Validity of the strengths and difficulties questionnaire in preschool-aged children.
The Strengths and Difficulties Questionnaire (SDQ) is widely used to screen for child mental health problems and measure common forms of psychopathology in 4- to 16-year-olds. Using longitudinal data, we examined the validity of a version adapted for 3- to 4-year-olds. We used SDQ data from 16,659 families collected by the Millennium Cohort Study, which charts the development of children born throughout the United Kingdom during 2000-2001. Parents completed the preschool SDQ when children were aged 3 and the standard SDQ at ages 5 and 7. The SDQ's internal factor structure was assessed by using confirmatory factor analysis, with a series of competing models and extensions used to determine construct, convergent, and discriminant validity and measurement invariance over time. Predictive validity was evaluated by examining the relationships of age 3 SDQ scores with age 5 diagnostic measures of attention-deficit/hyperactivity disorder, autism spectrum disorder/Asperger syndrome, and teacher-reported measures of personal, social, and emotional development. Confirmatory factor analysis supported a 5-factor measurement model. Internal reliability of subscales ranged from ω = 0.66 (peer problems) to ω = 0.83 (hyperactivity). Item-factor structures revealed measurement invariance over time. Strong positive correlations between ages 3 and 5 SDQ scores were not significantly different from correlations between age 5 and 7 scores. Conduct problems and hyperactivity subscales independently predicted developmental and clinical outcomes 2 years later. Satisfactory psychometric properties of the adapted preschool version affirm its utility as a screening tool to identify 3- to 4-year-olds with emotional and behavioral difficulties.


Azithromycin Causes a Novel Proarrhythmic Syndrome.
The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells. In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC50=110±3 μmol/L) and Na+ current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for INa in cardiomyocytes. Mild block occurred for K+ currents representing IKr (CHO cells expressing hERG; IC50=219±21 μmol/L) and IKs (CHO cells expressing KCNQ1+KCNE1; IC50=184±12 μmol/L), whereas azithromycin suppressed L-type Ca++ currents (rabbit ventricular myocytes, IC50=66.5±4 μmol/L) and IK1 (HEK cells expressing Kir2.1, IC50=44±3 μmol/L). Chronic exposure to azithromycin increases cardiac Na+ current to promote intracellular Na+ loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.


Long-term efficacy of selective laser trabeculoplasty in patients on prostaglandin therapy.
The aim of the study was to analyse the efficacy of selective laser trabeculoplasty in patients on medical therapy and to evaluate a possible influence of prostaglandin therapy on intraocular pressure reduction. A retrospective chart review was undertaken of patients with ocular hypertension or open angle glaucoma who underwent selective laser trabeculoplasty between 3/2008 and 12/2010. Data were collected preoperatively, on the day of intervention, 1 day, 1 month and then every 3 months post selective laser trabeculoplasty. The main outcome measure was mean intraocular pressure reduction. 109 eyes (76 on prostaglandins) were included. Mean preoperative intraocular pressure was 22.3 ± 4.5 mmHg (prostaglandin naïve) and 19.2 ± 4.8 mmHg (on prostaglandin) (p=0.003). Up to 1 year follow-up, intraocular pressure was statistically significantly reduced in both groups (p ≤ 0.019). Eyes with a higher preoperative intraocular pressure had a greater pressure reduction (Spearman rho=0.387, p=0.002). Eyes naïve to prostaglandins initially had a greater reduction in intraocular pressure, although after 1 year of follow-up the difference was no longer statistically significant. Selective laser trabeculoplasty significantly reduces intraocular pressure in patients already on medical therapy. A sustained influence of prostaglandin therapy on the efficacy of selective laser trabeculoplasty was not found.


The incremental benefit of functional imaging in pheochromocytoma/paraganglioma: a systematic review.
Computed tomography (CT) and magnetic resonance imaging (MRI) are the major imaging modalities used for the localization of catecholamine-producing tumors (pheochromocytoma and paraganglioma). Functional imaging (FI) offers an alternative approach to localize, evaluate, and stage these tumors. Our objective was to describe the additive benefit of FI studies for patients with pheochromocytoma and paraganglioma (PPG) who have undergone MRI or CT scan evaluation. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from database inception through June 2012 for studies that included patients with biochemically proven PPGs who underwent CT or MRI and additional FI for the localization of PPGs. We included 32 studies enrolling a total of 1,264 patients with a mean age of 43-years old. The studies were uncontrolled and evaluated six FI modalities. FI tests provided small additive value to CT/MRI, aiding in the localization of only 24/1,445 primary cases (1.4 %) and 28/805 metastatic cases (3.5 %). In metastatic cases, 6-[F-18]fluoro-L-dihydroxyphenylalanine (DOPA) and fluorodopamine-PET (FDA) were the FI tests most successful at identifying disease missed by CT/MRI, providing additional benefit in 6/60 (10 %) and 5/78 (6.4 %) cases, respectively. No clinically significant findings were observed in any of the predefined subgroups. No study evaluated the impact of FI on the completeness of surgical resection or other patient-important outcomes. Observational evidence suggests that FI tests have a limited additional role in patients with PPGs who have undergone CT/MRI evaluation. However, the role of FI tests in specific subgroups of patients with atypical presentations (metastatic, extra-adrenal) as well as the use of hybrid FI tests should be explored. Further research should also evaluate the impact of FI tests on patient-important outcomes.


Purification and some properties of myeloperoxidase and eosinophil peroxidase from human blood.
Myeloperoxidase and eosinophil peroxidase have been isolated from outdated human blood. Peroxidase activity was extracted from washed leucocytes using 0.5 M-CaCl2 and the extract further purified by chromatography on concanavalin A--Sepharose, phenyl-Sepharose and finally by gel filtration. The final enzyme preparations were highly purified according to spectral and gel-electrophoretic criteria. Under reducing and denaturing conditions on polyacrylamide-gel electrophoresis myeloperoxidase gave rise to bands of Mr 57 000, 39 000 and 15 500, whereas the eosinophil enzyme yielded bands of Mr 50 000 and 15 500. Both enzymes were very resistant to denaturation either by the chaotropic agents urea and guanidinium chloride or by elevated temperatures. Spectral properties of the native and reduced forms of the enzymes are reported.


Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice.
Excitatory amino-acid transporters (EAATs) transport glutamate into cells under physiologic conditions. Excitatory amino-acid transporter type 3 (EAAT3) is the major neuronal EAAT and also uptakes cysteine, the rate-limiting substrate for synthesis of glutathione. Thus, we hypothesize that EAAT3 contributes to providing brain ischemic tolerance. Male 8-week-old EAAT3 knockout mice on CD-1 mouse gene background and wild-type CD-1 mice were subjected to right middle cerebral artery occlusion for 90 minutes. Their brain infarct volumes, neurologic functions, and brain levels of glutathione, nitrotyrosine, and 4-hydroxy-2-nonenal (HNE) were evaluated. The EAAT3 knockout mice had bigger brain infarct volumes and worse neurologic deficit scores and motor coordination functions than did wild-type mice, no matter whether these neurologic outcome parameters were evaluated at 24 hours or at 4 weeks after brain ischemia. The EAAT3 knockout mice contained higher levels of HNE in the ischemic penumbral cortex and in the nonischemic cerebral cortex than did wild-type mice. Glutathione levels in the ischemic and nonischemic cortices of EAAT3 knockout mice tended to be lower than those of wild-type mice. Our results suggest that EAAT3 is important in limiting ischemic brain injury after focal brain ischemia. This effect may involve attenuating brain oxidative stress.


Cardiac monitoring in patients with syncope: making that elusive diagnosis.
Elucidating the cause of syncope is often a diagnostic challenge. At present, there is a myriad of ambulatory cardiac monitoring modalities available for recording cardiac rhythm during spontaneous symptoms. We provide a comprehensive review of these devices and discuss strategies on how to reach the elusive diagnosis based on current evidencebased recommendations.


Human blood basophils produce interleukin-13 in response to IgE-receptor-dependent and -independent activation.
Interleukin-13 (IL-13) is a recently discovered immunoregulatory cytokine. The cellular sources of IL-13 and the regulation of its expression are largely unknown. Here we show that human basophils produce IL-13 in response to IgE-receptor (IgER) crosslinking, IL-3, IL-3 plus C5a, but not C5a alone. Human basophils express IL-13 in a restricted manner since, apart from IL-4, no other cytokines encoded on the cytokine gene cluster (IL-3, IL-5, and granulocyte macrophage-colony-stimulating factor [GM-CSF]), are induced. Highest levels of IL-13 are formed after IgE-independent activation leading to a prolonged secretion of IL-13. The response to IgER-cross-linking is more transient preferentially inducing IL-4, IL-3 is a unique cytokine regulating IL-13 production by human basophils: Among a large number of cytokines tested, only IL-3 is capable of directly inducing IL-13 expression. Furthermore, although some IL-13 is produced in response to C5a in the presence of IL-5, GM-CSF, IGF-1 or IL-1 beta, IL-3 is by far the most effective. IL-13 production was blocked by actinomycin D and cycloheximide and conditions leading to IL-13 release also lead to the induction of IL-13 mRNA. This study supports an important immunoregulatory role of human blood basophils, owing to their capacity to simultaneously express IL-13 and IL-4 in a restricted manner.


Methanococcus jannaschii uses a pyruvoyl-dependent arginine decarboxylase in polyamine biosynthesis.
The genome sequence of the hyperthermophilic methanogen Methanococcus jannaschii contains homologs of most genes required for spermidine polyamine biosynthesis. Yet genomes from neither this organism nor any other euryarchaeon have orthologs of the pyridoxal 5'-phosphate-dependent ornithine or arginine decarboxylase genes, required to produce putrescine. Instead, as shown here, these organisms have a new class of arginine decarboxylase (PvlArgDC) formed by the self-cleavage of a proenzyme into a 5-kDa subunit and a 12-kDa subunit that contains a reactive pyruvoyl group. Although this extremely thermostable enzyme has no significant sequence similarity to previously characterized proteins, conserved active site residues are similar to those of the pyruvoyl-dependent histidine decarboxylase enzyme, and its subunits form a similar (alphabeta)(3) complex. Homologs of PvlArgDC are found in several bacterial genomes, including those of Chlamydia spp., which have no agmatine ureohydrolase enzyme to convert agmatine (decarboxylated arginine) into putrescine. In these intracellular pathogens, PvlArgDC may function analogously to pyruvoyl-dependent histidine decarboxylase; the cells are proposed to import arginine and export agmatine, increasing the pH and affecting the host cell's metabolism. Phylogenetic analysis of Pvl- ArgDC proteins suggests that this gene has been recruited from the euryarchaeal polyamine biosynthetic pathway to function as a degradative enzyme in bacteria.


New strategy to treat glomerular inflammation by inhibition of mesangial cell matrix metalloproteinases.
Therapy of inflammation often requires the attenuation of excess cell proliferation and of extracellular matrix (ECM) accumulation. It is increasingly recognised that matrix metalloproteinases (MMP) play an important role in the regulation of these two features. For our studies, experimental mesangial proliferative glomerulonephritis and cultured mesangial cells provided the inflammation model and the opportunity to evaluate a new therapeutic strategy based on MMP inhibition. In vitro inhibition of MMP activity and synthesis successfully returned the inflammatory mesangial cell phenotype to the normally occurring resting state. In vivo, excess mesangial cell proliferation and ECM accumulation in experimental mesangial proliferative glomerulonephritis were significantly ameliorated by the use of a synthetic MMP inhibitor. Interestingly, these inhibitors lead to increased mesangial cell apoptosis. In conclusion, the antiproliferative effect of MMP inhibitors opens new perspectives in the therapy of inflammation, probably even beyond the scope of kidney diseases.


Molecular simulation of PcCel45A protein expressed from Aspergillus nidulans to understand its structure, dynamics, and thermostability.
PACS and mathematical subject classification numbers as needed. Molecular dynamic simulation is a very usable tool to understand various factors, including structure temperature dependence, dynamics, and stability for protein structure. The three main components, namely endoglucanase, exoglucanase, and β-glucosidase, effectively convert lignocellulosic biomass into fermentable sugar. Cellulose is the major component of plant cell walls and is the most abundant organic compound on the earth. Somewhat organisms can use cellulose as a food source, possessing cellulases (cellobiohydrolases and endoglucanases) that can catalyze the hydrolysis of the β-(1,4) glycosidic bonds. In this work, we investigated conformational and structural properties of PcCel45A protein by changing at temperatures with 300 K, 333 K, and 352 K. We found that the ASN92 residue was the major contributor to the stability of structure; some other residues correlated significantly with thermal stability. We also compared the theoretical results of the current study with the experimental ones published in previous studies.


Bleeding index after the first course of endoscopic treatment for esophageal varices in liver cirrhotic patients with and without hepatocellular carcinoma.
We retrospectively evaluated variable clinical data on admission to reliably predict bleeding from esophageal varices after the first course of endoscopic treatment in liver cirrhosis patients with and without hepatocellular carcinoma. We analyzed 27 clinical factors from the medical records of 118 patients who received their first course of endoscopic treatment for esophageal varices. Factors significantly related to bleeding were extracted using Cox's regression model, and the bleeding index was prepared by combining these factors. The cumulative nonbleeding rates after treatment for esophageal varices were 82.1% at 1 year, 64.6% at 3 years and 53.7% at 5 years. By the multivariate analysis, age, the presence of hepatocellular carcinoma, hemoglobin, lactate dehydrogenase and alpha-fetoprotein were selected as significant factors that contributed independently to the post-therapeutic bleeding from esophageal varices (P<0.05). The bleeding index was calculated using the following formula: bleeding index = - 0.045 x Age + 0.934 x hepatocellular carcinoma - 0.151 x hemoglobin + 0.108 x lactate dehydrogenase + 0.842 x alpha-fetoprotein. The bleeding index, based on 5 factors, will in future be an appropriate index to predict the post-therapeutic bleeding from esophageal varices.


Evolution of universal review and disclosure of MRI reports to research participants.
Although incidental findings (IF) are commonly encountered in neuroimaging research, there is no consensus regarding what to do with them. Whether researchers are obligated to review scans for IF, or if such findings should be disclosed to research participants at all, is controversial. Objective data are required to inform reasonable research policy; unfortunately, such data are lacking in the published literature. This manuscript summarizes the development of a radiology review and disclosure system in place at a neuroimaging research institute and its impact on key stakeholders. The evolution of a universal radiology review system is described, from inception to its current status. Financial information is reviewed, and stakeholder impact is characterized through surveys and interviews. Consistent with prior reports, 34% of research participants had an incidental finding identified, of which 2.5% required urgent medical attention. A total of 87% of research participants wanted their magnetic resonance imaging (MRI) results regardless of clinical significance and 91% considered getting an MRI report a benefit of study participation. A total of 63% of participants who were encouraged to see a doctor about their incidental finding actually followed up with a physician. Reasons provided for not following-up included already knowing the finding existed (14%), not being able to afford seeing a physician (29%), or being reassured after speaking with the institute's Medical Director (43%). Of those participants who followed the recommendation to see a physician, nine (38%) required further diagnostic testing. No participants, including those who pursued further testing, regretted receiving their MRI report, although two participants expressed concern about the excessive personal cost. The current cost of the radiology review system is about $23 per scan. It is possible to provide universal radiology review of research scans through a system that is cost-effective, minimizes investigator burden, and does not overwhelm local healthcare resources.


IGF-I and its variant, des-(1-3)IGF-I, enhance growth in rats with reduced renal mass.
The efficacy of insulin-like growth factor I (IGF-I) in enhancing growth in animals with reduced renal mass was investigated in subtotally nephrectomized young male rats. Recombinant human IGF-I was administered by osmotic minipumps for 7 days at two doses, 0.9 and 2.2 mg.kg body wt-1. day-1, and the truncated analogue of IGF-I, des-(1-3)IGF-I, was given at a dose of 0.9 mg.kg body wt-1.day-1. The partial nephrectomy procedure resulted in significantly impaired renal function as evidenced by elevated serum urea and creatinine concentrations, reduced creatinine clearance, and increased average daily urine output. Carcass composition was significantly altered in animals with reduced renal mass; water content increased and fat content decreased, while protein content remained unchanged. Carcass composition was not affected by IGF treatment. Body weight gain, food utilization, and nitrogen balance during the treatment period were significantly increased in rats treated with IGF-I at both the lower and higher doses and in those treated with des-(1-3)IGF-I. The improved nitrogen balance in the des-(1-3)IGF-I group could at least partly be explained by a diminished rate of muscle protein breakdown, as indicated by the reduced urinary excretion rate of 3-methylhistidine. Compensatory hypertrophy of the remnant kidney was significantly increased in the group treated with the high dose of IGF-I. These results suggest that IGF-I may have beneficial effects on somatic growth and nitrogen balance in renal insufficiency, with des-(1--3)IGF-I being particularly effective in reducing the rate of muscle protein breakdown.


Evaluation of eHealth web sites for patients with chronic kidney disease.
Chronic kidney disease (CKD) affects up to 19.2 million Americans, and untreated kidney disease can progress to kidney failure. Patient education is an important part of slowing disease progression, but the ability of health professionals to provide this education is limited by time constraints. To date, there have been no systematic evaluations of CKD eHealth Web sites. Seven nonproprietary and 4 proprietary Web sites geared toward educating patients with CKD were identified by using the Internet to search for the terms "chronic kidney disease," "kidney disease," and "chronic renal failure." Web sites were evaluated according to (1) compliance with the principles of the Health on the Net (HON) Foundation Code of Conduct and (2) reading grade level. Nonproprietary sites were in compliance with an average of 5.2 principles, with a range of 3 to 8. Average compliance of proprietary Web sites with the HON Code of Conduct principles was 3.12, with a range of 2 to 4 (P = 0.021). Of nonproprietary Web sites, average reading grade level assessed by the Fry Readability Scale was greater than grade 14, with a range from grade 11 through graduate school. Of proprietary sites, average readability was grade 11, with a range from grades 7 through 16 (P = 0.575). The Internet has the potential to be a very powerful educational tool for patients with CKD. However, many easily accessed CKD public health Web sites do not comply with accepted standards for health Web sites and are written using language beyond the general public's reading comprehension.


[Hepatitis B vaccination among primary health care workers].
Health care workers' immunization against hepatitis B is an essential measure to avoid occupational transmission of hepatitis B virus at primary health care centers. The aims of this study were to investigate the prevalence of complete-series vaccination against hepatitis B, estimate the prevalence of confirmed immunity, and verify the factors associated with complete-series vaccination among primary health care workers in Florianópolis, Santa Catarina State, Southern Brazil. A total of 1,249 primary health care workers participated in this study. The prevalence of complete hepatitis B vaccination was 64.61%, and 29.82% of workers indicated knowing they were immunized after taking a serological test to confirm immunity. In the adjusted analysis, complete-series vaccination was positively associated with higher level of schooling and contact with potentially infectious materials or sharps, and negatively associated with precarious employment status and current smoking. Educational measures are recommended to achieve vaccination of health workers who have not been vaccinated or have not completed the series and to inform on the need for vaccine response monitoring.


Pregnancy outcomes from in-vitro fertilisation and intracytoplasmic sperm injection: a comparison.
The purpose of this study was to compare the obstetrical course of in-vitro fertilisation pregnancies with and without intracytoplasmic sperm injection, and to ascertain any difference in the outcome. Both singleton and multiple pregnancies were assessed individually in areas where they could confound results. This was a retrospective analysis of all successful in-vitro fertilisation pregnancies at the Singapore General Hospital during the period 1998-2003. A total of 271 pregnancies with and without intracytoplasmic sperm injection were evaluated. The details of the pregnancies were obtained from the Assisted Reproductive Technology Registry and Birth Defects Registry. The obstetrical outcome was comparable between the two groups, in terms of the number of deliveries, biochemical and ectopic pregnancies. There was no significant difference in the miscarriage rate. The preterm rates for an intracytoplasmic injection pregnancy were two times higher than that reported in literature for both singletons and multiple pregnancies. The singleton intracytoplasmic sperm injection pregnancies were more likely to deliver preterm (17.5 percent, p-value is 0.041) compared to the ones without intracytoplasmic injection (5.7 percent). The average singleton birth weight was lower for the former (2.94 [+/-0.53] kg) than for the latter (3.19 [+/-0.48] kg, p-value is 0.0173). No definite conclusion could be reached regarding the differences in congenital abnormalities between the two groups. The obstetrical course of an in-vitro fertilisation pregnancy with intracytoplasmic sperm injection pregnancy appears to be similar to one without intracytoplasmic sperm injection except for a slight increase in the preterm deliveries and a lower birth weight at delivery among the singletons.


Heart rate variability in emergency department patients with sepsis.
To test the hypothesis that heart rate variability (HRV) can provide an early indication of illness severity among patients presenting to the emergency department (ED) with sepsis. The authors enrolled a convenience sample of 15 ED patients meeting the American College of Chest Physicians/Society of Critical Care Medicine criteria for sepsis. Each patient had continuous Holter monitoring performed in the ED. Acute Physiology and Chronic Health II (APACHE II) and Sequential Organ Failure (SOFA) scores were calculated for the day of presentation. Holter tapes obtained in the ED were analyzed off-line to calculate HRV variables for the 5-minute segment with the least artifact and non-sinus beats. These variables were correlated with APACHE II and SOFA scores. LFnu (normalized low-frequency power), an assessment of the relative sympathetic contribution to overall HRV, was correlated with increased illness severity as calculated using APACHE II (r = -0.67, r(2) = 0.43) and SOFA (r = -0.80, r(2) = 0.64) scores. LF/HF ratio (low-frequency/high-frequency ratio), a measure of sympathovagal balance, was correlated with the SOFA score [r = -0.54 (95% CI = -0.83 to -0.01), r(2) = 0.29]. All five patients who required critical care monitoring or ventilatory support or who died during the first 5 days of their hospitalization had LFnu values below 0.5 and LF/HF ratios less than 1.0. None of the patients with measurements greater than these threshold values died or required these interventions during the five days following admission. A single variable, LFnu, which reflects sympathetic modulation of heart rate, accounted for 40-60% of the variance in illness severity scores among patients presenting to the ED with sepsis. HRV, as reflected in LFnu and the LF/HF ratio and measured with a single brief (5-minute) period of monitoring while in the ED, may provide the emergency physician with a readily available, noninvasive, early marker of illness severity. The threshold effect of LFnu and LF/HF in the prediction of early clinical deterioration was an unexpected finding and should be regarded as hypothesis-generating, pending further study.


Consecutive and temporally distant perseverations after right brain damage: A prospective study.
Objective: Right brain-damaged patients may show omissions and/or additional marks in target cancellation. The latter is classified as perseverative behavior and has been attributed to defective response inhibition or attentional disengagement deficit. This study aimed at (a) verifying that consecutive (immediate) and return (temporally distant) motor perseverations could be due to different mechanisms; (b) investigating the relationships among different types of perseveration (e.g., consecutive, return, scribble), spatial neglect and the impairment in specific components of executive functioning. Method: Seventeen right brain-damaged patients underwent letter, star, bell, and apple cancellation tasks. A global index for each type of perseveration found and Mean Position of Hits, as a neglect index, were calculated. The following components of executive functioning were evaluated: motor programming (Frontal Assessment Battery [FAB] subtest), inhibitory control FAB, interference sensitivity (FAB and Stroop color-word interference test), set-shifting (Weigl sorting test, Phonemic/semantic alternate fluencies), and working memory (Backward Digit span). Results: Ten patients out of 17 showed some degree of perseveration. Regularized linear regression analyses demonstrated that interference sensitivity and Stroop test performances were related to return perseverations and backward digit to scribble ones. No significant relationships were found for consecutive perseverations and between neglect and any type of perseverations. Conclusions: The present study showed that return perseverations might have a distinct etiology from consecutive ones, being related to an inability to update and shift between action programs according to the visual stimuli. A finer classification of perseverations could help in unveiling the neuropsychological mechanisms underlying each type of behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


CD40 ligand-deficient mice generate a normal primary cytotoxic T-lymphocyte response but a defective humoral response to a viral infection.
CD40 ligand is expressed on activated T cells and interacts with CD40 on B cells and monocytes. It is not known what role CD40 ligand plays in the generation of immune responses to viral infection. To address this issue, we examined virus-specific T- and B-cell responses in CD40 ligand-deficient (CD40L-/-) mice following infection with lymphocytic choriomeningitis virus (LCMV). We found that primary anti-LCMV specific antibody responses were severely impaired in CD40L-/- mice, with the defect being most striking for antibody of the immunoglobulin G1 (IgG1) isotype. Interestingly, low levels of LCMV-specific antibodies of the IgG2a, IgG2b, and IgG3 isotypes were made in the CD40L-/- mice, showing that IgG1 responses are totally dependent on CD40L but that at least some IgG2a, IgG2b, and IgG3 responses can be CD40L independent. However, unlike CD40L+/+ mice, CD40L-/- mice were unable to sustain virus-specific antibody responses and showed a gradual decline in serum antibody levels over time. The CD40L-/- mice were also deficient in the generation of memory B cells. In contrast to the severely impaired humoral responses, CD40L-/- mice generated potent virus-specific CD8+ cytotoxic T-lymphocyte responses after LCMV infection and were able to clear the virus. These results show that CD40L does not play a role in generating primary virus-specific CD8+ cytotoxic T-lymphocyte responses but does affect the primary antibody response and the generation of memory B cells.


Structural conflict and object relations conflict.
A hierarchical model of the mind is required for a more integrated understanding of psychic conflict. At a higher developmental level, the hierarchical model includes the tripartite model, and at a lower level it includes an object-relations model. Psychic conflicts may be classified into object relations conflicts and structural conflicts. The object-relations class of psychic conflict covers the phase of psychic development prior to id-ego-superego differentiation. The earlier psychoanalytic writings tended to ascribe all kinds of symptoms, conflicts, and disorders to structural conflicts. Logical and empirical evidence against the universality of structural conflicts in various disorders and symptoms, even psychoneurotic symptoms, has been summarized and discussed.


Loracarbef versus doxycycline in the treatment of acute bacterial maxillary sinusitis. Scandinavian Study Group.
In a double-blind, multicentre study, 662 patients with acute maxillary sinusitis were randomly assigned to receive either loracarbef 400 mg bd (332 patients) or doxycycline, 200 mg for the first dose followed by 100 mg od, (330 patients) for ten days. One hundred and sixty-eight patients in the loracarbef group and 164 in the doxycycline group were evaluable for efficacy. Streptococcus pneumoniae and/or Haemophilus influenzae were isolated from approximately 75% of patients. The clinical response rate (cure or improvement) was significantly higher for patients receiving loracarbef (98.2%) than for those who received doxycycline (92.2%). There was no significant difference between the two groups with respect to bacteriological outcome, although more of the pre-treatment isolates were resistant to doxycycline (35 strains) than to loracarbef (five strains). Adverse events related to the gastrointestinal tract occurred in 11.7% and 10.6% of loracarbef- and doxycycline-treated patients respectively; therapy was terminated prematurely in ten patients in the loracarbef group and in nine in the doxycycline group. The results indicate that loracarbef is effective and safe treatment for acute maxillary sinusitis.


Relative anemia and iron deficiency in cystic fibrosis.
Significant alterations in hemotologic function in cystic fibrosis are suggested by the observation that polycythemia is uncommon, even among cyanotic patients. To elucidate those factors that influence hematologic equilibrium, 39 stable patients with cystic fibrosis were evaluated with regard to hemoglobin, hematocrit, RBC indices, reticulocyte count, serum iron and total iron binding capacity, serum ferritin, vitamin E, and carboxyhemoglobin levels. Hemoglobin concentrations were below the 50th percentile for age in 90% of the patients, including the 23% who were cyanotic. Serum ferritin levels were below the mean for age in 85% and below 12 ng/mL in 33% of patients. Vitamin E levels were less than 5 micrograms/dL in 33%, indicating deficiency. Carboxyhemoglobin values were elevated in 64% of the patients. These data indicate that relative anemia is common in cystic fibrosis and suggest that iron and vitamin E deficiency may contribute to that anemia. Twenty-two patients with cystic fibrosis were then given 2 weeks of oral iron therapy followed by two to three additional weeks of iron and vitamin E. This therapeutic trial resulted in an increase in mean hemoglobin concentration from 13.87 to 14.50 g/dL (P less than 0.01) associated with a significant increase in levels of serum ferritin (P less than 0.001). The increase in hemoglobin occurred primarily during the second 2 weeks when patients were receiving both iron and vitamin E. However, we were unable to document evidence of increased hemolysis when patients were receiving iron therapy alone. This response to oral iron therapy is confirmation that iron deficiency contributes to the failure of some patients with cystic fibrosis to compensate hemotologically for hypoxia.


Chronic stimulation differentially modulates expression of mRNA for dihydropyridine receptor isoforms in rat fast twitch skeletal muscle.
This study examined the effects of low frequency chronic stimulation on expression of the mRNA encoding the two isoforms of the alpha1 subunit of the dihydropyridine receptor (DHPR) calcium channel, a critical component of skeletal muscle excitation-contraction coupling. RNase protection assay was used to determine alteration in isoform expression in 5-day, 9-day and 13-day chronically stimulated rat tibialis anterior muscle, and to compare it with soleus and extensor digitorum longus muscles. Low frequency chronic stimulation was associated not only with a significant decrease in the mRNA level of the skeletal isoform of the DHPR, but also with a significant increase in the mRNA level of the cardiac isoform of the DHPR, the overwhelming majority of which was the adult splice variant. Significant levels of cardiac DHPR mRNA expression were also found in normal adult slow twitch soleus muscle. These findings raise the question of a potential role for the cardiac DHPR in certain adult skeletal muscles.


Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.
Extensive population-based studies are much needed to accurately establish epidemiology and disease course in patients with primary sclerosing cholangitis (PSC). We aimed to obtain population-based prevalence and incidence figures, insight in disease course with regard to survival, liver transplantation (LT), and occurrence of malignancies, as well as risk factors thereof. Four independent hospital databases were searched in 44 hospitals in a large geographically defined area of the Netherlands, comprising 50% of the population. In addition, all PSC patients in the three Dutch liver transplant centers and all inflammatory bowel disease (IBD) patients in the adherence area of a large district hospital were identified. All medical records were reviewed on-site, verifying diagnosis. Five hundred and ninety PSC patients were identified, resulting in an incidence of 0.5 and a point prevalence of 6.0 per 100,000. Median follow up was 92 months. Estimated median survival from diagnosis until LT or PSC-related death in the entire cohort was 21.3 years, as opposed to 13.2 years in the combined transplant centers cohort (n = 422; P < 0.0001). Colorectal carcinoma (CRC) risk was 10-fold increased, as compared to ulcerative colitis controls, and developed at a much younger age (39 years; range, 26-64), compared to IBD controls (59 years; range, 34-73; P = 0.019). Colonoscopic surveillance was associated with significantly better outcome. This study exemplifies that, for relatively rare diseases, it is paramount to collect observational data from large, population-based cohorts, because incidence and prevalence rates of PSC are markedly lower and survival much longer than previously reported. The selection of a bias-free, population-based cohort showed a significantly longer survival, compared to the tertiary referral cohort. CRC can develop at an early age, warranting surveillance from time of PSC diagnosis.


Trends in dermatologic surgery research over the past decade.
We aimed to study the rate of change in number and categories of publications in dermatologic surgery in dermatology versus non-dermatology journals. PubMed was searched for articles on dermatologic surgery from January 1, 1998 to December 31, 2007, using the search word "dermatology" AND "surgery". Articles were characterized by publication and journal type per year. Regression analysis was used to determine the effect of year of publication on number of publications of each type. The search yielded 7570 publications on dermatologic surgery. Seventy-three percent appeared in dermatology journals. Overall, the number of publications increased linearly with time. Most of this increase was accounted for by publications in non-dermatology journals. However, there was an increase in randomized control trials over the course of the study period in dermatology journals only, while low quality-of-evidence publications accounted for most of the increase in non-dermatology journals. Over the past 10 years the field of dermatologic surgery has had a significant yearly increase in published original studies. It appears that high quality evidence on dermatologic surgery is mostly published in dermatology journals. Current trends towards evidence-based dermatology might impact future research and publications in the field of dermatologic surgery.


Osseointegration of Dental Implants in Ridges with Insufficient Bones using Different Membranes for Guided Bone Regeneration.
The use of membrane with the guided bone regeneration (GBR) has been a controversial aspect of the implant placement, which helps achieve the primary graft stabilization and inhibit early graft loss. The present clinical trial was aimed to determine the results of GBR with nonresorbable (expanded polytetrafluoroethylene [e-PTFE]) and resorbable (collagen) membrane both clinically and radiographically for 2 years with dental implant placement. 16 subjects having 32 sites for implant placement in a split-mouth pattern were included in the study. The sites for implant was prepared and grafted with the autogenous graft procured from the mandibular ramus area followed by graft coverage with either e-PTFE or collagen membrane. Various radiographic and clinical parameters were assessed for 2 years at an interval of 6 months each. The collected data were recorded for each study subject for all the implant sites and were statistically analyzed. The mean values for periodontal probing depth at 6 months, 12 months, 18 months, and 24 months were 2.25 ± 0.17, 2.67 ± 1.84, 2.64 ± 1.21, and 3.01 ± 0.52, respectively, for the e-PTFE group. For the collagen group, the probing depth mean values at 6 months, 12 months, 18 months, and 24 months were 2.30 ± 0.14, 2.59 ± 1.76, 2.62 ± 1.30, and 2.98 ± 0.81, respectively. The corresponding clinical and radiographic parameters at all time intervals were nonsignificant on the intergroup comparison. Dental implants placed with simultaneous GBR have an acceptable survival rate at the end of 2 years irrespective of the resorbable or non-resorbable membrane used.


New Fully Automated Preparation of High Apparent Molar Activity 68Ga-FAPI-46 on a Trasis AiO Platform.
A large number of applications for fibroblast activation protein inhibitors (FAPI)-based PET agents have been evaluated in conditions ranging from cancer to non-malignant diseases such as myocardial infarction. In particular, 68Ga-FAPI-46 was reported to have a high specificity and affinity for FAP-expressing cells, a fast and high accumulation in tumor lesions/injuries together with a fast body clearance when investigated in vivo. Due to the increasing interest in the use of the agent both preclinically and clinically, we developed an automated synthesis for the production of 68Ga-FAPI-46 on a Trasis AiO platform. The new synthetic procedure, which included the processing of the generator eluate using a strong cation exchange resin and a final purification step through an HLB followed by a QMA cartridge, yielded 68Ga-FAPI-46 with high radiochemical purity (>98%) and apparent molar activity (271.1 ± 105.6 MBq/nmol). Additionally, the in vitro and in vivo properties of the product were assessed on glioblastoma cells and mouse model. Although developed for the preparation of 68Ga-FAPI-46 for preclinical use, our method can be adapted for clinical production as a reliable alternative to the manual (i.e., cold kit) or modular systems preparations already described in the literature.


Effect of unilateral injection of MK-801 into the area of A10 cells on feeding evoked by stimulation of homologous area in the contralateral hemisphere.
It was found previously that unilateral electrolytic and 6-OHDA lesions of the ventral tegmental area (VTA) and unilateral intra-VTA injection of bicuculline resulted in facilitation of behavioral responses evoked by electrical stimulation of the symmetrical VTA area in the contralateral hemisphere. We postulated that "the contralateral facilitation effect", which may reflect the yet unexplored mechanism of immediate compensation after acute unilateral brain injury, is attributable to the A10 DA neurons and their regulatory inputs. The present study was aimed at examining the possible involvement of NMDA-mediated glutamatergic transmission in VTA in the "contralateral facilitation effect". The behavioral model of the VTA stimulation-induced feeding in rats was used. Latency to eat was measured as a function of stimulation frequency before and after unilateral intra-VTA injection of non-competitive NMDA receptors antagonist, MK-801, (doses 0.0, 1.25 and 2.5 micrograms). MK-801 caused a dose-dependent augmentation of feeding evoked by stimulation of the contralateral VTA, which manifested as a decrease in the reaction frequency threshold and a leftward shift of the latency/frequency curve. Dose 2.5 micrograms replicated the facilitatory effect of electrolytic and 6-OHDA lesions. The results are interpreted in terms of MK-801-evoked depression of excitatory glutamatergic tone over A10 DA cells and compensatory increase in DA release in the contralateral hemisphere.


Cryo-EM structure of the Rhodospirillum rubrum RC-LH1 complex at 2.5 Å.
The reaction centre light-harvesting 1 (RC-LH1) complex is the core functional component of bacterial photosynthesis. We determined the cryo-electron microscopy (cryo-EM) structure of the RC-LH1 complex from Rhodospirillum rubrum at 2.5 Å resolution, which reveals a unique monomeric bacteriochlorophyll with a phospholipid ligand in the gap between the RC and LH1 complexes. The LH1 complex comprises a circular array of 16 αβ-polypeptide subunits that completely surrounds the RC, with a preferential binding site for a quinone, designated QP, on the inner face of the encircling LH1 complex. Quinols, initially generated at the RC QB site, are proposed to transiently occupy the QP site prior to traversing the LH1 barrier and diffusing to the cytochrome bc1 complex. Thus, the QP site, which is analogous to other such sites in recent cryo-EM structures of RC-LH1 complexes, likely reflects a general mechanism for exporting quinols from the RC-LH1 complex.


Preventing psychological trauma in soldiers: the role of operational stress training and psychological debriefing.
Armed conflict is associated with significant long-term psychiatric morbidity. Interventions to reduce the incidence of psychiatric disorder following psychological trauma may be classified into three categories. Primary prevention includes the selection, preparation and training of individuals likely to be exposed to potentially traumatizing events. Secondary prevention comprises a variety of brief psychological techniques immediately or shortly after traumatizing life events, the best known of which is Psychological Debriefing. Tertiary interventions comprise the treatment of established PTSD and others. Psychiatric morbidity was studied in 106 British soldiers returning from UN peace-keeping duties in the former Republic of Yugoslavia. All 106 soldiers received an Operational Stress Training Package prior to their deployment and a randomly selected group also received a post-operational PD. Very low rates of PTSD and other psychopathology were found overall and the Operational Stress Training Package may have contributed to this. Elevated CAGE scores suggestive of significant alcohol misuse were observed in both groups and chemical avoidance behaviours arising from this may have masked psychopathology. CAGE scores diminished significantly in the debriefed group by the end of the follow-up period suggesting that PD may have been of benefit despite the apparent absence of PTSD. This study also demonstrates that a high incidence of psychiatric morbidity is not an inevitable consequence of military conflict.


Network pharmacology integrated with experimental verification reveals the antipyretic characteristics and mechanism of Zi Xue powder.
Zi Xue Powder (ZXP) is a traditional formula for the treatment of fever. However, the potential mechanism of action of ZXP remains unknown. This study elucidates the antipyretic characteristics of ZXP and the mechanism by which ZXP alleviates fever. The key targets and underlying fever-reducing mechanisms of ZXP were predicted using network pharmacology and molecular docking. The targets of ZXP anti-fever active ingredient were obtained by searching TCMSP, STITCH and HERB. Moreover, male Sprague-Dawley rats were randomly divided into four groups: control, lipopolysaccharide (LPS), ZXP (0.54, 1.08, 2.16 g/kg), and positive control (acetaminophen, 0.045 g/kg); the fever model was established by intraperitoneal LPS injection. After the fever model was established at 0.5 h, the rats were administered treatment by gavage, and the anal temperature changes of each group were observed over 10 h after treatment. After 10 h, ELISA and Western blot analysis were used to further investigate the mechanism of ZXP. Network pharmacology analysis showed that MAPK was a crucial pathway through which ZXP suppresses fever. The results showed that ZXP (2.16 g/kg) decreased PGE2, CRH, TNF-a, IL-6, and IL-1β levels while increasing AVP level compared to the LPS group. Furthermore, the intervention of ZXP inhibited the activation of MAPK pathway in LPS-induced fever rats. This study provides new insights into the mechanism by which ZXP reduces fever and provides important information and new research ideas for the discovery of antipyretic compounds from traditional Chinese medicine.


Tuberculosis in wildlife (review).
The cases of tuberculosis in wild animals of different systematic groups recorded and published in the world literature since the time of discovery of the agent of tuberculosis have been presented. The epizootiology, routes of dissemination of the infection, clinical manifestations and some other characteristics accounting for the present status of tuberculosis in wild animals have been described.


Changes in physical activity following total hip or knee arthroplasty: a matched case-control study from the EPIC-Norfolk cohort.
To assess self-reported physical activity changes pre- compared to post-operatively in patients undergoing total hip or knee arthroplasty, and to compare this to an age- and gender-matched cohort of people who have not undergone arthroplasty. Population-based prospective cohort study. Norfolk, United Kingdom. People who had undergone hip or knee arthroplasty, compared to an age- and gender-matched non-arthroplasty cohort. Primary total hip or knee arthroplasty. Physical activity, measured using the EPIC Physical Activity Questionnaire (EPAQ2). A total of 400 people from the EPIC-Norfolk community cohort were identified who had undergone hip or knee arthroplasty. In all, 767 people were identified to form an age- and gender-matched non-arthroplasty cohort. Mean post-operative follow-up was 43 months post-total hip and 41 months post-total knee arthroplasty. There was a statistically significant reduction from pre- to post-arthroplasty in the number of flights of stairs climbed weekly (hip: mean difference (MD): 6.8; P < 0.01; knee: MD: 10.2; P < 0.01), duration of walking (hip: MD: 1.4 hours/week; P = .02; knee: MD: 2.2 hours/week; P < 0.01) and duration of total recreational activity (hip: MD: 1.1 hours/week; P = 0.02). Compared to the non-arthroplasty cohort, duration of physical activity was lower post-total hip arthroplasty (MD: 1.8 hours/week; P = 0.01). The number of flights of stairs climbed weekly (MD: 12.0; P < 0.01), total recreational activity (MD: 1.7 hours/week; P = 0.04) and physical activity energy expenditure (MD: 5.7 Mets-hours/week; P = 0.05) were lower for people post-total knee arthroplasty compared to the matched controls. Physical activity did not increase, and in some instances decreased, following total hip or knee arthroplasty.


Genotoxicity of cadmium chloride in the marine gastropod Nerita chamaeleon using comet assay and alkaline unwinding assay.
This paper presents an evaluation of the genotoxic effects of cadmium chloride (CdCl2 ) on marine gastropod, Nerita chamaeleon following the technique of comet assay and the DNA alkaline unwinding assay (DAUA). In this study, the extent of DNA damage in gill cells of N. chamaeleon was measured after in vivo exposure to four different concentrations (10, 25, 50, and 75 µg/L) of CdCl2 . In vitro exposure of hydrogen peroxide (H2 O2 ; 1, 10, 25, and 50 µM) of the gill cells showed a significant increase in the percentage tail DNA, Olive tail moment, and tail length (TL). Significant changes in percentage tail DNA by CdCl2 exposure were observed in all exposed groups of snails with respect to those in control. Exposure to 75 µg/L of CdCl2 produced significant decrease in DNA integrity as measured by DAUA at all duration with respect to control. In vivo exposure to different concentrations of CdCl2 (10, 25, 50, and 75 µg/L) to N. chamaeleon showed considerable increase in DNA damage as observed by both alkaline comet assay and the DAUA. The extent of DNA damage in marine gastropods determined by the application of alkaline comet assay and DAUA clearly indicated the genotoxic responses of marine gastropod, N. chamaeleon to a wide range of cadmium concentration in the marine environment.


Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers.
Tremelimumab, a fully human monoclonal IgG2 antibody targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), is being developed by Pfizer for treatment of patients with advanced cancers. Treatment with an anti-CTLA4 mAb prevents normal downregulation of T cells and prolongs T cell activation, thereby enhancing immune function. In Phase I and II studies, tremelimumab was well tolerated with predictable and manageable side effects. Antitumor activity with monotherapy was observed in patients with advanced melanoma and colorectal cancer (objective response rates of approximately 10 and 2%, respectively), and most objective responses were durable (defined as lasting > 180 days). Additional Phase II and III studies in combination with other agents will assess antitumor activity in multiple tumor types as well as attempt to identify patient populations most likely to respond.


Traditional systemic treatments have not fully met the needs of psoriasis patients: results from a national survey.
Many psoriasis patients are dissatisfied with current therapies. However, patient-centered levels of satisfaction with individual treatments have not been well described. To assess patients' satisfaction with 4 systemic treatment options available before 2002. We used data from a recent national survey. Psoriasis patients were randomly recruited from the general US population, members of the Psoriasis Foundation, and persons who contacted the Psoriasis Foundation but did not join. The interview included questions about use and satisfaction with specific Psoriasis therapy. Of 1197 psoriasis patients interviewed, 311 (26%) indicated current or past use of methotrexate, psoralen plus ultaviolet A (PUVA), cyclosporin, and/or acitretin (users). Compared with those who had never used any of these systemic therapies, users reported more extensive disease (adjusted odds ratio [OR] = 2.90, 95% confidence interval [CI] = 1.87-4.49) and higher Psoriasis Disability Index scores (category V: adjusted OR = 2.31, 95% CI = 1.22-4.36). After adjusting for these variables, more than one third of patients were dissatisfied with each therapy, except for PUVA (14%). Patients were most satisfied with methotrexate and PUVA. However, less than 40% of the users indicated they were very satisfied with any of the 4 therapies assessed. Only 10% of persons who ever used cyclosporin were currently using it. In a paired analysis, cyclosporin users were significantly less satisfied with cyclosporin than with other therapies ( P = .01). For most patients, none of the 4 systemic therapies widely utilized in 2002 for psoriasis were highly satisfactory. If we are to learn whether new treatments satisfy patients' needs, long term, prospective, comparative studies of heterogeneous patient populations that include patients' assessments are needed.


The effectiveness of therapeutic assessment with an adult client: a single-case study using a time-series design.
This article presents the therapeutic assessment (TA; Finn, 2007) of a traumatized young woman named Claire. Claire reported feeling debilitated by academic demands and the expectations of her parents, and was finding it nearly impossible to progress in her studies. She was also finding it difficult to develop and sustain intimate relationships. The emotional aspects of close relationships were extremely difficult for her and she routinely blamed herself for her struggles in this arena. The assessor utilized the TA model for adults, with the exception of not including an optional intervention session. The steps of TA, particularly the extended inquiry and the discussion of test findings along the way, cultivated a supportive and empathic atmosphere with Claire. By employing the single-case time-series experimental design used in previous TA studies (e.g., Smith, Handler, & Nash, 2010; Smith, Wolf, Handler, & Nash, 2009), the authors demonstrated that Claire experienced statistically significant improvement correlated with the onset of TA. Results indicated that participation in TA coincided with a positive shift in the trajectory of her reported symptoms and with recognizing the affection she held for others in her life. This case illustrates the successful application of case-based time-series methodology in the evaluation of an adult TA. The potential implications for future study are discussed.


Comparison of latency and rate coding for the direction of whisker deflection in the subcortical somatosensory pathway.
The response of many neurons in the whisker somatosensory system depends on the direction in which a whisker is deflected. Although it is known that the spike count conveys information about this parameter, it is not known how important spike timing might be. The aim of this study was to compare neural codes based on spike count and first-spike latency, respectively. We extracellularly recorded single units from either the rat trigeminal ganglion (primary sensory afferents) or ventroposteromedial (VPM) thalamic nucleus in response to deflection in different directions and quantified alternative neural codes using mutual information. We found that neurons were diverse: some (58% in ganglion, 32% in VPM) conveyed information only by spike count; others conveyed additional information by latency. An issue with latency coding is that latency is measured with respect to the time of stimulus onset, a quantity known to the experimenter but not directly to the subject's brain. We found a potential solution using the integrated population activity as an internal timing signal: in this way, 91% of the first-spike latency information could be recovered. Finally, we asked how well direction could be decoded. For large populations, spike count and latency codes performed similarly; for small ones, decoding was more accurate using the latency code. Our findings indicate that whisker deflection direction is more efficiently encoded by spike timing than by spike count. Spike timing decreases the population size necessary for reliable information transmission and may thereby bring significant advantages in both wiring and metabolic efficiency.


Burnout Among Hospitalists During the Early COVID-19 Pandemic: a National Mixed Methods Survey Study.
BACKGROUND : Hospitalist physician stress was exacerbated by the pandemic, yet there have been no large scale studies of contributing factors. Assess remediable components of burnout in hospitalists. In this Coping with COVID study, we focused on assessment of stress factors among 1022 hospital-based clinicians surveyed between April to December 2020. We assessed variables previously associated with burnout (anxiety/depression due to COVID-19, work overload, fear of exposure or transmission, mission/purpose, childcare stress and feeling valued) on 4 point Likert scales, with results dichotomized with the top two categories meaning "present"; burnout was assessed with the Mini Z single item measure (top 3 choices = burnout). Quantitative analyses utilized multilevel logistic regression; qualitative analysis used inductive and deductive methods. These data informed a conceptual model. Of 58,408 HCWs (median response rate 32%), 1022 were hospital-based clinicians (906 (89%) physicians; 449 (44%) female; 469 (46%) White); 46% of these hospital-based clinicians reported burnout. Work overload was associated with almost 5 times the odds of burnout (OR 4.9, 95% CIs 3.67, 6.85, p < 0.001), and those with anxiety or depression had 4 times the odds of burnout (OR 4.2, CIs 3.21, 7.12, p < 0.001), while those feeling valued had half the burnout odds (OR 0.43, CIs 0.31, 0.61, p < 0.001). Regression models estimated 42% of burnout variance was explained by these variables. In open-ended comments, leadership support was helpful, with "great leadership" represented by transparency, regular updates, and opportunities to ask questions. In this national study of hospital medicine, 2 variables were significantly related to burnout (workload and mental health) while two variables (feeling valued and leadership) were likely mitigators. These variables merit further investigation as means of reducing burnout in hospital medicine.


Energetically optimal stride frequency in running: the effects of incline and decline.
At a given running speed, humans strongly prefer to use a stride frequency near their 'optimal' stride frequency that minimizes metabolic cost. Although there is no definitive explanation for why an optimal stride frequency exists, elastic energy usage has been implicated. Because the possibility for elastic energy storage and return may be impaired on slopes, we investigated whether and how the optimal stride frequency changes during uphill and downhill running. Presuming a smaller role of elastic energy, we hypothesized that altering stride frequency would change metabolic cost less during uphill and downhill running than during level running. To test this hypothesis, we collected force and metabolic data as nine male subjects ran at 2.8 m s(-1) on the level, 3 deg uphill and 3 deg downhill. Stride frequency was systematically varied above and below preferred stride frequency (PSF ±8% and ±15%). Ground reaction force data were used to calculate potential, kinetic and total mechanical energy, and to calculate the theoretical maximum possible and estimated actual elastic energy storage and return. Contrary to our hypothesis, we found that neither the overall relationship between metabolic cost and stride frequency nor the energetically optimal stride frequency changed substantially with slope. However, estimated actual elastic energy storage as a percentage of total positive power increased with increasing stride frequency on all slopes, indicating that muscle power decreases with increasing stride frequency. Combined with the increased cost of force production and internal work with increasing stride frequency, this leads to an intermediate optimal stride frequency and overall U-shaped curve.


Intrathoracic organ transplantation in the United Kingdom 1995-99: results from the UK cardiothoracic transplant audit.
To describe the current practice and outcomes of intrathoracic transplantation in the United Kingdom. Prospective observational cohort study. Multicentre study involving all nine UK intrathoracic transplant units. 2588 patients added to the national waiting list between April 1995 and March 1999 and 1737 patients who underwent heart, lung, or heart-lung transplantation in the same period. Waiting list mortality and post-transplant graft survival. There was a slight fall in transplant activity over the four years. Within six months of listing, 52.5% of patients on the heart transplant list had been transplanted and 11.0% had died, compared with 31.3% and 15.2% for lung, and 23.4% and 20.4% for heart-lung. The median time to transplant in days (95% confidence interval) was 133 (115 to 149) for heart, 386 (328 to 496) for lung, and 471 (377 to 577) for heart-lung. After three years, the waiting list mortality was 16.9% (6.1% to 46.8%) for heart, 33.1% (9.0% to 100%) for lung, and 36.5% (10.5% to 100%) for heart-lung. The three year graft survival after transplantation was 74.2% (71.2% to 77.0%) for heart, 53.8% (48.2% to 59.2%) for lung, and 57.2% (49.0% to 64.6%) for heart-lung. This validated database defines the current state of thoracic transplantation in the United Kingdom and is a useful source of data for workers involved in the field. Thoracic transplantation is still limited by donor scarcity and high mortality. Overoptimistic reports may reflect publication bias and are not supported by data from this national cohort.


Safety of the combination of lithium and neuroleptic drugs.
A retrospective study of 60 manic patients treated with neuroleptic medications alone and 69 manic patients treated with a combination of neuroleptic drugs and lithium revealed no difference between groups in side effects and complications of treatment. Similarly, when comparisons were made between patients treated with haloperidol only and those treated with haloperidol and lithium, there were no differences in side effects and complications. The results counter sporadic clinical reports suggesting a toxic interaction between lithium and neuroleptic drugs.


Midtrimester tubal pregnancy with markedly elevated maternal serum alpha-fetoprotein. A case report.
Elevated maternal serum alpha-fetoprotein levels have been reported to occur in a variety of pathologic conditions, including early tubal pregnancy. In this case, markedly elevated maternal serum alpha-fetoprotein was associated with a midtrimester tubal pregnancy. The breakdown of the normal fetomaternal circulatory barrier, allowing the transplacental exchange of alpha-fetoprotein, was the likely etiology of the elevation.


First-order excited state properties in the four-component Hartree-Fock approximation: the excited state electric dipole moments in CsAg and CsAu.
An implementation of the second-order residue of the quadratic response function is presented in the four-component Hartree-Fock approximation, and the calculation of first-order properties of electronically excited states can thereby be achieved. Results are presented for the excited state electric dipole moments of the valence excited states in CsAg and CsAu. For CsAg, and even more so for CsAu, nonscalar relativistic effects on this property may be substantial, e.g., at the four-component level of theory, the excited-to-ground state dipole moment difference Deltamu ranges from 1.994 to 4.110 a.u. for the six components of the 1 (3)Pi state in CsAg, whereas, at the scalar relativistic level of theory, the common value of Deltamu is 2.494 a.u.


Sustainability planning in the US response to the opioid crisis: An examination using expert and text mining approaches.
Between January 2016 and June 2020, the Substance Abuse and Mental Health Services Administration rapidly distributed $7.5 billion in response to the U.S. opioid crisis. These funds are designed to increase access to medications for addiction treatment, reduce unmet treatment need, reduce overdose death rates, and provide and sustain effective prevention, treatment and recovery activities. It is unclear whether or not the services developed using these funds will be sustained beyond the start-up period. Based on 34 (64%) State Opioid Response (SOR) applications, we assessed the states' sustainability plans focusing on potential funding sources, policies, and quality monitoring. We found variable commitment to sustainability across response plans with less than half the states adequately describing sustainability plans. States with higher proportions of opioid prescribing, opioid misuse, and poverty had somewhat higher scores on sustainment. A text mining/machine learning approach automatically rated sustainability in SOR applications with an 82% accuracy compared to human ratings. Because life saving evidence-based programs and services may be lost, intentional commitment to sustainment beyond the bolus of start-up funding is essential.


A bench study comparing between scalpel-bougie technique and cannula-to-Melker technique in emergency cricothyroidotomy in a porcine model.
The ideal emergency cricothyroidotomy technique remains a topic of ongoing debate. This study aimed to compare the cannula-to-Melker technique with the scalpel-bougie technique and determine whether yearly training in cricothyroidotomy techniques is sufficient for skill retention. We conducted an observational crossover bench study to compare the cannula-to-Melker with the scalpel-bougie technique in a porcine tracheal model. Twenty-eight anesthetists participated. The primary outcome was time taken for device insertion. Secondary outcomes were first-pass success rate, incidence of tracheal trauma, and technique preference. We also compared the data on outcome measures with the data obtained in a similar workshop a year ago. The scalpel-bougie technique was significantly faster than the cannula-to-Melker technique for cricothyroidotomy (median time of 45.2 s vs. 101.3 s; P = 0.001). Both techniques had 100% success rate within two attempts; there were no significant differences in the first-pass success rates and incidence of tracheal wall trauma (P > 0.999 and P = 0.727, respectively) between them. The relative risks of inflicting tracheal wall trauma after a failed cricothyroidotomy attempt were 6.9 (95% CI 1.5-31.1), 2.3 (95% CI 0.3-20.7) and 3.0 (95% CI 0.3-25.9) for the scalpel-bougie, cannula-cricothyroidotomy, and Melker-Seldinger airway, respectively. The insertion time and incidence of tracheal wall trauma were lower when the present data were compared with data from a similar workshop conducted the previous year. This study supports the use of a scalpel-bougie technique for cricothyroidotomy by anesthetists and advocates a yearly training program for skill retention.


Budding of alphaviruses.
Alphaviruses are small highly ordered enveloped RNA viruses, which replicate very efficiently in the infected cell. They consist of a nucleocapsid (NC) and a surrounding membrane with glycoproteins. In the NC the positive single stranded RNA genome of the virus is enclosed by a T=4 icosahedral shell of capsid (C) proteins. The glycoproteins form a second shell with corresponding symmetry on the outside of the lipid membrane. These viruses mature by budding at the plasma membrane (PM) of the infected cell and enter into new cells by acid-triggered membrane fusion in endosomes. The viral glycoprotein consists of two subunits, E1, which carries the membrane fusion function, and E2, which suppresses this function until acid activation occurs. In the infected cell the RNA replication and transcription are confined to the cytoplasmic surface of endosome-derived vesicles called cytopathic vacuoles type I (CPV I). These structures are closely associated with membranes of the endoplasmic reticulum (ER), thereby creating a microenvironment for synthesis of viral proteins, assembly of the glycoproteins and formation of genome-C complexes. The budding process of the virus is initiated by C-glycoprotein interactions, possibly already before the glycoproteins arrive at the PM. This might involve a premade, ordered NC or a less ordered form of the genome-C complex. In the latter case, the interactions in the glycoprotein shell provide the major driving force for budding. The nature of the C-glycoprotein interaction has been resolved at atomic resolution by modelling. It involves hydrophobic interactions between a Tyr-X-Leu tripeptide in the internal tail of the E2 subunit and a pocket on the surface of the C protein. When the virus enters the endosome of a new cell the acid conditions trigger rearrangements in the glycoprotein shell, which result in the dissociation of the interactions that drive budding and a concomitant activation of the membrane fusion function in the E1 subunit.


Synthesis of carbon/sulfur nanolaminates by electrochemical extraction of titanium from Ti₂SC.
Herein we electrochemically and selectively extract Ti from the MAX phase Ti2SC to form carbon/sulfur (C/S) nanolaminates at room temperature. The products are composed of multi-layers of C/S flakes, with predominantly amorphous and some graphene-like structures. Covalent bonding between C and S is observed in the nanolaminates, which render the latter promising candidates as electrode materials for Li-S batteries. We also show that it is possible to extract Ti from other MAX phases, such as Ti3AlC2, Ti3SnC2, and Ti2GeC, suggesting that electrochemical etching can be a powerful method to selectively extract the "M" elements from the MAX phases, to produce "AX" layered structures, that cannot be made otherwise. The latter hold promise for a variety of applications, such as energy storage, catalysis, etc.


Selective miR-21 detection technology based on photocrosslinkable artificial nucleic acid-modified magnetic particles and hybridization chain reaction.
Recently, microRNA (miRNA) detection in blood has attracted attention as a new early detection technology for cancer. The extraction of target miRNA is a necessary preliminary step for detection; however, currently, most extraction methods extract all RNA from the blood, which limits the detection selectivity. Therefore, a method for the selective extraction and detection of target miRNA from blood is very important. In this study, we utilized photocrosslinkable artificial nucleic acids and the hybridization chain reaction (HCR) in an attempt to improve upon the current standard method RT-qPCR, which is hampered by problems with primer design and enzymatic amplification. By introducing photocrosslinkable artificial nucleic acids to oligonucleotide probes modified with magnetic particles with a sequence complementary to that of the target miRNA and irradiating them with light, covalent bonds were formed between the target miRNA and the oligonucleotide probes. These tight covalent bonds enabled the capture of miRNA in blood, and intensive washing ensured that only the target miRNA were extracted. After extraction, two types of DNA (H1 and H2) modified with fluorescent dyes were added and the fluorescence signals were amplified by the HCR in the presence of the target miRNA bound to the photocrosslinkable artificial nucleic acids, allowing for isothermal and enzyme-free miRNA detection. The novel method is suitable for selective miRNA detection in real blood samples. Because the reaction proceeds isothermally and no specialized equipment is used for washing, this detection technology is simple and selective and suitable for application to point-of-care technology using microfluidic devices.


Caries Detection with Near-Infrared Transillumination Using Deep Learning.
Dental caries is the most prevalent chronic condition worldwide. Early detection can significantly improve treatment outcomes and reduce the need for invasive procedures. Recently, near-infrared transillumination (TI) imaging has been shown to be effective for the detection of early stage lesions. In this work, we present a deep learning model for the automated detection and localization of dental lesions in TI images. Our method is based on a convolutional neural network (CNN) trained on a semantic segmentation task. We use various strategies to mitigate issues related to training data scarcity, class imbalance, and overfitting. With only 185 training samples, our model achieved an overall mean intersection-over-union (IOU) score of 72.7% on a 5-class segmentation task and specifically an IOU score of 49.5% and 49.0% for proximal and occlusal carious lesions, respectively. In addition, we constructed a simplified task, in which regions of interest were evaluated for the binary presence or absence of carious lesions. For this task, our model achieved an area under the receiver operating characteristic curve of 83.6% and 85.6% for occlusal and proximal lesions, respectively. Our work demonstrates that a deep learning approach for the analysis of dental images holds promise for increasing the speed and accuracy of caries detection, supporting the diagnoses of dental practitioners, and improving patient outcomes.


Bench-to-bedside review: Erythropoietin and its derivatives as therapies in critical care.
Erythropoietin (EPO) is known to have numerous biological functions. Its primary function in the body is to increase red blood cell numbers by way of preventing the apoptosis of erythroid progenitor cells via the homodimeric EPO receptor. The discovery that the local production of EPO within the brain in response to hypoxia or ischemia protects neurons against injury via an anti-apoptotic effect formed the basis of the hypothesis that the local generation of EPO limits the extent of injury. Although the hypothesis proved to be true in pre-clinical models of ischemia/reperfusion injury and inflammation, the randomized, controlled clinical trials that followed demonstrated serious adverse events of EPO due to activation of the hematopoietic system. Consequently, derivatives of EPO that lacked erythropoietic activity were discovered to reduce injury in many pre-clinical models associated with ischemia and inflammation. Unfortunately, there are no published clinical trials to determine the efficacy of non-erythropoietic derivatives of EPO in humans.


Comparative genomic analyses highlight the contribution of pseudogenized protein-coding genes to human lincRNAs.
The regulatory roles of long intergenic noncoding RNAs (lincRNAs) in humans have been revealed through the use of advanced sequencing technology. Recently, three possible scenarios of lincRNA origins have been proposed: de novo origination from intergenic regions, duplication from other long noncoding RNAs, and pseudogenization from protein-coding genes. The first two scenarios are largely studied and supported, yet few studies focused on the evolution from pseudogenized protein-coding sequence to lincRNA. Due to the non-mutually exclusive nature of these three scenarios and the need of systematic investigation of lincRNA origination, we conducted a comparative genomics study to investigate the evolution of human lincRNAs. Combining with syntenic analysis and stringent Blastn e-value cutoff, we found that the majority of lincRNAs are aligned to intergenic regions of other species. Interestingly, 193 human lincRNAs could have protein-coding orthologs in at least two of nine vertebrates. Transposable elements in these conserved regions in human genome are much less than expectation. Moreover, 19% of these lincRNAs have overlaps with or are close to pseudogenes in the human genome. We suggest that a notable portion of lincRNAs could be derived from pseudogenized protein-coding genes. Furthermore, based on our computational analysis, we hypothesize that a subset of these lincRNAs could have potential to regulate their paralogs by functioning as competing endogenous RNAs. Our results provide evolutionary evidence of the relationship between human lincRNAs and protein-coding genes.


Overexpression of an ART1-Interacting Gene OsNAC016 Improves Al Tolerance in Rice.
Rice (Oryza sativa) exhibits tremendous aluminum (Al)-tolerance. The C2H2-transcription factor (TF) ART1 critically regulates rice Al tolerance via modulation of specific gene expression. However, little is known about the posttranscriptional ART1 regulation. Here, we identified an ART1-interacted gene OsNAC016 via a yeast two-hybrid (Y2H) assay. OsNAC016 was primarily expressed in roots and weakly induced by Al. Immunostaining showed that OsNAC016 was a nuclear protein and localized in all root cells. Knockout of OsNAC016 did not alter Al sensitivity. Overexpression of OsNAC016 resulted in less Al aggregation within roots and enhanced Al tolerance in rice. Based on transcriptomic and qRT-PCR evaluations, certain cell-wall-related or ART-regulated gene expressions such as OsMYB30 and OsFRDL4 were altered in OsNAC016-overexpressing plants. These results indicated that OsNAC016 interacts with ART1 to cooperatively regulate some Al-tolerance genes and is a critical regulatory factor in rice Al tolerance.


Anti-migraine Calcitonin Gene-Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice.
Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020;88:771-784.


Improving the electrical contact at a Pt/TiO2 nanowire interface by selective application of focused femtosecond laser irradiation.
In this paper, we show that tightly focused femtosecond laser irradiation is effective in improving nanojoining of an oxide nanowire (NW) (TiO2) to a metal electrode (Pt), and how this process can be used to modify contact states. Enhanced chemical bondings are created due to localized plasmonically enhanced optical absorption at the Pt/TiO2 interface as confirmed by finite element simulations of the localized field distribution during irradiation. Nano Auger electron spectroscopy shows that the resulting heterojunction is depleted in oxygen, suggesting that a TiO2-x layer is formed between the Pt electrode and the TiO2 NW. The presence of this redox layer at the metal/oxide interface plays an important role in decreasing the Schottky barrier height and in facilitating chemical bonding. After laser irradiation at the cathode for 10 s at a fluence of 5.02 mJ cm-2, the Pt/TiO2 NW/Pt structure displays different electrical properties under forward and reverse bias voltage, respectively. The creation of this asymmetric electrical characteristic shows the way in which modification of the electronic interface by laser engineering can replace the electroforming process in resistive switching devices and how it can be used to control contact states in a metal/oxide interface.


A molecular approach to optimize hIFN α2b expression and secretion in Yarrowia lipolytica.
In this work, we investigated the effect of codon bias and consensus sequence (CACA) at the translation initiation site on the expression level of heterologous proteins in Yarrowia lipolytica; human interferon alpha 2b (hIFN-α2b) was studied as an example. A codon optimized hIFN-α2b gene was synthesized according to the frequency of codon usage in Y. lipolytica. Both wild-type (IFN-wt) and optimized hIFN-α2b (IFN-op) genes were expressed under the control of a strong inducible promoter acyl-co-enzyme A oxidase (POX2). Protein secretion was directed by the targeting sequence of the extracellular lipase (LIP2): pre-proLIP2. Codon optimization increased protein production by 11-fold, whereas the insertion of CACA sequence upstream of the initiation codon of IFN-op construct resulted in 16.5-fold increase of the expression level; this indicates that translational efficiency plays an important part in the increase of hIFN-α2b production level. The replacement of the pre-proLIP2 signal secretion with the LIP2 pre-region sequence followed by the X-Ala/X-Pro stretch but without the pro-region also increased the secretion of the target protein by twofold, suggesting therefore that the LIP2 pro-region is not necessary for extracellular secretion of small heterologous proteins in Yarrowia lipolytica.


Characterization of multifocal T2*-weighted MRI hypointensities in the basal ganglia of elderly, community-dwelling subjects.
Multifocal T2*-weighted (T2*w) hypointensities in the basal ganglia, which are believed to arise predominantly from mineralized small vessels and perivascular spaces, have been proposed as a biomarker for cerebral small vessel disease. This study provides baseline data on their appearance on conventional structural MRI for improving and automating current manual segmentation methods. Using a published thresholding method, multifocal T2*w hypointensities were manually segmented from whole brain T2*w volumes acquired from 98 community-dwelling subjects in their early 70s. Connected component analysis was used to derive the average T2*w hypointensity count and load per basal ganglia nucleus, as well as the morphology of their connected components, while nonlinear spatial probability mapping yielded their spatial distribution. T1-weighted (T1w), T2-weighted (T2w) and T2*w intensity distributions of basal ganglia T2*w hypointensities and their appearance on T1w and T2w MRI were investigated to gain further insights into the underlying tissue composition. In 75/98 subjects, on average, 3 T2*w hypointensities with a median total volume per intracranial volume of 50.3ppm were located in and around the globus pallidus. Individual hypointensities appeared smooth and spherical with a median volume of 12mm(3) and median in-plane area of 4mm(2). Spatial probability maps suggested an association between T2*w hypointensities and the point of entry of lenticulostriate arterioles into the brain parenchyma. T1w and T2w and especially the T2*w intensity distributions of these hypointensities, which were negatively skewed, were generally not normally distributed indicating an underlying inhomogeneous tissue structure. Globus pallidus T2*w hypointensities tended to appear hypo- and isointense on T1w and T2w MRI, whereas those from other structures appeared iso- and hypointense. This pattern could be explained by an increased mineralization of the globus pallidus. In conclusion, the characteristic spatial distribution and appearance of multifocal basal ganglia T2*w hypointensities in our elderly cohort on structural MRI appear to support the suggested association with mineralized proximal lenticulostriate arterioles and perivascular spaces.


Validation of a novel procedure for quantification of the formation of phosphoramide mustard by individuals treated with cyclophosphamide.
Use of the patient's body surface area (mg m(-2)) as a basis for dosing does not take individual variation in metabolic capacity and rate of clearance into account. Here, we evaluated a novel approach for individual monitoring of short-lived cytotoxic agents formed from cytostatic drugs such as cyclophosphamide (CP). The accumulated blood dose of the cytotoxic active agent phosphoramide mustard (PAM) formed from CP was measured as a reaction product with hemoglobin (Hb adduct). This adduct, N-[2-(2-oxazolidonyl)ethyl]-valyl Hb (OzVal-Hb), was detached from Hb with the adduct FIRE procedure™, and the formed analyte was quantified using LC-MS/MS. This dose biomarker for PAM and the analytical procedure was evaluated in accordance with the guidelines on bioanalytical method validation formulated by the European Medicine Agency. The evaluated method was applied to quantify blood dose levels of PAM in female breast cancer patients (n = 12) before and after three cycles of polychemotherapy regimes containing CP. OzVal-Hb, a specific and stable biomarker, could be measured with great sensitivity (lower limit of quantification = 33 pmol g(-1) Hb), high accuracy (within ±20 %) and good repeatability (CV < 20 %). The inter-individual variability in the blood level of this adduct in women with breast cancer (n = 12) who received three doses of CP in combination with one or two other cytostatic drugs was 250 % following the first dose and approximately 150 % after each subsequent dose. Measurement of the biomarker OzVal-Hb can be used to quantify the short-lived cytotoxic agent PAM in a single blood sample drawn several days after therapy. This procedure may aid in individualizing doses of CP, thereby improving efficacy while both reducing the risk of and increasing the predictability of side-effects.


Coronary atherosclerotic burden in patients with infection by CagA-positive strains of Helicobacter pylori.
Cytotoxic associated gene-A (CagA)-positive strains of Helicobacter pylori emerged as a possible atherosclerotic stimulus. Nevertheless, whether CagA-positivity is associated with more extensive or severe atherosclerotic coronary burden has never been studied. Forty consecutive patients with coronary artery disease (CAD) and twenty consecutive patients with normal coronary arteries undergoing coronary angiography were enrolled. All patients underwent evaluation of classical atherogenic risk factors and assessment of anti-urease B and anti-CagA antibodies titer. Either the severity of coronary stenosis (stenosis score) or the extent of coronary atherosclerosis (extent score) was evaluated in CAD patients. The anti-CagA antibody titer was significantly higher in patients with CAD as compared with normal coronary arteries patients [85 (10-108.75) vs. 47.3 (17-64) RU/ml, P=0.02], whereas there were no differences in anti-urease B titer between the two groups. A significant correlation was found between anti-CagA antibody titer and extent score (R=0.35, P=0.03), whereas stenosis score was similar (R=0.25, P=0.11). On the contrary, no significant correlation was found between anti-urease B antibody titer and either extent or stenosis score. Moreover, CagA-positive patients had a more extensive CAD (P=0.029) when compared with CagA-negative patients. Interestingly, whereas serum glucose, LDL levels, anti-urease B, and anti-CagA antibodies were predictors of extent score at univariate analysis, at multivariate analysis anti-CagA antibody titer only was an independent predictor of the extent of coronary atherosclerosis (B=0.051, standard error of B=0.042, P=0.04). These results support the association between CagA-positive H. pylori infection and coronary atherosclerotic burden. Further studies are needed to better elucidate the mechanism by which CagA-positive strains may promote atherosclerosis.


Sex-specific educational attainment is associated with telomere length in an Australian rural population.
There is limited understanding on whether and how socioeconomic status (SES), particularly educational attainment and household income, impacts on telomere length in an Australian rural context. Additionally, it is unknown whether access to health services via the Australian public or private health system influences telomere length. This study investigates whether there is a relationship between telomere length and SES indicators (income, education) as well as health insurance status in a rural Australian population. Samples were drawn from the Australian Rural Victoria cross-sectional Crossroads Study. Leucocyte telomere length (LTL) was measured using a multiplex quantitative polymerase chain reaction method. Among 1424 participants, we did not find a significant main effect association with LTL across education, income level and health insurance. An exploratory finding was sex may influence the relationship between educational attainment and LTL (P = 0.021). In males, but not females, higher education was associated with longer LTL by 0.033 [95% confidence interval (CI) 0.002-0.063, P = 0.035]; in those with low education attainment, male participants had shorter LTL by 0.058 (95% CI -0.086 to -0.029) than female participants (P < 0.0001). Being male and having lower education attainment was associated with shorter telomere length in our rural population. Evidence from our study supports the importance of education on LTL in males in rural Australia. Our studies also support previous findings that LTL in later life may not be closely associated with indicators of SES.


Gondeshapur Revisited; What Historical Evidence?
In recent years, in European academic circles, there has been a trend to dismiss Gondeshapur as a myth perpetrated by the Bokhtishu family in early Islamic era, despite many historiographical attestations. The writings of Islamic historians such as Al-Qifti and Ibn Abi Usaibia have been discounted as exaggerations by non-contemporary historians, and the lack of primary Pahlavi sources blamed for historical hyperbole. In this essay, I have attempted to show through primary Syriac Christian texts, that there was both a medical school and a bimarestan in Gondeshapur in pre-Islamic Sassanid era, and that Galenic medical texts had been translated and taught in that institution.


Fish consumption and its motives in households with versus without self-reported medical history of CVD: a consumer survey from five European countries.
The purpose of this study was to explore the cross-cultural differences in the frequency of fish intake and in motivations for fish consumption between people from households with (CVD+) or without (CVD-) medical history of cardiovascular disease, using data obtained in five European countries. A cross-sectional consumer survey was carried out in November-December 2004 with representative household samples from Belgium, the Netherlands, Denmark, Poland and Spain. The sample consisted of 4,786 respondents, aged 18-84 and who were responsible for food purchasing and cooking in the household. Individuals from households in the CVD+ group consumed fish more frequently in Belgium and in Denmark as compared to those in the CVD- group. The consumption of fatty fish, which is the main sources of omega-3 PUFA associated with prevention of cardiovascular diseases, was on the same level for the two CVD groups in the majority of the countries, except in Belgium where CVD+ subjects reported to eat fatty fish significantly more frequently than CVD- subjects. All respondents perceived fish as a very healthy and nutritious food product. Only Danish consumers reported a higher subjective and objective knowledge related to nutrition issues about fish. In the other countries, objective knowledge about fish was on a low level, similar for CVD+ as for CVD- subjects, despite a higher claimed use of medical information sources about fish among CVD+ subjects. Although a number of differences between CVD- and CVD+ subjects with respect to their frequency of fish intake are uncovered, the findings suggest that fish consumption traditions and habits - rather than a medical history of CVD - account for large differences between the countries, particularly in fatty fish consumption. This study exemplifies the need for nutrition education and more effective communication about fish, not only to the people facing chronic diseases, but also to the broader public. European consumers are convinced that eating fish is healthy, but particular emphasis should be made on communicating benefits especially from fatty fish consumption.


Reconstitution of succinate dehydrogenase in Bacillus subtilis by protoplast fusion.
Bacillus subtilis succinate dehydrogenase (SDH) is composed of two unequal subunits designated Fp (Mr, 65,000) and Ip (Mr. 28,000). The enzyme is structurally and functionally complexed to cytochrome b 558 (Mr, 19,000) in the membrane. A total of 21 B. subtilis SDH-negative mutants were isolated. The mutants fall into five phenotypic classes with respect to the presence and localization of the subunits of the SDH-cytochrome b558 complex. One class contains mutants with an inactive membrane-bound complex. Membrane-bound enzymatically active SDH could be reconstituted in fused protoplasts of selected pairs of SDH-negative mutants. Most likely reconstitution is due to the assembly of preformed subunits in the fused cells. On the basis of the reconstitution data, the mutants tested could be divided into three complementation groups. The combined data of the present and previous work indicate that the complementation groups correspond to the structural genes for the three subunits of the membrane-bound SDH-cytochrome b558 complex. A total of 31 SDH-negative mutants of B. subtilis have now been characterized. The respective mutations all map in the citF locus at 255 degrees on the B. subtilis chromosomal map. In the present paper, we have revised the nomenclature for the genetics of SDH in B. subtilis. All mutations which give an SDH-negative phenotype will be called sdh followed by an isolation number. The designation citF will be omitted, and the citF locus will be divided into three genes: sdhA, sdhB, and sdhC. Mutations in sdhA affect cytochrome b558, mutations in sdhB affect Fp, and mutations in sdhC affect Ip.


Skin picking phenomenology and severity comparison.
Despite the substantial distress and impairment often associated with skin picking, there currently is only limited research examining various phenomenological aspects of this behavior. The present research contributes to the existing literature by investigating phenomenological variables related to skin picking, such as family involvement, anxiety, depression, and the emotional consequences of skin picking. Moreover, on the basis of symptom severity level, differences were explored between individuals with skin picking who were from a psychiatric population. Forty individuals with various clinician-ascertained DSM-IV diagnoses in addition to skin picking symptomatology participated in the present study, which was conducted from September 2002 through January 2003. Participants were administered a self-report questionnaire (which assessed demographic, symptom, and past diagnostic information) as well as the Beck Depression Inventory, the Beck Anxiety Inventory, and the Self-Injury Interview. Phenomenological data on various aspects of individuals with skin picking are presented. Individuals with mild skin picking and individuals with severe skin picking were compared and found to differ in the level of distress they experienced (t = -2.35, p = .05) and the amount of damage caused by their picking behavior (t = -3.06, p = .01). Overall, skin picking represents a behavior with its own unique characteristics and accompanying levels of distress and impairment that warrants specific attention by clinicians.