Nearly 200 genetic causes of early-onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease.


Force-velocity properties of fast-twitch and slow-twitch muscles of the kitten.
The characteristics of the isometric and force-velocity properties of the fast-twitch flexor digitorum longus (f.d.l.) and the slow-twitch soleus muscles of the developing kitten were determined at post-natal ages of 2 days and 1,2,4 and 6 weeks. The contractile properties of the isometric twitch and tetanus were similar to those previously reported by other authors. The minimum stimulation frequency required for isotonic contractions to achieve the maximum speed of shortening at any given load was 200 Hz for f.d.l. and 150 Hz for soleus at all ages. The extrapolated maximum speed of sarcomere (sarc.) shortening (Vmax) was significantly different between the f.d.l. (22.3 microns s-1 sarc.-1) and soleus (13.1 microns s-1 sarc.-1) at 2 days of age. The f.d.l. Vmax achieved adult values by 4 weeks of age, while there was little or no change in the soleus Vmax. The force-velocity properties are discussed and compared to the changes which have been observed in other contractile properties of the cat f.d.l. and soleus muscles.


Computation of the intensities of parametric holographic scattering patterns in photorefractive crystals.
The present work represents a first attempt to perform computations of output intensity distributions for different parametric holographic scattering patterns. Based on the model for parametric four-wave mixing processes in photorefractive crystals and taking into account realistic material properties, we present computed images of selected scattering patterns. We compare these calculated light distributions to the corresponding experimental observations. Our analysis is especially devoted to dark scattering patterns as they make high demands on the underlying model.


Quantitative structure-activity relationships in prooxidant cytotoxicity of polyphenols: role of potential of phenoxyl radical/phenol redox couple.
The aim of this work was to characterize the role of the potential of phenoxyl radical/phenol redox couple, E(7)(2), in the cytotoxicity of polyphenols. The cytotoxicity of polyphenols in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK), and human promyelocytic leukemia cells (line HL-60) was partly inhibited by catalase, by the antioxidant N,N'-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis-(2-chloro-ethyl)-1-nitrosourea, thus showing its prooxidant character. Dapsone, an inhibitor of myeloperoxidase, did not affect the cytotoxicity of polyphenols in HL-60 cells, whereas dicumarol, an inhibitor of DT-diaphorase, showed controversial effects on their cytotoxicity in FLK cells. Inhibitors of cytochromes P-450, alpha-naphthoflavone and izoniazide, decreased the cytotoxicity of several polyphenols, whereas 3,5-dinitrocatechol, an inhibitor of catechol-o-methyltransferase (COMT), increased it. The cytotoxicity of 13 polyhydroxybenzenes was described by the equations: logcL50 (microM) = -0.67 + 5.46E(7)(2) (V) - 0.16 logD (FLK), and logcL50 (microM) = -1.39 + 6.90E(7)(2) (V) - 0.20logD (HL-60), where cL50 is compound concentration for 50% cell survival, and D is octanol/water distribution coefficient at pH 7.0. The flavonoids comprise a separate series of compounds with lower cytotoxicity. The correlations obtained quantitatively confirm the parallelism between the polyphenol cytotoxicity and the rates of their single-electron oxidation, and point to the leading role of formation of the reactive oxygen species in their cytotoxicity. Depending on the examined system, this parallelism may be distorted due to the cytochrome P-450 and COMT-catalyzed transformation of polyphenols.


A systematic review and meta-analysis of the efficacy of the long-term treatment and support of substance use disorders.
The reconceptualization of substance use disorders (SUD) as a chronic phenomenon calls for a paradigm shift in service provision, particularly by way of long-term treatment and support. Studies that have evaluated the efficacy of long-term treatment models seem to indicate that they are an improvement on more standard short-term treatments, even though these studies do not take the durations into consideration. Measure the efficacy of SUD treatments and support lasting 18 months or more regarding their ability to decrease substance use as compared to shorter treatments. A meta-analysis based on a systematic literature review was conducted. Eight databases were consulted for peer-reviewed studies. Certain variables were coded as moderators: intervention length, participant characteristics, and treatment characteristics. The main results suggest that the people who received a planned long-term treatment or support had a 23.9 % greater chance of abstaining or consuming moderately than did people who received a shorter standard treatment (OR = 1.347 [CI 95 % = 1.087-1.668], p < .006, adjusted OR = 1.460 [CI 95 % = 1.145-1.861]). None of the moderation analyses revealed any variation in the efficacy of the long-term treatments and support. The reconceptualization of the SUD as a chronic disorder among people with this problem leads us to reconsider both the length of the services provided and the paradigms underlying their organization.