Neurobehavioral performance of Inuit children with increased prenatal exposure to methylmercury.
Exposure to methylmercury from marine mammals and other seafood may affect the development of the central nervous system. In a traditional Inuit community in Qaanaaq, Greenland, mercury concentrations in cord blood and maternal hair have been examined in connection with all births. We examined 43 children at age 7-12 years with a battery of neurobehavioral tests. The average mercury concentration in hair was 5.0 microg/g and 1.5 microg/g in children and mothers, respectively. Clinical neurological examination did not reveal any obvious deficits. However, neuropsychological tests showed possible exposure-associated deficits, though only in a few cases reaching statistical significance. In conjunction with data from other studies, peak latencies on brainstem auditory evoked potentials tended to be prolonged at increased exposure levels. The data from the present study therefore appears in accordance with other evidence that prenatal or early postnatal exposures to methylmercury may cause subtle neurobehavioral deficits.


LPT1 encodes a membrane-bound O-acyltransferase involved in the acylation of lysophospholipids in the yeast Saccharomyces cerevisiae.
Phospholipids are major components of cellular membranes that participate in a range of cellular processes. Phosphatidic acid (PA) is a key molecule in the phospholipid biosynthetic pathway. In Saccharomyces cerevisiae, SLC1 has been identified as the gene encoding lysophosphatidic acid acyltransferase, which catalyzes PA synthesis. However, despite the importance of PA, disruption of SLC1 does not affect cell viability (Nagiec, M. M., Wells, G. B., Lester, R. L., and Dickson, R. C. (1993) J. Biol. Chem. 268, 22156-22163). We originally aimed to identify the acetyl-CoA:lyso platelet-activating factor acetyltransferase (lysoPAF AT) gene in yeast. Screening of a complete set of yeast deletion clones (4741 homozygous diploid clones) revealed a single mutant strain, YOR175c, with a defect in lysoPAF AT activity. YOR175c has been predicted to be a member of the membrane-bound O-acyltransferase superfamily, and we designated the gene LPT1. An Lpt1-green fluorescent protein fusion protein localized at the endoplasmic reticulum. Other than lysoPAF AT activity, Lpt1 catalyzed acyltransferase activity with a wide variety of lysophospholipids as acceptors, including lysophosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, and lysophosphatidylserine. A liquid chromatography-mass spectrometry analysis indicated that lysophosphatidylcholine and lysophosphatidylethanolamine accumulated in the Deltalpt1 mutant strain. Although the Deltalpt1 mutant strain did not show other detectable defects, the Deltalpt1 Deltaslc1 double mutant strain had a synthetic lethal phenotype. These results indicate that, in concert with Slc1, Lpt1 plays a central role in PA biosynthesis, which is essential for cell viability.


Multiple imputation with compatibility for high-dimensional data.
Multiple Imputation (MI) is always challenging in high dimensional settings. The imputation model with some selected number of predictors can be incompatible with the analysis model leading to inconsistent and biased estimates. Although compatibility in such cases may not be achieved, but one can obtain consistent and unbiased estimates using a semi-compatible imputation model. We propose to relax the lasso penalty for selecting a large set of variables (at most n). The substantive model that also uses some formal variable selection procedure in high-dimensional structures is then expected to be nested in this imputation model. The resulting imputation model will be semi-compatible with high probability. The likelihood estimates can be unstable and can face the convergence issues as the number of variables becomes nearly as large as the sample size. To address these issues, we further propose to use a ridge penalty for obtaining the posterior distribution of the parameters based on the observed data. The proposed technique is compared with the standard MI software and MI techniques available for high-dimensional data in simulation studies and a real life dataset. Our results exhibit the superiority of the proposed approach to the existing MI approaches while addressing the compatibility issue.


A Distorted Hybrid Corannulene-Dibenzobistetracene.
We have designed and synthesized a new type of distorted nanographene by Diels-Alder and Scholl reactions that contains one dibenzobistetracene (DBT, 1) core and two end-capping corannulene units. Single-crystal X-ray diffraction analyses demonstrate that nanographene 1 contains two [5] helicene subunits with a dihedral angle of 62°, consequently leading to the distorted DBT core. In addition, the photophysical properties and (non)aromaticity of 1 were investigated by the absorption and emission spectra in combination with theoretical calculations.


Evaluating Success Factors of a Medication Adherence Tracker Pilot Program in Improving Part D Medication Adherence Metrics in a Medicare Advantage Plan: Importance of Provider Engagement.
Health plans and providers can increase quality by improving adherence to chronic disease medications included in star ratings among Medicare Advantage Part D (MAPD) plan enrollees. Research is needed to evaluate effective means of collaboration between health plans and providers. The Medication Adherence Tracker (MAT) is a health plan initiative to help primary care providers use outreach to improve their patients' adherence. To quantify the contribution of structural and process factors on the success of a health plan-initiated tracking system in improving chronic disease medication adherence over 6 months. The MAT quality improvement initiative was carried out in South Texas from June to December 2016. Health plan pharmacists used claims data to identify MAPD enrollees at risk of nonadherence to triple-weighted star medications: renin-angiotensin system antagonists, oral diabetes medications, and statins. Actionable reports were delivered biweekly to each provider, either by fax or in person, by embedded health plan nurses. Multivariable regression was used to evaluate sociodemographic and clinical factors as well as the role of provider outreach in increasing paid pharmacy claims and medication adherence as measured by proportion of days covered (PDC) > 0.8. Of 3,542 patients in 5 Texas physician-organized delivery system groups whose 67 providers received tracking reports from June through December 2016, 1,901 (54%) patients had more than 1 related prescription, and 3,064 (87%) received provider outreach on at least 1 prescription. 2,493 (70%) had at least 1 paid pharmacy claim. Provider outreach was associated with greater likelihood of paid prescription claims (relative risk [RR] = 4.59, 95% CI = 3.74-5.62) and greater year-end adherence (PDC > 0.8, RR = 1.86, 95% CI = 1.63-2.12) in multivariable predictive models. 95% CIs for age, gender, low-income subsidy eligibility, and number of prescriptions did not exclude the null value. Provider engagement is critical to effective health plan-provider partnerships to overcome barriers, change behavior, and improve chronic disease care quality and population outcomes. This study was funded by Cigna. The manuscript was prepared as a work for hire. Hong, Esse, Gallardo, Serna, Fosshat, and Mamvou are employees of CareAllies, a Cigna company. Bruce was employed by Cigna at the time of the study. Vadhariya reports a past internship at Regeneron Pharmaceuticals, unrelated to this work. Abughosh reports grants from Regeneron Pharmaceuticals, Valeant Pharmaceuticals, Sanofi, and BMS/Pfizer, unrelated to this work.


The Significance of Myriophyllum elatinoides for Swine Wastewater Treatment: Abundance and Community Structure of Ammonia-Oxidizing Microorganisms in Sediments.
Myriophyllum elatinoides was reported to effectively treat wastewater by removing nitrogen (N) and phosphorus (P). However, little is known about the abundance and community structure of ammonia-oxidizing microorganisms associated with M. elatinoides purification systems. The objective of this research was to characterize the abundance and community structure of ammonia-oxidizing microorganisms in swine wastewater and determine the main nitrogen removal pathways. In this study, five different waters were treated by M. elatinoides in microcosms for one month. The five waters included tap water (Control), swine wastewater (SW), 50% diluted swine wastewater (50% SW), and two synthetic wastewaters: 200 mg NH4+-N L(-1) (200 NH4+-N) and 400 mg NH4+-N L(-1) (400 NH4+-N). The most dramatic changes were in NH4+-N and total N (TN) concentrations, with average removal rates of 84% and 90%, respectively, in the treatments containing swine wastewater. On days 7, 14, and 28, the dissolved oxygen (DO) increased by 81.8%, 210.4% and 136.5%, respectively, compared with on day 0, in the swine wastewater. The results also showed that the bacterial amoA (AOB) copy numbers in the sediments of the treatments were significantly higher than those of archaeal amoA (AOA) copy numbers (p = 0.015). In addition, the high DO concentrations in swine wastewater responded well to the high abundance of AOB. The AOA and AOB community distributions were positively related with NO3-N and were negatively related with DO in swine wastewater treatments. In summary, our experimental results suggested that the M. elatinoides purification system could improve the activity of ammonia-oxidizing microorganisms and consequently might contribute to the significant N removal from the swine wastewater.


Impact of chronotropic effect of cilostazol after acute myocardial infarction: insights from change in left ventricular volume and function.
Cilostazol, a phosphodiesterase inhibitor, is an antiplatelet agent with positive chronotropic effect, the impact of which on left ventricular (LV) volume and function in acute myocardial infarction (AMI) was evaluated in the present study. In 56 patients with AMI treated with primary coronary stenting, serial echocardiographic studies within 24 h and at 6 months were performed. Patients received a conventional antiplatelet regimen either without cilostazol (group 1, n=29) or with cilostazol (group 2, n=27). At 6 months, the difference in the change in heart rate between group 1 and group 2 was statistically significant (9.9 beats/min; p=0.04). However, changes in LV end-systolic volume (LVESV) (7.1+/-8.2 vs 10.0+/-21.7 ml, p=0.60), LV ejection fraction (EF) (8.2+/-9.9 vs 9.0+/-12.6%, p=0.85) and the ratio of early mitral inflow velocity to the mitral annular velocity (E/E') (0.6+/-3.7 vs -1.7+/-3.2) were not different between the 2 groups. Cardiac event rate was similar between the 2 groups. On multivariate regression analyses, cilostazol therapy had no significant influence on the changes in LVESV, LVEF or E/E'. In this study, the addition of cilostazol on conventional drug therapy had no adverse influence on LV remodeling or LV function after AMI.


Cortisol as a Stress Indicator in Fish: Sampling Methods, Analytical Techniques, and Organic Pollutant Exposure Assessments.
Cortisol is the main glucocorticoid released during stress responses in most fish and has been employed to investigate different stressors, including organic pollutants. This review discusses shifts in cortisol concentrations and examines different matrix sampling methods (invasive vs. minimally or non-invasive) and the main analytical cortisol determination techniques (immunoassays and liquid chromatography-tandem mass spectrometry). Assessments on organic pollutant exposure in fish and associated adverse effects are also discussed. Studies in this regard may aid in identifying organic pollutant toxicological modes of action, mechanistic response, toxicokinetics, and toxicodynamics, as well as pollution sources and associated health risks in fish, ultimately aiding in the development of effective management strategies to mitigate the impacts of organic pollutants on fish populations and their associated ecosystems.


ILK participates in renal interstitial fibrosis by altering the phenotype of renal tubular epithelial cells via TGF-β1/smad pathway.
To explore the specific role of ILK (integrin-linked kinase) in regulating renal fibrosis and its underlying mechanism. NRK-52E cells were induced by transforming growth factor-β1 (TGF-β1) for observing phenotype change. Renal tubular epithelial cell marker, fibrosis marker and expression level of ILK in NRK-52E cells were also detected. After overexpression of ILK, phenotype change of NRK-52E cells was observed. For in vivo experiments, we constructed UUO (unilateral ureteral obstruction) model in CD1 mice. Renal tubular epithelial cell marker, fibrosis marker and expression level of ILK in UUO mice were detected. The regulatory effect of ILK on renal fibrosis was detected after injection of ILK overexpression plasmid. Western blot was performed to detect related genes in the TGF-β1/smad pathway. Accompanied by the TGF-β1-induced phenotype change in NRK-52E cells, both mRNA and protein levels of ILK were upregulated. Overexpression of ILK remarkably stimulated the phenotype change in NRK-52E cells. Similarly, ILK was highly expressed in UUO mice. Renal fibrosis was aggravated after injection of ILK overexpression plasmid in UUO mice. Western blot results showed that expressions of p-smad3 and smad3 were upregulated during the process of renal fibrosis. ILK is upregulated during the process of renal fibrosis. ILK participates in the development of renal fibrosis by altering phenotypes of renal tubular epithelial cells via a TGF-β1/smad pathway.


Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF).
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.


Impact of prenatal diagnosis in families.
Results are presented from a study of the experiences of families in which mothers utilized prenatal diagnostic testing. Responses indicate that many parents are discussing prenatal testing even with their very young children. Potentially stressful areas for children were seen in their expressed concerns about possibilities of detecting a defect, harm to the mother, and abortion. Preschool age children seemed especially vulnerable to becoming frightened by fantasies about the medical procedures. Recommendations are made for increased social work involvement in screening for and delivering services to families and children who encounter difficulties with the prenatal testing experience.


Complex bursting dynamics in an embryonic respiratory neuron model.
Pre-Bötzinger complex (pre-BötC) network activity within the mammalian brainstem controls the inspiratory phase of the respiratory rhythm. While bursting in pre-BötC neurons during the postnatal period has been extensively studied, less is known regarding inspiratory pacemaker neuron behavior at embryonic stages. Recent data in mouse embryo brainstem slices have revealed the existence of a variety of bursting activity patterns depending on distinct combinations of burst-generating INaP and ICAN conductances. In this work, we consider a model of an isolated embryonic pre-BötC neuron featuring two distinct bursting mechanisms. We use methods of dynamical systems theory, such as phase plane analysis, fast-slow decomposition, and bifurcation analysis, to uncover mechanisms underlying several different types of intrinsic bursting dynamics observed experimentally including several forms of plateau bursts, bursts involving depolarization block, and various combinations of these patterns. Our analysis also yields predictions about how changes in the balance of the two bursting mechanisms contribute to alterations in an inspiratory pacemaker neuron activity during prenatal development.


Treatment of open femoral and tibial shaft fractures preliminary report on external fixation and secondary intramedullary nailing.
From January 1987 to May 1989, a total of 38 adult cases were treated with 15 femoral and 25 tibial shaft shifting procedures from external fixation to reamed intramedullary nailing and followed up for at least 1 year (average, 23 months) at the authors' institution. The indications for the shifting procedures included routine sequential femoral external fixation and failed tibial external fixation treatment such as loss of reduction, atrophic healing process and inability of patients to tolerate casting. The delay period for the shifting procedure was 5 days in the femur and 48 days in the tibia. The union rate for the femur was 93% (14/15), and the tibia, 96% (24/25). The union period after the shifting procedure was 4.8 +/- 1.7 months in the femur, and 5.2 +/- 1.8 months in the tibia. Range of motion of the knee and ankle were satisfactory. Deep infection was the most serious complication, and the tibia was involved more often than the femur (20% to 13%) (p greater than 0.05). The most favorable management of deep infection was local drainage till bony union. We conclude that a shifting operation can be considered as one of the alternative procedures for several femoral or tibial shaft open fractures after fixation with external fixation. Wound and pin tract care, a shorter period of external fixation, a longer delay period before nailing, and perioperative antibiotic use may significantly lessen the infection rate.


The feasibility of a street-intercept survey method in an African-American community.
This study evaluates the feasibility of a nonquota, street-intercept survey method that utilized random selection of interview sites. The street-intercept survey was compared with a random digit-dial telephone survey conducted in the same catchment area among African-American adults aged 18 or older. The street-intercept survey's response rate was 80.2%; residence rate, 85.3%; interview completion rate, 97.9%; interference rate, 4.0%; and yield rate, 2.5 interviews per interviewer per hour. The street-intercept method produced more representative distributions of age and sex than the random-digit-dial survey. The street-intercept method is a feasible alternative to traditional population survey methods and may provide better access to harder-to-reach segments of the urban population in a safe manner.


Hypometric saccades and low-gain pursuit resulting from a thalamic hemorrhage.
Saccadic and pursuit eye movements were measured in a patient with a right thalamic hemorrhage using an infrared reflection technique. Saccades were hypometric when directed away from the side of the lesion, and pursuit was low in gain, with many interposed saccades, when directed toward the side of the lesion. This eye movement pattern is similar to that observed in hemidecorticate patients. We postulate that the ocular abnormalities observed in our patients were secondary to an interruption of the efferent pathways from the right cerebral areas mediating saccadic and smooth-pursuit eye movements.


Anti-Escherichia coli O157:H7 as Natural Preservative to Control and Prevent Food Contamination in Meat and Fish Products.
Shiga toxin-producing Escherichia coli O157:H7 is a troubled foodborne pathogen associated with contamination of meat, fish and poultry. The present work aimed to evaluate plant extracts as natural preservatives anti- Escherichia coli O157:H7 in meat and fish products. Antibacterial activity and minimum inhibitory concentrations (MICs) of seven herbal plants, clove, marjoram, sage, pomegranate peel, turmeric, Cassia fistula and black pepper and their different 6 mixes were examined against Escherichia coli O157:H7. Phytochemical qualitative analysis, phenolic compounds (HPLC), total phenolic, total flavonoid contents and antioxidant activities of individual extracts and their 6 mixes were evaluated. Combination Mix 5 extract was applied on meat and fish-fillet, then its antimicrobial effect against E. coli O157:H7 and sensory evaluation were assessed. Five extracts exhibited good antibacterial activity against Escherichia coli O157:H7. The greatest inhibition zone was recorded by clove aqueous extract (25 mm). Mix 5 (clove, sage, pomegranate and Cassia fistula) showed the highest inhibition with MIC of 3.0 mg mL-1. This mix exhibited strong anti-bactericidal effect against E. coli O157:H7 in meat and fish-fillet products throughout 8 days of cold storage (4°C). The sensory evaluation revealed that Mix 5 was acceptable by panelists with concentration of 0.50% in beef burgers and 0.25% in fish-fillet. This study suggests that the use of herbal extracts provide antibacterial potentials against food pathogens in meat and fish products.


[Regional differences in hospitalisations for complications of chronic hepatitis C in 2012].
Objective: Only limited recent information is available concerning the regional incidence and prevalence of chronic hepatitis C (CHC), but this information is critical for optimal definition of public health policies for the management of hepatitis C. The objective of this study was to evaluate the feasibility of mapping potential regional differences in the prevalence of CHC and its complications using data from a health administrative database. Methods: The 2012 PMSI MCO hospital database contains information on diagnosis and healthcare resource use, essentially related to all hospitalisations in France. Hospital stays related to CHC were identified on the basis of ICD-10 disease codes. Hospital stays were classified according to stage of liver disease: non-cirrhotic liver disease, compensated cirrhosis, decompensated cirrhosis or hepatocellular carcinoma (HCC). All study variables were documented for each French administrative region in 2012. Results: In 2012, 12,040 patients were hospitalised in France for a reason related to CHC, corresponding to a standardised age- and gender- adjusted prevalence rate of 19.3/100,000 persons. The highest prevalences of CHC and HCC were observed in the Ile de France, Alsace and Provence-Alpes-Côte-d'Azur regions. Conclusions: This study demonstrates the feasibility of using the PMSI database to identify regional differences in the prevalence of CHC. This information may be useful for planning regional healthcare resource provision for CHC.


Biochemical and ultrastructural investigation of the effect of Stelazine (trifluoperazine) on Hymenolepis diminuta (Cestoda).
The effects of the phenothiazine, Stelazine, on Hymenolepis diminuta were investigated. The cestode was incubated for 10 min at 37 degrees C with 1 mM trifluoperazine, in the presence and absence of Ca2+. Assay of brush border enzymes showed that drug treatment lowered the activities of alkaline phosphatase, Ca2+-ATP'ase, 5'-nucleotidase and type 1 phosphodiesterase. This occurred in parallel with a significant reduction in tegumental protein. Under these conditions gross changes in ultrastructural appearance and cellular organization were observed. There was a lack of ordered microtriches and the distal cytoplasm was absent. Glycogen granules were scattered throughout the cytoplasm within the subtegumental layer. The connective tissue also appeared to be in some disarray. The effects of Stelazine appeared to be dependent on time and were significantly increased when Ca2+ was included in the incubation medium. Incubation with the less hydrophobic phenothiazine trifluoperazine sulphoxide had minimal effect on the integrity of the cestode. The results reported here support the premise that certain phenothiazines may be considered as potential cestocidal agents.


Effects of intraperitoneal insulin versus subcutaneous insulin administration on sex hormone-binding globulin concentrations in patients with type 1 diabetes mellitus.
Elevated sex hormone-binding globulin (SHBG) concentrations have been described in patients with type 1 diabetes mellitus (T1DM), probably due to low portal insulin concentrations. We aimed to investigate whether the route of insulin administration, continuous intraperitoneal insulin infusion (CIPII), or subcutaneous (SC), influences SHBG concentrations among T1DM patients. Post hoc analysis of SHBG in samples derived from a randomized, open-labeled crossover trial was carried out in 20 T1DM patients: 50% males, mean age 43 (±13) years, diabetes duration 23 (±11) years, and hemoglobin A1c (HbA1c) 8.7 (±1.1) (72 (±12) mmol/mol). As secondary outcomes, testosterone, 17-β-estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were analyzed. Estimated mean change in SHBG was -10.3nmol/L (95% CI: -17.4, -3.2) during CIPII and 3.7nmol/L (95% CI: -12.0, 4.6) during SC insulin treatment. Taking the effect of treatment order into account, the difference in SHBG between therapies was -6.6nmol/L (95% CI: -17.5, 4.3); -12.7nmol/L (95% CI: -25.1, -0.4) for males and -1.7nmol/L (95% CI: -24.6, 21.1) for females, respectively. Among males, SHBG and testosterone concentrations changed significantly during CIPII; -15.8nmol/L (95% CI: -24.2, -7.5) and -8.3nmol/L (95% CI: -14.4, -2.2), respectively. The difference between CIPII and SC insulin treatment was also significant for change in FSH 1.2U/L (95% CI: 0.1, 2.2) among males. SHBG concentrations decreased significantly during CIPII treatment. Moreover, the difference in change between CIPII and SC insulin therapy was significant for SHBG and FSH among males. These findings support the hypothesis that portal insulin administration influences circulating SHBG and sex steroids.


Commentary: Closing the gender gap in depression through the lived experience of young women - a response to 'Don't mind the gap: Why do we not care about the gender gap in mental health?', Patalay and Demkowicz (2023).
Most mental health research largely ignores or minimises gender and age differences in depression. In 'Don't mind the gap: Why do we not care about the gender gap in mental health?', Patalay and Demkowicz identify a dearth of research on the causal factors of depression in young women. They attribute this to an over-reliance on biological accounts of gender differences in depression. Patalay and Demkowicz conclude that a person-centred approach that meaningfully engages with the reports of young women with depression is more likely to expose the social drivers of depression that impact this group. This commentary focuses on Patalay and Demkowicz's call to examine the patient's lived experience. We argue that there is an urgent need to reflect upon the methodologies involved in examining lived experience and how they can be best utilised. Ultimately, we advocate for an approach known as 'phenomenological psychopathology', through a phenomenological investigation of depression in young women, we can go some way towards closing the gender gap.


Periventricular leukomalacia (PVL): an identical twin case study illustration of white matter dysfunction and nonverbal learning disability (NLD).
This paper discusses the implications of Periventricular Leukomalacia (PVL) lesions for the development of Nonverbal Learning Disabilities (NLD) as illustrated through an identical twin case study. PVL lesions were identified in an 8-year-old child, but were not detected in his identical twin brother who served as a matched comparison. While the nonclinical twin displayed a largely unremarkable neuropsychological profile, the clinical twin evidenced a distinct pattern of social, intellectual, academic, and neuropsychological test results often identified among children with PVL and those with the NLD syndrome. The clinical and theoretical implications for this case study are discussed.


Congenital lumbar hernias: A case report.
Congenital lumbar hernias are rare and associated with other malformations. There have been 42 cases reported to date. The authors report the first case in the literature of isolated bilateral congenital lumbar hernias.


The high-level similarity of some disparate gene expression measures.
Probe-level data from Affymetrix GeneChips can be summarized in many ways to produce probe-set level gene expression measures (GEMs). Disturbingly, the different approaches not only generate quite different measures but they could also yield very different analysis results. Here, we explore the question of how much the analysis results really do differ, first at the gene level, then at the biological process level. We demonstrate that, even though the gene level results may not necessarily match each other particularly well, as long as there is reasonably strong differentiation between the groups in the data, the various GEMs do in fact produce results that are similar to one another at the biological process level. Not only that the results are biologically relevant. As the extent of differentiation drops, the degree of concurrence weakens, although the biological relevance of findings at the biological process level may yet remain.


[The maturation steps of human immunodeficiency virus and the role of proteolysis].
HIV-1 virions are as immature noninfectious particles lacking a central core. Shortly after budding, virions temporally mature and acquire cores and infectious activity. The cause of maturation remains poorly studied. We have revealed that the virions produced early after infection following 24-36 hours, never mature and remain noninfectious, and only virions produced 48-72 hours after infection mature. The mature virions contain 3 times more genomic viral RNA than "early" virus. The "early" virions contain the same proteolytically cleaved Gag proteins as mature virions in contrast to the accepted version. The virus protease inhibitor Indinavir sulfate (IS) fully blocks infectivity when added early after infection. The early proteolysis of Gag precursor in the infected cells and inclusion into the virions of cellularly cleaved matrix protein (cMA) are shown in the IS-treated cells. cMA is associated with genomic viral RNA.


Role of Aberrant Lipid Metabolism of Cancer Stem Cells in Cancer Progression.
Cancer stem cells (CSCs) represent a small population of cancer cells that are able to self-renew and initiate tumors, which undergo epigenetic, epithelial-mesenchymal, immunological, and metabolic reprogramming to adapt to the tumor microenvironment as well as survive host defense or therapeutic insults. The metabolic reprogramming that accompanies cancer onset is known to be critical for the disease pathogenesis. A coordinated dysregulation of lipid metabolism is observed in nearly all cancer types. In addition to fulfilling the basic requirements of structural lipids for membrane synthesis, lipids function importantly as signaling molecules and contribute to energy homeostasis. In this review, we summarize the current progress in the attractive research field of aberrant lipid metabolism regarding CSCs in cancer progression, which provides insights into therapeutic agents targeting CSCs based upon their modulation of lipid metabolism.


A rotational study of laser ablated thiourea.
A laser ablation device in combination with a molecular beam Fourier-transform microwave spectrometer has allowed the observation of the rotational spectrum of solid thiourea for the first time. The sensitivity reached in the experiment allowed the observation of the isotopomers (34)S, (13)C, and (15)N in their natural abundance. The spectrum of D(4)-thiourea was also analyzed from an enriched sample. The complicated hyperfine structure arising from the presence of two (14)N quadrupolar nuclei has been fully resolved and analyzed. The substitution r(s) structure has been derived from the experimental moments of inertia. Thiourea in gas phase presents a planar heavy atom skeleton. Experimental inertial defect values and high-level ab initio calculations reveal that the amino groups hydrogen atoms lie out-of-plane with a C(2) symmetry configuration and are involved in large amplitude inversion motions.


When does experience of psychosis result in a need for care? A prospective general population study.
Not all individuals with experience of psychosis develop a need for care. The present study investigated differences in coping strategies and associated levels of perceived control over psychotic symptoms, in relation to need for care status. The influence of coping on need for care was assessed in 47 individuals incident for psychosis in a general population sample of 4,722. Need for care was associated with severity of psychotic experiences rather than associated distress, mean level of control, or average number of coping strategies used. Qualitative differences were apparent, however, in that those who resorted to the strategy of symptomatic coping (a coping strategy characterized by going along with and indulging in symptoms) experienced less control over their symptoms (odds ratio [OR] = 0.79, 95% confidence interval [CI]: 0.63-0.98) and had a higher probability of need for care (OR = 6.07, 95% CI: 1.94-18.95). The results suggest that qualitative differences in self-initiated coping modify the risk for need for care and subsequent patient status in those who experience psychotic symptoms and point to the possible importance of early coping-based interventions.


Association Between Blood Pressure Control and Arterial Stiffness in Middle-Aged and Elderly Chinese Patients with Hypertension.
BACKGROUND The severity of arterial stiffness can be evaluated by pulse wave velocity (PWV). This study investigated the association between blood pressure (BP) control and arterial stiffness in middle-aged and elderly Chinese patients with hypertension. MATERIAL AND METHODS Three hundred and twelve hypertensive patients were divided according to whether their hypertension was well-controlled or uncontrolled and stratified according to age. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). The effect of BP control on arterial stiffness and its severity was assessed by multivariate linear and logistic regression analyses. RESULTS Moderate and severe arterial stiffness was detected significantly more often in patients with uncontrolled hypertension than in those with well-controlled hypertension, regardless of age. BaPWV increased by 8.467 cm/s in the study population overall for every 1-mmHg increment in systolic BP and by 8.584, 8.616, and 8.199 cm/s, respectively, in patients aged 45-65, 65-80, and ≥80 years. Regardless of age, the risk of arterial stiffness was 5.93 times higher (95% confidence interval 2.78-12.64) and the risk of a one-grade increase in the severity of arterial stiffness was 4.01 times higher (95% confidence interval 2.51-6.42) in patients with uncontrolled hypertension than in those with well-controlled hypertension. CONCLUSIONS This study found a positive relationship between baPWV and BP and identified uncontrolled BP as a risk factor for arterial stiffness and its severity. Management of BP within a reasonable range may help to ameliorate arterial stiffness.


Incidental maxillary sinus findings on cranial computerized tomographic scan in a tropical setting.
Abnormalities in the maxillary sinuses are occasional findings on routine CT scans of the head. To study the incidental findings in the CT scans of the maxillary sinuses in patients with indications other than sinuses-related diseases. Jos University Teaching Hospital, Jos, Nigeria. Images of patients who underwent CT scan of the head over a 5-month period (January 2015- May 2015) were retrospectively reviewed with the exclusion of those whose indication for the scan was trauma or sinus related disease. A total of 121 CT scan images were reviewed comprising 72 males and 49 females with a male to female ratio of 1.5 to 1.0. Their age range was between 5 and 90 years with a mean of 47.5 ± 20.4 years. The mean age of males was 48.7± 21.2 years while that of females is 45.7± 19.1years. The weight of the patients ranged between 12kg and 109kg with a mean weight of 64.7 ± 16.6kg. The most frequent indications for cranial CT scan were cerebrovascular accident (57; 47.1%), suspected space occupying lesion (23; 19.0%) and persistent headache (5; 4.1%). In all, 93(76.8%) patients had normal scan while 28 (23.2%) patients were observed with sinus pathology. Maxillary mucosal thickening with associated fluid level constituted 11 (9.1%) of the pathologic findings, and this was found bilaterally in 4(3.3%) patients. Seven (5.8%) patients had maxillary mucosal thickening only, with this occurring bilaterally in 4(3.3%) patients and 10 (8.3%) patients had polypoid masses, with bilateral polyps in 1(1.2%) individual. There was no statistical significance with the patient's weight in relation to the sinus findings. Incidental maxillary sinus pathologies on cranial CT scan are not infrequent. Vigilance is necessary during routine review and reporting of CT scans of the head for appropriate inclusion and interpretation of these findings towards optimal patient's care.


Comparison of Fecal Collection Methods for Microbiota Studies in Bangladesh.
To our knowledge, fecal microbiota collection methods have not been evaluated in low- and middle-income countries. Therefore, we evaluated five different fecal sample collection methods for technical reproducibility, stability, and accuracy within the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Fifty participants from the HEALS provided fecal samples in the clinic which were aliquoted into no solution, 95% ethanol, RNAlater, postdevelopment fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT) tubes. Half of the aliquots were frozen immediately at -80°C (day 0) and the remaining samples were left at ambient temperature for 96 h and then frozen (day 4). Intraclass correlation coefficients (ICC) were calculated for the relative abundances of the top three phyla, for two alpha diversity measures, and for four beta diversity measures. The duplicate samples had relatively high ICCs for technical reproducibility at day 0 and day 4 (range, 0.79 to 0.99). The FOBT card and samples preserved in RNAlater and 95% ethanol had the highest ICCs for stability over 4 days. The FIT tube had lower stability measures overall. In comparison to the "gold standard" method using immediately frozen fecal samples with no solution, the ICCs for many of the microbial metrics were low, but the rank order appeared to be preserved as seen by the Spearman correlation. The FOBT cards, 95% ethanol, and RNAlater were effective fecal preservatives. These fecal collection methods are optimal for future cohort studies, particularly in low- and middle-income countries.IMPORTANCE The collection of fecal samples in prospective cohort studies is essential to provide the opportunity to study the effect of the human microbiota on numerous health conditions. However, these collection methods have not been adequately tested in low- and middle-income countries. We present estimates of technical reproducibility, stability at ambient temperature for 4 days, and accuracy comparing a "gold standard" for fecal samples in no solution, 95% ethanol, RNAlater, postdevelopment fecal occult blood test cards, and fecal immunochemical test tubes in a study conducted in Bangladesh. Fecal occult blood test cards and fecal samples stored in 95% ethanol or RNAlater adequately preserve fecal samples in this setting. Therefore, new studies in low- and middle-income countries should include collection of fecal samples using fecal occult blood test cards, 95% ethanol, or RNAlater for prospective cohort studies.


Plasma dexamethasone concentrations and differential suppression response of cortisol and corticosterone in depressives and controls.
After a dexamethasone suppression test (DST), cortisol, corticosterone, and the test substance were determined by a direct radioimmunoassay in 42 samples obtained from 22 depressed patients and 8 controls. The DST results of both glucocorticoids agreed in most of the tests. In all seven cases with elevated but not definitely abnormal post-DST (1600 hr) cortisol levels (transitional range 30-50 ng/ml) the concurrent determination of corticosterone indicated that this corticosteroid may serve as a potent additional discriminator. Dexamethasone plasma concentrations at 1600 hr after a 1-mg test dose of dexamethasone at 2300 hr were significantly (p less than 0.01) lower in cortisol and corticosterone nonsuppressors than in suppressors. Since these data were obtained 17 hr after ingestion of dexamethasone (half-life 3.5-5 hr) any conclusions about an inverse correlation between dexamethasone and corticosteroid plasma concentrations would be speculative. However, the dexamethasone pharmacokinetics might be an important variable and may contribute to some of the recent uncertainty about the DST.


Cutting edge: macrophage migration inhibitory factor is necessary for progression of experimental autoimmune encephalomyelitis.
Macrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of inflammatory and autoimmune diseases. The role of MIF in the progression of experimental autoimmune encephalomyelitis (EAE) was explored using MIF-/- mice. Wild-type mice showed a progressive disease course, whereas MIF-/- mice exhibited acute signs but no further progression of clinical disease. MIF-/- mice displayed markedly elevated corticosterone levels and significant decreases in the inflammatory cytokines TNF-alpha, IFN-gamma, IL-2, and IL-6 before, during, and after EAE onset. Taken together, these findings support that MIF is an important mediator of EAE progression through glucocorticoid antagonism and up-regulation of the inflammatory response.


Absence of pantothenic acid in gramicidin S synthetase 2 obtained from some mutants of Bacillus brevis.
The pantothenic acid content of gramicidin S synthetase 2(GS 2) was estimated microbiologically with enzymes obtained from the wild strain and gramicidin S-lacking mutant strains of Bacillus brevis. Four mutant enzymes from BI-4, C-3, E-1, and E-2 lacked pantothenic acid. Other mutant enzymes from BII-3, BI-3, BI-9, and BI-2 contained the same amount of pantothenic acid as the wild-type enzyme. Pantothenic acid-lacking GS 2 belonged to group V of mutant enzymes, which could activate all amino acids related to gramicidin S; their complementary enzyme, gramicidin S synthetase 1(GS 1), lacked racemizing activity. To ascertain whether 4'-phosphopantetheine is involved in the formation of D-phenylalanyl-L-prolyl diketopiperazine (DKP) and gramicidin S, combinations were tested of intact GS 1 from the wild strain with various mutant GS 2 either containing or lacking pantothenic acid. Only the combinations of wild-type GS 1 with mutant GS 2 containing pantothenic acid could synthesize DKP. Combinations with pantothenic acid-lacking GS 2 also failed to elongate peptide chains. Pantothenic acid-lacking GS 2 could bind the four amino acids which constitute gramicidin S as acyladenylates and thioesters, but the binding abilities were lower than those of the wild-type enzyme and other mutant enzymes containing the pantothenic group.


Injuries to the profunda femoris artery and its branches.
Six cases of uncommon profunda femoris artery injury are analyzed. One half of the cases were not treated surgically at the time of injury and resulted in chronic arteriovenous fistulas. Even after operative correction, residual symptoms persisted in two of these three cases. The generous use of arteriography is recommended in cases of proximal thigh penetrating injuries to avoid this problem. Either repair or ligation of the injured vessel yielded the same good results. The postoperative hospital stay was short in all instances, ranging from four to eight days, and there were no deaths.


Interplant signalling through hyphal networks.
Mycorrhizal fungi can form common mycelial networks (CMNs) that interconnect plants. Here, we provide an insight into recent findings demonstrating that CMNs can be conduits for interplant signalling, influencing defence against insect herbivores and foliar necrotrophic fungi. A likely mechanism is direct transfer of signalling molecules within hyphae. However, electrical signals, which can be induced by wounding, may also enable signalling over relatively long distances, because the biophysical constraints imposed by liquid transport in hyphae and interaction with soil are relieved. We do not yet understand the ecological, evolutionary and agronomic implications of interplant signalling via CMNs. Identifying the mechanism of interplant signalling will help to address these gaps.


On the use of C-arm fluoroscopy for treatment planning in high dose rate brachytherapy.
Treatment planning for brachytherapy requires the acquisition of geometrical information of the implant applicator and the patient anatomy. This is typically done using a simulator or a computed tomography scanner. In this study, we present a different method by which orthogonal images from a C-arm fluoroscopic machine is used for high dose rate brachytherapy treatment planning. A typical C-arm is not isocentric, and it does not have the mechanical accuracy of a simulator. One solution is to place a reconstruction box with fiducial markers around the patient. However, with the limited clearance of the C-arm this method is very cumbersome to use, and is not suitable for all patients and implant sites. A different approach is adopted in our study. First, the C-arm movements are limited to three directions only between the two orthogonal images: the C-orbital rotation, the vertical column, and the horizontal arm directions. The amounts of the two linear movements and the geometric parameters of the C-arm orbit are used to calculate the location of the crossing point of the two beams and thus the magnification factors of the two images. Second, the fluoroscopic images from the C-arm workstation are transferred in DICOM format to the planning computer through a local area network. Distortions in the fluoroscopic images, with its major component the "pincushion" effect, are numerically removed using a software program developed in house, which employs a seven-parameter polynomial filter. The overall reconstruction accuracy using this method is found to be 2 mm. This filmless process reduces the overall time needed for treatment planning, and greatly improves the workflow for high dose rate brachytherapy procedures. Since its commissioning nearly three years ago, this system has been used extensively at our institution for endobronchial, intracavitary, and interstitial brachytherapy planning with satisfactory results.


Amyloidosis and the lung.
Amyloidosis is a disorder of protein folding in which normally soluble plasma proteins aggregate in an abnormal fibrillar form causing progressive disruption to tissue structure and organ function. This review covers systemic AA and AL amyloidosis which may arise as a consequence of chronic respiratory conditions; the manifestations of both systemic and of localised amyloid deposition within the respiratory tract and provides a summary of current approaches to diagnosis and management.


Erythropoietin gene transfer and expression in adult normal mice: use of an adenovirus vector.
A hormonal model of erythropoietin (Epo) delivery by use of an adenovirus vector was investigated. We constructed a replication-defective adenovirus carrying the monkey (cynomolgus) Epo cDNA under control of the Rous sarcoma virus long terminal repeat promoter. Fifty 8-week-old mice were injected with escalating doses of the recombinant virus from 10(6) to 10(10) plaque-forming units (pfu). Different modes of administration were studied. Intravenous (i.v.) injection was the most effective mode of administration and exhibited a dose-dependent response. After a single i.v. injection with high doses (5 x 10(9) and 10(10) pfu), a dramatic increase in hematocrit (Hct) and long-term Epo expression (6 months at this time) were observed. Intravenous administration with lower doses and intramuscular (i.m.) administration were inefficient or had a very transient effect. A localized muscle attrition prior to i.m. administration of 10(10) pfu enhanced Hct response. This initial study opens the way for high level and durable Epo therapy by gene transfer. Moreover, this recombinant virus provides a convenient means to study the efficacy, duration, and safety aspects of hormonal delivery by an adenoviral vector.


Seismic anisotropy evidence for dehydration embrittlement triggering intermediate-depth earthquakes.
It has been proposed that dehydration embrittlement of hydrous materials can trigger intermediate-depth earthquakes and form a double seismic zone in a subducting slab. Seismic anisotropy may provide a possible insight into intermediate-depth intraslab seismicity, because anisotropic properties of minerals change with varying water distribution, temperature and pressure. Here we present a high-resolution model of P-wave radial anisotropy tomography of the Japan subduction zone down to ~400 km depth, which is obtained using a large number of arrival-time data of local earthquakes and teleseismic events. Our results reveal a close correlation between the pattern of intermediate-depth seismicity and anisotropic structures. The seismicity occurs in portions of the Pacific and Philippine Sea slabs where positive radial anisotropy (i.e., horizontal velocity being faster than vertical one) dominates due to dehydration, whereas the inferred anhydrous parts of the slabs are found to be aseismic where negative radial anisotropy (i.e., vertical velocity being faster than horizontal one) dominates. Our anisotropic results suggest that intermediate-depth earthquakes in Japan could be triggered by dehydration embrittlement of hydrous minerals in the subducting slabs.


Antibody-dependent plaque enhancement: its antigenic specificity in relation to Togaviridae.
The antigenic specificity of antibody-dependent plaque enhancement (ADPE) on the macrophage cell line P388D1 has been investigated using viruses in the flavivirus and alphavirus genera. Whereas ADPE detected group-specific antigenic determinants in the flaviviruses, narrower specificity (type and subgroup) was seen with alphaviruses. ADPE titres correlated well with haemagglutination inhibition titres.


A new atraumatic and simple method of taking sural nerve grafts.
Because the sural nerve has become the most frequently used nerve as graft material in peripheral nerve reconstruction, an atraumatic method was developed for its harvesting. The nerve is easily identified in the popliteal region by stretching it slightly behind the lateral malleolus. Only two short skin incisions are needed for centrifugal liberation of the nerve. The advantages of the method presented lie in shorter operation time, a superior cosmetic result and a fairly intact nerve for grafting.


Age and Gender Differences in the Pseudo-Haptic Effect on Computer Mouse Operation in a Desktop Environment.
Pseudo-haptics is a method that can provide a haptic sensation without requiring a physical haptic device. The effect of pseudo-haptics is known to depend on the individual, but it is unclear which factors cause individual differences. As the first study establishing a calibration method for these differences in future research, we examined the differences in the pseudo-haptic effect on mouse cursor operation in a desktop environment depending on the age and gender of the user. We conducted an online experiment and collected data from more than 400 participants. The participants performed a task of lifting a virtual object with a mouse pointer. We found that the effect of pseudo-haptics was greater in younger or male participants than in older or female participants. We also found that the effect of pseudo-haptics, which varied with age and gender, can be explained by habituation to the mouse in daily life and the accuracy of detecting the pointer position using vision or proprioception. Specifically, the pseudo-haptic effect was higher for those who used the mouse more frequently and had higher accuracy in identifying the pointer position using proprioception or vision. The results of the present study not only indicate the factors that cause age and gender differences but also provide hints for calibrating these differences.


Carbohydrate Recognition Specificity of Trans-sialidase Lectin Domain from Trypanosoma congolense.
Fourteen different active Trypanosoma congolense trans-sialidases (TconTS), 11 variants of TconTS1 besides TconTS2, TconTS3 and TconTS4, have been described. Notably, the specific transfer and sialidase activities of these TconTS differ by orders of magnitude. Surprisingly, phylogenetic analysis of the catalytic domains (CD) grouped each of the highly active TconTS together with the less active enzymes. In contrast, when aligning lectin-like domains (LD), the highly active TconTS grouped together, leading to the hypothesis that the LD of TconTS modulates its enzymatic activity. So far, little is known about the function and ligand specificity of these LDs. To explore their carbohydrate-binding potential, glycan array analysis was performed on the LD of TconTS1, TconTS2, TconTS3 and TconTS4. In addition, Saturation Transfer Difference (STD) NMR experiments were done on TconTS2-LD for a more detailed analysis of its lectin activity. Several mannose-containing oligosaccharides, such as mannobiose, mannotriose and higher mannosylated glycans, as well as Gal, GalNAc and LacNAc containing oligosaccharides were confirmed as binding partners of TconTS1-LD and TconTS2-LD. Interestingly, terminal mannose residues are not acceptor substrates for TconTS activity. This indicates a different, yet unknown biological function for TconTS-LD, including specific interactions with oligomannose-containing glycans on glycoproteins and GPI anchors found on the surface of the parasite, including the TconTS itself. Experimental evidence for such a scenario is presented.


Relationship of COPD Exacerbation Severity and Frequency on Risks for Future Events and Economic Burden in the Medicare Fee-For-Service Population.
To quantify the effects of moderate and/or severe chronic obstructive pulmonary disease (COPD) exacerbations on future exacerbations and healthcare costs in Medicare Fee-For-Service beneficiaries. A retrospective cohort study of patients ≥40 years of age, with continuous enrollment from 2015 to 2018, with an index COPD diagnosis defined as first hospitalization, emergency department visit, or first of two outpatient visits (≥30 days apart) in 2015 with a claim for chronic bronchitis, emphysema, or chronic airway obstruction. Patients were stratified by baseline exacerbation categories in year one (YR1) and subsequently evaluated in YR2 and YR3: (A) none; (B) 1 moderate; (C) ≥2 moderate; (D) 1 severe; and (E) ≥2, one being severe. Moderate exacerbations were defined as COPD-related outpatient/ED visits with a corticosteroid/antibiotic claim within ±7 days of the visit and severe exacerbations as hospitalizations with a primary COPD diagnosis. Total all-cause costs for Categories B-E were compared to reference Category A using generalized linear models and inflation adjusted to 2019 dollars. A total of 1,492,108 patients met study criteria with a mean (±SD) age of 70.9±10.9. In YR1, nearly 40% of patients experienced ≥1 moderate and/or severe exacerbations. Patients having multiple exacerbations, regardless of severity were 2-4 times more likely to experience an exacerbation during YR2 and YR3. Adjusted costs ranged between $24,000 and $26,600 for all categories for YR2 and YR3. Adjusted YR2 costs for Category D and E were $1421 and $1548 higher than those without an exacerbation (Category A YR2 $25,084, YR3 $24,282; p<0.0001). The respective YR3 adjusted costs were $2062 and $2117 higher than those without an exacerbation (Category A; p<0.0001), representing an increase of 6-8% and 8-9% for YR2 and YR3. Medicare patients with recent moderate or severe exacerbations, or at least two exacerbations per year are at significant risk for future exacerbations and incur higher all-cause costs.


Protein phosphorylation plays a key role in sucrose-mediated transcriptional regulation of a phloem-specific proton-sucrose symporter.
Assimilate partitioning refers to the systemic distribution of sugars and amino acids from sites of primary assimilation (source tissue) to import-dependent tissues and organs (sinks). One of the defining questions in this area is how plants balance source productivity with sink demand. Recent results from our laboratory showed that sucrose transport activity is directly proportional to the transcription rate of the phloem-specific proton-sucrose symporter BvSUT1 in Beta vulgaris L. Moreover, symporter gene transcription is regulated by sucrose levels in the leaf. Here we show that sucrose-dependent regulation of BvSUT1 transcription is mediated, at least in part, by a protein phosphorylation relay pathway. Protein phosphatase inhibitors decreased sucrose transport activity, symporter protein and mRNA abundance, and the relative transcription rate of the symporter gene. In contrast, protein kinase inhibitors had no effect or increased sucrose transport, protein and mRNA abundance, and transcription. Furthermore, pre-treating leaves with kinase inhibitors before feeding with sucrose blocked the sucrose-dependent decrease in symporter transcription and transport activity. The latter observation provides direct evidence for a protein phosphorylation cascade operating between the sucrose-sensor and the transcriptional regulator that controls BvSUT1 expression and, ultimately, phloem loading.


The spatial representations acquired in CA3 by self-organizing recurrent connections.
Neural computation models have hypothesized that the dentate gyrus (DG) drives the storage in the CA3 network of new memories including, e.g., in rodents, spatial memories. Can recurrent CA3 connections self-organize, during storage, and form what have been called continuous attractors, or charts-so that they express spatial information later, when aside from a partial cue the information may not be available in the inputs? We use a simplified mathematical network model to contrast the properties of spatial representations self-organized through simulated Hebbian plasticity with those of charts pre-wired in the synaptic matrix, a control case closer to the ideal notion of continuous attractors. Both models form granular quasi-attractors, characterized by drift, which approach continuous ones only in the limit of an infinitely large network. The two models are comparable in terms of precision, but not of accuracy: with self-organized connections, the metric of space remains distorted, ill-adequate for accurate path integration, even when scaled up to the real hippocampus. While prolonged self-organization makes charts somewhat more informative about position in the environment, some positional information is surprisingly present also about environments never learned, borrowed, as it were, from unrelated charts. In contrast, context discrimination decreases with more learning, as different charts tend to collapse onto each other. These observations challenge the feasibility of the idealized CA3 continuous chart concept, and are consistent with a CA3 specialization for episodic memory rather than path integration.


Effects of 8 weeks of resistance training in combination with a high protein diet on body composition, muscular performance, and markers of liver and kidney function in untrained older ex-military men.
The effects of a high protein diet in combination with chronic resistance training (RT) on skeletal muscle adaptation responses in untrained older ex-military men is unknown. Therefore, we compared the effects of 8 weeks of RT in combination with either a high (1.6 g/kg/d) or low protein diet (0.8 g/kg/d) on body composition [skeletal muscle mass (SMM) and body fat percentage (BFP)], muscular strength, power, and endurance (upper and lower body), markers of liver [alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] and kidney (creatinine and urea) function, and lipid profile low-density lipoprotein (LDL), high-density lipoprotein (HDL), and cholesterol levels in a cohort of healthy, untrained older ex-military males. Forty healthy untrained older ex-military males (age: 61 ± 2 yr, body mass index: 23.2 ± 1.3 kg.m-2) performed 8 weeks (three sessions·w-1) of RT with either 1.6 g/kg/d (RHP; n = 20) or 0.8 g/kg/d of protein (RLP; n = 20). Body composition (assessed by Inbody 720), muscular strength (1-RM for chest and leg press), power (Wingate test), endurance (75% 1-RM for chest and leg press), and markers of liver and kidney function (biochemical kits) were assessed pre and post-intervention. SMM and muscular strength (upper and lower body) increased post-intervention in both groups and were significantly greater in RHP compared to RLP, while muscular power increased to the same extent in both groups (p < 0.05) with no between-group differences (p > 0.05). In contrast, there were no post-intervention changes in muscular endurance, HDL, and BFP remained in either group (p > 0.05). ALT and creatinine significantly increased in RHP compared to RLP while GGT, AST, and urea only increased in the RLP group (p < 0.05). LDL and cholesterol significantly decreased in both groups (p < 0.05). A daily intake of 1.6 g/kg/d protein was superior to 0.8 g/kg/d (current recommended daily intake) for promoting greater improvements in SMM and muscle strength and thus may be a more suitable level of intake for promoting such adaptive responses. Notwithstanding observed between-group differences in ALT and creatinine and the fact that levels remained within normal ranges, it is feasible to conclude that this daily protein intake is efficacious and well tolerated by healthy, untrained older ex-military males.


Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model.
Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and nonmalignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To combine these requirements, we have developed a nonmyeloablative conditioning regimen, consisting of low-dose total body irradiation and cyclophosphamide-based chemotherapy. In a haploidentical F1 --> F1 mouse model, this nonmyeloablative transplantation protocol resulted in stable full donor chimerism, but also in the development of severe GVHD. Administration of keratinocyte growth factor (KGF) reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis, compared to saline-treated controls. KGF preserved plasma citrulline and tumor necrosis factor-alpha levels, both indicative for reduced injury to the gastrointestinal tract. This was confirmed by histological findings. At 6 months after transplantation, survival rates were significantly higher in KGF-treated animals as compared to phosphate buffered saline-treated controls. These results indicate that KGF preserves gut integrity and might therefore contribute substantially to reduction of lethal GVHD in (nonmyeloablative) haploidentical transplantation.


Roux-en-Y gastric bypass could slow progression of retinopathy in type 2 diabetes: a pilot study.
Type 2 diabetes mellitus (T2DM) is a well-recognised complication of obesity. One of the microvascular complications of T2DM is diabetic retinopathy (DR). Bariatric surgery has been shown to effectively treat obesity and can induce remission of T2DM. It is not known what effect this improvement may have on pre-existing DR. We aimed to investigate this. A dual-centre, observer-blinded, case-control study investigated the progression of DR in patients who received Roux-en-Y gastric bypass (treatment group (TG)), compared with controls who received medical therapy (control group (CG)) for their T2DM. Retinal images were taken pre-operatively and approximately 2 years post-operatively for the TG and over a 2-year interval for the CG. Data were collected for confounding variables, including glycaemic control (HbA(1c)) and BMI. Forty-five patients were recruited (TG = 21, CG = 24). Groups were significantly heterogeneous. DR showed significant progression for those in the CG (p = 0.03) but not in TG (p = 0.135), no significant difference was found when adjusting for confounding variables (p = 0.480). There was a significant trend in favour of surgery in improvement of glycaemic control (p = 0.017). The trends within these pilot data may represent a real difference in the progression of DR in patients who have received surgery, compared with medical treatment alone. Due to heterogeneity of group characteristics, further work needs to be done to validate these results. Should there be a true difference, there will be potential cost savings for the National Health Service (NHS) along with a reduced burden of disease for patients.


Developing an IV Ketamine Clinic for Treatment-Resistant Depression: a Primer.
The efficacy of subanesthetic intravenous ketamine for treatment resistant depression (TRD) has spurred a growth of clinics nationwide that provide this service. Ketamine is an FDA-approved drug as an anesthetic but remains unapproved for psychiatric indications, and this status raises a number of short- and long-term safety and efficacy concerns that need to be addressed when implementing and developing this type of clinic. Using a framework of systems, provider, and patient domains, we provide a review of the key challenges in providing ketamine infusions and suggest potential approaches. Under systems issues, we highlight broad stakeholder engagement involving cross-departmental and multidisciplinary considerations, business case development, and delineation of administrative standard operating procedures. In the provider domain, we highlight specific roles for different treatment team members as well as suggested training requirements. In the patient domain, we identify a variety of standard operating procedures involving initial patient assessment parameters, ketamine dosing and administration guidelines, and safety monitoring procedures. Together, this review provides key considerations for developing a ketamine clinic for depression, in an effort to meet the pressing demand for this novel treatment option while helping to ensure its safe implementation.


Sunitinib versus sorafenib plus transarterial chemoembolization for inoperable hepatocellular carcinoma patients.
To compare sunitinib vs sorafenib plus transarterial chemoembolization (TACE) for inoperable hepatocellular carcinoma (HCC) patients. From January 2010 to December 2016, 104 patients with inoperable stage III HCC were included and randomly divided into two groups. Patients in the sunitinib+TACE (SU+TACE) group received sunitinib orally 37.5 mg daily, while patients in the sorafenib+TACE (SO+TACE) group received sorafenib 400 mg twice daily. The two groups were given sunitinib or sorafenib on an interrupted schedule, with a 4-7 days interval before or after TACE sessions. TACE treatment was repeated every 6-8 weeks. Patients were treated for about 4-6 cycles until the occurrence of toxicity or patient refusal, or progressive disease. The median overall survival (OS) and the median progression-free survival (PFS) in the SO+TACE group were significantly higher than that in the SU+TACE (OS: p=0.017; PFS: p=0.036, respectively). The rates of response and disease control were higher in the SO+TACE group (58%, 79%, respectively) compared to the SU+TACE group (37%, 66%, respectively), although without statistical significance. Regarding the toxicities, we found higher rates of hand-foot skin reaction (HFSR) in the SO+TACE group, while frequent occurrence of thrombocytopenia and neutropenia in the SU+TACE group. The SO+TACE regimen was more effective and well tolerated in patients with unresectable stage III HCC compared to the SU+TACE regimen. The SO+TACE regimen may be a better alternative to the current standard regimens.


Low Indeterminate Rates Associated With Use of the QuantiFERON-TB Gold In-Tube Test in Children With Inflammatory Bowel Disease on Long-term Infliximab.
Tumor necrosis factor alpha (TNF-α) inhibitors are linked with increased risk of reactivation of active tuberculosis. The QuantiFERON-TB Gold In-Tube test is approved for screening latent tuberculosis infection in children and adults. There are limited data on the test performance in children on long-term treatment with TNF-α inhibitors. The objective of this study was to assess the proportion of indeterminate results for the QuantiFERON-TB Gold In-Tube in children with inflammatory bowel disease (IBD) on long-term infliximab treatment and to evaluate the range of interferon-γ responses to mitogen. A single-center prospective study of children 5 to 19 years of age with IBD on long-term infliximab treatment (>3 months). Each child was assessed for tuberculosis exposure risk and had blood drawn for the QuantiFERON-TB Gold In-Tube. Data on the range of interferon-γ responses and final QuantiFERON-TB Gold In-Tube test results were collected. Ninety-three children were included, with a median age of 16 years. The median total duration of infliximab therapy was 34 months (range, 3-119 months). The QuantiFERON-TB Gold In-Tube was indeterminate in 1 patient (1.1%), positive in 2 patients, and negative in 90 patients. The maximum interferon-γ response to mitogen (10 IU/mL) was observed in 82 patients (88%), with only 1 patient having an inadequate response. The proportion of indeterminate results was significantly lower than the prospectively hypothesized rate of 8%, based on prior studies in nonimmunosuppressed patients (P = 0.004). Pediatric patients with IBD on long-term treatment with infliximab had an adequate interferon-γ response to mitogen and a low indeterminate rate when assessed with the QuantiFERON-TB Gold In-Tube test. This study demonstrates a robust interferon gamma response to phytohemagglutinin stimulation in a pediatric population on long-term therapy with infliximab. The QuantiFERON-TB Gold In-Tube test may therefore be useful as a periodic screening tactic for latent TB in children on long-term infliximab therapy.


Repair of DNA double-strand breaks as a determinant of RBE of alpha particles.
The role of repair of DNA double-strand breaks (dsb) in the determination of the RBE-value of alpha particles was studied using the temperature conditional radiosensitive diploid yeast mutant rad 54-3. This mutant is proficient in the repair of dsb at the permissive temperature of 23 degrees C at which it yields a shouldered survival curve, but it is dsb repair-deficient at the restrictive temperature of 36 degrees C at which it yields an exponential survival curve. At the permissive temperature the rad 54-3 mutant also shows liquid holding recovery of colony forming ability as a function of the liquid holding period. Thus, with this mutant it is possible to obtain survival curves involving no repair of dsb (immediate plating, 36 degrees C), partial repair of dsb (immediate plating, 23 degrees C) and gradually increasing levels of dsb repair by delayed plating after liquid holding periods of 24, 48 and 72 h. The RBE-values of densely ionizing 3.5 MeV alpha particles for cell killing relative to sparsely ionizing 30 MeV electrons have been determined as a function of the level of dsb repair. It is shown that the RBE-value is low and independent of dose when no repair of dsb is involved, whereas it becomes gradually larger with a gradual increase in the level of dsb repair.


The photodynamic action of methylene blue on the ion channels of Paramecium causes cell damage.
The photodynamic effects of methylene blue (MB) on wild-type and mutant strains of Paramecium Were studied. From measurements of survival and cell motility under the continuous application of light in the presence of MB, the mutant strains remained alive for about three times longer than the wild-type strain. Although the resting potential of the mutant cells was similar to that of wild-type cells, the continuous photodynamic action shifted the membrane potentials of the mutant and wild-type cells to a depolarized level and a hyperpolarized level, respectively, from that before light application. Under voltage clamping, the mutant cells reduced not only the outward current elicited by the photodynamic action but also the outward tail current elicited by the preceding pulse of hyperpolarization. We conclude that the mutant strain is defective in the activation of Ca(2+)-dependent K+ channels. This defect might cause a reduction in the Ca2+ influx because of the suppression of the membrane hyperpolarization, which results in the elongation of survival time under the photodynamic action.


High fatty acids modulate P2X(7) expression and IL-6 release via the p38 MAPK pathway in PC12 cells.
Diabetic neuropathy (DNP) is the most common chronic complication of diabetes. Elevated free fatty acids (FFAs) have been recently recognized as a major cause of nervous system damage in diabetes. P2X receptors play a primary role in regulation of neuronal interleukin (IL)-6 release, which is of paramount relevance to the functional changes of nerve system. The present study aimed to investigate the effects of high FFAs on the P2X7 expression and IL-6 release in PC12 cells. High FFAs induced P2X7 expression and IL-6 release significantly in PC12 cells. Moreover, high FFAs enhanced ATP or BzATP-induced Ca(2+) signals in PC12 cells. Inhibition of P2X7 by transfection with P2X7-siRNA or co-culture with BBG (a specific P2X7 inhibitor) at high concentrations of FFAs decreased ATP or BzATP-promoted Ca(2+) signals and IL-6 release in PC12 cells. High FFAs induced the phosphorylation of p38 in PC12 cells. Blockade of p38 pathways by SB-203580 inhibited P2X7 up-expression, ATP or BzATP-evoked [Ca(2+)]i rises as well as IL-6 release in PC12 cells exposed to high FFAs. Therefore, high concentrations of FFAs increased the expression of P2X7 in PC12 cells via activation of p38 mitogen-activated protein kinase (MAPK) signaling pathway, which contributed to P2X7-mediated IL-6 release from PC12 cells.


Physical fitness training in patients.
Patients recovering after heart valve surgery are not in an optimum state of 'cardiorespiratory fitness'. To examine this proposition a controlled trial of physical training was undertaken in patients recovering from the replacement of a single heart valve. Patients were allocated to a test or control group two weeks after operation. Each patient performed a submaximal exercise test at entry, and twelve and twenty-four weeks after this test. The Canadian Air Force exercise programme was undertaken by the test group, while the control group continued normal activities for the twenty-four weeks between the first and last exercise test. A regression line of submaximal heart rate on oxygen consumption was calculated from the data of each exercise test in each patient. Alterations in this line were used as an 'index' of changes in 'cardiorespiratory fitness'. The individual results showed a consistent improvement in 'cardiorespiratory fitness' over the first 12 weeks in both groups. Only patients in the test group continued to improve between 12 and 24 weeks. Thus the exercise programme modified the recovery of 'cardiorespiratory fitness' after operation. A physical fitness rehabilitation programme may help these patients gain maximum benefit from correctiv surgery.


Defining Peer Roles and Status Among Community Health Workers and Peer Support Specialists in Integrated Systems of Care.
Current strategies for integrating general medical and behavioral health services focus primarily on improving the coordination of care and expanding team-based services. Absent from most discussion has been a focus on the workforces that provide the bulk of community-based outreach, engagement, activation, motivational support, and self-management: community health workers (CHWs) and peer support specialists (PSSs). CHWs have primarily been deployed in general medical care and PSSs in behavioral health care. Understanding the unique contributions that CHWs and PSS provide for health promotion and wellness and improved population health outcomes is an important challenge. This Open Forum reviews the key elements of peer status as a way to help illustrate the differences between these workforces and the best deployment strategies for each workforce. A framework is proposed that outlines key support roles provided by the CHW and PSS workforces.


Interns' depressive symptoms evolution and training aspects: a prospective cohort study.
To study depression symptoms' incidence of medical interns (first year of medical residency) and its correlation with occupational characteristics, satisfaction and stress about their training program. Prospective Cohort Study conducted at Escola Paulista de Medicina, Universidade Federal de São Paulo. First year residents, N = 166, from a teaching hospital were invited to answer the Beck Depression Inventory (BDI) and an occupational questionnaire in a prospective longitudinal study. BDI score variation was related with socio-demographic aspects and occupational characteristics using linear regression models. 111 subjects participated (67%); the BDI-score increased in 8 months (mean = 2.75 ± 3.29 vs. 7.00 ± 5.66; p<0.0001). The depressive symptoms' incidence was 9.01% (score>15). BDI-score variation had mean = 4.25 ± 4.93, ranging from -8 to 28. Residents not satisfied with professional training acquired (β = 3.44; p = 0.004), with their personal life (β = 2.97; p = 0.001), or who felt stressed in the relationship with senior residents (β = 2.91; p = 0.015) presented 3 more points of BDI-score after 8 months comparing to those without these perceptions; and being unsatisfied with the nursing team increased BDI-score after 8 months in 2 more points (β = 1.95; p = 0.025). Among the factors that interfere with depression in interns is the occupational characteristics, which might be enhanced by the training facility. Addressing these dissatisfaction and stressful issues should help the university provide better care of interns' mental health.


Evaluation of Ranson, Glasgow, APACHE-II, and APACHE-O criteria to predict severity in acute biliary pancreatitis.
There are a few prospective studies assessing the severity of acute pancreatitis with exclusive criteria for biliary etiology. In a cohort prospective study, Ranson (biliary etiology), Glasgow-modified, APACHE-II, and APACHE-O prognostic criteria were assessed in 65 patients with acute biliary pancreatitis (ABP). Local complications such as necrosis with fluid peripancreatic collection (3 patients), fluid collection with pancreas enlargement (3 patients), pancreatic fistula (1 patients), and pancreatic pseudocyst (1 patients); and organic failure such as renal (5 patients), hemodynamic (3 patients), and respiratory (3 patients) were found. The prognostic criteria performance, according to parameter number or positive variables evidenced that relative risk (RR) varied from 4.7 to 11.2, sensibility from 33.3% to 83.3%, specificity from 79.2% to 98.1%, positive predictive value from 45.0% to 83.3%, negative predictive value from 86.4% to 95.5%, and accuracy from 78.5% to 89.6%. In isolation, most important parameters correlated to severity included white blood cell count >18,000/mm3, lactate dehydrogenase (LDH) >400 UI/l, 10% drop of the hematocrit, serum calcium <8 mg/dl, increase of urea nitrogen >2 mg/dl, aspartate aminotransferase (AST) >200 mg/dl, LDH >600 UI/l, white blood cell count >15,000/mm3, urea >45 mg/dl, arterial pH < or = 7.33 or > or = 7.49, creatinin < or = 0.6 or > or = 1.4, hematocrit < or = 30 or > or = 45.9, white blood cell count < or = 3,000/mm3 or > or = 14,900/mm3. Ranson, Glasgow-modified, APACHE-II, and APACHE-O acute biliary pancreatitis severity criteria all present good sensibility and excellent specificity.


Acoustic neuroma surgery: results of translabyrinthine tumour removal in 300 patients. Discussion of choice of approach in relation to overall results and possibility of hearing preservation.
The results from the Danish model of acoustic neuroma surgery are presented. In the period from 1976 to 1985, 300 patients with acoustic neuromas were operated upon using the translabyrinthine procedure. Only one small intrameatal tumour was encountered; 96 tumours were medium sized and 203 were larger than 25 mm. Of these 118 measured more than 40 mm. Mortality rate was 2%, CSF leaks occurred in 11%, and had to be closed surgically in 5%. Facial nerve function was postoperatively normal in 66%, slightly reduced in 17%, moderately reduced in 8% and abolished in 9%. Reconstruction, most often as a XII-VII anastomosis, was performed in only 6% of the patients. Cerebellar symptoms, which occurred in 45% preoperatively were present in only 7% after surgery. The preoperative hearing in both the tumour and non-tumour ear was analysed in 72 patients with tumours smaller than 2 cm. In the tumour ear, only four patients had a PTA of 0-20 dB and SDS of 81-100%; eight patients had a PTA of 0-40 dB and SDS of 61-100%; 14 had a PTA of 0-50 dB and SDS of 51-100%. This means that only a maximum of 5% of the patients, using the broadest criteria, could be candidates for hearing-conserving surgery. In all these patients the contralateral ear had hearing within normal limits (PTA 0-20 dB and SDS 95-100%). Since preservation of hearing would be achieved in only half of those subjected to suboccipital removal and since the hearing retained in patients with successful operations generally is poorer than the preoperative level, the number of patients obtaining serviceable hearing is so modest that preservation of hearing cannot be considered a valid argument in favour of suboccipital tumour removal. From a statistical point of view the risk of losing hearing in the opposite ear after tumour removal is negligible. The general morbidity after suboccipital surgery is higher than after translabyrinthine surgery, and hearing loss must be listed low among the other sequelae after tumour removal.


Polysomnographic studies of unmedicated depressed men before and after cognitive behavioral therapy.
Differentiation of stable, trait-like characteristics from more episodic or state-dependent disturbances will be helpful in gaining a better understanding of the pathophysiology of depression. However, research in this area has been complicated by artifactual and clinical problems associated with pharmacologic treatment. In this investigation the authors used EEG sleep studies to assess medication-free depressed male patients before and after cognitive behavioral therapy. Forty-five male patients with the diagnosis of major depression according to the DSM-III-R criteria and the Research Diagnostic Criteria underwent EEG sleep studies before and after 16 weeks of cognitive behavioral therapy, during which they were free of medication. In addition to the documentation of changes within these patients, the findings were compared with those for 47 healthy subjects, including 15 who were restudied 12-24 months after their baseline assessments. The EEG sleep profiles of the depressed patients showed a significant reduction in REM sleep density after treatment, suggesting "normalization" of an abnormal state-dependent process. By contrast, slow wave sleep and tonic REM measures, including reduced REM latency, were unchanged after treatment. These findings suggest that early in remission there is disaggregation of irreversible, trait-like correlates of depression (e.g., diminished slow wave sleep and reduced REM latency) from more reversible disturbances (e.g., increased REM density).


GENOTYPE-BY-ENVIRONMENT INTERACTIONS FOR FITNESS OF ERIGERON ANNUUS SHOW FINE-SCALE SELECTIVE HETEROGENEITY.
The results of natural selection depend critically on whether variation in fitness is finegrained or coarse-grained with respect to dispersal, but little is known of the spatial scale of fitness variation in natural populations. For most evolutionary questions, environmental heterogeneity must be defined by reversals in the relative fitness of genotypes; absolute fitness may vary, but if genotypes respond in parallel then selection is uniform. Thus, measurements of genotype-by-environment (G × E) interactions for fitness are necessary to understand patterns of variation in natural selection.


Adie's Tonic Pupil in Systemic Sclerosis: A Rare Association.
We report a rare association of Adie's tonic pupil in a patient with systemic sclerosis who was otherwise systemically stable. This paper is an effort to unravel whether the tonic pupil and systemic sclerosis are an association by chance (which may be the case) or systemic sclerosis is the source of the tonic pupil.


In vitro evaluation of a fibrin gel antibiotic delivery system containing mesenchymal stem cells and vancomycin alginate beads for treating bone infections and facilitating bone formation.
Bone infection and defects are two major problems that occur in the course of treating posttraumatic open bone fractures and osteomyelitis for which local antibiotic delivery is efficacious. Further, hemostasis is an essential treatment after removal of infected bones. Herein we report a new antibiotics delivery system made of vancomycin alginate beads embedded in a fibrin gel (Vanco-AB-FG) to treat bone infections, with the addition of bone marrow-derived mesenchymal stem cells (BMMSCs) seeded in the fibrin gel to promote bone formation. The proliferation of BMMSCs was measured under different conditions of three-dimensional (3D) gel or monolayer, with or without Vanco-AB; cells were labeled by enhanced green fluorescence protein, and their morphology and distribution were observed. The alkaline phosphatase (ALP) activity, real-time RT-PCR, and von Kossa staining were used for determining the osteogenic differentiation of BMMSCs. The concentrations of vancomycin resulting from the antibiotic delivery were determined; the antibiotic activity was evaluated by an assay with standard Staphylococcus aureus (ATCC 25923) as a biological target. The results showed that for Vanco-AB-FG, vancomycin concentrations remained above the breakpoint sensitivity for 22 days. The 3D culture within the gel and the addition of Vanco-AB affected the cell behavior. The morphology of BMMSCs within the 3D gel was different from that in monolayer. The proliferation of the cells within the 3D gel was lower than that in monolayer in early stage, but in later stage the number of BMMSCs in Vanco-AB-FG was similar to that in monolayer. The ALP activity was higher in the 3D gel, and the addition of Vanco-AB slightly increased ALP activity. The osteogenic gene expression levels of ALP, osteopontin, and alpha1 chain of collagen I were higher in the 3D gel than those in monolayer, and additional Vanco-AB could also increase their expression. The von Kossa staining showed that the deposition of mineralization was observed in both the 3D gel and monolayer cultures, but the mineralization nodule size in monolayer was bigger and the number of them in 3D gel was greater. In conclusion, this system could be an alternative treatment for bone infections and defects.


Methylene Tetrahydrofolate Reductase Gene Polymorphism is Associated with Severity of Liver Steatosis in Chronically Infected Patients with HCV Genotype 4.
Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism was reported as a genetic variant in liver steatosis and fibrosis. This is a study of the association between MTHFR C677T polymorphism and HCV core with severity of steatosis in HCV GT4 patients. 111 HCV patients and 112 control subjects were recruited. Polymorphism was detected by RFLP analysis, core Ag was detected by ELISA. Combined HCV infection and MTHFR C677T polymorphism increases the risk to develop steatosis by 3.63- and 5.21-fold in subjects with single (CT) and double (TT) substitutions, respectively. Patients with chronic HCV infection had a 2.88- and 8.57-fold higher risk to develop steatosis in CT and TT genotypes, respectively, than patients with the (CC) genotype. No significant difference in core Ag titers were observed. MTHFR C677T polymorphism is a valuable genetic marker for steatosis, while HCV core Ag titer had no association with grades of steatosis in GT4 infections.


Contribution of phosphoproteomics in understanding SRC signaling in normal and tumor cells.
The membrane-anchored, non-receptor tyrosine kinase (non-RTK) SRC is a critical regulator of signal transduction induced by a large variety of cell-surface receptors, including RTKs that bind to growth factors to control cell growth and migration. When deregulated, SRC shows strong oncogenic activity, probably because of its capacity to promote RTK-mediated downstream signaling even in the absence of extracellular stimuli. Accordingly, SRC is frequently deregulated in human cancer and is thought to play important roles during tumorigenesis. However, our knowledge on the molecular mechanism by which SRC controls signaling is incomplete due to the limited number of key substrates identified so far. Here, we review how phosphoproteomic methods have changed our understanding of the mechanisms underlying SRC signaling in normal and tumor cells and discuss how these novel findings can be used to improve therapeutic strategies aimed at targeting SRC signaling in human cancer.


H2O and temperature measurements in propagating hydrogen/oxygen flames using a broadband swept-wavelength ECQCL.
We present experimental results using a swept-wavelength external cavity quantum cascade laser (swept-ECQCL) diagnostic to measure broadband absorption spectra over a range of 920-1180c m -1 (8.47-10.87 µm) with 2 ms temporal resolution in premixed hydrogen/oxygen flames propagating inside an enclosed chamber. Broadband spectral fits are used to determine time-resolved temperatures and column densities of H 2 O produced during combustion. Modeling of the flowfield within the test chamber under both equilibrium conditions and using a 1D freely propagating flame model is compared with the experiment in terms of temporal dynamics, temperatures, and H 2 O column density. Outputs from the numerical models were used to simulate radiative transport through an inhomogeneous combustion region and evaluate the performance of the spectral fitting model. Simulations show that probing hot-band H 2 O transitions in the high-temperature combustion regions minimizes errors due to spatial inhomogeneity. Good agreement is found between the experimental and modeling results considering experimental uncertainties and model assumptions.


Septal grafts and evoked acetylcholine release in the rat hippocampus after 192 IgG-saporin lesions.
Adult rats received intraseptal injections of 192 IgG-saporin and intrahippocampal grafts of septal cells. Between 6 and 10 months later, we assessed baseline and electrically-evoked release of tritium in hippocampal slices preloaded with [(3)H]choline, and the uptake of [(3)H]choline, [(3)H]noradrenaline and [(3)H]serotonin by hippocampal synaptosomes. The lesions reduced the accumulation of [(3)H]choline by approximately 40%, the evoked release of [(3)H]acetylcholine by approximately 90%, and the uptake of [(3)H]choline by synaptosomes by 90% in the dorsal hippocampus, but increased the relative baseline release of [(3)H]choline by +43%, and the synaptosomal uptake of [(3)H]noradrenaline (66%) and [(3)H]serotonin (58%) in the ventral hippocampus. The increased noradrenaline uptake may account for sympathetic ingrowth. Although the grafts of fetal septal neurons produced modest cholinergic effects, these effects were positive and significant.


Isoflurane's effect on interfacial dynamics in GAPDH influences methylglyoxal reactivity.
Diabetic surgical patients are at risk for peri- and post-operative complications, which can be prevented by maintaining tight glycemic control during anesthesia. Control of blood sugar would decrease unwanted chemical reactions, such as protein glycation, minimizing tissue dysfunction. Methylglyoxal (MG) is a major contributor to protein modification and tissue dysfunction seen in diabetic patients. We hypothesized that inhaled anesthetics may play a role in protein glycation and examined the effects of isoflurane on MG-induced modification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Isoflurane promoted MG-induced modification of GAPDH as evidenced by an increase in fluorescent glycation products, a change in chromatographic elution patterns and a loss of enzyme activity. Isoflurane's effect may be mediated by altering interfacial events. Our working model involves the binding of isoflurane to GAPDH, increasing the susceptibility to MG-induced modification of residues involved in oligomerization. These findings suggest a molecular basis for maintaining glycemic control during anesthesia.


Long-term therapeutic effect in nonhuman primate eye from a single injection of anti-VEGF controlled release hydrogel.
Wet age-related macular degeneration (wet-AMD) is a leading cause of irreversible blindness. Current treatment of AMD requires monthly intravitreal injection, which is difficult to be implemented in many parts of the world. In recent years, controlled release of anti-vascular endothelial growth factor (VEGF) therapeutics has attracted intense research interest aiming to reduce the injection frequency to one or two times per year. In this study, we evaluated the in vivo pharmacokinetics and the long-term therapeutic efficacy of an in situ hydrogel encapsulating an anti-VEGF antibody in nonhuman primates. We show that after a single injection of anti-VEGF controlled release hydrogel, a relatively constant concentration of drug can be maintained in the monkey eye for at least 5 months and the dose was sufficient for the treatment of recurrent choroidal neovascularization induced by repeat laser photocoagulation in monkeys. Our result suggested that when formulated into a controlled release formulation, a single dose of anti-VEGF may be sufficient for a half-year treatment and controlled release may be a suitable strategy to reduce the injection frequency in the treatment of AMD in human.


Cryopreservation of the bovine oocyte: current status and perspectives.
This review presents some of the most noticeable aspects related with the oocyte cryopreservation procedures, emphasizing their evolution in the bovine, which points towards the critical points determining the reduced survival rates of female gametes to freezing and vitrification. Factors such as the maturation status, the cytoskeleton and membrane sensitivity, the role of the cumulus cells, the impact of the cryoprotectants agents and the protocols utilized and the future of this tool have been extensively reviewed.


Plasmon enhanced light harvesting: multiscale modeling of the FMO protein coupled with gold nanoparticles.
Plasmonic systems, such as metal nanoparticles, are becoming increasingly important in spectroscopies and devices because of their ability to enhance, even by several orders of magnitude, the photophysical properties of neighboring systems. In particular, it has been shown both theoretically and experimentally that combining nanoplasmonic devices with natural light-harvesting proteins substantially increases the fluorescence and absorption properties of the system. This kind of biohybrid device can have important applications in the characterization and design of efficient light-harvesting systems. In the present work, the FMO light-harvesting protein was combined with gold nanoparticles of different sizes, and its photophysical properties were characterized using a multiscale quantum-mechanical classical-polarizable and continuum model (QM/MMPol/PCM). By optimal tuning of the plasmon resonance of the metal nanoparticles, fluorescence enhancements of up to 2 orders of magnitude were observed. Orientation effects were found to be crucial: amplifications by factors of up to 300 were observed for the absorption process, while the radiative decay of the emitting state increased at most by a factor of 10, mostly as a result of poor alignment of the emitting state with the considered metal aggregates. Despite being a limiting factor for high-fluorescence-enhancement devices, the strong orientation dependence may represent an important feature of the natural light-harvesting system that could allow selective enhancement of a specific excited state of the complex.