Therapeutic management of small cell lung cancer. Fewer toxic reactions with lower chemotherapeutic drug dosages.
A treatment protocol for small cell lung cancer used attenuated drug dosages in an attempt to reduce toxic reactions without compromising effectiveness. Treatment consisted of cyclophosphamide, 50 mg orally daily, methotrexate, 1.25 mg orally daily, procarbazine hydrochloride, 50 mg orally daily, and vincristine sulfate, 10 micrograms/kg intravenously weekly, and was continued until relapse or for two years. Patients with limited disease were given concurrent radiation (4,000 to 5,000 rad, using standard fractionation) to the primary lesion and draining nodes. Fifty patients were evaluable for toxic reactions and survival: 22 with limited and 28 with extensive disease. Fifty-four percent of the patients with extensive disease responded; one (4%) had a complete response. Median survival of the patients with extensive disease was 20 weeks. Ninety-five percent of the patients with limited disease responded; 57% had a complete response. Median survival of these patients was 55 weeks; one-year survival was 59%, and 18-month survival was 36%. Three patients have discontinued therapy without relapse for 48, 22, and seven months. One patient remains disease free after undergoing therapy for 84 weeks. There were no treatment-related deaths, and only 4% of patients experienced WBC count nadirs of less than 1,000/cu mm. Patients with limited disease had long-term survivals comparable with those of other more toxic protocols.


The Pho4 transcription factor mediates the response to arsenate and arsenite in Candida albicans.
Arsenate (As (V)) is the dominant form of the toxic metalloid arsenic (As). Microorganisms have consequently developed mechanisms to detoxify and tolerate this kind of compounds. In the present work, we have explored the arsenate sensing and signaling mechanisms in the pathogenic fungus Candida albicans. Although mutants impaired in the Hog1 or Mkc1-mediated pathways did not show significant sensitivity to this compound, both Hog1 and Mkc1 became phosphorylated upon addition of sodium arsenate to growing cells. Hog1 phosphorylation upon arsenate challenge was shown to be Ssk1-dependent. A screening designed for the identification of transcription factors involved in the arsenate response identified Pho4, a transcription factor of the myc-family, as pho4 mutants were susceptible to As (V). The expression of PHO4 was shortly induced in the presence of sodium arsenate in a Hog1-independent manner. Pho4 level affects Hog1 phosphorylation upon As (V) challenge, suggesting an indirect relationship between Pho4 activity and signaling in C. albicans. Pho4 also mediates the response to arsenite as revealed by the fact that pho4 defective mutants are sensitive to arsenite and Pho4 becomes phosphorylated upon sodium arsenite addition. Arsenite also triggers Hog1 phosphorylation by a process that is, in this case, independent of the Ssk1 kinase. These results indicate that the HOG pathway mediates the response to arsenate and arsenite in C. albicans and that the Pho4 transcription factor can differentiate among As (III), As (V) and Pi, triggering presumably specific responses.


[Methadone treatment and its dangers].
Methadone is a long-acting synthetic opioid with high affinity for various opioid receptors, especially for m-opioid receptors. Methadone has been used as a successful pharmacologic intervention for the treatment of heroin dependence and acute and chronic pain. This treatment is effective for opiate addiction, reducing morbidity and mortality associated with heroin use. However, overdosing with methadone has become a growing phenomenon because of the increased availability of this drug. Patients enrolled in a methadone maintenance treatment program may become physically dependent and may experience methadone withdrawal symptoms. In this review article, there are discussed about pharmacokinetic and pharmacodynamic properties of methadone, clinical symptoms of its overdose, dosage problems, detection of methadone in biological samples, treatment, and causes of methadone overdose-related deaths.


IL-22: Immunity's bittersweet symphony.
Epithelial cells play a crucial role in barrier defense. Here, Moniruzzaman et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230106) discovered that interleukin-22 (IL-22) represses MHC class II expression by epithelial cells with an opposite impact on chronic inflammatory disease and viral infection.


[Influence of meteopathogenic factors on population visits for emergency medical care].
To study the features of the impact of the extreme climate and weather factors of an arid area, which cause exacerbations of circulatory system diseases (CSD). The authors have studied 32,339 visits for emergency medical care (EMC) because of exacerbations of CSD (coronary heart disease, angina pectoris (n = 29,932), myocardial infarction (n = 306), hypertensive crises (n = 2,101) and their events) when the Afghan wind forms in winter and spring and on heat discomfort days in summer. Meteological parameters, synoptic patterns, partial oxygen density (AOD) in the atmosphere, atmospheric electric potential gradient, and human heat sensation (equivalent and effective air temperatures (EEAT)) were estimated using the generally accepted three-hour gradations. In the formation of the Afghan wind (24-48 hours before its surge, i.e. in the prodromal phase), the atmospheric electric potential gradient increased by 4-10 times. Atmospheric pressure fell by 15-20 mbar; air temperature rose by 10-15oC, AOD dropped by 15-25 g/m3--a hypoxic type of weather formed. In the surge phase, the hypoxic type drastically changed to the spastic one - there was an increase in atmospheric pressure and a decrease in air temperature (by 12-19 degrees C), which gave rise to circulatory hypoxia due to vascular spasm. The average daylight air temperature changed from +31.1 to +42.2 degrees C, amounting to +36.6 +/- 1.2 degrees C; EEAT was in the gradation of heat (27-30 degrees C) and very heat (32 degrees C or higher), AOD decreased (248.6 +/- 1.3 g/m3), a hyperthermia-and-hypoxia type of weather was observed. The rates of EMC visits by the population for CSD exacerbations were strongly correlated with the formation of the Afghan wind (Spearman rank correlation 0.82). In the prodromal and Afghan wind surge phases, the number of exacerbations of CSD increased by an average of 2.2-3.6 times. Analysis of annual patient visits by hours during a day showed that their first rise was seen at 9.00 to 12.00 and the second (more substantial) one at 18.00 to 21.00 (p < 0.05). However, in summer, the patient visit rates increased at 15.00 local legal time when there was human thermal sensation at the gradation of heat under hyperthermal hypoxia more frequently in people older than 70 years. The rates of EMC visits by patients for CSD exacerbations increased in the formation of the Afghan wind and in summer during significant heat discomfort; hypoxia (external weather and internal circulatory hypoxia) is a major pathophysiological factor in these situations.


[Hospitalisations for ambulatory care sensitive conditions in a Brazilian metropolis].
This study describes the profile of Hospitalisations for Ambulatory Care Sensitive Conditions (ACSCs) in Curitiba from 2005 to 2007. An ecological study was conducted using the data obtained from the Brazilian Hospital Information System (Sistema de Informações Hospitalares). Descriptive statistics was used for analysis. It was observed that there was a trend toward stabilisation in ACSCs in Curitiba, the most frequent causes being angina and heart failure, with an increased frequency in females and individuals aged ≥65 years. The results were similar to those observed in other studies, and almost in their entirety, were highly significant from a statistical point of view. However, the studies should be viewed with caution because it is an indicator presenting some limitations, including the reliability of diagnosis and the use of secondary data.


Body-focused repetitive behaviors and non-suicidal self-injury: A comparison of clinical characteristics and symptom features.
Body-focused repetitive behaviors (BFRBs) and non-suicidal self-injury (NSSI) are recognized as distinct categories in the DSM-5. However, definitions and assessment of NSSI sometimes encompasses behaviors similar to BFRBs, and little data exist about their clinical differences. The current study examined clinical characteristics and symptom features associated with NSSI vs. BFRBs. The current sample included 1523 individuals who endorsed moderate to severe NSSI (n = 165) or BFRBs: hair pulling group (n = 102), skin picking group (n = 216), nail picking group (n = 253), nail biting group (n = 487), and cheek biting group (n = 300). Responders were asked to complete questionnaires on clinical features relevant for BFRBs and NSSI. NSSI and BFRBs had significant differences on several clinical features. Individuals in the NSSI group were more likely than individuals with BFRBs to report engaging in the behavior for social-affective reasons (i.e., to get out of doing something, or receive attention from others). Individuals in the NSSI group were also more likely to engage in the behavior to regulate tension and feelings of emptiness, and to experience relief during the act. In contrast, individuals in the BFRB groups were more likely to engage in the behavior automatically without reflective awareness, to reduce boredom, or to fix appearance. The NSSI group obtained significantly higher scores on questionnaires assessing stress, anxiety, depression, and harm avoidance. Overall, the results showed several notable differences between NSSI and BFRBs that are consistent with clinical literature and definitions of these problems in the DSM-5.


Luminal buffer transport in rat cortical tubule: relationship to potassium metabolism.
Free-flow micropuncture studies were performed on superficial rat tubules and titratable acid (TA), sodium and potassium concentrations, and tubular pH were measured in control, acutely K-loaded, and chronically K-depleted animals. The proximal tubule is a key site of TA formation. Under control conditions, significant amounts of TA were lost along the loop of Henle. TA delivery (in pmol X min-1) to the late proximal tubule (LP) was 23.66 +/- 2.38 (mean +/- SE), that to the early distal tubule (ED) was 17.24 +/- 1.73, and little further loss occurred along more distally located nephron sites. In acute hyperkalemia, urinary TA excretion (in mumol X min-1) was lower than under control conditions (0.56 +/- 0.04 vs. 1.01 +/- 0.07); TA delivery to the LP (18.50 +/- 1.93) was slightly reduced compared with the controls (a change not reaching statistical significance). TA delivery to the ED was also reduced (11.54 +/- 1.04); significant amounts of TA were lost along the loop of Henle and a significant further loss occurred along the distal tubule since TA delivery to the late distal tubule (LD) was only 7.41 +/- 0.83. As luminal pH along both proximal and distal tubules in K-loaded rats was indistinguishable from that of control rats, a major factor responsible for decreased distal TA formation in K-loaded animals was diminished buffer delivery. In chronic potassium depletion urinary TA excretion was also lowered (0.30 +/- 0.06); only a moderate part of this effect was due to increased pH along the nephron. Increased buffer reabsorption along the proximal tubule (TA delivery to LP was 14.32 +/- 2.01) contributed mainly to the reduced rate of titratable acid excretion.


The effects of alcohol hangover on cognitive functions in healthy subjects.
A hangover is characterized by the constellation of unpleasant physical and mental symptoms that occur between 8 and 16 h after drinking alcohol. We evaluated the effects of experimentally-induced alcohol hangover on cognitive functions using the Luria-Nebraska Neuropsychological Battery. A total of 13 normal adult males participated in this study. They did not have any previous histories of psychiatric or medical disorders. We defined the experimentally-induced hangover condition at 13 h after drinking a high dose of alcohol (1.5 g/kg of body weight). We evaluated the changes of cognitive functions before drinking alcohol and during experimentally-induced hangover state. The Luria-Nebraska Neuropsychological Battery was administrated in order to examine the changes of cognitive functions. Cognitive functions, such as visual, memory, and intellectual process functions, were decreased during the hangover state. Among summary scales, the profile elevation scale was also increased. Among localization scales, the scores of left frontal, sensorimotor, parietal-occipital dysfunction, and right parietal-occipital scales were increased during the hangover state. These results indicate that alcohol hangovers have a negative effect on cognitive functions, particularly on the higher cortical and visual functions associated with the left hemisphere and right posterior hemisphere.


Epigallocatechin-3-gallate improves nonalcoholic steatohepatitis model mice expressing nuclear sterol regulatory element binding protein-1c in adipose tissue.
We examined whether or not epigallocatechin-3-gallate (EGCG) improves liver injury of nonalcoholic steatohepatitis (NASH) model mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue. nSREBP-1c transgenic C57BL6 mice aged 30 weeks were divided into group 1 (no treatment), group 2 (ascorbic acid alone), group 3 (ascorbic acid and 0.05% EGCG), and group 4 (ascorbic acid and 0.1% EGCG). At 42 weeks, we performed measurement of liver weight to body weight, biochemical assays, morphometry of liver specimens, immunohistochemistry for 8-hydro-2'-deoxyguanosine (8-OhdG), and Western blotting for insulin and TNF-alpha signalings. Ratio of liver weight to body weight in the high dose EGCG-treated group (group 4) was significantly lower than those of groups 1 and 2 (p<0.05 and <0.01, respectively). Blood ALT, glucose, total cholesterol, and triglyceride levels of group 4 were significantly low compared with those of the EGCG-non-treated group (groups 1 and 2) (p<0.05, respectively). The degrees of steatosis, inflammation, ballooning hepatocytes and Mallory-Denk bodies in group 4 significantly improved compared with those in other groups (p<0.05, respectively). The 8-OhdG immunolocalization in liver tissues of the group 4 obviously decreased compared with those of groups 2 and 3. For Western blotting, the expressions of insulin receptor substrate-1 (IRS-1) and phosphorylated IRS-1 (pIRS-1) in liver tissues of group 4 increased compared with those of groups 2 and 3. On the other hand, the expressions of pAkt, pIKKbeta and pNF-kappaB decreased compared with those of groups 2 and 3. From these results, EGCG reduces inflammation, insulin resistance and oxidative stress, and suppresses liver injury in nSREBP-1c transgenic mice.


Electrode-Skin Impedance Model Parameter Estimation in the Frequency-Domain.
This paper presents a method for identifying parameter values for a double parallel resistor/constant-phase-element model of the electrode-skin interface for individual silver and silver/silver chloride electrodes. The impedance of each electrode was measured in five from 1 Hz-10 kHz. Phase features of these data were used to guide initial estimates for parameter values which were refined using a least squares algorithm. Resultant model impedances were compared with experimental data across a typical biosignal bandwidth (1 Hz-500 Hz). The method was effective in estimating component values in most datasets, and resulted in a mean relative RMS error of 7 % (σ = 8.3%) across the biosignal bandwidth.Clinical relevance- This work establishes a feature-based method for finding component parameter estimates for an electrode contact impedance model.


Antibiotics and Wolbachia in filarial nematodes: antifilarial activity of rifampicin, oxytetracycline and chloramphenicol against Onchocerca gutturosa, Onchocerca lienalis and Brugia pahangi.
The activity against filarial parasites of the antibiotics rifampicin, oxytetracycline and chloramphenicol was examined. In addition, transmission electron microscopy was used to study the effects of rifampicin and oxytetracycline on filarial tissues and on the endosymbiont bacterium, Wolbachia. When tested in vitro at a concentration of 50.0 microM, each of the three antibiotics significantly reduced the motility levels of male Onchocerca gutturosa. Rifampicin, however, was the most active, virtually immobilizing the parasite by the end of the 40-day trial and producing an 84% reduction in viability (as measured by formazan-based colorimetry). In tests against O. lienalis microfilariae (mff) in CBA mice, the numbers of mff recovered after treatment with oxytetracycline at 100, 25 or 6.5 mg/kg daily, for 15 days, were 56% (P < or = 0.03), 38% (P> 0.05) and 45% (P = 0.05) less than that recovered from the untreated controls, respectively. In another trial in mice, rifampicin (100 mg/kg daily for 15 days) was found to be the most active (causing a 74% reduction in the number of mff recovered--approximately equal to that achieved with the positive control of a single dose of ivermectin at 2 microg/kg), with chloramphenicol also showing significant activity (39% reduction). In further, in-vivo trials, at three dose levels (100, 25 or 6.25 mg/kg daily, for 15 days), all three antibiotics were tested against adult Brugia pahangi in the peritoneal cavities of jirds. None of the antibiotics produced a significant reduction in the numbers of live worms recovered, although a marginal effect was observed in eight of the nine antibiotic-treated groups. A further extended trial with rifampicin and oxytetracycline resulted in 43% and 38% reductions in worm recoveries, respectively (not statistically significant but consistent with a marginal effect); some of these worms appeared less motile and qualitatively in poor condition compared with those recovered from untreated jirds. Ultrastructural studies of these treated worms revealed that virtually all of the endosymbiont bacteria had been cleared from the parasite tissues. The tissues of the adult worms appeared to be largely intact but with a granulomatous response of host cells adhering to some specimens. However, developing uterine forms appeared to be abnormal and extensively damaged, showing an abrogation of embryogenesis. In contrast, worms recovered from control animals contained large numbers of Wolbachia, had no adherent host cells, and showed normal ultrastructure; the female worms exhibited a full range of intra-uterine developing stages from eggs to stretched mff. It is likely that the activity of these antibiotics against the endosymbiont Wolbachia causes the observed antifilarial activity, although some direct effect of each drug on filarial viability cannot be ruled out.


Neuronal and glial advanced glycation end product [Nepsilon-(carboxymethyl)lysine]] in Alzheimer's disease brains.
The cellular distribution of an advanced glycation end product [Nepsilon-(carboxymethyl)lysine (CML)] in aged and Alzheimer's disease (AD) brains was assessed immunohistochemically. CML was localized in the cytoplasm of neurons, astrocytes, and microglia in both aged and AD brains. Glial deposition was far more marked in AD brains than in aged brains, and neuronal deposition was also increased. On electron microscopic immunohistochemistry, neuronal CML formed granular or linear deposits associated with lipofuscin, and glial deposits formed lines around the vacuoles. Neuronal and glial deposits were prominent throughout the cerebral cortex and hippocampus, but were sparse in the putamen, globus pallidus, substantia nigra, and cerebellum, with glial deposits being far more prominent in AD brains. The distribution of neuronal and glial deposits did not correspond with the distribution of AD pathology. The extent of CML deposits was inversely correlated with neurofibrillary tangle formation, particularly in the hippocampus. Most hippocampal pyramidal neurons with neurofibrillary tangles did not have CML, and most of the neurons with heavy CML deposits did not have neurofibrillary tangles. In the hippocampus, neuronal CML was prominent in the region where neuronal loss was mild. These observations suggest that CML deposition does not directly cause neurofibrillary tangle formation or neuronal loss in AD.


Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk.
The purpose of this study was to evaluate whether soluble vascular cell adhesion molecule-1 (sVCAM-1) is a marker for increased cardiovascular risk. Soluble forms of cellular adhesion molecules (CAMs) may be useful markers of endothelial activation and local or systemic inflammation. Recent studies indicate that plasma concentration of soluble intercellular adhesion molecule-1 (sICAM-1) is elevated many years before a first myocardial infarction (MI) occurs. However, only a few prospective studies have evaluated whether sVCAM-1 is also a marker for increased cardiovascular risk. Baseline plasma samples were obtained prospectively from 14,916 healthy participants in the Physicians' Health Study. In a nested, case-control study design, the plasma concentration of sVCAM-1 was measured in 474 men with confirmed MI during the nine-year follow-up period, and in an equal number of control subjects who remained free of reported cardiovascular disease and who were matched for age, smoking status and length of follow-up. No significant difference in the median baseline sVCAM-1 concentration was found between case and control subjects (638 vs. 634 ng/ml; p = NS). Cardiovascular risk was similar between patients with sVCAM-1 levels in the highest quartile and those in the lowest quartile, in both crude (relative risk [RR] 1.28, 95% confidence interval [CI] 0.85 to 1.92) and adjusted (RR 1.17, 95% CI 0.71 to 1.91) matched-pairs analyses. In contrast to previous data on sICAM-1, we found no evidence of an association between sVCAM-1 levels and the risk of future MI in a large cohort of apparently healthy men. These data suggest important pathophysiologic differences between sVCAM-1 and sICAM-1 in the genesis of atherothrombosis.


Autoantibodies targeting cytokines and connective tissue disease autoantigens are common in acute non-SARS-CoV-2 infections.
The widespread presence of autoantibodies in acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is increasingly recognized, but the prevalence of autoantibodies in infections with organisms other than SARS-CoV-2 has not yet been reported. We used protein arrays to profile IgG autoantibodies from 317 samples from 268 patients across a spectrum of non-SARS-CoV-2 infections, many of whom were critically ill with pneumonia. Anti-cytokine antibodies (ACA) were identified in > 50% of patients infected with non-SARS-CoV-2 viruses and other pathogens, including patients with pneumonia attributed to bacterial causes. In cell-based functional assays, some ACA blocked binding to surface receptors for type I interferons (Type I IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-6 (IL-6). Autoantibodies against traditional autoantigens associated with connective tissue diseases (CTDs) were also commonly observed in these cohorts, including newly-detected antibodies that emerged in longitudinal samples from patients infected with influenza. We conclude that autoantibodies, some of which are functionally active, may be much more prevalent than previously appreciated in patients who are symptomatically infected with diverse pathogens.


Variability of daily creatinine excretion in healthy adults.
In order to determine the within-subject variability of creatinine excretion, the 24-h output was measured over 5 consecutive d in 12 subjects. The mean within-subject coefficient of variation was 3.6 per cent. There was much greater variation between subjects. The creatinine excretion in g/d was 30-40 per cent lower in Burmese subjects than in Europeans and North Americans, but the excretion per kg was slightly higher, suggesting that the Burmese are more muscular.


A simplified evaluation system of surface-related lung lesions of pigs for official meat inspection under industrial slaughter conditions in Germany.
European and national administrative legislation require objective evaluation systems for organ lesions at pig slaughter. These results can be used as basis for herd health improvement programs by farmers and their consulting veterinarians. Various studies have shown that the current evaluation and recording of lesions by authorized meat inspectors are not reliable and produce significant inter-rater disagreement especially for lung lesions in pigs. The objectives of this study were to increase the usability of official meat inspection data by a developed and validated scheme and to analyze potential improvements in the reliability of the proposed system under industrialized slaughter conditions. A simplified evaluation scheme for surface-related lung lesions was developed based on morphometric evaluations of unaffected lungs with quantitative relationships of each lobe to the whole lung ("Rule of Tens"). Furthermore, a theoretical as well as a hands-on training program for meat inspectors was developed and applied. Based on 5,183 lungs, the authors established a baseline of the inter-rater reliability of current routine assessments of lung lesions as documented by meat inspectors compared with the assessments of an independent veterinarian using the developed simplified evaluation scheme. Most frequent inter-rater disagreements greater than 75% were found for moderate pneumonia. Sources of the deviations most frequently included misinterpretations of technical artifacts, which were erroneously assessed by the meat inspectors as pneumonic lung lesions. Results of the post-training investigation based on 4,646 lungs showed a significantly improved reliability of lung lesion evaluation and the inter-rater agreement increased in all respects. Especially the disagreement of recording moderate cases of pneumonia decreased in total to 15% deviations from reference. The presented simplified lung evaluation scheme showed its capability to standardize the evaluation of lung lesions according to administrative legislation under industrialial slaughter conditions. The reliability of official meat inspections can be significantly increased with the help of the presented scheme to assess surface-related lung lesions of slaughter pigs. Continuous standardization and optimization can be achieved by personalized training programs in the framework of quality assurance systems for meat inspectors.


Serotonin-1D hypothesis of obsessive-compulsive disorder: an update.
Support for the serotonin-1D (5-HT(1D)) hypothesis of obsessive-compulsive disorder (OCD) and related conditions comes from a variety of sources. Some pharmacologic challenges with the 5-HT(1D) agonist sumatriptan, and case reports in which prolonged administration of 5-HT(1D) agonists was associated with a therapeutic effect, suggest that 5-HT(1D) may play a role in obsessive-compulsive symptoms. Genetic studies have also found that polymorphism of the 5-HT(1D) gene may be preferentially transmitted to those patients with OCD. However, taking into account that OCD is a heterogeneous syndrome, the 5-HT(1D) hypothesis requires further investigation in order to disentangle the role of the 5-HT(1D) receptor in this common and often severe disorder.


Clobetasol propionate shampoo 0.05% is efficacious and safe for long-term control of scalp psoriasis.
Clobetasol propionate (CP) shampoo 0.05% is an efficacious and safe treatment for scalp psoriasis. The aim of this double-blind, randomized, placebo-controlled study was to determine if CP shampoo is suitable for long-term disease control. Participants with moderate to severe scalp psoriasis (global severity score [GSS] of 3 or 4 on a scale of 0 [clear] to 5 [very severe]) first received once daily CP shampoo treatment for up to 4 weeks. Responders were subsequently randomized to receive the CP shampoo or vehicle twice weekly maintenance regimen for up to 6 months. When relapse occurred (defined as GSS > 2), participants resumed once daily CP shampoo treatment; when symptoms diminished (GSS < or = 2), they readopted the twice weekly maintenance regimen. At all visits significantly more participants treated with CP shampoo did not relapse compared with participants treated with vehicle (P < .001). Only approximately one-third of participants treated with vehicle remained relapse free at 1 month, while this rate was observed approximately 3.5 months later (4.5 months after baseline of maintenance phase) in the CP shampoo group. After 6 months 31.1% (33/106) of participants in the CP shampoo group were still relapse free versus 8.1% (9/111) of participants in the vehicle group. There was no greater incidence of skin atrophy, telangiectasia, or hypothalamic-pituitary-adrenal (HPA) axis suppression in the CP shampoo group compared with the vehicle group. Clobetasol propionate shampoo is efficacious and safe for acute management and long-term maintenance of moderate to severe scalp psoriasis.


Analgesic Prescription Patterns and Pain Outcomes in Southeast Asia: Findings From the Analgesic Treatment of Cancer Pain in Southeast Asia Study.
To identify patterns of analgesic prescription and to explore patient-reported pain intensity, sleep disturbance, and quality of life among cancer patients with pain in Southeast Asia (SEA). This cross-sectional observational study included 465 adult outpatients prescribed analgesics for cancer pain for 1 month or longer at 22 sites in Indonesia, Malaysia, Philippines, Singapore, Thailand, and Vietnam. Data on analgesic prescription and cancer characteristics were extracted from medical records. Pain intensity, sleep disturbance, and quality of life measures were recorded via questionnaires. Most patients (84.4%) had stage III or IV cancer. A total of 419 patients (90.7%) were prescribed opioids; of these, 42.2% received only weak opioids, whereas 57.8% received at least one strong opioid. The mean worst pain intensity during the past 24 hours was 4.76 (standard deviation [SD], 2.47) on a scale of 0 (no pain) to 10 (worst possible pain); the mean current pain intensity was 4.10 (SD, 2.61). More than half of patients (54.8%) reported sleep disturbance caused by pain in the past 7 days. The majority of patients reported problems with pain/discomfort (82.3%), usual activities (65.8%), mobility (58.2%), and anxiety/depression (56.3%). The median daily dose prescribed in oral morphine equivalents was 30 mg for both morphine and tramadol. Despite unrelieved pain, sleep disturbance, and issues with quality of life, a notable proportion of patients were prescribed only weak opioids, and opioid doses prescribed were generally low. Efforts focused on encouragement of prescriptions with analgesic strength and/or doses proportional to the pain management needs of patients are vital to improve the status of cancer pain management in the region.


[Graft of hematopoietic stem cells in the treatment of acute leukemia].
Formerly an exceptional treatment, transplantation of haematopoietic stem cells from an HLA (major histocompatibility complex) identical sibling donor is now an effective treatment of acute leukaemia, with well established indications. It still entails the drawback of severe toxicity, but progress has been made in the last 15 years, particularly with regard to improved prevention and treatment of host-versus-graft disease and severe cytomegalovirus infection. Given the improvement in registries of volunteer donors and the reliability of HLA typing using molecular biology, in some cases transplantation can be made using unrelated donors. Autologous transplantation of haematopoietic stem cells entails less toxicity. On the other hand, the autologous transplanted patient does not benefit from the "graft versus leukaemia" reaction observed after an allogeneic graft, and relapses are thus much more common than after allografting. The indications of autologous transplantation are still debated and are the subject of numerous prospective studies.


Oncogenic roles of EMT-inducing transcription factors.
The plasticity of cancer cells underlies their capacity to adapt to the selective pressures they encounter during tumour development. Aberrant reactivation of epithelial-mesenchymal transition (EMT), an essential embryonic process, can promote cancer cell plasticity and fuel both tumour initiation and metastatic spread. Here we discuss the roles of EMT-inducing transcription factors in creating a pro-tumorigenic setting characterized by an intrinsic ability to withstand oncogenic insults through the mitigation of p53-dependent oncosuppressive functions and the gain of stemness-related properties.


Coverage of chest wall defect with pectoralis-breast myocutaneous flap: a report of two cases.
Reconstruction of a chest wall defect remains a challenging problem, especially where such defects are radiation related. Two cases of modified breast flaps associated with pectoralis major muscle were performed to cover a huge mediastinal defect, with heart lung exposure and a post-mastectomy radiation-related chest wall defect with partial rib resection. Both modified breast flaps healed uneventfully. No respiratory distress was encountered post-operatively. The breast flap associated with pectoralis major muscle ensured flap reliability and minimized flap complication. It is easy to raise and its size is large enough to cover of large chest wall defect which is radiation related, or those internal mammary arteries and thoracodorsal arteries compromised in previous surgery where the transverse rectus abdominis myocutaneous (TRAM) flap and latissimus dorsi flap become unreliable. In such cases a contralateral modified breast flap associated with pectoralis major muscle is the better choice.


A paleogenomic perspective on evolution and gene function: new insights from ancient DNA.
The publication of partial and complete paleogenomes within the last few years has reinvigorated research in ancient DNA. No longer limited to short fragments of mitochondrial DNA, inference of evolutionary processes through time can now be investigated from genome-wide data sampled as far back as 700,000 years. Tremendous insights have been made, in particular regarding the hominin lineage. With rare exception, however, a paleogenomic perspective has been mired by the quality and quantity of recoverable DNA. Though conceptually simple, extracting ancient DNA remains challenging, and sequencing ancient genomes to high coverage remains prohibitively expensive for most laboratories. Still, with improvements in DNA isolation and declining sequencing costs, the taxonomic and geographic purview of paleogenomics is expanding at a rapid pace. With improved capacity to screen large numbers of samples for those with high proportions of endogenous ancient DNA, paleogenomics is poised to become a key technology to better understand recent evolutionary events.


What dose of aspirin should be used in the initial treatment of Kawasaki disease? A meta-analysis.
The use of IVIG plus high- or low-dose aspirin for the initial treatment of Kawasaki disease remains controversial. The aim of this study was to evaluate the efficacy of IVIG plus high-dose aspirin compared with IVIG plus low-dose aspirin in the treatment of Kawasaki disease. Studies related to aspirin therapy for Kawasaki disease were selected by searching the databases of Medline (PubMed), Embase and the Cochrane Library before March 2019. Statistical analyses were performed by using a Review Manager Software package and STATA v.15.1. Eight retrospective cohort studies, characterizing 12 176 patients, were analysed. Overall, no significant difference was found in the incidence of coronary artery abnormalities between the high- and low-dose aspirin groups [relative risk (RR) 1.15; 95% CI: 0.93, 1.43; P = 0.19; random-effects model]. The patients treated with high-dose aspirin had slightly faster resolution of fever [mean difference (MD) -0.30; 95% CI: -0.58, -0.02; P = 0.04; random-effects model]. but the rates of IVIG resistance (RR, 1.26; 95% CI: 0.55, 2.92; P = 0.59; random-effects model) and days in hospital (MD, 0.22; 95% CI: -0.93, 1.37; P = 0.71; random-effects model) were similar between the two groups. Low-dose aspirin plus IVIG might be as effective as high-dose aspirin plus IVIG for the initial treatment of Kawasaki disease. Considering that high-dose aspirin may cause more adverse reactions than low-dose aspirin, low-dose aspirin plus IVIG should be recommended as the first-line therapy in the initial treatment of Kawasaki disease.


Synthesis and antifungal activity of the proposed structure of a volatile compound isolated from the edible mushroom Hypsizygus marmoreus.
We synthesized the proposed structure of an antifungal compound detected in the culture broth of the edible mushroom Hypsizygus marmoreus. Using the Evans aldol and Abiko-Masamune aldol reactions as the key steps, we synthesized all of the stereoisomers of the compound with high stereoselectivity. The GC retention times and the fragmentation patterns in the mass spectra of the synthesized isomers did not match those of the natural product. Therefore, this result may imply that it is necessary to reisolate the natural product and reconsider its structure. All of the synthesized isomers were found to exhibit antifungal activity against the phytopathogenic fungus Alternaria brassicicola. Due to their simple structures, the obtained isomers could be lead compounds for new pesticides.


Line bisection performance in patients with generalized anxiety disorder and treatment-resistant depression.
The line bisection error to the left of the true center has been interpreted as a relative right hemisphere activation, which might relate to the subject's emotional state. Considering that patients with generalized anxiety disorder (GAD) or treatment-resistant depression (TRD) often have negative emotions, we hypothesized that these patients would bisect lines significantly leftward. We tried the line bisection task in the right-handed healthy volunteers (n = 56), GAD (n = 47) and TRD outpatients (n = 52). Subjects also completed the Zuckerman - Kuhlman Personality Questionnaire, the Zuckerman Sensation Seeking Scales, and the Plutchik-van Praag Depression Inventory. GAD patients scored highest on the Neuroticism-Anxiety trait, TRD patients scored highest on depression, and both patients scored lower on the Sociability trait. Patients with GAD also bisected lines significantly leftward compared to the healthy subjects. The Frequency of the bisection error was negatively correlated with Disinhibition-Seeking in the healthy subjects, and with Total sensation-seeking and Experience-Seeking in GAD patients, while the Magnitude of the line bisection error was negatively correlated with depression in TRD patients. The study suggests a stronger right hemispheric activation, a weaker left activation, or both in the GAD, instead of TRD patients.


[Four new records of the phlebotominic fauna of the Genus Lutzomyia França (Diptera: Psychodidae, Phlebotominae) of the rural district of Brejo do Mutambal, Varzelândia, State of Minas Gerais, Brazil].
During April and May 2006, experiments were carried out in Brejo do Mutambal, Varzelândia Town, Minas Gerais State, to evaluate the attractiveness of phlebotomine sandflies to CDC light traps, baited with kairomones. Of the 19 species of Lutzomyia already registered for the region, L. lutziana (Costa Lima), L. longipennis (Barreto), L. goiana (Martins, Falcão & Silva) and L. brasiliensis (Costa Lima) were recorded for the first time, thus increasing the diversity of phlebotomine sandflies fauna in this area to 23 species. The new registered species and distribution are shown and discussed herein.


Selective expression of lysyl oxidase (LOX) in the stromal reactions of broncho-pulmonary carcinomas.
Lysyl oxidase (LOX) is the extracellular enzyme that initiates the main pathway of collagen and elastin cross-linking. LOX has also been correlated with the ras recision gene, a putative tumour suppressor isolated from revertants of ras-transformed fibroblasts. The present study investigates the potential correlation of LOX-dependent matrix protein cross-linking in the stromal reaction of lung carcinomas, with reference to the architecture of the main stromal reactions accompanying the neoplastic breast tissues. A strong LOX expression was associated with the hypertrophic scar-like stromal reaction found at the front of tumour progression in squamous carcinomas, adenocarcinomas, large cell carcinomas, or at sites of initial extense in bronchiolo-alveolar carcinomas. In contrast, little or no LOX expression was found within the stromal reaction of invasive carcinomas, small cell carcinomas, and neuro-endocrine carcinomas. The significance of LOX expression and of the stromal reaction are discussed, in light of data that associate LOX expression with tumours displaying a rather good prognosis.


[Menorrhagia: uterine extirpation remains the final option].
The conclusion of a recent cost-effectiveness analysis shows that hysterectomy is the preferred strategy in women with heavy menstrual bleeding. However, this conclusion is not directly applicable in general daily practice. Deciding about certain treatment is not only based on the best-available treatment but also on the experience of a physician and more importantly, on the patient's preferences. For heavy menstrual bleeding, it is known that patients are willing to accept a treatment failure rate of up to 50% in order to avoid hysterectomy. Adequate knowledge on the different treatment options in terms of success, effectiveness, and quality of life are necessary to be able to give each patient solid advice regarding the different treatment options. Patients' preferences were not taken into account in the recent cost-effectiveness analysis of the treatment of heavy menstrual bleeding; therefore, the results of the study are not directly applicable in daily practice.


Molecular cloning, sequence, and expression of a cDNA encoding the chicken myristoylated alanine-rich C kinase substrate (MARCKS).
Little is known about the important cellular substrates for protein kinase C (PKC) and their function in the cellular processes influenced by this kinase. This paper describes the molecular characteristics of a prominent cellular substrate for PKC in chicken cells, known as the myristoylated alanine-rich C kinase substrate, or MARCKS protein. The chicken protein was studied because it was apparently at least 20 kilodalton smaller than its mammalian counterpart; we hoped that regions of sequence similarity might point to conserved regions of biological importance. Using the bovine MARCKS cDNA as a probe, we selected a positive clone from a chicken brain cDNA library that contained an insert of about 1.5 kilobase, in which a single open reading frame encoded a protein of 281 amino acids, 27.7 kilodaltons, pI 5.26. This protein contained the sequences of ten tryptic peptides derived from the purified chicken brain protein. Expression of the cDNA insert in mammalian cells confirmed that the open reading frame encoded a protein that comigrated on two-dimensional electrophoresis with the authentic chicken protein, and could be phosphorylated by exposure of the cells to active phorbol esters. When the chicken and bovine protein sequences were compared, the two major regions of sequence identity were: 1) the amino terminal region containing a myristoylation consensus sequence and an mRNA splice site, and 2) a highly basic internal domain of 25 amino acids that contained all of the serines known to be phosphorylated by PKC in the intact protein. These conserved regions are likely to represent domains of some functional importance for this widely distributed cellular substrate for PKC.


Redox regulation in respiring Saccharomyces cerevisiae.
In biological systems, redox reactions are central to most cellular processes and the redox potential of the intracellular compartment dictates whether a particular reaction can or cannot occur. Indeed the widespread use of redox reactions in biological systems makes their detailed description outside the scope of one review. Here we will focus on how system-wide redox changes can alter the reaction and transcriptional landscape of Saccharomyces cerevisiae. To understand this we explore the major determinants of cellular redox potential, how these are sensed by the cell and the dynamic responses elicited. Redox regulation is a large and complex system that has the potential to rapidly and globally alter both the reaction and transcription landscapes. Although we have a basic understanding of many of the sub-systems and a partial understanding of the transcriptional control, we are far from understanding how these systems integrate to produce coherent responses. We argue that this non-linear system self-organises, and that the output in many cases is temperature-compensated oscillations that may temporally partition incompatible reactions in vivo. Redox biochemistry impinges on most of cellular processes and has been shown to underpin ageing and many human diseases. Integrating the complexity of redox signalling and regulation is perhaps one of the most challenging areas of biology. This article is part of a Special Issue entitled Systems Biology of Microorganisms.


Retroperitoneal sarcoma: the University of Florida experience.
Retroperitoneal sarcomas are rare mesenchymal neoplasms. Analysis of their characteristics and their impact upon a particular patient population is of significant importance to the surgeon. From 1970 to 1994, 63 adult patients underwent resection of primary retroperitoneal sarcomas at the University of Florida. A retrospective analysis was performed to determine the biologic behavior of these tumors, surgical management of primary and recurrent disease, predictive variables influencing survival, and the effect of multimodality therapy. There were 39 females and 24 males and the mean age was 55 years. The median weight of the tumors was 1,815 g (range 25 to 10,800 g). There were 33 percent leiomyosarcomas, 30 percent malignant fibrous histiocytomas, and 22 percent liposarcomas. Low-grade tumors accounted for 46 percent of the total, and grade was a significant predictor of survival (p=0.002). Seventy-eight percent of the lesions were totally resected, and this clearly influenced outcome (p<0.0001). In 75 percent of cases, adjacent organs were resected concurrently, and 34 percent of the tumors involved local vascular structures. Survival was enhanced by multiple resections in the 40 percent of patients who had a recurrence (p=0.0001). None of the adjuvant therapy regimens demonstrated survival advantage. Thirty-one percent of the study group patients were alive and 21 percent were disease free at the conclusion of the study. Median survival has been 41 months after total resection, nine months after debulking, and five months after biopsy only. Complete resection and low grade continue to be the most important prognostic factors for this tumor. The survival advantage of multiple resections has seldom been noted and justifies an aggressive surgical follow-up.


Tight junction properties of the immortalized human bronchial epithelial cell lines Calu-3 and 16HBE14o-.
Tight junctions (TJs) make a vital contribution to the barrier properties of the airway lining. Opening of TJs, or their frank cleavage, is suspected as a pathophysiological event in the lung, but research into the cellular and molecular mechanisms involved has been impeded by technical limitations of available experimental models. The authors have compared the properties of two epithelial cell lines derived from bronchial epithelium to explore whether these cell lines could constitute appropriate tools for the study of TJ regulation in bronchial epithelium. Investigations of TJs in 16HBE14o- cells and Calu-3 cells were made by fluorescent antibody labelling in conjunction with wide-field, confocal or 2-photon molecular excitation microscopy (2PMEM). The presence of TJ proteins was confirmed by immunoblotting and functional properties of the monolayers were studied by measurements of transepithelial electrical resistance and mannitol permeability. Cells of both lines formed confluent monolayers in which the cells expressed the TJ proteins occludin and ZO-1 in continuous circumferential patterns suggestive of functional TJs. This interpretation was supported by the development of transepithelial electrical resistances and of low paracellular permeability to solutes. Within the limits of resolution offered by 2PMEM, occludin and ZO-1 appeared to colocalize at TJs. These studies suggest that the 16HBE14o- cells and Calu-3 cell lines are potentially useful in vitro models to study how tight junction opening or cleavage changes the functional barrier properties of bronchial epithelium.


[Heterotopic mesodermal tumor of the fallopian tube].
An observation of heterologous mesodermal tumor of the fallopian tube in a woman of 53 is described. The tumor had the structure of adenoacanthocarcinosarcoma with inclusions of atypical cartilage. The patient died 6 months after the operation from generalized process. The rare localization of this tumor is noted.


Novel biallelic variants in MSTO1 associated with mitochondrial myopathy.
Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear-encoded mitochondrial fusion gene MSTO1 (Misato 1) has been implicated in mitochondrial myopathy and ataxia. Here we report on a 30-yr-old man presenting with a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited arr[GRCh37] 1q22(155581773_155706887) × 1 deletion encompassing exons 7-14 of MSTO1 His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and electromyogram results were consistent with longstanding generalized myopathy. These phenotypic features overlap well with previously reported patients harboring biallelic MSTO1 variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not previously reported for MSTO1-associated disorders. The majority of patients with disease-associated variants in MSTO1 present with biallelic variants suggesting autosomal recessive inheritance; however, one family has been reported with a single variant and presumed autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the majority of previous reports suggesting an autosomal recessive disorder. We add to our knowledge of the syndrome caused by variants in MSTO1 and provide additional evidence supporting autosomal recessive inheritance. We also describe phenotypic features not reported in previous cases, although further research is needed to confirm they are associated with defects in MSTO1.


New Trans-Arctic shipping routes navigable by midcentury.
Recent historic observed lows in Arctic sea ice extent, together with climate model projections of additional ice reductions in the future, have fueled speculations of potential new trans-Arctic shipping routes linking the Atlantic and Pacific Oceans. However, numerical studies of how projected geophysical changes in sea ice will realistically impact ship navigation are lacking. To address this deficiency, we analyze seven climate model projections of sea ice properties, assuming two different climate change scenarios [representative concentration pathways (RCPs) 4.5 and 8.5] and two vessel classes, to assess future changes in peak season (September) Arctic shipping potential. By midcentury, changing sea ice conditions enable expanded September navigability for common open-water ships crossing the Arctic along the Northern Sea Route over the Russian Federation, robust new routes for moderately ice-strengthened (Polar Class 6) ships over the North Pole, and new routes through the Northwest Passage for both vessel classes. Although numerous other nonclimatic factors also limit Arctic shipping potential, these findings have important economic, strategic, environmental, and governance implications for the region.


ZD9331 in combination with topotecan: phase I and II experience.
ZD9331, a novel, direct-acting thymidylate synthase inhibitor, and the topoisomerase inhibitor topotecan have antitumour activity in a range of solid tumours. We report results from two open-label, multicentre, phase I and phase II trials, investigating the pharmacokinetics, tolerability and efficacy of ZD9331, when used in combination with topotecan in patients with relapsed or refractory tumours. Patients in the phase II trial had progressed following first- or second-line treatment with platinum and paclitaxel. The recommended dose (RD) from the phase I study was subsequently used in the phase II trial. ZD9331 was given as a 30-min i.v. infusion on days 1 and 8 combined with a 30-min i.v. infusion of topotecan on days 1-5 of each 3-week cycle. Sixteen patients with a selection of solid tumours were recruited to the phase I trial. Forty-one patients were included in the combination therapy arm of the phase II study; 95% of which had ovarian cancer and 5% had peritoneal cancer. Three patients experienced dose-limiting toxicity during the phase I trial, one at dose level 1 (ZD9331 65 mg/m2, topotecan 0.5 mg/m2) and two at dose level 2 (ZD9331 65 mg/m2, topotecan 0.75 mg/m2). The RD for the phase II study was ZD9331 65 mg/m2, topotecan 0.5 mg/m2. In both trials, the most common grade 3 and 4 adverse events were thrombocytopenia (15 of 57 patients, 26.3%), neutropenia (11 of 57 patients, 19.3%) and anaemia (9 of 57 patients, 15.8%). One patient (2.4%) in the phase II trial experienced a complete response and six patients overall experienced a partial response [one (6.3%) in phase I, five (12.2%) in phase II]. Seventeen patients achieved stable disease [three (18.8%) in phase I, 14 (34.1%) in phase II]. ZD9331, in combination with topotecan, showed manageable toxicity and some evidence of activity in patients with ovarian cancer.


Microcirculation and arterial hypertension.
A large part of the pressure gradient takes place in the microvascular network (which corresponds to vessels less than 150 microns in diameter). Most of the changes in the peripheral resistance associated with hypertension affect the microvascular network. From the brief review presented here, it appears that the functional characteristics of arterioles are significantly modified in hypertension. Sensitivity to numerous vasoconstrictive substances is increased. Local ACE activity is considerably higher, and endothelium-dependent dilation is lower, in genetically hypertensive animals than in control models. The myogenic response, which represents the vasoconstriction of arterioles in response to a stepped increase in pressure, is also amplified by mechanisms dependent on both prostanoids and endothelin. Changes also affect the structure of the microvascular network. Morphological alterations in the arteriolar wall are not observed for all types of hypertension. Conversely, arteriolar and capillary rarefaction appears to be the most commonly observed change affecting the structure of the microvascular network. The first stage of rarefaction is functional and affects the number of vessels perfused but not the total number of vessels of the microvascular network. At this stage, potent dilators can induce a recruitment of microvessels, which may cancel the difference between the number of perfused vessels in hypertensive and normotensive animals. The second stage is the anatomical rarefaction corresponding to a decrease in arterioles and/or the total number or density of capillaries. Microvascular rarefaction has also been described in patients even in the early stages of hypertension. This led us to consider the microvascular network not only as one of the putative factors responsible for increased pressure but also as a key target of hypertension. Consequently, antihypertensive drugs should also be assessed and differentiated in terms of their efficacy in preventing or reversing the microcirculatory damage associated with hypertension.


Sensory acceptability of meat and dairy products and dietary fat in male collegiate swimmers.
This study was undertaken to determine whether high-level training alters food choice behavior with regard to meat and dairy products because of their high fat content. Twenty male collegiate swimmers were compared to 20 male sedentary students for dietary fat intake, nutrition knowledge, and liking of meat and dairy products. There was no significant difference between the two groups for restraint, energy intake, dietary fat intake, and energy derived from fat. Nutrition knowledge, energy derived from saturated fat, and cholesterol intake, however, were significantly higher in the athletes. The two groups did not differ in their hedonic ratings of flavor or in their overall degree of liking of the meat and dairy products, and the athletes actually liked the appearance and texture of the products significantly more than did the sedentary students. This study shows that the sensory appeal of fat-containing animal products is not affected in male swimmers by a high level of exercise.


Studies on the initiation of simian virus 40 replication in vitro: RNA primer synthesis and its elongation.
DNA primase-dependent synthesis of oligoribonucleotides 10-15 nucleotides long was observed in the presence of ATP, UTP, GTP, and CTP by using the purified components of the simian virus 40 (SV40) DNA replication system. The DNA primase-catalyzed reaction required the SV40 large tumor antigen (T antigen), DNA polymerase alpha (pol-alpha), the three-subunit human single-stranded DNA binding protein (HSSB), and topoisomerase I. The synthesis of small RNAs was unaffected by the addition of activator 1, proliferating cell nuclear antigen, and DNA polymerase delta, proteins that can support extensive leading-strand synthesis. The RNA primers were derived predominantly from transcription of the lagging-strand template, even after prolonged incubation, indicating that the leading strand did not serve as a template. When the four dNTPs were added after oligoribonucleotide synthesis, pol-alpha extended the RNA primers hybridized to SV40 DNA. Pulse-chase experiments revealed that the small RNA chains were elongated to Okazaki-sized products. T7 DNA polymerase was also shown to rapidly extend oligoribonucleotide primers in the presence of aphidicolin or antibodies against pol-alpha, conditions under which pol-alpha was markedly inhibited. These findings suggest that interactions between T antigen, pol-alpha-primase, and HSSB position the pol-alpha-primase complex on the lagging-strand template for RNA primer synthesis.


Biophysical mimicry of lung surfactant protein B by random nylon-3 copolymers.
Non-natural oligomers have recently shown promise as functional analogues of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Here we present an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of beta-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers, inspired by the post-translational modifications found in SP-C, affords further improvements by reducing the percent surface area compression to reach low minimum surface tension. Cytotoxic effects of the copolymers are diminished relative to that of an SP-B-derived peptide and a peptoid-based mimic. The current study provides evidence that sequence-random copolymers can mimic the in vitro surface-active behavior of lung surfactant proteins in a mixed lipid film. These findings raise the possibility that random copolymers might be useful for developing a lung surfactant replacement, which is an attractive prospect given that such polymers are easier to prepare than are sequence-specific oligomers.


The Role of Revision Total Joint Arthroplasty for Periprosthetic Fractures With Unstable Implants.
The management of periprosthetic fractures with unstable prosthetic implants is a challenging and commonly encountered problem. It is important to address the many current issues and controversies regarding the treatment of periprosthetic fractures with revision total joint arthroplasty. Key strategies to optimize surgical decision making around the use of arthroplasty and management of complications following these complex injuries will be addressed.


Halostella limicola sp. nov., isolated from saline soil sampled at the Tarim Basin.
A halophilic archaeaon, strain LT12T, was isolated from saline soil sampled at the Tarim Basin, PR China. The novel strain stained Gram-negative, cells were rod-shaped, and formed light red-pigmented colonies on agar plate. Strain LT12T grew optimally at 3.1 M NaCl, 0.05 M MgCl2, 37 °C and pH 7.5. The cells lysed in distilled water and the minimal NaCl concentration to prevent cell lysis was 1.4 M. Based on the results of phylogenetic analyses of the 16S rRNA and rpoB' genes, strain LT12T was most closely related to Halostella salina CBA1114T(94.4-95.9 and 93.6 % similarities, respectively). The average nucleotide identity and in silico DNA-DNA hybridization values between strain LT12T and H. salina CBA1114T were 81.0 and 24.3 %, respectively. The major polar lipids of strain LT12T were phosphatidic acid, phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and three unidentified glycolipids. The DNA G+C content was 67.2 mol % (genome). Based on the phenotypic, chemotaxonomic and phylogenetic properties, strain LT12T represents a novel species of the genus Halostella for which the name Halostellalimicola sp. nov. is proposed. The type strain is LT12T (=CGMCC 1.14941T=JCM 30667T).


Role of Histamine Release Test for the Evaluation of Patients with Immediate Hypersensitivity Reactions to Clavulanic Acid.
Immediate hypersensitivity reactions to clavulanic acid (CLV) seem to be on the increase. Diagnosis is mainly based on skin testing and the drug provocation test (DPT), procedures that are not risk free. The aim of this study was to evaluate whether the histamine release test (HRT) could help evaluate patients with selective hypersensitivity to CLV. Eighteen patients with immediate selective hypersensitivity reactions to CLV (positive skin tests to CLV but negative to the major and minor determinants of benzylpenicillin and amoxicillin; negative DPT to benzylpenicillin and amoxicillin) and 21 controls with tolerance to CLV were included. Direct and passive HRT, using patient whole blood or 'IgE-stripped' donor blood sensitized by patient serum, respectively, were performed by stimulating the blood with CLV, and basophil histamine release was detected by fluorometric determination. The clinical symptoms were anaphylaxis (n = 6), urticaria (n = 9) and urticaria-angioedema (n = 3). The median time interval between the reaction and the study was 225 days (interquartile range, IQR: 120-387.5) and between drug intake and the development of symptoms 30 min (IQR: 6.25-30). We obtained similar data for both the direct and passive HRT, with a sensitivity and specificity of 55 and 85%, respectively, a positive predictive value of 76% and a negative predictive value of 69%. The sensitivity of both the direct and passive HRT for diagnosing patients with immediate allergy to CLV is less than 60%. However, the passive HRT has the advantage that it is based on the testing of serum samples that can be handled more easily than fresh blood samples.


Aspirin inhibits surface glycoprotein IIb/IIIa, P-selectin, CD63, and CD107a receptor expression on human platelets.
Platelet inhibition after aspirin therapy reduces the risk for the development of acute coronary syndromes. However, the mechanism by which aspirin affect platelets other than by prostaglandin blockade is unclear. We sought to determine the in vitro effects of aspirin on the surface expression of nine platelet receptors using whole blood flow cytometry. Blood from 24 healthy volunteers was incubated for 30 min with 1.8 and 7.2 mg/l phosphate-buffered saline-diluted acetylsalicylic acid in the presence or absence of apyrase. Platelet serotonin release, and the surface expression of platelet receptors with or without apyrase were determined using the following monoclonal antibodies: anit-CD41 [glycoprotein (GP)IIb/IIIa], CD42b (GPIb), CD62p (P-selectin), CD51/CD61 (vitronectin receptor), CD31 [platelet/endothelial cellular adhesion molecule-1 (PECAM-1)], CD107a [lysosomal associated membrane protein (LAMP)-1], CD107b (LAMP-2), CD63 (LIMP or LAMP-3), and CD151 (PETA-3). Samples were then immediately fixed with 2% paraformaldehyde, and run on the flow cytometer within 48 h. Aspirin does not affect serotonin release from human platelets. Dose-dependent inhibition of GPIIb/IIIa, P-selectin, CD63, and CD107a receptor expression was observed in the aspirin-treated whole-blood samples. Apyrase potentiates the effects of aspirin, and independently inhibits PECAM-1. In addition to the known effect of irreversibly inhibiting platelet cyclooxygenase-1, thereby blocking thromboxane A(2) synthesis, it appears that aspirin exhibits direct effects on selective major platelet receptors.


Persistent occiput posterior.
Persistent occiput posterior (OP) is associated with increased rates of maternal and newborn morbidity. Its diagnosis by physical examination is challenging but is improved with bedside ultrasonography. Occiput posterior discovered in the active phase or early second stage of labor usually resolves spontaneously. When it does not, prophylactic manual rotation may decrease persistent OP and its associated complications. When delivery is indicated for arrest of descent in the setting of persistent OP, a pragmatic approach is suggested. Suspected fetal macrosomia, a biparietal diameter above the pelvic inlet or a maternal pelvis with android features should prompt cesarean delivery. Nonrotational operative vaginal delivery is appropriate when the maternal pelvis has a narrow anterior segment but ample room posteriorly, like with anthropoid features. When all other conditions are met and the fetal head arrests in an OP position in a patient with gynecoid pelvic features and ample room anteriorly, options include cesarean delivery, nonrotational operative vaginal delivery, and rotational procedures, either manual or with the use of rotational forceps. Recent literature suggests that maternal and fetal outcomes with rotational forceps are better than those reported in older series. Although not without significant challenges, a role remains for teaching and practicing selected rotational forceps operations in contemporary obstetrics.


Spin in RCTs of anxiety medication with a positive primary outcome: a comparison of concerns expressed by the US FDA and in the published literature.
This study aimed to determine the presence of spin in papers on positive randomised clinical trials (RCTs) of antidepressant medication for anxiety disorders by comparing concerns expressed in the Food and Drug Administration (FDA) reviews with those expressed in the published paper. For every positive anxiety medication trial with a matching publication (n=41), two independent reviewers identified the concerns raised in the US FDA reviews and those in the published literature. Spin was identified when concerns or limitations were expressed by the FDA (about the efficacy of the study drug) but not in the corresponding published paper. Concerns mentioned in the papers but not by the FDA were scored as 'non-FDA' concerns. Only six out of 35 (17%) of the FDA concerns pertaining to drug efficacy were reported in the papers. Two papers mentioned a concern that fit the FDA categories, but was not mentioned in the corresponding FDA review. Eighty-seven non-FDA concerns were counted, which often reflected general concerns or concerns related to the study design. Results indicate the presence of substantial spin in the clinical trial literature on drugs for anxiety disorders. In papers describing RCTs on anxiety medication, the concerns raised by the authors differed from those raised by the FDA. Published papers mentioned a large number of generic concerns about RCTs, such as a lack of long-term research and limited generalisability, while they mentioned few concerns about drug efficacy. These results warrant the promotion of independent statistical review, reporting of patient-level data, more study of spin, and an increased expectation that authors report FDA concerns.


Carbon and Nitrogen Mineralization in Dark Grey Calcareous Floodplain Soil Is Influenced by Tillage Practices and Residue Retention.
Very little is known about the changes that occur in soil organic carbon (SOC) and total nitrogen (TN) under an intensive rice-based cropping system following the change to minimal tillage and increased crop residue retention in the Gangetic Plains of South Asia. The field experiment was conducted for 3 years at Rajbari, Bangladesh to examine the impact of tillage practices and crop residue retention on carbon (C) and nitrogen (N) cycling. The experiment comprised four tillage practices-conventional tillage (CT), zero tillage (ZT), strip-tillage (ST), and bed planting (BP) in combination with two residue retention levels-increased residue (R50%) and low residue (R20%-the current practice). The TN, SOC, and mineral N (NH4+-N and NO3--N) were measured in the soil at different crop growth stages. After 3 years, ZT, ST, and BP sequestered 12, 11, and 6% more SOC, and 18, 13, and 10% more TN, respectively than the conventional crop establishment practice at 0-5 cm soil depth. The accumulation of SOC and TN was also higher compared to the initial SOC and TN in soil. Among the tillage practices, the maximum SOC and TN sequestration were recorded with ST and with R50% that might be attributed to reduced mineralization of C and N in soil particularly with increased residue retention, since decay rates of potentially mineralizable C was lower in the ST with both the residue retention practices. Increased residue retention and minimum tillage practices after nine consecutive crops has altered the C and N cycling by slowing the in-season turnover of C and N, reducing the level of nitrate-N available to plants in the growing season and increasing retained soil levels of SOC and TN.


The auxiliary region method: a hybrid method for coupling PDE- and Brownian-based dynamics for reaction-diffusion systems.
Reaction-diffusion systems are used to represent many biological and physical phenomena. They model the random motion of particles (diffusion) and interactions between them (reactions). Such systems can be modelled at multiple scales with varying degrees of accuracy and computational efficiency. When representing genuinely multiscale phenomena, fine-scale models can be prohibitively expensive, whereas coarser models, although cheaper, often lack sufficient detail to accurately represent the phenomenon at hand. Spatial hybrid methods couple two or more of these representations in order to improve efficiency without compromising accuracy. In this paper, we present a novel spatial hybrid method, which we call the auxiliary region method (ARM), which couples PDE- and Brownian-based representations of reaction-diffusion systems. Numerical PDE solutions on one side of an interface are coupled to Brownian-based dynamics on the other side using compartment-based 'auxiliary regions'. We demonstrate that the hybrid method is able to simulate reaction-diffusion dynamics for a number of different test problems with high accuracy. Furthermore, we undertake error analysis on the ARM which demonstrates that it is robust to changes in the free parameters in the model, where previous coupling algorithms are not. In particular, we envisage that the method will be applicable for a wide range of spatial multi-scales problems including filopodial dynamics, intracellular signalling, embryogenesis and travelling wave phenomena.


catena-Poly[[(di-2-pyridylamine)silver(I)]-mu-nicotinato] and catena-poly[[(di-2-pyridylamine)silver(I)]-mu-2,6-dihydroxybenzoato].
In catena-poly[[(di-2-pyridylamine-kappa(2)N,N')silver(I)]-mu-nicotinato-kappa(2)N:O], [Ag(C(6)H(4)NO(2))(C(10)H(9)N(3))](n), the Ag(I) atom is tetracoordinated by two N atoms from the di-2-pyridylamine (BPA) ligand [Ag-N = 2.3785 (18) and 2.3298 (18) angstroms] and by one N atom and one carboxylate O atom from nicotinate ligands [Ag-N = 2.2827 (15) angstroms and Ag-O = 2.3636 (14) angstroms]. Bridging by nicotinate N and O atoms generates a polymeric chain structure, which extends along [100]. The carboxyl O atom not bonded to the Ag atom takes part in an intrachain C-H...O hydrogen bond, further stabilizing the chain. Pairs of chains are linked by N-H...O hydrogen bonds to generate ribbons. There are no pi-pi interactions in this complex. In catena-poly[[(di-2-pyridylamine-kappa(2)N,N')silver(I)]-mu-2,6-dihydroxybenzoato-kappa(2)O(1):O(2)], [Ag(C(7)H(5)O(4))(C(10)H(9)N(3))](n), the Ag(I) atom has a distorted tetrahedral coordination, with three strong bonds to two pyridine N atoms from the BPA ligand [Ag-N = 2.286 (5) and 2.320 (5) angstroms] and to one carboxylate O atom from the 2,6-dihydroxybenzoate ligand [Ag-O = 2.222 (4) angstroms]; the fourth, weaker, Ag-atom coordination is to one of the phenol O atoms [Ag...O = 2.703 (4) angstroms] of an adjacent moiety, and this interaction generates a polymeric chain along [100]. Pairs of chains are linked about inversion centers by N-H...O hydrogen bonds to form ribbons, within which there are pi-pi interactions. The ribbons are linked about inversion centers by pairs of C-H...O hydrogen bonds and additional pi-pi interactions between inversion-related pairs of 2,6-dihydroxybenzoate ligands to generate a three-dimensional network.


Asynchronous Telepsychiatry: A Component of Stepped Integrated Care.
Integrated behavioral healthcare models typically involve a range of consultation options for mental healthcare. Asynchronous telepsychiatry (ATP) consults may be an additional potential choice, so we are conducting a 5-year clinical trial comparing ATP with synchronous telepsychiatry (STP) consultations. Patients referred by primary care providers are randomly assigned to one of the two treatment groups, ATP or STP. Clinical outcome, satisfaction, and economic data are being collected from patients for 2 years at 6-month intervals. Baseline characteristics for the first 158 patients and case examples of ATP are presented. Implementing ATP in existing integrated behavioral healthcare models could make mental healthcare more efficient.


A study of functional viability and metabolic degeneration of human skin stored at 4 degrees C.
We sought to ascertain whether an in vitro assay could be as reliable as an in vivo assay in determining the viability of human skin stored at 4 degrees C. Allografts from six human donors were stored in RPMI 1640 tissue culture medium at 4 degrees C. At fixed intervals during the storage period, all skin specimens were tested concurrently by two different viability assays: (1) transplantation onto surgically created defects on nude mice, and (2) intracellular enzyme activity with use of a 4-hour semiquantitative micromethod system activity (API ZYM; Biomerieux Vitek Inc., Hazelwood, Mo.). Human graft survival on the nude mice was 100% for the first 15 days of storage, and then declined to 50% on storage day 30. The API ZYM assay showed a comparable progressive decrease in enzyme activity over skin storage time. The API ZYM assay is a simple, rapid system that produces reproducible results and is cost-effective when compared to the biologic model.


Tissue tablet method: an efficient tissue banking procedure applicable to both molecular analysis and frozen tissue microarray.
Frozen human tissues are necessary for research purposes, but tissue banking methods have not changed for more than a decade. Many institutions use cryovial tubes or plastic molds with an optimal cutting temperature compound. However, these methods are associated with several problems, such as samples sticking to one another and the need for a larger storing space. We established an efficient tissue freezing and storing procedure ("tissue tablet method") applicable to both molecular analysis and frozen tissue microarray. Tissue samples were chopped into tiny fragments and embedded into tablet-shaped frozen optimal cutting temperature compound using our original tissue-freezing plate. These tablets can be sectioned and stored in cryovial tubes. We compared the tissue quality of tablet-shaped samples with that of conventional optimal cutting temperature blocks and found no significant difference between them. Tissue microarray is a key method to utilize tissue-banking specimens. However, most tissue microarrays require the coring out of cylindrically shaped tissues from formalin-fixed, paraffin-embedded tissue blocks. Antigenic changes and mRNA degradation are frequently observed with formalin-fixed, paraffin-embedded samples. Therefore, we have applied tablet-shaped samples to construct frozen tissue microarrays with our original mounting base. Constructed tissue microarray sections showed good morphology without obvious artifact and good immunohistochemistry and in situ hybridization results. These results suggest that the quality of arrayed samples was sufficiently appropriate for research purposes. In conclusion, the tissue tablet method and frozen tissue microarray procedure can save time, provides easy tissue handling and processing, and satisfies the demands of research methodologies and tissue banking.


Design of hybrid lipid/retroviral-like particle gene delivery vectors.
Recombinant retroviruses provide highly efficient gene delivery and the potential for stable gene expression. The retroviral envelope protein, however, is the source of significant disadvantages such as immunogenicity, poor stability (half-life of transduction activity of 5-7 h at 37 °C for amphotropic murine leukemia virus), and difficult production and purification. To address these problems, we report the construction of efficient hybrid vectors through the association of murine leukemia virus (MLV)-like particles (M-VLP) with synthetic liposomes comprising DOTAP, DOPE, and cholesterol (φ/M-VLP). We conclude that the lipid composition is a significant determinant of the transfection efficiency and uptake of φ/M-VLP in HEK293 cells with favorable compositions for transfections being those with low DOTAP, low DOPE, and high cholesterol content. Cellular uptake, however, was dependent on DOTAP content alone. By extrusion of liposomes prior to vector assembly, the size of these hybrid vectors could also be decreased to ≈300 nm, as confirmed via DLS and TEM. φ/M-VLP were also robust on storage in terms of vector size and transfection efficiency and provided stable transgene expression over a period of three weeks. We conclude that the noncovalent combination of biocompatible synthetic lipids with inactive retroviral particles to form a highly efficient hybrid vector is a significant extension to the development of novel gene delivery platforms.


A tailored implementation intervention to implement recommendations addressing polypharmacy in multimorbid patients: study protocol of a cluster randomized controlled trial.
Multimorbid patients frequently receive complex medication regimens and are at higher risk for adverse drug reactions and hospitalisations. Managing patients with polypharmacy is demanding, because it requires coordination of multiple prescribers and intensive monitoring. Three evidence-based recommendations addressing polypharmacy in primary care are structured medication counselling, use of medication lists and medication reviews to avoid potentially inappropriate medication (PIM). Although promising to improve patient outcomes, these recommendations are not well implemented in German routine care. Implementation of guidelines is often hindered by specific "determinants of change". "Tailored" interventions are designed to specifically address previously identified determinants. This study examines a tailored intervention to implement the aforementioned recommendations into German primary care practices. This study is part of the European Tailored Interventions for Chronic Diseases project, which aims at contributing knowledge about the methods used for tailoring. The study is designed as a cluster randomized controlled trial with primary care practices of general practitioners (GPs) who are organized in quality circles. Quality circles will be the unit of randomization with a 1:1 ratio. Follow-up time is 6 months. GPs and healthcare assistants in the intervention group will receive training on medication management. Each GP will create a tailored concept of how to implement the three recommendations into his/her practice. Evidence-based checklists for medication counselling and medication reviews will be provided for physicians. A tablet PC with an interactive educational tool and information leaflets will be provided for use by patients to inform about the necessity of continuous medication management. Control practices will not receive special training and will provide care as usual. Primary outcome is the degree of implementation of the three recommendations, which will be measured using a prespecified set of indicators. Additionally, the PIM prescription rate, patient activation, patients' beliefs about medicine, medication adherence and patients' social support will be measured. This study will contribute knowledge about the feasibility of implementing recommendations for managing patients with polypharmacy in primary care practices. Additionally, this study will contribute knowledge about methods for tailoring of implementation interventions. Clinicaltrials.gov ISRCTN34664024.


Cuminum cyminum Ameliorates Urotoxic Effects of Cyclophosphamide by Modulating Antioxidant, Inflammatory Cytokines, and Urinary Bladder Overactivity: In vivo and in Silico Investigations.
Interstitial Cystitis (IC) is a chronic inflammatory disease that lacks effective treatment. The present study aimed to investigate the potential of aqueous ethanol extract of Cuminum cyminum (AEECC) on oxidative stress, inflammation and overactivity of urinary bladder induced by cyclophosphamide (CYP). Female Sprague-Dawley rats received intraperitoneal administration of cyclophosphamide (150 mg/kg, i. p. 1st , 4th , and 7th days). To investigate the urothelial damage, the bladder weight, nociception behavior, and Evans blue dye extravasation method was used. The antioxidants CAT, GPX and NO were measured. ELISA determined the IL-6 and TNF-α levels. The spasmolytic effect of AEECC was investigated on isolated bladder strips and its mechanisms were determined. The enhanced nociception behavior, bladder weight, vascular permeability, edema, hemorrhage, nitric oxide, IL-6 and TNF-α levels by CYP administration were significantly reduced by AEECC (250 and 500 mg/kg). A significant increase in serum antioxidant system such as CAT and GPx was also observed in AEECC-treated rats. The AEECC (3 mg/ml) significantly reduced urinary bladder tone in the strips pre-contracted with carbachol in both control and CYP-treated rats. This relaxation was demolished by atropine, nifedipine, glibenclamide, and indomethacin but not with propranolol. The plant extract showed the presence of antioxidant and anti-inflammatory phytochemicals. These results suggest that Cuminum cyminum offers uroprotective activity and can ameliorate CYP-induced bladder toxicity by modulating antioxidant parameters, pro-inflammatory cytokine levels and bladder smooth muscle overactivity. The in silico binding interactions of antioxidant 2I3Y and anti-inflammatory protein 1TNF with various ligands from Cuminum cyminum seeds revealed potential bioactive compounds with promising antioxidant and anti-inflammatory properties, providing valuable insights for drug development and nutraceutical research.


Leptin levels and risk of type 2 diabetes: gender-specific meta-analysis.
This meta-analysis aimed to assess the gender-specific differences in the relationship between circulating leptin levels and risk of type 2 diabetes. Published prospective studies that reported the association of leptin levels with risk of type 2 diabetes for a certain gender or those that reported gender-specific associations were considered. Dose-response relationships were assessed by the generalized least squares trend estimation and summary relative risks (RRs) with 95% confidence interval (CI) were computed with the random-effects model. Stratified and sensitivity analyses were also performed to investigate potential sources of heterogeneity. Overall, 11 prospective studies were identified. The summary RR for an increment in leptin levels of 1-log ng mL(-1) was 1.37 (95% CI, 1.13-1.66) for men and 0.96 (95% CI, 0.90-1.03) for women. The differences between genders were statistically significant (P for interaction = 0.006). Subgroup and sensitivity analyses generally confirmed the robustness of these findings. Furthermore, the increased risk in men appeared non-linear, with a tendency to plateau at high levels (P for non-linearity = 0.03). Little evidence of publication bias was found. Collectively, higher leptin levels were found to be associated with elevated risk of type 2 diabetes in men but not in women.


Self-management of Type 1 Diabetes Across Adolescence.
The purpose of this study was to examine differences in self-management behaviors (Collaboration with Parents, Diabetes Care Activities, Diabetes Problem Solving, Diabetes Communication, and Goals) between early, middle, and late adolescence. The role of regimen and gender as covariates in self-management behaviors was also examined. This was a secondary analysis with a cross-sectional descriptive survey design. A sample of 504 participants ages 13 to 21 years from the Self-Management of Diabetes-Adolescent instrument development study were analyzed to determine self-management behaviors in early, middle, and late adolescence. This study was partially guided by the Self and Family Management Framework. This framework contains broad conceptual areas that are thought to pose a risk to or have a protective influence on self-management and family management behaviors and associated outcomes. Significant findings included a decline between early, middle, and late adolescence in the Collaboration with Parents scale as well as an increase between early and late adolescence on the Diabetes Problem Solving scale. Regimen was a significant covariate for Collaboration with Parents, Diabetes Care Activities, and Diabetes Problem Solving, and gender was a significant covariate for Diabetes Care Activities and Diabetes Communication. Clinicians should consider the influence of adolescent stage and development on self-management when educating adolescents. Youth and their families should be educated to consider the implications that regimen will have on daily self-management when making treatment decisions. Furthermore, gender variations can necessitate different educational approaches to meet different needs. Future research should identify other variables that can influence self-management at different points across adolescence.


The ecology of eating: smaller portion sizes in France Than in the United States help explain the French paradox.
Part of the "French paradox" can be explained by the fact that the French eat less than Americans. We document that French portion sizes are smaller in comparable restaurants, in the sizes of individual portions of foods (but not other items) in supermarkets, in portions specified in cookbooks, and in the prominence of "all you can eat" restaurants in dining guides. We also present data, from observations at McDonald's, that the French take longer to eat than Americans. Our results suggest that in the domain of eating, and more generally, more attention should be paid to ecological factors, even though their mechanism of operation is transparent, and hence less revealing of fundamental psychological processes. Ironically, although the French eat less than Americans, they seem to eat for a longer period of time, and hence have more food experience. The French can have their cake and eat it as well.


Impact of feeder space on laying hen feeding behavior and production performance in enriched colony housing.
Current feeder space recommendations in laying hen welfare guidelines are inconsistent among and within countries. One determining criterion forming the recommendations (e.g. 12.0 cm/hen for the EU guideline) is that all birds can feed simultaneously. However, if there are other resources in the environment, as in enriched colony housing (ECH), it is unknown whether group-housed hens will choose to feed simultaneously. This study assesses the impact of feeder space on feeding behavior of 60 laying hens (W-36) in ECH using a ultra-high frequency radio-frequency identification-based tracking system. The feeder spaces investigated were 12.0, 9.5, 8.5 and 6.5 cm/hen, achieved by blocking portions of the overall feeder access to keep hens at the same stocking density. Each feeder space treatment, randomly assigned over the course of the experiment, lasted for 7 consecutive days. Feeding behaviors were characterized as daily time spent at the feeder (TS, min/hen-day), daily frequency of visits to the feeder (FV, #/hen-day), and maximum or average percentage of hens feeding simultaneously (MPB, APB, %). Group-average daily feed intake (FI, g/hen-day), water use (WU, g/hen-day), and hen-day egg production (HDEP, %) were also measured. The results revealed that at 12.0 cm/hen, where unoccupied feeder space was present, a maximum of 59.0±1.4% (average of 31.7±0.3%) hens fed simultaneously. No significant differences were detected among 12.0, 9.5 and 8.5 cm/hen in TS (293±10, 286±10 and 281±10 min/hen-day) and MPB (59.0±1.4, 57.3±1.4 and 53.3±1.4%) (P>0.05). The outcome of no significant differences also held true between 12.0 and 9.5 cm/hen in APB (31.7±0.3 v. 30.8±0.3%) and between 9.5 and 8.5 cm/hen in all response variables measured (P>0.05). However, there were significant differences in APB between 6.5 cm/hen and all other treatments; in TS and FV between 6.5 and 9.5 cm/hen; and in MPB between 6.5 and 12 cm/hen (P0.05). The results revealed that synchronous feeding of hens in the ECH did not increase with increasing feeder space. However, it is worth noting that lower feeder space may lead to aggression or frustration which was not quantified in the current study.


Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes.
Murine melanoma B16-F1 cells of low metastatic potential were transfected with the human gene for the prepro form of urokinase in an SV40 expression vector (plasmid pSV2-uPA), and cells expressing high amounts of the human urokinase gene product were selected for by an enzyme-linked immunosorbent assay specific for human high molecular weight urokinase. Southern analysis showed one of the cell lines (clone 7) had incorporated 150 copies of the pSV2-uPA plasmid into its genomic DNA. The human urokinase synthesized by the pSV2-uPA-transfected murine B16 cells was found to be glycosylated and did not bind to the murine cell surface urokinase receptor sites. In an in vivo assay that measures metastasis from a primary tumor (spontaneous metastatic assay), clone 7 cells showed an increased ability to metastasize (12 of 12 mice showed metastatic tumors), while control cells showed a lower ability to metastasize (only 2 of 11 mice showed metastatic tumors). In a second in vivo assay, which measures only the steps of the metastatic migration process during which tumor cells extravasate from the blood and then grow into pulmonary tumors (lung colonization assay), a significant multifold increase in the ability to form lung tumors was shown by the high human urokinase-secreting B16-F1 cells. In B16-F10 cells incorporating an antisense sequence to preprourokinase (plasmid pSV1-ASuPA-265) and secreting significantly decreased amounts of murine urokinase, a corresponding significant decrease in lung colonization was observed. These results provide direct experimental support for a role of secreted (non-surface-bound) urokinase in the colonization steps of the metastatic process. Furthermore, the data indicate that the higher lung colonization ability of the B16-F10 line than of the B16-F1 line is primarily based on the quantitative differences in their abilities to produce urokinase.


Fear-related behaviors in Lurcher mutant mice exposed to a predator.
The Lurcher mutant mice are characterized by massive cerebellar cortex degeneration. Besides their motor and cognitive disturbances, they exhibit both exaggerated blood corticosterone (CORT) level surge and behavioral disinhibition when confronted to anxiogenic conditions (i.e. to a potential threat). In this study, we assessed if such physiological and behavioral hyperactivity was also detectable in a fear-eliciting situation (actual threat). For this purpose, the behaviors and CORT level elevations in Lurcher mice were compared with those of littermate controls in the predator exposure test: mice were exposed either to a rat (exposure) or to a brief wave of the experimenter's hand (sham exposure). While the basal CORT concentrations (24 h before testing) were not significantly different between mice of both genotypes, the post-exposure ones were higher in Lurcher than in control mice whatever the condition of the experimental design (exposure or sham exposure). Predator exposure did not provoke significant increase of CORT levels whatever the genotype. On the contrary, our data clearly showed that fear-related behaviors of cerebellar mutants facing a real threat were exacerbated in comparison to those of control mice. These results suggest that the cerebellar cortex not only participates to fear conditioning and anxiety but also actively contributes to the modulation of the innate fear-related behaviors.


Methionine enkephalin increases CNS suppressive control exerted over gill reflex behaviours and associated neural activity in Aplysia california.
Suprafusion of methionine (Met) enkephalin (10(-9) to 10(-12) M) over the abdominal ganglion of Aplysia californica suppressed the amplitude of the siphon-evoked gill withdrawal reflex (GWR), increased the rate at which the GWR habituated and decreased the number of action potentials evoked in identified central gill motor neurons. The suppressive effects of Met-enkephalin could be blocked by pretreatment with naloxone; in addition, the presentation of a sensitizing stimulus immediately but transiently reversed the effects induced by the peptide. Met-Enkephalin did not affect the passive membrane properties of the gill motor neurons and thus it may act by affecting the activity of neurons which exert suppressive control over both gill reflex behaviours and afferent activity to the gill motor neurons.


Early Thromboembolic Stroke Risk of Postoperative Atrial Fibrillation Following Cardiac Surgery.
The authors aimed to study the association between postoperative atrial fibrillation (POAF) and thromboembolic stroke and to determine risk factors for thromboembolic stroke after cardiac surgery. The authors performed a secondary analysis from a randomized controlled trial (GRIP-COMPASS). The patients with thromboembolic stroke were compared with those without thromboembolic stroke, and the difference in the incidence of POAF between these groups was assessed. Odds ratios (OR) were calculated using logistic regression analyses. Brain imaging was studied for the occurrence of thromboembolic stroke during hospital admission, and POAF was monitored for seven days. To assess which characteristics were associated with occurrence of thromboembolic stroke, stepwise backward regression analysis was performed. All adult consecutive cardiac surgery patients admitted postoperatively to the intensive care unit. Academic tertiary care medical center. None. Of the 910 patients included in this study, 26 patients (2.9%) had a thromboembolic stroke during hospital admission. The incidence of POAF during the first seven days after cardiac surgery in those with thromboembolic stroke was 65%, compared with 39% in those without thromboembolic stroke: adjusted OR 3.01 (95% confidence interval, 1.13-8.00). POAF, a history of peripheral vascular disease, a higher EuroSCORE, and a longer duration of surgery were associated with thromboembolic stroke. POAF within seven days after cardiac surgery was associated with a three-fold increased risk for a thromboembolic stroke during hospital admission. Expeditious treatment of POAF may, therefore, reduce early stroke risk after cardiac surgery.


51st North American Chemical Residue Workshop.
Manuscripts collected in this 51st North American Chemical Residue Workshop (NACRW) Symposium issue of the Journal of Agricultural and Food Chemistry (JAFC) were originally presented at the 51st NACRW meeting. The 2014 NACRW JAFC symposium collects 14 publications representing the broad range of topics in chemical analyses presented at the 2014 meeting. These include the analysis of chemical residues and contaminants in food, environment, feed, botanical, and bee samples as well as the application of quality control/quality assurance protocols in routine and method development.