Intracerebral injection of proinflammatory cytokines or leukocyte chemotaxins induces minimal myelomonocytic cell recruitment to the parenchyma of the central nervous system.
Neither excitotoxic neurodegeneration nor lipopolysaccharide induces an acute myelomonocytic exudate in the murine central nervous system (CNS) parenchyma (Andersson, P.-B., V. H. Perry, and S. Gordon. 1991. Neuroscience, 42:201; Andersson, P.-B., V. H. Perry, and S. Gordon. 1992. Neuroscience 48:169). In this study formyl-methionyl-leucyl-phenylalanine, platelet-activating factor, interleukin 8 (IL-8), IL-1, or tumor necrosis factor alpha were injected into the hippocampus to assess whether these leukocyte chemotaxins and known mediators of recruitment could bypass this block. They induced morphologic activation of microglia and widespread leukocyte margination but little or no cell exudation into the CNS parenchyma. By contrast, there was acute myelomonocytic cell recruitment to the choroid plexus, meninges, and ventricular system, comparable to that in the skin after subcutaneous injection. The normal CNS parenchyma appears to be a tissue unique in its resistance to leukocyte diapedesis, which is shown here to be at a step beyond chemotactic cytokine secretion or induction of leukocyte adhesion to cerebral endothelium.


Mechanical unfolding of cardiac myosin binding protein-C by atomic force microscopy.
Cardiac myosin-binding protein-C (cMyBP-C) is a thick-filament-associated protein that performs regulatory and structural roles within cardiac sarcomeres. It is a member of the immunoglobulin (Ig) superfamily of proteins consisting of eight Ig- and three fibronectin (FNIII)-like domains, along with a unique regulatory sequence referred to as the M-domain, whose structure is unknown. Domains near the C-terminus of cMyBP-C bind tightly to myosin and mediate the association of cMyBP-C with thick (myosin-containing) filaments, whereas N-terminal domains, including the regulatory M-domain, bind reversibly to myosin S2 and/or actin. The ability of MyBP-C to bind to both myosin and actin raises the possibility that cMyBP-C cross-links myosin molecules within the thick filament and/or cross-links myosin and thin (actin-containing) filaments together. In either scenario, cMyBP-C could be under mechanical strain. However, the physical properties of cMyBP-C and its behavior under load are completely unknown. Here, we investigated the mechanical properties of recombinant baculovirus-expressed cMyBP-C using atomic force microscopy to assess the stability of individual cMyBP-C molecules in response to stretch. Force-extension curves showed the presence of long extensible segment(s) that became stretched before the unfolding of individual Ig and FNIII domains, which were evident as sawtooth peaks in force spectra. The forces required to unfold the Ig/FNIII domains at a stretch rate of 500 nm/s increased monotonically from ∼30 to ∼150 pN, suggesting a mechanical hierarchy among the different Ig/FNIII domains. Additional experiments using smaller recombinant proteins showed that the regulatory M-domain lacks significant secondary or tertiary structure and is likely an intrinsically disordered region of cMyBP-C. Together, these data indicate that cMyBP-C exhibits complex mechanical behavior under load and contains multiple domains with distinct mechanical properties.


Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism.
Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancy among women in developed countries. New therapeutic strategies evaluated with relevant preclinical models are urgently needed to improve survival rates. Here, we have assessed the effect of pantethine on tumor growth and metabolism using magnetic resonance imaging and high-resolution proton magnetic resonance spectroscopy (MRS) in a model of ovarian cancer. To evaluate treatment strategies, it is important to use models that closely mimic tumor growth in humans. Therefore, we used an orthotopic model of ovarian cancer where a piece of tumor tissue, derived from an ovarian tumor xenograft, is engrafted directly onto the ovary of female mice, to maintain the tumor physiological environment. Treatment with pantethine, the precursor of vitamin B5 and active moiety of coenzyme A, was started when tumors were ~100 mm3 and consisted of a daily i.p. injection of 750 mg/kg in saline. Under these conditions, no side effects were observed. High-resolution 1H MRS was performed on treated and control tumor extracts. A dual-phase extraction method based on methanol/chloroform/water was used to obtain lipid and water-soluble fractions from the tumors. We also investigated effects on metastases and ascites formation. Pantethine treatment resulted in slower tumor progression, decreased levels of phosphocholine and phosphatidylcholine, and reduced metastases and ascites occurrence. In conclusion, pantethine represents a novel potential, well-tolerated, therapeutic tool in patients with ovarian cancer. Further in vivo preclinical studies are needed to confirm the beneficial role of pantethine and to better understand its mechanism of action.


Bifunctional catalysis in the stereocontrolled synthesis of tetrahydro-1,2-oxazines.
This study demonstrates that the annulation of a tetrahydro-1,2-oxazine ring can be realized via bifunctional catalysis, employing nitroolefins and a recently introduced group of aminooxylating reagents as starting materials. The developed cascade reactivity proceeds in a sequence aza-Michael-Michael reaction. The target products, bearing three contiguous stereocenters, have been obtained with high yields (up to 97%) and excellent stereocontrol (>20 : 1 dr, up to 99.5 : 0.5 er).


A phase II clinical trial of a dental health education program delivered by aboriginal health workers to prevent early childhood caries.
Early Childhood Caries (ECC) is a widespread problem in Australian Aboriginal communities causing severe pain and sepsis. In addition dental services are difficult to access for many Aboriginal children and trying to obtain care can be stressful for the parents. The control of dental caries has been identified as a key indictor in the reduction of Indigenous disadvantage. Thus, there is a need for new approaches to prevent ECC, which reflect the cultural norms of Aboriginal communities. This is a Phase II single arm trial designed to gather information on the effectiveness of a dental health education program for Aboriginal children aged 6 months, followed over 2 years. The program will deliver advice from Aboriginal Health Workers on tooth brushing, diet and the use of fluoride toothpaste to Aboriginal families. Six waves of data collection will be conducted to enable estimates of change in parental knowledge and their views on the acceptability of the program. The Aboriginal Health Workers will also be interviewed to record their views on the acceptability and program feasibility. Clinical data on the child participants will be recorded when they are 30 months old and compared with a reference population of similar children when the study began. Latent variable modeling will be used to interpret the intervention effects on disease outcome. The research project will identify barriers to the implementation of a family centered Aboriginal oral health strategy, as well as the development of evidence to assist in the planning of a Phase III cluster randomized study. ACTRN12612000712808.


Bactericidal efficacy of hydrogen peroxide on Cutibacterium acnes.
The purpose of this study was to examine the bactericidal efficacy of hydrogen peroxide (H2O2) on Cutibacterium acnes (C. acnes). We hypothesize that H2O2 reduces the bacterial burden of C. acnes. The effect of H2O2 was assessed by testing bactericidal effect, time course analysis, growth inhibition, and minimum bactericidal concentration. To assess the bactericidal effect, bacteria were treated for 30 minutes with 0%, 1%, 3%, 4%, 6%, 8%, or 10% H2O2 in saline or water and compared with 3% topical H2O2 solution. For time course analysis, bacteria were treated with water or saline (controls), 3% H2O2 in water, 3% H2O2 in saline, or 3% topical solution for 5, 10, 15, 20, and 30 minutes. Results were analyzed with a two-way analysis of variance (ANOVA) (p < 0.05). Minimum inhibitory concentration of H2O2 after 30 minutes is 1% for H2O2 prepared in saline and water. The 3% topical solution was as effective when compared with the 1% H2O2 prepared in saline or water. The controls of both saline and water showed no reduction of bacteria. After five minutes of exposure, all mixtures of H2O2 reduced the percentage of live bacteria, with the topical solution being most effective (p < 0.0001). Maximum growth inhibition was achieved with topical 3% H2O2. The inexpensive and commercially available topical solution of 3% H2O2 demonstrated superior bactericidal effect as observed in the minimum bactericidal inhibitory concentration, time course, and colony-forming unit (CFU) inhibition assays. These results support the use of topical 3% H2O2 for five minutes before surgical skin preparation prior to shoulder surgery to achieve eradication of C. acnes for the skin.Cite this article: P. Hernandez, B. Sager, A. Fa, T. Liang, C. Lozano, M. Khazzam. Bactericidal efficacy of hydrogen peroxide on Cutibacterium acnes. Bone Joint Res 2019;8:3-10. DOI: 10.1302/2046-3758.81.BJR-2018-0145.R1.


Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial.
Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.


Dietary Total Antioxidant Capacity and Cardiovascular Disease Risk Factors: A Systematic Review of Observational Studies.
Measurement of dietary total antioxidant capacity (DTAC) is considered a new holistic dietary approach and assesses total antioxidants present in the overall diet. Our aim was to perform a comprehensive review of the literature on the association between DTAC and cardiovascular disease (CVD) risk factors. PubMed, Web of Science, and Scopus were used to conduct a comprehensive search for articles published on this topic through September 2017. There was no limit on earliest year of publication. The search was based on the following keywords: dietary total antioxidant capacity, nonenzymatic antioxidant capacity, total radical-trapping antioxidant parameter, ferric reducing ability of plasma, oxygen radical absorbance capacity, Trolox equivalent antioxidant capacity, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total cholesterol (TC), waist circumference (WC), insulin resistance, homeostatic model assessment of insulin resistance (HOMA-IR), insulin, obesity, glucose, C-reactive protein (CRP), blood pressure (BP), and body mass index. In total, 16 papers were identified for inclusion in the present systematic review. Most well-designed studies that evaluated associations between DTAC and CVD risk factors showed inverse associations for fasting blood glucose, CRP, BP, and WC and positive associations for HDL-C. However, there was no association between DTAC and LDL-C or TC in any of the studies. Results regarding the association of DTAC with insulin, HOMA-IR, high-sensitivity CRP, and TG in the published literature were inconsistent. Findings indicated a substantial association between high DTAC and most CVD-related risk factors.


Malleability of the self: electrophysiological correlates of the enfacement illusion.
Self-face representation is fundamentally important for self-identity and self-consciousness. Given its role in preserving identity over time, self-face processing is considered as a robust and stable process. Yet, recent studies indicate that simple psychophysics manipulations may change how we process our own face. Specifically, experiencing tactile facial stimulation while seeing similar synchronous stimuli delivered to the face of another individual seen as in a mirror, induces 'enfacement' illusion, i.e. the subjective experience of ownership of the other's face and a bias in attributing to the self, facial features of the other person. Here we recorded visual Event-Related Potentials elicited by the presentation of self, other and morphed faces during a self-other discrimination task performed immediately after participants received synchronous and control asynchronous Interpersonal Multisensory Stimulation (IMS). We found that self-face presentation after synchronous as compared to asynchronous stimulation significantly reduced the late positive potential (LPP; 450-750 ms), a reliable electrophysiological marker of self-identification processes. Additionally, enfacement cancelled out the differences in LPP amplitudes produced by self- and other-face during the control condition. These findings represent the first direct neurophysiological evidence that enfacement may affect self-face processing and pave the way to novel paradigms for exploring defective self-representation and self-other interactions.


World Health Organization Estimates of the Global and Regional Disease Burden of 22 Foodborne Bacterial, Protozoal, and Viral Diseases, 2010: A Data Synthesis.
Foodborne diseases are important worldwide, resulting in considerable morbidity and mortality. To our knowledge, we present the first global and regional estimates of the disease burden of the most important foodborne bacterial, protozoal, and viral diseases. We synthesized data on the number of foodborne illnesses, sequelae, deaths, and Disability Adjusted Life Years (DALYs), for all diseases with sufficient data to support global and regional estimates, by age and region. The data sources included varied by pathogen and included systematic reviews, cohort studies, surveillance studies and other burden of disease assessments. We sought relevant data circa 2010, and included sources from 1990-2012. The number of studies per pathogen ranged from as few as 5 studies for bacterial intoxications through to 494 studies for diarrheal pathogens. To estimate mortality for Mycobacterium bovis infections and morbidity and mortality for invasive non-typhoidal Salmonella enterica infections, we excluded cases attributed to HIV infection. We excluded stillbirths in our estimates. We estimate that the 22 diseases included in our study resulted in two billion (95% uncertainty interval [UI] 1.5-2.9 billion) cases, over one million (95% UI 0.89-1.4 million) deaths, and 78.7 million (95% UI 65.0-97.7 million) DALYs in 2010. To estimate the burden due to contaminated food, we then applied proportions of infections that were estimated to be foodborne from a global expert elicitation. Waterborne transmission of disease was not included. We estimate that 29% (95% UI 23-36%) of cases caused by diseases in our study, or 582 million (95% UI 401-922 million), were transmitted by contaminated food, resulting in 25.2 million (95% UI 17.5-37.0 million) DALYs. Norovirus was the leading cause of foodborne illness causing 125 million (95% UI 70-251 million) cases, while Campylobacter spp. caused 96 million (95% UI 52-177 million) foodborne illnesses. Of all foodborne diseases, diarrheal and invasive infections due to non-typhoidal S. enterica infections resulted in the highest burden, causing 4.07 million (95% UI 2.49-6.27 million) DALYs. Regionally, DALYs per 100,000 population were highest in the African region followed by the South East Asian region. Considerable burden of foodborne disease is borne by children less than five years of age. Major limitations of our study include data gaps, particularly in middle- and high-mortality countries, and uncertainty around the proportion of diseases that were foodborne. Foodborne diseases result in a large disease burden, particularly in children. Although it is known that diarrheal diseases are a major burden in children, we have demonstrated for the first time the importance of contaminated food as a cause. There is a need to focus food safety interventions on preventing foodborne diseases, particularly in low- and middle-income settings.


Biochemical characterization and antioxidant and antiproliferative activities of different Ganoderma collections.
The aim of this study was to conduct a molecular and biochemical characterization and to compare the antioxidant and antiproliferative activities of four Ganoderma isolates belonging to Ganoderma lucidum (Gl-4, Gl-5) and Ganoderma resinaceum (F-1, F-2) species. The molecular identification was performed by ITS and IGS sequence analyses and the biochemical characterization by enzymatic and proteomic approaches. The antioxidant activity of the ethanolic extracts was compared by three different methods and their flavonoid contents were also analyzed by high-performance liquid chromatography. The antiproliferative effect on U937 cells was determined by MTT assay. The studied mycelia differ both in the enzymatic activities and protein content. The highest content in total phenol and the highest antioxidant activity for DPPH free radical scavenging and chelating activity on Fe(2+) were observed with the Gl-4 isolate of G. lucidum. The presence of quercetin, rutin, myricetin, and morin as major flavonoids with effective antioxidant activity was detected. The ethanolic extracts from mycelia of G. lucidum isolates possess a substantial antiproliferative activity against U937 cells in contrast to G. resinaceum in which the antiproliferative effects were insignificant. This study provides a comparison between G. lucidum and G. resinaceum mycelial strains, and shows that G. resinaceum could be utilized to obtain several bioactive compounds.


Enhancement of CO2 adsorption on oxygen-functionalized epitaxial graphene surface under near-ambient conditions.
The functionalization of graphene is important in practical applications of graphene, such as in catalysts. However, the experimental study of the interactions of adsorbed molecules with functionalized graphene is difficult under ambient conditions at which catalysts are operated. Here, the adsorption of CO2 on an oxygen-functionalized epitaxial graphene surface was studied under near-ambient conditions using ambient-pressure X-ray photoelectron spectroscopy (AP-XPS). The oxygen-functionalization of graphene is achieved in situ by the photo-induced dissociation of CO2 with X-rays on graphene in a CO2 gas atmosphere. The oxygen species on the graphene surface is identified as the epoxy group by XPS binding energies and thermal stability. Under near-ambient conditions of 1.6 mbar CO2 gas pressure and 175 K sample temperature, CO2 molecules are not adsorbed on the pristine graphene, but are adsorbed on the oxygen-functionalized graphene surface. The increase in the adsorption energy of CO2 on the oxygen-functionalized graphene surface is supported by first-principles calculations with the van der Waals density functional (vdW-DF) method. The adsorption of CO2 on the oxygen-functionalized graphene surface is enhanced by both the electrostatic interactions between the CO2 and the epoxy group and the vdW interactions between the CO2 and graphene. The detailed understanding of the interaction between CO2 and the oxygen-functionalized graphene surface obtained in this study may assist in developing guidelines for designing novel graphene-based catalysts.


Adipose tissue accumulation of d-limonene with the consumption of a lemonade preparation rich in d-limonene content.
d-limonene is a bioactive food component found in high concentration in citrus peel oil with anticancer effects in preclinical studies of mammary carcinogenesis. Extrapolation of preclinical data to human cancer is limited, in part, by inadequate information on the oral bioavailability and tissue disposition of d-limonene in humans. As a fat-soluble compound, d-limonene is more likely to deposit in fatty tissues such as the breast. To assess disposition of d-limonene in humans, we conducted a pilot study of oral d-limonene-rich lemonade. Following a 1-wk washout period devoid of citrus, healthy adults consumed 40 oz. of freshly prepared lemonade containing 500 to 600 mg d-limonene daily for 4 wk. On the first and last consumption days, blood and buttock fat biopsy were collected. Matched preintervention and postintervention fat biopsies (n = 7), and matched preintervention and postintervention plasma samples (n = 6), were analyzed for d-limonene levels using gas chromatography and mass spectrometry. There was a significant increase in d-limonene levels in the fat biopsies after 4 wk (P = 0.009); initial levels ranged from nondetectable to 7.79 micromol/kg tissue, and postintervention levels ranged from 53.6 to 294 micromol/kg tissue. Plasma d-limonene levels increased from 0.35 to 0.72 micromol/l initially to postintervention levels of 0.54 to 1.65 micromol/l (P = 0.016). Postintervention adipose d-limonene levels were 51.0 to 195 times higher than plasma levels (P = 0.009). Our results demonstrate accumulation of d-limonene in adipose tissue after oral dosing and support additional studies of d-limonene for chemoprevention in tissues such as the breast that are comprised of a significant fat fraction.


Control of lipid oxidation at the mitochondrial level.
The rate of lipid oxidation during exercise is controlled at several sites, and there is a reciprocal dependency between oxidation of lipids and carbohydrates (CHO). It is well known that the proportion of the 2 fuels oxidized is influenced by substrate availability and exercise intensity, but the mechanisms regulating fuel preferences remain unclear. During intense exercise, oxidation of long-chain fatty acids (LCFAs) decreases, and the major control is likely to be at the mitochondrial level. Potential mitochondrial sites for control of lipid oxidation include transport of LCFAs into mitochondrial matrix, beta-oxidation, the tricarboxylic acid cycle, and the electron transport chain (ETC). CHO catabolism may impair lipid oxidation by interfering with the transfer of LCFAs into mitochondria and by competing for mutual cofactors (i.e., nicotinamide adenine dinucleotide and (or) coenzyme A (CoA)). The different effect of energy state on the catabolism of CHO and lipids is likely to be of major importance in explaining the shift in fuel utilization during intensive exercise. Formation of acetyl-CoA from CHO is activated by a low energy state, and will lead to accumulation of products that are inhibitory to lipid oxidation. In contrast, beta-oxidation of LCFAs to acetyl-CoA is not stimulated by a low energy state. Further interaction between CHO and LCFAs may occur by substrate competition for electron carriers at ETC, due to provisions of electrons through different complexes. Feedback inhibition of beta-oxidation by redox state is thought to be an important mechanism for the slowing of lipid oxidation during intensive exercise.


Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes.
Once considered inoperable lesions in inviolable territory, brainstem cavernous malformations (BSCM) are now surgically curable with acceptable operative morbidity. Recommending surgery is a difficult decision that would be facilitated by a grading system designed specifically for BSCMs that predicted surgical outcomes. Informed by our efforts to develop a supplementary grading system for arteriovenous malformations, we hypothesized that a similar system might predict long-term outcomes and guide clinical decision-making. A consecutive, single-surgeon series of 104 patients was used to assess preoperative clinical and imaging predictors of microsurgical outcomes. Univariable logistic regression identified predictors and a multivariable logistic regression model tested the association of the combined predictors with final modified Rankin Scale scores. A grading system assigned points for lesion size, location crossing the brainstem's midpoint, presence of developmental venous anomaly, age, and time from last hemorrhage to surgery. Average maximal diameter of BSCMs was 19.5 mm; 50% crossed the axial midpoint; 54.8% had developmental venous anomalies; mean age was 42.1 years; and median time from last hemorrhage to surgery was 60 days. One patient died (0.96%), and 15 patients (14.4%) experienced worsened cranial nerve or motor dysfunction, of which 10 increased their modified Rankin Scale scores (9.6%). BSCM grades ranged from 0 to 7 points and predicted outcomes with high accuracy (receiver operating characteristic = 0.86, 95% confidence interval: 0.78-0.94). Rather than developing a grading system for all cerebral cavernous malformations that is weak with BSCMs, we propose a system for the patients who need it most. The BSCM grading system differentiates patients who might expect favorable surgical outcomes and offers guidance to neurosurgeons forced to select these patients.


Purification and characterization of autophagosomes from rat hepatocytes.
To investigate the properties and intracellular origin of autophagosomes, a procedure for the purification and isolation of these organelles from rat liver has been developed. Isolated hepatocytes were incubated with vinblastine to induce autophagosome accumulation; the cells were then homogenized and treated with the cathepsin C substrate glycyl-l-phenylalanine 2-naphthylamide to cause osmotic disruption of the lysosomes. Nuclei were removed by differential centrifugation, and the postnuclear supernatant was fractionated on a discontinuous Nycodenz density gradient. The autophagosomes, recognized by their content of autophagocytosed lactate dehydrogenase (LDH), could be recovered in an intermediate-density fraction, free from cytosol and mitochondria. Finally, the autophagosomes were separated from the endoplasmic reticulum and other membranous elements by centrifugation in a Percoll colloidal density gradient, followed by flotation in iodixanol to remove the Percoll particles. The final autophagosome preparation represented a 24-fold purification of autophagocytosed LDH relative to intact cells, with a 12% recovery. The purified autophagosomes contained sequestered cytoplasm with a normal ultrastructure, including mitochondria, peroxisomes and endoplasmic reticulum in the same proportions as in intact cells. However, immunoblotting indicated a relative absence of cytoskeletal elements (tubulin, actin and cytokeratin), which may evade autophagic sequestration. The autophagosomes showed no enrichment in protein markers typical of lysosomes (acid phosphatase, cathepsin B, lysosomal glycoprotein of 120 kDa), endosomes (early-endosome-associated protein 1, cation-independent mannose 6-phosphate receptor, asialoglycoprotein receptor) or endoplasmic reticulum (esterase, glucose-regulated protein of 78 kDa, protein disulphide isomerase), suggesting that the sequestering membranes are not derived directly from any of these organelles, but rather represent unique organelles (phagophores).


A new rapid immunoperoxidase diagnostic staining of herpes simplex virus 1 indolent corneal ulcer.
A tear film aspirate, from the lower fornix of a 64-year-old man with the clinical diagnosis of a herpes simplex indolent corneal ulcer, was examined via a new, rapid immunoperoxidase staining technique. This 4-hour modified immunoperoxidase stain is both sensitive and specific for herpes simplex virus type 1. The corneal epithelial cells shed in the tear film from the indolent ulcer were strongly positive for herpes simplex type 1 viral antigen using this new technique. This case report supports the theory that the pathogenesis of indolent herpetic corneal ulcers involves both a hypersensitivity response to viral antigen and an active viral infection.


Is there a weekend effect after hip fracture surgery? A study of 74,410 hip fractures reported to the Norwegian Hip Fracture Register.
Background and purpose - The term "weekend effect" describes differences in outcomes between patients treated at weekends compared with weekdays. We investigated whether there is a weekend effect for the risk of reoperation and mortality after hip fracture surgery at Norwegian hospitals.Patients and methods - We included data from 76,410 hip fractures in patients 60 years and older reported to the Norwegian Hip Fracture Register (NHFR) between 2005 and 2017. Cox survival analyses with adjustments for age, sex, ASA class, type of fracture, operating method, and waiting time from fracture to surgery were used to calculate the risk of reoperation and death after surgeries performed at weekends compared with surgeries performed on weekdays.Results - The mean age for all patients was 82 years, and 71% were female. 73% of fractures occurred on weekdays (Monday to Friday) and 27% during weekends (Saturday and Sunday). 71% of fractures were operated on a weekday and 29% at a weekend. Slightly increased mortality was observed during the 2 first months after weekend admission with hip fracture (HR 1.08; 95% CI 1.03-1.14). This did not continue in subsequent months, but the initial effect of weekend presentation was still apparent at 1-year follow-up. Further, there was no difference in mortality between patients who were operated at a weekend and patients operated on a weekday. Neither were there any differences in the risk of reoperation between weekday and weekend when comparing day of fracture or day of surgery.Interpretation - Patients who suffered a hip fracture during a weekend had slightly increased mortality in the first 2 months postoperatively. Whether the surgery was done on weekdays or at weekends did not affect mortality or the risk of reoperation.


Fresh onion juice enhanced copulatory behavior in male rats with and without paroxetine-induced sexual dysfunction.
Onion (Allium cepa) is one of the most commonly cultivated species of the family Liliaceae, and has long been used in dietary and therapeutic applications. Treatment with fresh onion juice has been reported to promote testosterone production in male rats. Testosterone is the male sex hormone responsible for enhancing sexual libido and potency. This study aimed to investigate the effects of onion juice on copulatory behavior of sexually potent male rats and in male rats with paroxetine-induced sexual dysfunction. Sexually experienced male rats were divided into seven groups: a control group, three onion juice-treated groups, a paroxetine-treated group, and two groups treated with paroxetine plus different doses of onion juice. At the end of the treatments, sexual behavior parameters and testosterone levels were measured and compared among the groups. Administration of onion juice significantly reduced mount frequency and latency and increased the copulatory efficacy of potent male rats. In addition, administration of onion juice attenuated the prolonged ejaculatory latency period induced by paroxetine and increased the percentage of ejaculating rats. Serum testosterone levels increased significantly by onion juice administration. However, a significant reduction in testosterone because of paroxetine therapy was observed. This reduction was restored to normal levels by administration of onion juice. This study conclusively demonstrates that fresh onion juice improves copulatory behavior in sexually potent male rats and in those with paroxetine-induced sexual dysfunction by increasing serum testosterone levels.


Synergistic interaction of CLAVATA1, CLAVATA2, and RECEPTOR-LIKE PROTEIN KINASE 2 in cyst nematode parasitism of Arabidopsis.
Plant-parasitic cyst nematodes secrete CLAVATA3 (CLV3)/ENDOSPERM SURROUNDING REGION (CLE)-like effector proteins. These proteins act as ligand mimics of plant CLE peptides and are required for successful nematode infection. Previously, we showed that the CLV2/CORYNE (CRN) heterodimer receptor complex is required for nematode CLE signaling. However, there was only a partial reduction in nematode infection when this signaling was disrupted, indicating that there might be additional nematode CLE receptors. In this study, we demonstrate that CLV1 and RECEPTOR-LIKE PROTEIN KINASE 2/TOADSTOOL2 (RPK2), two additional receptors that can transmit the CLV3 signal independent of CLV2/CRN for shoot apical meristem maintenance, also play a role in nematode CLE perception. Localization studies showed that both receptors are expressed in nematode-induced syncytia. Infection assays with clv1 and rpk2 single mutants revealed a decrease in both nematode infection and syncytium size. Significantly, further reduction in nematode infection was observed when rpk2 was combined with clv1 and clv2 mutants. Taken together, our results indicate that parallel signaling pathways involving CLV1, CLV2, and RPK2 are important for nematode parasitism.


Rising rates of syphilis in the era of syphilis elimination.
The objective of this study was to assess the impact of syphilis control activities in King County, Washington. We calculated rates of early syphilis and trends in numbers of persons tested and diagnosed through screening and partner notification from 1998 to 2005. Early syphilis cases increased from 38 in 1998 to 188 in 2005 with 92% occurring among men who have sex with men (MSM). Our health department conducted public awareness campaigns, increased publicly financed syphilis screening among MSM by 179%, and intensified partner notification efforts. Despite these efforts, the prevalence of syphilis among screened populations was only 1.1%, and 71% syphilis cases were diagnosed after seeking care for symptoms. The proportion of cases diagnosed through screening and partner notification did not significantly change during the evaluation period. Early syphilis incidence among MSM more than doubled between 2003 and 2005. New, innovative approaches to syphilis control are needed.


Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics.
Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. Patients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types. Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.


A comparison of two generic trap types for monitoring mosquitoes through an annual cycle in tropical Australia.
We compare the community composition, abundance, and seasonality of mosquito species detected by the encephalitis virus surveillance (EVS) CO2 traps and Centers for Disease Control and Prevention (CDC) light traps. Traps were run concurrently for a year during routine weekly monitoring in the vicinity of the city of Darwin in northern Australia. The EVS CO2 traps detected far more individuals than CDC light traps notwithstanding a weaker suction fan, but species richness was similar. Regardless of variation in community composition among sites, differences between trap types were remarkably consistent. Seasonal trends in the abundance of 5 key species from each trap type were similar, but markedly more so in strongly seasonal species. Although EVS CO2 traps outperformed CDC light traps for routine monitoring, the historical transition from the latter to the former is unlikely to have major consequences for the identification of community composition or detection of seasonal trends in key species.


Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial.
The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate > or =20 mL/min/1.73m and <90 mL/min/1.73 m) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.


Coaching and/or education intervention for parents with overweight/obesity and their children: study protocol of a single-centre randomized controlled trial.
In Canada, a majority of children and adults are insufficiently active for health gains, and about one in seven children and over 20% of adults are overweight or obese. Overweight and obesity are risk factors for many chronic diseases in both adults and children and can result in lower quality and quantity of life. Children whose parents are overweight or obese are more likely to become overweight themselves. Thus, parent/child interventions are important for reducing obesity and promoting long-term healthy weights among members of the family unit. Programs using Co-Active coaching have resulted in positive behaviour changes among adults with overweight/obesity; however, little research has explored the effects of Co-Active coaching on parents, and the consequent impact on the family unit (i.e. all parents and children in the same household). This protocol paper provides a detailed methodological account of a coaching-based program targeting parent and child dyads, in hopes of enhancing health behaviours within the family unit. Using a randomized controlled trial design, the researchers aim to identify the impact of coaching plus education (intervention) compared to education only (control) on parents with overweight/obesity and their children (ages 2.5-10, of any weight). A total of 50 dyads are being recruited and randomly assigned using a 1:1 ratio into the control or intervention group. The control group receive 6 webinar-based education sessions focused on physical activity and nutrition. The intervention group receive the same education sessions and nine, 20-min telephone-based sessions with a certified coach. Coaching and health education sessions are conducted with the parent/guardian of the dyad. This paper provides a detailed methodological account of this program. The expected findings from this research will advance coaching literature, research, and practice on this topic by determining whether coaching and education are more effective than education alone at producing behaviour changes among a family unit. If proven effective, this approach may be applied more broadly through public health interventionists to parent and child populations in hopes of affecting change with both individuals and their families. ISRCTN ISRCTN69091372 . Retrospectively registered 24 September 2018.


Mucosal healing and deep remission: what does it mean?
The use of specific terms under different meanings and varying definitions has always been a source of confusion in science. When we point our efforts towards an evidence based medicine for inflammatory bowel diseases (IBD) the same is true: Terms such as "mucosal healing" or "deep remission" as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are altered. It appears to be useful to first have a look at the development of terms and their definitions, to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and trials. The purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the terms. It may also lead to a better defined use of those terms for future studies. The terms "mucosal healing" and "deep remission" have been introduced in recent years as new therapeutic targets in the treatment of IBD patients. Several clinical trials, cohort studies or inception cohorts provided data that the long term disease course is better, when mucosal healing is achieved. However, it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical remission. Clinical trials are under way to answer this question. Attention should be paid to clearly address what levels of IBD activity are looked at. In the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists.


An optimized protocol for DNA extraction in plants with a high content of secondary metabolites, based on leaves of Mimosa tenuiflora (Willd.) Poir. (Leguminosae).
Some species are characterized by a high content of tannins, alkaloids, and phenols in their leaves. These secondary metabolites are released during DNA extraction and might hinder molecular studies based on PCR (polymerase chain reaction). To provide an efficient method to extract DNA, Mimosa tenuiflora, an important leguminous plant from Brazilian semiarid region used in popular medicine and as a source of fuelwood or forage, was used. Eight procedures previously reported for plants were tested and adapted from leaf tissues of M. tenuiflora stored at -20°C. The optimized procedure in this study encompassed the utilization of phenol during deproteinization, increased concentrations of cetyltrimethylammonium bromide and sodium chloride, and a shorter period and lower temperature of incubation concerning other methods. The extracted DNA did not present degradation, and amplification via PCR was successful using ISSR, trnL, ITS, and ETS primers. Besides M. tenuiflora, this procedure was also tested and proved to be efficient in genetic studies of other plant species.


Methionine 129 variant of human prion protein oligomerizes more rapidly than the valine 129 variant: implications for disease susceptibility to Creutzfeldt-Jakob disease.
The human PrP gene (PRNP) has two common alleles that encode either methionine or valine at codon 129. This polymorphism modulates disease susceptibility and phenotype of human transmissible spongiform encyphalopathies, but the molecular mechanism by which these effects are mediated remains unclear. Here, we compared the misfolding pathway that leads to the formation of beta-sheet-rich oligomeric isoforms of the methionine 129 variant of PrP to that of the valine 129 variant. We provide evidence for differences in the folding behavior between the two variants at the early stages of oligomer formation. We show that Met(129) has a higher propensity to form beta-sheet-rich oligomers, whereas Val(129) has a higher tendency to fold into alpha-helical-rich monomers. An equimolar mixture of both variants displayed an intermidate folding behavior. We show that the oligomers of both variants are initially a mixture of alpha- and beta-rich conformers that evolve with time to an increasingly homogeneous beta-rich form. This maturation process, which involves no further change in proteinase K resistance, occurs more rapidly in the Met(129) form than the Val(129) form. Although the involvement of such beta-rich oligomers in prion pathogenesis is speculative, the misfolding behavior could, in part, explain the higher susceptibility of individuals that are methionine homozygote to both sporadic and variant Creutzfeldt-Jakob disease.


Tunable reaction potentials in open framework nanoparticle battery electrodes for grid-scale energy storage.
The electrical energy grid has a growing need for energy storage to address short-term transients, frequency regulation, and load leveling. Though electrochemical energy storage devices such as batteries offer an attractive solution, current commercial battery technology cannot provide adequate power, and cycle life, and energy efficiency at a sufficiently low cost. Copper hexacyanoferrate and nickel hexacyanoferrate, two open framework materials with the Prussian Blue structure, were recently shown to offer ultralong cycle life and high-rate performance when operated as battery electrodes in safe, inexpensive aqueous sodium ion and potassium ion electrolytes. In this report, we demonstrate that the reaction potential of copper-nickel alloy hexacyanoferrate nanoparticles may be tuned by controlling the ratio of copper to nickel in these materials. X-ray diffraction, TEM energy dispersive X-ray spectroscopy, and galvanostatic electrochemical cycling of copper-nickel hexacyanoferrate reveal that copper and nickel form a fully miscible solution at particular sites in the framework without perturbing the structure. This allows copper-nickel hexacyanoferrate to reversibly intercalate sodium and potassium ions for over 2000 cycles with capacity retentions of 100% and 91%, respectively. The ability to precisely tune the reaction potential of copper-nickel hexacyanoferrate without sacrificing cycle life will allow the development of full cells that utilize the entire electrochemical stability window of aqueous sodium and potassium ion electrolytes.


[Predictive genomic markers for severe adverse drug reactions].
Severe adverse drug reactions are an important issue to be considered during proper drug usage in postmarketing period. Most severe adverse reactions are idiosyncratic and unrelated to their pharmacological actions via primary targets. Although these reactions were not predictable, recent developments in the field of genomics have revealed closely associated markers responsible for some severe adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review demonstrates genomic biomarkers for SJS/TEN and drug-induced liver injury (DILI) that were found mainly in Japanese patients and reveal ethnic differences. We and other groups have found the following associations of SJS/TEN with susceptible drugs: 1) HLA-B*58:01 for allopurinol-related cases; 2) HLA-B*15:11 and HLA-A*31:01 for carbamazepine-related cases; 3) HLA-B*51:01 for phenobarbital-related cases; 4) HLA-A*02:07 for zonisamide-related cases; 5) CYP2C9*3 for phenytoin-related cases; and 6) HLA-A*02:06 for cold medicine-related cases. The allele frequencies of these related HLA types vary among Asian populations. In addition, direct (noncovalent) binding of carbamazepine or an allopurinol metabolite, oxypurinol, to the associated HLA-type proteins was suggested. Associated genomic biomarkers are also summarized for DILI in Japanese and Caucasian populations. The application of these genomic biomarkers to prevent the onset of a reaction has been utilized in a few countries. However, in Japan, the package inserts only contain precautions that cite the research findings. To overcome this limitation, the following points should be addressed: 1) factors responsible for the development of SJS/TEN should be identified in addition to the above-mentioned HLA alleles; and 2) an inexpensive genotyping strategy and assay methods should be developed to provide a pharmacoeconomical viewpoint. Further research on severe adverse reactions is warranted.


Factors influencing women's willingness to volunteer in the healthcare system: evidence from the Islamic Republic of Iran.
This case-control study evaluated the factors influencing volunteering in the Islamic Republic of Iran's Women's Health Volunteer (WHV) programme, which is implemented in 150 centres in Khorasan-e-Razavi Province. We recruited 145 cases (volunteers) and 146 controls (non-volunteers) from the centres. Data were collected by questionnaire. Sociodemographic variables included were: length of residence in neighbourhood, number of siblings, husband's age and education and job, family size, quality of life, self-rated health status, neighbourhood intimacy, child under 2 years, house ownership, wealth index. Social network variables included were: ego network size, type of acquaintance, intimacy with others, relationship communication, relationship duration, emotional support, advisory support, monetary support, physical support, time support. There were significant associations (P<0.05) between women's propensity to volunteer and family size, presence of a child under 2 years in the family, neighbourhood intimacy, social network composition, and emotional and advisory support.


Information and order of information effects on consumers' acceptance and valuation for genetically modified edamame soybean.
This study examines two different strategies with respect to managing the order in which information about genetically modified (GM) technology would reach and impact consumers of edamame, often referred to as the "vegetable soybean". Edamame are soybeans harvested while the beans are young and soft. We capture consumers' willingness to pay (WTP) for unlabeled edamame, non-GM edamame, and GM edamame using a non-hypothetical random nth price auction. We elicit consumers' valuation for each edamame product before and after introducing information, and test two strategies where the order of providing positive and negative information is reversed. The results suggest that negative information affects WTP to a much greater extent than positive information. Hence a strategy to proactively deal with eventual negative press about GM technology did not lead to a different result than a strategy that would react to or attempt to thwart negative information with positive information at a later date. These findings suggest that it would be difficult to introduce new GM edamame as edible products in the market as marginally negative preconceptions about GM at the time of the experiment were easier to reinforce with negative information than to combat with positive information about GM.


The Use of the Bolk Model for Positive Health and Living Environment in the Development of an Integrated Health Promotion Approach: A Case Study in a Socioeconomically Deprived Neighborhood in The Netherlands.
Despite considerable efforts, health disparities between people with high and low socioeconomic status (SES) have not changed over the past decades in The Netherlands. To create a culture of health and an environment in which all people can flourish, a shift in focus is needed from disease management towards health promotion. The Bolk model for Positive Health and Living Environment was used as a tool to guide this shift. This study aimed to describe how this model was used and perceived by stakeholders in a case study on an integrated health promotion approach for residents with low SES. An instrumental case study was undertaken in Venserpolder, a neighborhood in Amsterdam South East of approximately 8500 residents. A participatory action approach was used that allowed continuous interaction between the residents, health care professionals, researchers, and other stakeholders. The Bolk model is a tool, based on the conceptual framework of positive health, that was developed to guide health promotion practice. Its use in the case study was evaluated by means of semistructured interviews with stakeholders, using qualitative directed content analyses. The Bolk model was found to be a useful tool to identify and map the needs and strengths of residents with low SES. The model facilitated the development and implementation of eight health promotion pilots by transforming the needs and strengths of residents into concrete actions carried out by responsible actors in the neighborhood. Although the Bolk model seemed to be accepted by all stakeholders, the shift towards positive health thinking appeared to be more embodied by local professionals than by residents. Adjustments were proposed to enhance the applicability of the model in a multicultural setting, to increase its cultural sensitivity and to use language more familiar to residents. The Bolk model for positive health and living environment seems to be promising in the guidance of health promotion practices in Amsterdam South East. Further research and development are needed to improve its cultural sensitivity and to investigate its applicability in a broader range of public health settings.


Guidance on priority setting in health care (GPS-Health): the inclusion of equity criteria not captured by cost-effectiveness analysis.
This Guidance for Priority Setting in Health Care (GPS-Health), initiated by the World Health Organization, offers a comprehensive map of equity criteria that are relevant to health care priority setting and should be considered in addition to cost-effectiveness analysis. The guidance, in the form of a checklist, is especially targeted at decision makers who set priorities at national and sub-national levels, and those who interpret findings from cost-effectiveness analysis. It is also targeted at researchers conducting cost-effectiveness analysis to improve reporting of their results in the light of these other criteria. THE GUIDANCE WAS DEVELOP THROUGH A SERIES OF EXPERT CONSULTATION MEETINGS AND INVOLVED THREE STEPS: i) methods and normative concepts were identified through a systematic review; ii) the review findings were critically assessed in the expert consultation meetings which resulted in a draft checklist of normative criteria; iii) the checklist was validated though an extensive hearing process with input from a range of relevant stakeholders. The GPS-Health incorporates criteria related to the disease an intervention targets (severity of disease, capacity to benefit, and past health loss); characteristics of social groups an intervention targets (socioeconomic status, area of living, gender; race, ethnicity, religion and sexual orientation); and non-health consequences of an intervention (financial protection, economic productivity, and care for others).


Upregulation of cellular glutathione levels in human ABCB5- and murine Abcb5-transfected cells.
Previously, we have demonstrated that human ABCB5 is a full-sized ATP-binding cassette transporter that shares strong homology with ABCB1/P-glycoprotein. ABCB5-transfected cells showed resistance to taxanes and anthracyclines. Herein, we further screened ABCB5 substrates, and explored the mechanism of resistance. Sensitivity of the cells to test compounds was evaluated using cell growth inhibition assay. Cellular levels of buthionine sulfoximine (BSO), glutathione and amino acids were measured using HPLC and an enzyme-based assay. Cellular and vesicular transport of glutathione was evaluated by a radiolabeled substrate. Expression levels of glutathione-metabolizing enzymes were assessed by RT-PCR. Human ABCB5-transfected 293/B5-11 cells and murine Abcb5-transfected 293/mb5-8 cells showed 6.5- and 14-fold higher resistance to BSO than the mock-transfected 293/mock cells, respectively. BSO is an inhibitor of gamma-glutamylcysteine ligase (GCL), which is a key enzyme of glutathione synthesis. 293/B5-11 and 293/mb5-8 cells also showed resistance to methionine sulfoximine, another GCL inhibitor. A cellular uptake experiment revealed that BSO accumulation in 293/B5-11 and 293/mb5-8 cells was similar to that in 293/mock cells, suggesting that BSO is not an ABCB5 substrate. The cellular glutathione content in 293/B5-11 and 293/mb5-8 cells was significantly higher than that in 293/mock cells. Evaluation of the BSO effect on the cellular glutathione content showed that compared with 293/mock cells the BSO concentration required for a 50 % reduction in glutathione content in 293/B5-11 and 293/mb5-8 cells was approximately 2- to 3-fold higher. This result suggests that the BSO resistance of the ABCB5- and Abcb5-transfected cells can be attributed to the reduced effect of BSO on the transfectants. Cellular and vesicular transport assays showed that the transport of radiolabeled glutathione in 293/B5-11 cells was similar to that in 293/mock cells. The mRNA expression of genes encoding glutathione-metabolizing enzymes in 293/B5-11 cells was similar to that in 293/mock cells. The cellular content of Glu, a precursor of glutathione, in 293/B5-11 and 293/mb5-8 cells was higher than that in 293/mock cells. ABCB5/Abcb5-transfected cells showed resistance to BSO, which is not a substrate of ABCB5. Our results suggest that ABCB5/Abcb5 upregulates cellular glutathione levels to protect cells from various poisons.


Applying the genetic theories of ageing to the cytoplasm: cytoplasmic genetic covariation for fitness and lifespan.
Two genetic models exist to explain the evolution of ageing - mutation accumulation (MA) and antagonistic pleiotropy (AP). Under MA, a reduced intensity of selection with age results in accumulation of late-acting deleterious mutations. Under AP, late-acting deleterious mutations accumulate because they confer beneficial effects early in life. Recent studies suggest that the mitochondrial genome is a major player in ageing. It therefore seems plausible that the MA and AP models will be relevant to genomes within the cytoplasm. This possibility has not been considered previously. We explore whether patterns of covariation between fitness and ageing across 25 cytoplasmic lines, sampled from a population of Drosophila melanogaster, are consistent with the genetic associations predicted under MA or AP. We find negative covariation for fitness and the rate of ageing, and positive covariation for fitness and lifespan. Notably, the direction of these associations is opposite to that typically predicted under AP.


Clinic attendances during the first 12 months of life for Aboriginal children in five remote communities of northern Australia.
The vast majority (>75%) of Aboriginal people in the Northern Territory (NT) live in remote or very remote locations. Children in these communities have high attendance rates at local Primary Health Care (PHC) centres but there is a paucity of studies documenting the reason and frequency of attendance. Such data can be used to help guide public health policy and practice. Clinic presentations during the first year of life were reviewed for 320 children born from 1 January 2001-31 December 2006. Data collected included reason for infectious presentation, antibiotic prescription and referral to hospital. The median number of presentations per child in the first year of life was 21 (IQR 15-29) with multiple reasons for presentation. The most prominent infectious presentations per child during the first year of life were upper respiratory tract infections (median 6, IQR 3-10); diarrhoea (median 3, IQR 1-5); ear disease (median 3, IQR 1-5); lower respiratory tract infection (median 3, IQR 2-5); scabies (median 3, IQR 1-5); and skin sores (median 3, IQR 2-5). Infectious diseases of childhood are strongly linked with poverty, poor living conditions and overcrowding. The data reported in our study were collected through manual review, however many remote communities now have established electronic health record systems, use the Key Performance Indicator System and are engaged in CQI (continuous quality improvement) processes. Building on these recent initiatives, there is an opportunity to incorporate routine monitoring of a range of infectious conditions (we suggest diarrhoea, LRTI, scabies and skin sores) using both the age at first presentation and the median number of presentations per child during the first year of life as potential indicators of progress in addressing health inequities in remote communities.


The Caenorhabditis elegans ABL-1 tyrosine kinase is required for Shigella flexneri pathogenesis.
Shigellosis is a diarrheal disease caused by the gram-negative bacterium Shigella flexneri. Following ingestion of the bacterium, S. flexneri interferes with innate immunity, establishes an infection within the human colon, and initiates an inflammatory response that results in destruction of the tissue lining the gut. Examination of host cell factors required for S. flexneri pathogenesis in vivo has proven difficult due to limited host susceptibility. Here we report the development of a pathogenesis system that involves the use of Caenorhabditis elegans as a model organism to study S. flexneri virulence determinants and host molecules required for pathogenesis. We show that S. flexneri-mediated killing of C. elegans correlates with bacterial accumulation in the intestinal tract of the animal. The S. flexneri virulence plasmid, which encodes a type III secretory system as well as various virulence determinants crucial for pathogenesis in mammalian systems, was found to be required for maximal C. elegans killing. Additionally, we demonstrate that ABL-1, the C. elegans homolog of the mammalian c-Abl nonreceptor tyrosine kinase ABL1, is required for S. flexneri pathogenesis in nematodes. These data demonstrate the feasibility of using C. elegans to study S. flexneri pathogenesis in vivo and provide insight into host factors that contribute to S. flexneri pathogenesis.


Direct Orthogonal Distance to Quadratic Surfaces in 3D.
Discovering the orthogonal distance to a quadratic surface is a classic geometric task in vision, modeling, and robotics. I describe a simple, efficient, and stable direct solution for the orthogonal distance (foot-point) to an arbitrary quadratic surface from a general finite 3D point. The problem is expressed as the intersection of three quadratic surfaces, two of which are derived from the requirement of orthogonality of two non-coincident planes with the tangent plane to the quadric. A sixth order single-variable polynomial is directly generated in one coordinate of the surface point. The method detects intersection points at infinity and operates smoothly across all real quadratic surface classes. The method also geometrically detects continuums of orthogonal points (i.e., from the exact center of a sphere). I discuss algorithm performance, compare it to a state-of-the-art estimator, demonstrate the algorithm on synthetic data, and describe extension to arbitrary dimension.


Recurrent SETBP1 mutations in atypical chronic myeloid leukemia.
Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.


Prevalence Rates of Acute Stress Disorder Symptomatology and Association to Juvenile Crime Involvement.
Little is known about the relationship between acute stress disorder and criminal behavior among youth. This study examined data from the National Comorbidity Survey-Adolescent Supplement (NCS-A). Participants in this survey, which took place between February 2001 and January 2003, consisted of 10,148 youth between the ages of 13 and 18 years. Because the NCS-A was conducted prior to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), symptoms of posttraumatic stress disorder from the fourth edition of the DSM were mapped to DSM-5 criteria for ASD. Due to changes in the DSM-5 criteria for ASD, youth in this study were described as having "ASD symptomatology." Youth with ASD symptomatology were significantly more likely to report involvement in crimes than youth without any lifetime diagnosis, regardless of whether the crimes resulted in arrest. The data presented here provide a more accurate picture of the relationship between ASD and crime. These data suggest that it may be useful to develop prevention and intervention strategies that provide education and support to at-risk youth who develop ASD symptoms. The quality of life for untreated youth decreases significantly, and untreated youth are likely at risk for criminal involvement, suicide, and other comorbid psychiatric disorders.


Smoking patterns and sociodemographic factors associated with tobacco use among Chinese rural male residents: a descriptive analysis.
Although evidence has shown high prevalence rates of tobacco use in the general urban populations in China, relatively little is known in its rural population. The purposes of this study were to examine smoking patterns and sociodemographic correlates of smoking in a sample of rural Chinese male residents. The study employed a cross-sectional, multi-stage sampling design. Residents (N = 4,414; aged 15 years and older) were recruited from four geographic regions in China. Information on participants' tobacco use (of all forms), including their daily use, and sociodemographic characteristics were collected via survey questionnaires and the resultant data were analyzed using chi-square tests and logistic regression procedures. The overall smoking prevalence in the study sample was 66.8% (n = 2,950). Of these, the average use of tobacco products per day was 12.70 (SD = 7.99) and over 60% reported daily smoking of more than 10 cigarettes. Geographic regions of the study areas, age of the participants, marital status, ethnicity, education, occupation, and average personal annual income were found to be significantly associated with an increased likelihood of smoking among rural Chinese male residents. There is a high smoking prevalence in the Chinese rural population and smoking behaviors are associated with important sociodemographic factors. Findings suggest the need for tobacco control and intervention policies aimed at reducing tobacco use in Chinese rural smoking populations.


Expression of the pyrG gene determines the pool sizes of CTP and dCTP in Lactococcus lactis.
The pyrG gene from Lactococcus lactis encodes CTP synthase (EC 18.104.22.168), an enzyme converting UTP to CTP. A series of strains were constructed with different levels of pyrG expression by insertion of synthetic constitutive promoters with different strengths in front of pyrG. These strains expressed pyrG levels in a range from 3 to 665% relative to the wild-type expression level. Decreasing the level of CTP synthase to 43% had no effect on the growth rate, showing that the capacity of CTP synthase in the cell is in excess in a wild-type strain. We then studied how pyrG expression affected the intracellular pool sizes of nucleotides and the correlation between pyrG expression and nucleotide pool sizes was quantified using metabolic control analysis in terms of inherent control coefficients. At the wild-type expression level, CTP synthase had full control of the CTP concentration with a concentration control coefficient close to one and a negative concentration control coefficient of -0.28 for the UTP concentration. Additionally, a concentration control coefficient of 0.49 was calculated for the dCTP concentration. Implications for the homeostasis of nucleotide pools are discussed.


Chronic Obstructive Pulmonary Disease and Cardiac Repolarization: Data from a Randomized Controlled Trial.
Altered cardiac repolarization is a risk factor for sudden cardiac death and seems to be increased in chronic obstructive pulmonary disease (COPD) patients. Lung volume reduction surgery (LVRS) has been shown to improve breathing mechanics and lung function in patients with severe COPD and emphysema and possibly also improve altered cardiac repolarization. Thirty patients scheduled for LVRS were randomized to LVRS or to the control group. We investigated the treatment effect 3 months after LVRS on measures of cardiac repolarization and dispersion of repolarization (QTc interval, QT dispersion) derived from electrocardiography. Univariable and multivariable analyses were used to identify possible confounders influencing the treatment effect. LVRS was associated with an improvement in lung function (mean ± SD residual volume/total lung capacity of -9 ± 11% and forced expiratory volume in 1 s of +30 ± 29%). LVRS did not significantly reduce QTc (median -5.3 ms, 95% confidence interval, CI -15.5 to 3.7, p = 0.214) and QT dispersion (median -3.0 ms, 95% CI -13.0 to 7.0, p = 0.536) compared to the control group. No significant association between change in QTc and change in QT dispersion, respectively, and change in possible confounders was found. LVRS seems to have no effect on cardiac repolarization in patients with COPD. Thus, lung hyperinflation seems not to be a causal mechanism for altered cardiac repolarization in COPD patients.


Toward Pervasive Gait Analysis With Wearable Sensors: A Systematic Review.
After decades of evolution, measuring instruments for quantitative gait analysis have become an important clinical tool for assessing pathologies manifested by gait abnormalities. However, such instruments tend to be expensive and require expert operation and maintenance besides their high cost, thus limiting them to only a small number of specialized centers. Consequently, gait analysis in most clinics today still relies on observation-based assessment. Recent advances in wearable sensors, especially inertial body sensors, have opened up a promising future for gait analysis. Not only can these sensors be more easily adopted in clinical diagnosis and treatment procedures than their current counterparts, but they can also monitor gait continuously outside clinics - hence providing seamless patient analysis from clinics to free-living environments. The purpose of this paper is to provide a systematic review of current techniques for quantitative gait analysis and to propose key metrics for evaluating both existing and emerging methods for qualifying the gait features extracted from wearable sensors. It aims to highlight key advances in this rapidly evolving research field and outline potential future directions for both research and clinical applications.


Sensory activity affects sensory axon development in C. elegans.
The simple nervous system of the nematode C. elegans consists of 302 neurons with highly reproducible morphologies, suggesting a hard-wired program of axon guidance. Surprisingly, we show here that sensory activity shapes sensory axon morphology in C. elegans. A class of mutants with deformed sensory cilia at their dendrite endings have extra axon branches, suggesting that sensory deprivation disrupts axon outgrowth. Mutations that alter calcium channels or membrane potential cause similar defects. Cell-specific perturbations of sensory activity can cause cell-autonomous changes in axon morphology. Although the sensory axons initially reach their targets in the embryo, the mutations that alter sensory activity cause extra axon growth late in development. Thus, perturbations of activity affect the maintenance of sensory axon morphology after an initial pattern of innervation is established. This system provides a genetically tractable model for identifying molecular mechanisms linking neuronal activity to nervous system structure.


A Functional Cartography of Cognitive Systems.
One of the most remarkable features of the human brain is its ability to adapt rapidly and efficiently to external task demands. Novel and non-routine tasks, for example, are implemented faster than structural connections can be formed. The neural underpinnings of these dynamics are far from understood. Here we develop and apply novel methods in network science to quantify how patterns of functional connectivity between brain regions reconfigure as human subjects perform 64 different tasks. By applying dynamic community detection algorithms, we identify groups of brain regions that form putative functional communities, and we uncover changes in these groups across the 64-task battery. We summarize these reconfiguration patterns by quantifying the probability that two brain regions engage in the same network community (or putative functional module) across tasks. These tools enable us to demonstrate that classically defined cognitive systems-including visual, sensorimotor, auditory, default mode, fronto-parietal, cingulo-opercular and salience systems-engage dynamically in cohesive network communities across tasks. We define the network role that a cognitive system plays in these dynamics along the following two dimensions: (i) stability vs. flexibility and (ii) connected vs. isolated. The role of each system is therefore summarized by how stably that system is recruited over the 64 tasks, and how consistently that system interacts with other systems. Using this cartography, classically defined cognitive systems can be categorized as ephemeral integrators, stable loners, and anything in between. Our results provide a new conceptual framework for understanding the dynamic integration and recruitment of cognitive systems in enabling behavioral adaptability across both task and rest conditions. This work has important implications for understanding cognitive network reconfiguration during different task sets and its relationship to cognitive effort, individual variation in cognitive performance, and fatigue.


An examination of ethnic identity and self-esteem with diverse populations: exploring variation by ethnicity and geography.
The current study examined the relationships among ethnic identity and self-esteem across multiple ethnic groups within two distinct geographical locations (N = 1,344). In the current study, for same ethnic group members, the components of ethnic identity (i.e., exploration, resolution, and affirmation) were differentially related to self-esteem based on geographical context. Furthermore, within each geographical context, the strength of the relation between each ethnic identity component and self-esteem varied based on group membership, suggesting that the variables may be more or less influential on self-esteem depending on one's group membership. Based on these results, the exploration and resolution subscales of the Ethnic Identity scale (EIS) appear to be valid and reliable with diverse samples, whereas support for the affirmation subscale of the EIS is more tenuous. Finally, these findings suggest that ethnic identity may have varying salience and meaning for same ethnic group members in different geographical contexts (e.g., Asian Americans in California vs. Asian Americans in the Midwest).


Value of the neutrophil-to-lymphocyte ratio in predicting left ventricular recovery in patients with peripartum cardiomyopathy.
The aim of this study was to assess the value of the neutrophil-to-lymphocyte ratio (NLR) in predicting left ventricular (LV) recovery in patients with peripartum cardiomyopathy (PPCM). Patients with PPCM (n = 40), who were admitted to our tertiary reference hospital between 2007 and 2015 were retrospectively analyzed. All patients were followed-up for at least 12 months after the diagnosis. All patients had standard echocardiographic examination at baseline and the last follow-up visit. Recovery of LV function was defined as the presence of LV ejection fraction (EF) >45%. Data on blood parameters were also collected at baseline. Univariate and multivariate analysis were used to assess the significant predictive variables for persistent LV systolic dysfunction. Of the patients 21 (52.5%) did not recover LV function at the last follow-up visit (nonrecovery group), while 19 of the patients (47.5%) exhibited LV recovery (recovery group). The LV EF and fractional shortening (FS) were significantly lower in the nonrecovery group. The baseline LV end-diastolic diameter, LV end-systolic diameter (LVESD) and systolic pulmonary arterial pressure were significantly increased in the nonrecovery group. The NLR, C‑reactive protein and troponin levels were significantly higher in the nonrecovery group. In multivariate logistic regression analysis only NLR and LVESD were identified as independent predictors of persistent LV systolic dysfunction in patients with PPCM (p = 0.020 and p = 0.009 respectively). Elevated NLR and increased LVESD were independent prognostic factors in predicting persistent LV dysfunction in patients with PPCM. The NLR might assist in identifying high risk patients with PPCM.


Effects of drug resistance mutations L100I and V106A on the binding of pyrrolobenzoxazepinone nonnucleoside inhibitors to the human immunodeficiency virus type 1 reverse transcriptase catalytic complex.
We have previously described a novel class of nonnucleoside reverse transcriptase (RT) inhibitors, the pyrrolobenzoxazepinone (PBO) and the pyridopyrrolooxazepinone (PPO) derivatives, which were effective inhibitors of human immunodeficiency virus type 1 (HIV-1) RT, either wild type or carrying known drug resistance mutations (G. Campiani et al., J. Med. Chem. 42:4462-4470, 1999). The lead compound of the PPO class, (R)-(-)-PPO464, was shown to selectively target the ternary complex formed by the viral RT with its substrates nucleic acid and nucleotide (G. Maga et al., J. Biol. Chem. 276:44653-44662, 2001). In order to better understand the structural basis for this selectivity, we exploited some PBO analogs characterized by various substituents at C-3 and by different inhibition potencies and drug resistance profiles, and we studied their interaction with HIV-1 RT wild type or carrying the drug resistance mutations L100I and V106A. Our kinetic and thermodynamic analyses showed that the formation of the complex between the enzyme and the nucleotide increased the inhibition potency of the compound PBO354 and shifted the free energy (energy of activation, DeltaG(#)) for inhibitor binding toward more negative values. The V106A mutation conferred resistance to PBO 354 by increasing its dissociation rate from the enzyme, whereas the L100I mutation mainly decreased the association rate. This latter mutation also caused a severe reduction in the catalytic efficiency of the RT. These results provide a correlation between the efficiency of nucleotide utilization by RT and its resistance to PBO inhibition.


Quality of traditional surveillance for public reporting of nosocomial bloodstream infection rates.
Central line-associated bloodstream infection (BSI) rates, determined by infection preventionists using the Centers for Disease Control and Prevention (CDC) surveillance definitions, are increasingly published to compare the quality of patient care delivered by hospitals. However, such comparisons are valid only if surveillance is performed consistently across institutions. To assess institutional variation in performance of traditional central line-associated BSI surveillance. We performed a retrospective cohort study of 20 intensive care units among 4 medical centers (2004-2007). Unit-specific central line-associated BSI rates were calculated for 12-month periods. Infection preventionists, blinded to study participation, performed routine prospective surveillance using CDC definitions. A computer algorithm reference standard was applied retrospectively using criteria that adapted the same CDC surveillance definitions. Correlation of central line-associated BSI rates as determined by infection preventionist vs the computer algorithm reference standard. Variation in performance was assessed by testing for institution-dependent heterogeneity in a linear regression model. Forty-one unit-periods among 20 intensive care units were analyzed, representing 241,518 patient-days and 165,963 central line-days. The median infection preventionist and computer algorithm central line-associated BSI rates were 3.3 (interquartile range [IQR], 2.0-4.5) and 9.0 (IQR, 6.3-11.3) infections per 1000 central line-days, respectively. Overall correlation between computer algorithm and infection preventionist rates was weak (ρ = 0.34), and when stratified by medical center, point estimates for institution-specific correlations ranged widely: medical center A: 0.83; 95% confidence interval (CI), 0.05 to 0.98; P = .04; medical center B: 0.76; 95% CI, 0.32 to 0.93; P = .003; medical center C: 0.50, 95% CI, -0.11 to 0.83; P = .10; and medical center D: 0.10; 95% CI -0.53 to 0.66; P = .77. Regression modeling demonstrated significant heterogeneity among medical centers in the relationship between computer algorithm and expected infection preventionist rates (P < .001). The medical center that had the lowest rate by traditional surveillance (2.4 infections per 1000 central line-days) had the highest rate by computer algorithm (12.6 infections per 1000 central line-days). Institutional variability of infection preventionist rates relative to a computer algorithm reference standard suggests that there is significant variation in the application of standard central line-associated BSI surveillance definitions across medical centers. Variation in central line-associated BSI surveillance practice may complicate interinstitutional comparisons of publicly reported central line-associated BSI rates.


Cannabinoids in Oral Fluid: Limiting Potential Sources of Cannabidiol Conversion to Δ9- and Δ8-Tetrahydrocannabinol.
In late 2019, the National Laboratory Certification Program (NLCP) published an article reporting on the potential analytical conversion of 7-carboxy cannabidiol (CBD-COOH) to 11-nor-9-carboxy-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in urine samples. The same conversion is possible in oral fluid with the parent analyte cannabidiol (CBD) converting to Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-tetrahydrocannabinol (Δ8-THC) under strong acidic conditions. With the recent rise in states legalizing the use of THC and the availability of products containing only CBD, unless the analytical in vitro conversions are controlled, the detection of Δ9-THC or Δ8-THC in oral fluid may not clarify whether the donor was using a CBD product or licit or illicit THC product. Authentic oral fluid samples submitted for cannabinoid analysis were subjected to multiple sample preparation procedures and extraction methods to determine the conditions that allow CBD to convert to THC. CBD single analyte controls prepared from a certified THC-free source were added to the batch to monitor the rate of conversion. Samples were prepared using a base hydrolysis, solid phase extraction, derivatization and analysis by liquid chromatography with tandem mass spectrometry (LC-MS-MS). The base hydrolysis and derivatization were tested independently and did not contribute to the conversion rate. Adjusting the pH of the sample preparation and extraction from pH 2.0 to pH 5.0 changed the conversion rate from 5 to 1%. A pH of 6.0 was not strong enough to extract the cannabinoids efficiently. Removing the acid component of the preparation and extraction procedure eliminated the conversion to THC; however, this did reduce the analyte recovery depending on which extraction column was used. Processing time also contributed to the conversion rate. With smaller trial runs, conversion was not always seen, but with larger validation batches low-level conversion of 1-2% was observed. A fully validated LC-MS-MS method utilizing solid-phase extraction was developed for CBD, Δ9-THC, Δ8-THC and cannabinol. The method specifically targets those analytes found in oral fluid after CBD administration and those that are seen during in vitro CBD conversion. CBD administration was performed using a certified THC-free CBD control.


Primary Care Providers' Perspectives on Providing Care to Women Veterans with Histories of Sexual Trauma.
One in four women Veterans who use the Veterans Health Administration (VA) screen positive for military sexual trauma and may need trauma-sensitive care and coordination. VA primary care providers (PCPs), women veterans' main source of care, need to be well-versed in trauma-sensitive approaches to care. Women veterans' numerical minority in the VA can make provider exposure to female patients inconsistent, which may impede PCP experience in providing appropriate care. To inform strategies for improving trauma-sensitive primary care, we sought to better understand PCPs' current approaches to providing care to women veterans with sexual trauma histories. We conducted semistructured telephone interviews with PCPs (n = 28) practicing in VA primary care clinics. Participants were asked about their experiences delivering trauma-sensitive care as well as best practices. Interviews were recorded, transcribed, and analyzed for major themes regarding barriers to and facilitators of trauma-sensitive care. Participants expressed challenges delivering care to women with sexual trauma histories, including 1) insufficient time, 2) lack of perceived proficiency and/or personal comfort (with general physical examinations as well as gender-specific care such as Pap, breast, and pelvic examinations), and 3) difficulties with fostering positive patient-provider relationships. Access to mental health resources was noted as a key facilitator of providing trauma-sensitive care. Participants also shared existing (and potential) best practices and recommendations, such as paying special attention to patient behavioral cues related to comfort. PCPs delivering care to women in VA facilities may benefit from an increased awareness of best practices to facilitate the delivery of trauma-sensitive care.


Effect of neuroleptics on altered cerebral glucose metabolism in schizophrenia.
This study examines whether the duration of treatment with antipsychotic drugs influences the regional distribution of cerebral [18F]2-fluoro-2-deoxy-D-glucose utilization as measured by positron emission tomography. Two groups of schizophrenic patients are compared with normal volunteers (n = 10). One group (n = 5) consisted of patients treated for one year, and the second (n = 12) of patients medicated for four to 14 years (mean +/- SD duration, 7.4 +/- 3.4 years). The first group was also examined before patients received their first dose ever of antipsychotic medication. One year of medication was not sufficient to alter the schizophrenic profile of cerebral cortical glucose activity but did elevate activity of the corpus striatum. Medication for 7.4 years also did not alter the schizophrenic pattern of frontal hyperactivity and posterior hypoactivity, although deviations from control values appeared less marked than after one year. On the other hand, in patients medicated for 7.4 years, there was perhaps an even greater increase in the activity of the corpus striatum and of the thalamus. Thus, duration of exposure to antipsychotic medication may affect the pattern of cerebral glucose activity; possibly, even longer exposure may contribute to the hypofrontality noted by others, although this can be confounded with the duration of illness as a factor. In considering the biological significance of the observed profile of cortical glucose activity, we introduce the concept of cerebral metabolic tone. We suggest that a disturbance of this tonus may account for some symptoms of schizophrenia and could be consistent with the hypothesis of abnormal developmental changes in the brains of schizophrenics.


Seasonal variations in plasma micronutrients and antioxidants.
Plasma samples were collected at monthly intervals for a period of 1 year from a group of healthy nonsmoking men and women (n = 21) living in Honolulu, HI. Analysis of plasma cholesterol and triglyceride levels showed marked seasonal variations, with higher mean levels in winter months and lower values in the summer. Cholesterol and triglycerides were highly and inversely correlated with plasma levels of the provitamin A carotenoids. Mean beta- and alpha-carotene levels were highest in late summer and fall. Plasma retinol levels were significantly lower in the summer and higher in the winter. Variations (either between individuals or seasonally) in plasma retinol were unrelated to plasma provitamin A carotenoid levels. Plasma levels of alpha-tocopherol, gamma-tocopherol, beta-cryptoxanthin, and lutein were also higher in the winter and lower in the summer. Significant seasonal correlations, both positive and negative, with environmental variables, such as temperature, solar UV radiation, and rainfall, are noted for many of these plasma micronutrients. The number of samples required to accurately characterize long-term plasma levels for an individual generally ranged from 1 to 4. However, plasma retinol levels exhibited the highest ratio of intra- to interindividual variability, suggesting the need for multiple sampling (> 8 samples) for this micronutrient. Some of this variability for retinol was associated with seasonal changes. Assessment by a diet history of food and supplement intake of micronutrients and phytochemicals for 1 year showed good agreement with 1-year mean plasma levels for most carotenoids, vitamin C, and alpha-tocopherol. Retinol, gamma-tocopherol, cholesterol, and triglyceride levels in plasma were unrelated to estimates of dietary intake.(ABSTRACT TRUNCATED AT 250 WORDS)


Association study between Apolipoprotein L and schizophrenia by exhaustive and rule-based combination analysis for identification of multilocus interactions.
Several single marker association and haplotypic analyses have been performed to identify susceptible genes for various common diseases, but these approaches using candidate genes did not provide accurate and consistent evidence in each analysis. This inconsistency is partly due to the fact that the common diseases are caused by complex interactions among various genetic factors. Therefore, in this study, to evaluate exhaustive genotype or allele combinations, we applied the binomial and random permutation test (BRP) proposed by Tomita et al. [IPSJ Digital Courier, 2, 691-709 (2006)] for the association analysis between an Apolipoprotein L gene cluster and schizophrenia. Using the seven selected representative single nucleotide polymorphisms (SNPs) based on the results of linkage disequilibrium evaluation, we analyzed 845 schizophrenic patients and 707 healthy controls, and investigated the validation of risk and protective factors with two randomly divided data sets. A comparative study of a method for analyzing the interactions was performed by conventional methods. Even if all the tested methods were used for analysis, the risk factor with a high significance was not commonly selected from both independent data sets. However, the significant interactions for the protective factor against disease development were commonly obtained from both data sets by BRP analysis. In conclusion, although it is considered that the causality of schizophrenia is too complex to identify a susceptible interaction using a small sample size, it was suggested that the healthy controls tend to have the same combination of certain alleles or genotypes for protection from disease development when BRP as a new exhaustive combination analytical method was used.


The Forgotten Agenda of Wasting in Southeast Asia: Burden, Determinants and Overlap with Stunting: A Review of Nationally Representative Cross-Sectional Demographic and Health Surveys in Six Countries.
Childhood wasting is among the most prevalent forms of undernutrition globally. The Southeast Asia region is home to many wasted children, but wasting is not recognized as a public health problem and its epidemiology is yet to be fully examined. This analysis aimed to determine the burden of wasting, its predictors, and the level of wasting and stunting concurrence. Datasets from Demographic and Health Surveys and Multiple Indicator Cluster Surveys in six countries in the region were analyzed. The pooled weighted prevalence for wasting and concurrent wasting and stunting among children 0-59 months in the six countries was 8.9%, 95% CI (8.0-9.9) and 1.6%, 95% CI (1.5-1.8), respectively. This prevalence is approximately 12-fold higher than the 0.7% prevalence of high-income countries; and translated into an absolute number of 1,088,747 children affected by wasting and 272,563 concurrent wasting and stunting. Wasting prevalence was 50 percent higher in the 0-23-month age group. Predictors for wasting included source of drinking water, wealth index, urban residence, child's age and history of illness and mother's body mass index. In conclusion, our analysis showed that wasting is a serious public health problem in the region that should be addressed urgently using both preventive and curative approaches.


Relationship between white spot syndrome virus and indicators of quality in Penaeus monodon postlarvae in Karnataka, India.
White spot disease (WSD) is a viral disease of shrimp caused by white spot syndrome virus (WSSV). Stocking WSSV-infected seed has been implicated as a major risk factor for outbreaks of WSD. In addition, the quality of postlarvae batches has been proposed as a predictor for good crops. This paper describes the relationship between indicators of quality and WSSV in postlarvae (PL) of Penaeus monodon from Karnataka, India, over the period September 1999 to January 2000. Three outcome variables were considered: the WSSV status of the PL, as determined by PCR, and 2 subjective assessments of PL quality, namely the activity of the PL and the quality of the PL as determined by research assistants and farmers, respectively. Of the 73 batches of PL, 49.3% from a random sample of farms tested positive for WSSV. After adjusting for confounding, stocking earlier in the growing season and duration of transportation were the main risk factors for the presence of WSSV. The quality assessed by farmers and the PL activity assessed by research assistants showed only fair agreement (kappa 0.252) reaffirming the subjective nature of such techniques. The only variables consistently associated with either assessment of quality in univariate analysis were PL length, number per bag and salinity of the water in the delivery bags. After adjusting for confounding, no single variable was consistently associated with PL quality and activity. The research assistants' assessment of PL activity was also associated with the hatchery and a brown-orange hepatopancreas in univariate analysis. After adjusting for confounding, a brown-orange hepatopancreas was still significant and fitted into the model together with the salinity of the water in the PL bags. The farmers' assessment of quality was associated with PL length, date of stocking and duration of transportation in both univariate and multivariable analyses. There was no relationship between quality assessment and WSSV in PCR-positive PL.