Criteria to define anti-idiotypic antibodies carrying the internal image of an antigen.
Anti-idiotypic antibodies which carry the internal image of a foreign antigen, i.e. so-called Ab2 beta antibodies, have been successfully used as vaccines to pathogens, as tools to isolate cellular receptors or as reagents in cancer therapy. An attempt is made to establish structural, immunochemical and and functional criteria to define anti-idiotypic antibodies of the Ab2 beta type.


Role of breast cancer resistance protein (Bcrp/Abcg2) in fetal protection during gestation in rat.
Breast cancer resistance protein (BCRP/ABCG2) is an ABC family drug efflux transporter expressed in a number of physiological tissues including placenta. Here we investigated the expression and function of Bcrp in the rat placenta and fetus during pregnancy. We show that the expression of Bcrp mRNA in placenta peaks on gestation day (gd) 15 and declines significantly to one third up to term. In fetal body tissue, 6.9 and 7.4-fold Bcrp mRNA increase was detected on gds 15 and 18, respectively, compared to the early gd 12. The expression of Bcrp mRNA in fetal organs on gds 18 and 21 is also demonstrated. Additionally, the function of placental and fetal Bcrp during pregnancy was studied by fetal exposure to cimetidine infused to the maternal circulation. The relative amount of drug that penetrated to fetus was highest on gd 12 and decreased to one tenth thereafter. Studies on cimetidine distribution in fetus revealed 2- and 4.4-times lower penetration to the brain on gds 18 and 21, respectively, compared to the whole fetal tissue. Our results indicate that the rat fetus is protected by Bcrp against potentially detrimental substances from gd 15 onwards. Moreover, we propose that the protection of fetus by placental Bcrp is further strengthened by fetal Bcrp.


OPERA: perception of information in patients with gastroenteropancreatic neuroendocrine tumors on lanreotide autogel.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can affect patient health-related quality of life (HRQoL). Appropriate information may improve their adherence to treatment and quality of life. To evaluate the change in patient's perceptions of the level of information at lanreotide (LAN) treatment initiation for GEP-NETs vs after 6 months. OPERA (NCT03562091) was a prospective, longitudinal, noninterventional study. Thirty-one centers in France specialized in the management of patients with NETs. Planned clinical visits at enrollment and end-of-study visits at month 6, with completion of the European Organisation for Research and Treatment of Cancer 25-item Quality of Life Questionnaire-Information Module (QLQ-INFO25) and 30-item Quality of Life Questionnaire-Core. Absolute change in the patient's perception of the information between baseline and month 6, using the relevant domains of the QLQ-INFO25. Endpoints measured at baseline and month 6 for at least 1 of the 3 targeted QLQ-INFO25 dimensions of the primary endpoint. Ninety-three of the 115 patients enrolled completed ≥1 primary endpoint information dimension. Mean (SD) scores for the primary endpoint information dimensions were high at baseline (disease, 63.41 [20.71]; treatment, 58.85 [19.00]; supportive care, 26.53 [24.69]; maximum 100). There were no significant changes between baseline (98.34% CI) and 6 months (disease, -2.84 [-8.69, 3.01; P = .24]; treatment, -4.37 [-11.26, 2.52; P = .13]; supportive care, 0.46 [-6.78, 7.70; P = .88]), and in HRQoL between baseline and 6 months. The lack of change in patient's perceptions of the disease, treatment, and supportive care information provided over the first 6 months of LAN treatment may suggest that physicians provided adequate information at the treatment initiation.


Shorter, more frequent mechanical loading sessions enhance bone mass.
The beneficial effects of exercise on bone mass and strength can be attributed to the sensitivity of bone cells to mechanical stimuli. However, bone cells lose mechanosensitivity soon after they are stimulated. We investigated whether the osteogenic response to a simulated high-impact exercise program lasting 4 months could be enhanced by dividing the daily protocol into brief sessions of loading, separated by recovery periods. The right forelimbs of adult rats were subjected to 360 load cycles x d(-1), 3 d x wk(-1), for 16 wk. On each loading day, one group received all 360 cycles in a single, uninterrupted bout (360 x 1); the other group received 4 bouts of 90 cycles/bout (90 x 4), with each bout separated by 3 h. After sacrifice, bone mineral content (BMC), and areal bone mineral density (aBMD) were measured in the loaded (right) and nonloaded control (left) ulnae using DXA. Volumetric BMD (vBMD) and cross-sectional area (CSA) were measured at midshaft and the olecranon by using pQCT. Maximum and minimum second moments of area (I(MAX) and I(MIN)) were measured from the midshaft tomographs. After 16 wk of loading, BMC, aBMD, vBMD, midshaft CSA, I(MAX), and I(MIN) were significantly greater in right (loaded) ulnae compared with left (nonloaded) ulnae in the two loaded groups. When the daily loading regimen was broken into four sessions per day (90x4), BMC, aBMD, midshaft CSA, and I(MIN) improved significantly over the loading schedule that applied the daily stimulus in a single, uninterrupted session (360x1). Human exercise programs aimed at maintaining or improving bone mass might achieve greater success if the daily exercise regime is broken down into smaller sessions separated by recovery periods.


Acute cataract by a high-intensity focused ultrasound procedure: a case report.
We report a case of acute onset of cataract after eyelid rejuvenation tightening with intense focused ultrasound (IFUS) treatment without using a protection device. A 47-year-old female patient presented at the outpatient clinic with blurred vision in her left eye immediately after undergoing an eyelid tightening procedure, using IFUS, seven days prior. The patient had decreased vision in her left eye, caused by an acute cataract with several drop-like opacities and a rosette-like posterior subcapsular cataract. One month after her first visit, the patient's visual acuity in her left eye decreased to 20/630. A Swept-Source Anterior Segment optical coherence tomography confirmed that the posterior capsule was not ruptured. The patient underwent uneventful phacoemulsification cataract surgery with intraocular lens implantation, which resulted in full visual recovery. This case emphasized the need to evaluate possible ocular side effects, resulting from periocular IFUS without a protection device, including severe cataract requiring surgery.


Chronic heat stress affects the photosynthetic apparatus of Solanum lycopersicum L. cv Micro-Tom.
Tomato (Solanum lycopersicum L.) is one of the most widely cultivated crops in the world. Tomato is a plant model and the relationship between yield and biotic/abiotic stress has attracted increasing scientific interest. Tomato cultivation under sub-optimal conditions usually negatively impacts growth and development; in particular, heat stress affects several cellular and metabolic processes, such as respiration and photosynthesis. In this work, we studied the effects of chronic heat stress on various cytological and biochemical aspects using the Micro-Tom cultivar as a model. Photosynthetic efficiency decreased during heat stress while levels of post-photosynthetic sugars (sucrose, fructose, glucose and glucose 6-phosphate) oscillated during stress. Similarly, photosynthetic pigments (lutein, chlorophyll a, chlorophyll b and β-carotene) showed an oscillating downward trend with partial recovery during the stress-free phase. The energetic capacity of leaves (e.g. ATP and ADP) was altered, as well as the reactive oxygen species (ROS) profile; the latter increased during stress. Important effects were also found on the accumulation of Rubisco isoforms, which decreased in number. Heat stress also resulted in a decreased accumulation of lipids (oleic and linoleic acid). Photosynthetically alterations were accompanied by cytological changes in leaf structure, particularly in the number of lipid bodies and starch granules. Prolonged heat stress progressively compromised the photosynthetic efficiency of tomato leaves. The present study reports multi-approach information on metabolic and photosynthetic injuries and responses of tomato plants to chronic heat stress, highlighting the plant's ability to adapt to stress.


Trichoderma strains accelerate maturation and increase available phosphorus during vermicomposting enriched with rock phosphate.
To suggest microbial inoculation as a tool to shorten organic residues stabilization and increase rock phosphate (RP) solubilization through vermicomposting, thus increasing nutrient content in plants and making it more appealing to farmers. Two Trichoderma strains were inoculated alone or combined in a RP apatite-enriched vermicompost. Stability and plant-available phosphorus levels were monitored for 120 days. Observable higher total organic carbon reduction in the treatment with the combined Trichoderma strains, followed by the inoculation with T. asperellum and T. virens. Combined Trichoderma and inoculation with T. virens increased humic acids (HA) content in 38·2 and 25·0%, respectively; non-inoculated vermicompost with T. asperellum increased it by 15·0%. The combined Trichoderma strains and T. virens achieved the stability index based on the humic/fulvic acids (HA/FA) ratio after 120 days. T. asperellum, combined Trichoderma and T. virens increased the citric acid soluble-P content in 83·2, 62·2 and 49·5%, respectively, compared to the non-inoculated vermicompost. Inoculation with combined T. asperellum and T. virens efficiently accelerated vermicompost stabilization; T. asperellum increased the citric acid soluble-P in the final product. Combined Trichoderma inoculation and RP enrichment improves the vermicompost quality, increasing HA and citric acid soluble-P, recycling organic waste nutrients and reducing agricultural dependence on phosphate fertilizers.


Antidote strategies to reverse anticoagulation with TB-402, a long-acting partial inhibitor of factor VIII.
TB-402 is a partially inhibiting antibody of factor VIII that is under development as a long-acting anticoagulant. The reversibility of FVIII inhibition by TB-402 was evaluated in vitro after spiking with recombinant human FVIII (rhFVIII), human plasma-derived FVIII (hpdFVIII), recombinant activated human FVII (rhFVIIa), FVIII inhibitor bypassing activity (FEIBA), and prothrombin complex concentrate (PCC). Twelve subjects were randomized to placebo or 35 or 70 IU kg(-1) rhFVIII 48 h after a single dose of 620 μg kg(-1) TB-402. TB-402 concentrations, FVIII activity (FVIII:C), activated partial thromboplastin time (APTT) and thrombin generation were measured over a period of 8 weeks. In spiked samples, TB-402 inhibited FVIII:C by 30%, prolonged APTT by 4.5 s, and reduced the peak height in the thrombin generation assay to 56% ± 13% of the control value. In the presence of 10 μg mL(-1) TB-402, rhFVIII restored FVIII:C and APTT to the values obtained in the absence of TB-402. The inhibitory effect of TB-402 on thrombin generation was entirely reversed by rhFVIII, hpdFVIII, rhFVIIa, FEIBA, and PCC. In men, the mean half-life (t(1/2) ) of TB-402 was 14.2 days. TB-402 lowered the endogenous thrombin potential by 23% for ~ 35 days. Infusion of 35 IU kg(-1) rhFVIII had a marginal effect, whereas 70 IU kg(-1) rhFVIII restored FVIII:C, reduced APTT back to baseline for 9 h, and restored thrombin generation for ~ 3 h. TB-402 resulted in a stable long-term anticoagulant effect. rhFVIII and other procoagulants counteracted the effect of TB-402 temporarily, and may be effective antidotes for future clinical practice.


Raltitrexed increases radiation sensitivity of esophageal squamous carcinoma cells.
Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Many strategies have been developed to increase the radiosensitivity of esophageal cancer, with some success. This study was conducted to determine whether raltitrexed can enhance radiosensitivity of esophageal squamous cell carcinoma (ESCC). ESCC cell lines 24 h were incubated with raltitrexed or DMSO with or without subsequent irradiation. Cell Counting Kit assay-8 assay and clonogenic survival assay were used to measure the cell proliferation and radiosensitization, respectively. Flow cytometry was utilized to examine cell apoptosis and cell cycle distribution in different groups. Immunofluorescence analysis was performed to detect deoxyribonucleic acid (DNA) double-strand breaks. In addition, the expression levels of proteins that are involved in radiation induced signal transduction including Bax, Cyclin B1, Cdc2/pCdc2, and Cdc25C/pCdc25C were examined by western blot analysis. The results indicated that raltitrexed enhanced radiosensitivity of ESCC cells with increased DNA double-strand breaks, the G2/M arrest, and the apoptosis of ESCC cells induced by radiation. The sensitization enhancement ratio of 1.23-2.10 was detected for ESCC cells with raltitrexed treatment in TE-13 cell line. In vitro, raltitrexed also increased the therapeutic effect of radiation in nude mice. Raltitrexed increases the radiosensitivity of ESCC. This antimetabolite drug is promising for future clinical trials with concurrent radiation in esophageal cancer.


Effectiveness of acromioclavicular joint mobilization and physical therapy vs physical therapy alone in patients with frozen shoulder: A randomized clinical trial.
The objective of this trial was to compare the efficacy of acromioclavicular joint mobilization and standard physical-therapy versus physical-therapy alone in the treatment of the frozen shoulder. Single-blind randomized clinical trial. Outpatient setting. Patients with frozen shoulder. Participants were randomly allocated into mobilization + physical-therapy (n = 28), and physical-therapy alone (n = 28) groups for one month. The primary outcomes were the shoulder pain and disability index and the shoulder range of motion. The secondary outcome was the visual analogue scale. Measures were performed at the baseline, immediately and one month after the beginning of the treatment. Visual analogue scale and the shoulder pain and disability index improved more significantly in the mobilization group compared to the physical-therapy group immediately [-4.63 (-5.58--3.67) vs. -2.22 (-2.96--1.47), P < 0.001 and -23.08 (-28.63--17.53) vs. -13.04 (-17.93--8.16), P = 0.008, respectively] and one month after the beginning of the treatment [-5.58 (-6.45--4.72) vs. -3.61 (-4.60--2.62), P < 0.001 and -33.43 (-40.85--26.01) vs. -20.03 (-26.00--14.07), P = 0.001, respectively]. Active abduction range of motion was also improved more significantly immediately after the treatment in the mobilization group compared to the physical-therapy group [25.83 (11.45-40.13) vs. 10.17 (1.02-19.15), P = 0.025], however there were no significant differences between two groups concerning other measured range of motions. Adding acromioclavicular mobilization to standard physical-therapy was more efficient in decreasing pain and disability and improving active abduction range of motion compared to standard physical-therapy in frozen shoulder patients.


The Notch1/Hes1 signaling pathway affects autophagy by adjusting DNA methyltransferases expression in a valproic acid-induced autism spectrum disorder model.
As a pervasive neurodevelopmental disease, autism spectrum disorder (ASD) is caused by both hereditary and environmental elements. Research has demonstrated the functions of the Notch pathway and DNA methylation in the etiology of ASD. DNA methyltransferases DNMT3 and DNMT1 are responsible for methylation establishment and maintenance, respectively. In this study, we aimed to explore the association of DNA methyltransferases with the Notch pathway in ASD. Our results showed Notch1 and Hes1 were upregulated, while DNMT3A and DNMT3B were downregulated at the protein level in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of VPA-induced ASD rats compared with Control (Con) group. However, the protein levels of DNMT3A and DNMT3B were augmented after treatment with 3,5-difluorophenacetyl-L-alanyl-S-phenylglycine-2-butyl ester (DAPT), suggesting that abnormal Notch pathway activation may affect the expression of DNMT3A and DNMT3B. Besides, our previous findings revealed that the Notch pathway may participate in development of ASD by influencing autophagy. Therefore, we hypothesized the Notch pathway adjusts autophagy and contributes to ASD by affecting DNA methyltransferases. Our current results showed that after receiving the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza-2'dc), the VPA + DAPT+5-Aza-2'dc (V + D + Aza) group exhibited reduced social interaction ability and increased stereotyped behaviors, and decreased expression of DNMT3A, DNMT3B and autophagy-related proteins, but did not show changes in Notch1 and Hes1 protein levels. Our results indicated that the Notch1/Hes1 pathway may adjust DNMT3A and DNMT3B expression and subsequently affect autophagy in the occurrence of ASD, providing new insight into the pathogenesis of ASD.


Obesity due to high fat diet decreases the sympathetic nervous and cardiovascular responses to intracerebroventricular leptin in rats.
Obesity is associated with an increase in plasma leptin levels primarily derived from enhanced expression of the leptin gene in the adipose tissue. Leptin levels and expression are higher in females than males. The main functions of leptin are to decrease food intake and increase sympathetic nerve activity, especially in the brown adipose tissue. The high levels of leptin in obese, female rats suggest leptin resistance. In this article we describe experiments designed to investigate the effect of the intracerebroventricular (i.c.v.) administration of leptin on lumbar sympathetic nerve activity (LSNA) and cardiovascular parameters in female rats fed a low fat diet (control), a high fat diet (obese), or high fat diet followed by a period of food restrictions (reduced). The i.c.v. leptin administration increased LSNA in control rats, but decreased it in obese rats. In weight reduced animals the LSNA response to leptin returned to control levels. The i.c.v. leptin increased the mean arterial pressure in control and wt. reduced rats, but not in obese animals. The heart rate did not respond to leptin in any animal group. These results suggest that obesity decreases the central nervous system (CNS)-mediated lumbar sympathetic nervous and cardiovascular responses to leptin and that these responses recover following food restriction and wt. reduction. We conclude that obesity is associated with a decreased CNS response to leptin leading to a decrease in leptin effects to increase the activities of the autonomic nervous and cardiovascular systems.


Graves' disease and celiac disease in a patient with myotonic dystrophy type 2.
We report a patient with progressive proximal muscle weakness in her legs, early-onset cataract and perceptive hearing loss, who was recently diagnosed with myotonic dystrophy type 2 (DM2). She also had two autoimmune disorders in her history, namely Graves' disease and celiac disease. Previous studies have shown a high frequency of autoimmune diseases (21%) in patients with DM2. This is the first report of a patient with DM2 and two autoimmune diseases which both have not yet been described in DM2. The cause of this association might be explained at DNA, mRNA and protein levels, including genetic mutation in flanking genes and the toxic effect of the DM2 mutation on proteins involved in inflammation. This case report widens the spectrum of autoimmune diseases in DM2 and has implications both for clinical practice and for research.


[Lymphedema and lymphonodovenous anastomosis. Preoposal of a technical modification].
After some considerations about lymphedema and the progresses in its study, the surgical procedures to its treatment are exposed, considering this treatment technically and also orientate to lymphedema etiology. Afterwards, a clinical case, its treatment, and its discussion are exposed.


First case of Penicillium marneffei fungemia in Greece and strain susceptibility to five licensed systemic antifungal agents and posaconazole.
We report the first case of Penicillium marneffei infection in a Greek bisexual man who is a frequent traveler to China. Penicilliosis and AIDS were diagnosed and antifungal treatment plus highly active antiretroviral therapy were administered successfully. In nonendemic areas travel history, clinical suspicion and laboratory alertness are critical for infection management.


Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana.
Before introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana. We extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009-2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 ≥350 and ART for CD4 <350, and again in 2013-2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB). Among 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7). Adverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception.


When do luminance changes capture attention?
In two experiments, we examined the ability of task-irrelevant changes in luminance to capture attention in an irrelevant singleton search. By using uniform increment and decrement arrays, we were able to create changes of the same absolute magnitude, but resulting in a singleton with either higher or lower contrast magnitude, relative to other elements in the search array. A condition where a singleton changed contrast polarity without a concomitant change in the overall contrast magnitude was also included. It was found that only luminance changes resulting in a singleton having increased contrast (or saliency) were effective in capturing attention. In addition, no attentional capture was observed when the irrelevant singleton was characterized by the equivalent amount of static luminance differences, suggesting a unique attentional prioritization of luminance changes that increase singleton saliency.


Vascular adhesion protein-1 defines a unique subpopulation of human hematopoietic stem cells and regulates their proliferation.
Although the development of hematopoietic stem cells (HSC) has been studied in great detail, their heterogeneity and relationships to different cell lineages remain incompletely understood. Moreover, the role of Vascular Adhesion Protein-1 in bone marrow hematopoiesis has remained unknown. Here we show that VAP-1, an adhesin and a primary amine oxidase producing hydrogen peroxide, is expressed on a subset of human HSC and bone marrow vasculature forming a hematogenic niche. Bulk and single-cell RNAseq analyses reveal that VAP-1+ HSC represent a transcriptionally unique small subset of differentiated and proliferating HSC, while VAP-1- HSC are the most primitive HSC. VAP-1 generated hydrogen peroxide acts via the p53 signaling pathway to regulate HSC proliferation. HSC expansion and differentiation into colony-forming units are enhanced by inhibition of VAP-1. Contribution of VAP-1 to HSC proliferation was confirmed with mice deficient of VAP-1, mice expressing mutated VAP-1 and using an enzyme inhibitor. In conclusion, VAP-1 expression allows the characterization and prospective isolation of a new subset of human HSC. Since VAP-1 serves as a check point-like inhibitor in HSC differentiation, the use of VAP-1 inhibitors enables the expansion of HSC.


Manganese, monoamine metabolite levels at birth, and child psychomotor development.
Several studies have demonstrated neurobehavioral impairment related to manganese (Mn) exposure in the workplace. Exposure to high doses of manganese is associated with irreversible neurodegenerative disorders resembling idiopathic Parkinson disease. Although there is a risk of Mn accumulation in the foetus during pregnancy, little information exists about developmental effects of environmental low-level exposure in human. For this reason, we conducted a prospective epidemiological study in 247 healthy pregnant women and their babies to determine the long-term effect of in utero Mn levels on child's psychomotor development. Concurrently, we examined the relationship between Mn tissue levels at delivery and foetal plasma monoamine metabolites. Of the newborns, 195 were examined at 9 months, 126 at 3 years and 100 at 6 years. At 9 months, the Brunet-Lézine scales were administered. The McCarthy scales of children's abilities were used at 3 and 6 years. After adjustment for potential confounding co-factors (child's gender, mother's educational level), negative relationships were observed between cord blood Mn levels and several psychomotor sub-scales at age of 3 years: "attention" (partial r=-0.33, P<0.001), "non-verbal memory" (partial r=-0.28, P<0.01), and "hand skills" (partial r=-0.22, P<0.05). No significant relationships were observed between Mn measures at birth and the general psychomotor indices, Brunet-Lézine developmental quotient (DQ) at 9 months or McCarthy general cognitive index (GCI) at 3 and 6 years. Maternal blood Mn levels were negatively associated with foetal plasma HVA and 5-HIAA concentrations (adjusted for labour duration, child's gender, and smoking during pregnancy), but the adjustment for monoamine levels at birth did not change the association between the Mn levels and the psychomotor scores. These results suggest that environmental Mn exposure in utero could affect early psychomotor development.


Distorting gene pools by conservation: Assessing the case of doomed turtle eggs.
Sea turtles have a high reproductive output and high mortality at early stages of the life cycle. In particular, many nests are laid below or close to high tide lines, and subsequently large numbers of eggs may be inundated and destroyed. A common conservation procedure is to relocate such doomed eggs to higher ground. This article examines this practice in the light of recent data revealing that some individual turtles tend to nest relatively near the water and others relatively higher up the beach. Discussion is focused on the question of why apparently poor placement of nests has not been selected against. Comparison between the ecology of leatherback and hawksbill turtle nesting beaches suggests that predictability of environmental conditions on the nesting beaches has an important influence on patterns of nest-site selection. Options are outlined for the management of nesting beaches where a high proportion of turtle eggs is subject to destruction by flooding.


Impact of tannins on intraoral aroma release and retronasal perception, including detection thresholds and temporal perception by taste, in model wines.
Tannins, as an important wine nonvolatile matrix component, can cause astringency, which may affect aroma perception through cross-modal interactions during wine consumption. An aromatic model wine with tannin extracts was evaluated by intraoral aroma release and sensory analysis after wine spitting. Overall, tannin extracts could significantly decrease all initial aroma release, while they could not reduce most aroma release at 150 s after wine spitting. Regarding the sensory evaluation results, the retronasal detection threshold of most aromas increased. The temporal aroma intensity showed a significant decrease at early time points and was almost unaffected at later time points. In addition, temporal dominance of sensation (TDS) curves revealed that the presence of astringency could reduce the dominant time of most aromas. Therefore, although there was good consistency between instrumental analysis and sensory evaluation, the effect of astringency induced by tannins on retronasal perception cannot be ignored.


Heparin-induced thrombocytopenia associated with interleukin-8-dependent platelet activation in a patient with antiphospholipid syndrome.
Platelet factor 4 heparin enzyme immunoassay, platelet aggregation test, and serotonin release assay are commonly used to diagnose and confirm heparin-induced thrombocytopenia. We describe a case of recurrent thrombocytopenia appearing in a few hours after each heparin administration and who tested negative for the three assays. Further analysis revealed anti-interleukin (IL)-8 antibodies and IL-8-dependent platelet activation facilitated by heparin, which may explain this unusual case of heparin-induced thrombocytopenia.


Erratum for Pirson et al., Highly purified mycobacterial phosphatidylinositol mannosides drive cell-mediated responses and activate NKT cells in cattle.
Volume 22, no. 2, p. 178–184, 2015. Page 180, column 1, final line: "IgG2a" should read "IgG1."


Prothymosin-alpha preconditioning activates TLR4-TRIF signaling to induce protection of ischemic retina.
Prothymosin-alpha protects the brain and retina from ischemic damage. Although prothymosin-alpha contributes to toll-like receptor (TLR4)-mediated immnunopotentiation against viral infection, the beneficial effects of prothymosin-alpha-TLR4 signaling in protecting against ischemia remain to be elucidated. In this study, intravitreal administration of prothymosin-alpha 48 h before induction of retinal ischemia prevented retinal cellular damage as evaluated by histology, and retinal functional deficits as evaluated by electroretinography. Prothymosin-alpha preconditioning completely prevented the ischemia-induced loss of ganglion cells with partial survival of bipolar and photoreceptor cells, but not amacrine cells, in immunohistochemistry experiments. Prothymosin-alpha treatment in the absence of ischemia caused mild activation, proliferation, and migration of retinal microglia, whereas the ischemia-induced microglial activation was inhibited by prothymosin-alpha preconditioning. All these preventive effects of prothymosin-alpha preconditioning were abolished in TLR4 knock-out mice and by pre-treatments with anti-TLR4 antibodies or minocycline, a microglial inhibitor. Prothymosin-alpha preconditioning inhibited the retinal ischemia-induced up-regulation of TLR4-related injury genes, and increased expression of TLR4-related protective genes. Furthermore, the prothymosin-alpha preconditioning-induced prevention of retinal ischemic damage was abolished in TIR-domain-containing adapter-inducing interferon-β knock-out mice, but not in myeloid differentiation primary response gene 88 knock-out mice. Taken together, the results of this study suggest that prothymosin-alpha preconditioning selectively drives TLR4-TIR-domain-containing adapter-inducing interferon-β signaling and microglia in the prevention of retinal ischemic damage. We propose the following mechanism for prothymosin-alpha (ProTα) preconditioning-induced retinal prevention against ischemia: ProTα preconditioning-induced prevention of retinal ischemic damage is mediated by selective activation of the TIR-domain-containing adapter-inducing interferon-β (TRIF)- interferon regulatory factor 3 (IRF3) pathway downstream of toll-like receptor 4 (TLR4) in microglia, resulting in up-regulation of TRIF-IRF3-dependent protective genes and down-regulation of myeloid differentiation primary response gene 88 (MyD88)-Nuclear factor (NF)κB-dependent injury genes. Detailed investigations would be helpful to test the efficacy of ProTα as a therapeutic agent for the prevention of ischemic disorders.


Frontline treatment with chemoimmunotherapy for limited-stage ocular adnexal MALT lymphoma with adverse factors: a phase II study.
Radiotherapy is a commonly used treatment for limited-stage ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) but showed a substantial relapse risk if the disease involves beyond-conjunctiva or bilateral conjunctivae. Systemic chemoimmunotherapy may be an alternative frontline therapy for the limited disease with those adverse prognostic factors. We designed a multicenter, phase II study of the chemoimmunotherapy, rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) for the treatment of patients with limited-stage OAML with bilateral or beyond-conjunctival involvement. Thirty-three patients with Ann Arbor stage I OAML with the adverse factors were enrolled. Patients received six cycles of R-CVP followed by two cycles of rituximab therapy. At the end of treatment, all the enrolled patients had responded. The cumulative complete response achievement was 93.9% at 2 years. At a median follow-up of 50.6 months, three patients had progressed. Progression-free survival and overall survival at 4 years was 90.3±5.3% and 100%, respectively. This phase II study demonstrated durable efficacy of R-CVP chemoimmunotherapy, which has promise as an alternative frontline therapy for the limited-stage OAML patients with adverse prognostic factors. NCT01427114.


Voice Change Following Adenotonsillectomy in Pediatric Population: Myth or Reality?-A Pilot Study.
Modifications in the structure of pharynx following adenotonsillectomy are presumed to cause changes in the voice characteristics of patients. Data on effect of tonsillectomy/adenotonsillectomy on changes in voice among Indian children are sparse. This study was thus conducted to study the effect of adenotonsillectomy/tonsillectomy on childrens' voice. It was a prospective observational study of children aged 4-15 years undergoing tonsillectomy with or without adenoidectomy. Measures of voice were noted preoperatively, 1 and 3 months post-operatively. Subjective evaluation was done using Paediatric Voice Outcome Survey (PVOS) questionnaire administered to participants' parents. Objective evaluation was done by recording and analyzing using PRAAT voice analysis software which is an open-software tool. Statistical analysis was done using the statistical software SPSS 17.0 version. There were 31 children between 4 and 14 years of age 65% being male. Adenotonsillectomy was done in 83.5%. There was statistically significant difference in the subjective scores (PVOS) pre-operatively and 3 month postoperative score (p value = 0.001). However, there was no statistically significant difference between any other pre op and post op parameters. Though the only significant post tonsillectomy voice changes noted was subjective by parents 3 months later, it does raise concern whether this could be a reality and not a myth. Further studies with larger number of patients, including involving the subjective evaluation (PVOS) by another person in addition to patients' parent need to be undertaken to address this issue.


Use of the surfactant 3-(3-cholamidopropyl)-dimethyl-ammoniopropane sulfonate in hydrophobic interaction chromatography of proteins.
Isocratic hydrophobic interaction chromatography of five proteins has been carried out using mobile phases containing the surfactant 3-(3-cholamidopropyl)-dimethylammoniopropane sulfonate (CHAPS). Linear relationships were found between log k' and ammonium sulfate concentrations for all the proteins with CHAPS in the submicellar concentration range. The slope of such a plot decreases monotonically as CHAPS concentration is increased. To a first approximation, the effect of CHAPS on protein retention can be explained in terms of a competitive binding model. However, CHAPS does show differential effects on the elution of proteins, substantially altering selectivity. The use of a normalized capacity factor, k'/k'o, proves useful for comparing retention times of different proteins as a function of CHAPS concentration. The magnitudes of k'/k'o were found to be inversely correlated with the slopes of plots of log k' vs. ammonium sulfate concentration in the absence of CHAPS. Adsorption isotherms for CHAPS were determined over the working range of ammonium sulfate. The binding of CHAPS to the SynChropak Propyl stationary phase and its effects on retention were found to be readily reversible. For each protein, plots of k'/k'o vs. surface concentration of CHAPS were superposable for data obtained at different salt concentrations. These findings support a competitive binding model. A simple geometric argument for stationary phase occupancy provides a qualitative explanation for the observed surfactant selectivity.


Usefulness of a ventricular extrastimulus from the summit of the ventricular septum in diagnosis of septal accessory pathway in patients with supraventricular tachycardia.
To compare usefulness of a ventricular extrastimulus (VES) from the right ventricular (RV) apex versus the RV septum in patients with a septal accessory pathway (AP), VES was applied from the RV apex and the summit of the RV septum in patients with septal APs. A VES from the RV apex and from the summit was diagnostic of the presence of an AP in 13 of 28 patients (83%) and in 10 of 12 patients, respectively (46% p <0.05), and VES proved an AP as a part of the tachycardia circuit in 5 of 28 patients (18%) and 6 of 12 patients, respectively (50%, p <0.05). A VES during His bundle refractoriness from the RV summit increases the diagnostic yield for both the presence of an AP and its participation in the tachycardia circuit with respect to RV apical VES.


Inhibitory effect of ginsenoside on the mediator release in the guinea pig lung mast cells activated by specific antigen-antibody reactions.
We reported that some components of ginsenosides decreased mediator release which was evoked by the activation of mast cells caused by specific antigen-antibody reactions. This study aimed to assess the effects of ginsenoside, Rb1, which belongs to the protopanaxadiol, on the mechanism of mediator release during mast cell activation. Pretreatment of Rb1 (100 microg) significantly decreased histamine and leukotriene in a dose-dependent manner during mast cell activation. The PLD activity during mast cell activation decreased in the pretreatment of Rb1 (300 microg). The amount of DAG produced by PLC activity decreased because of Rb1 pretreatment. The amount of mass DAG decreased due to Rb1 pretreatment during mast cell activation. Rb1 (300 microg) pretreatment strongly inhibited the incorporation of the [3H]methyl moiety into phospholipids. The data suggest that Rb1, purified from Korean Red Ginseng Radix, inhibits an increase of DAG production during mast cell activation caused by antigen-antibody reactions, which is mediated via phosphatidylcholine-PLD and phosphatidylinositol-PLC systems. This is then followed by the inhibition of histamine releases. Furthermore, Rb1 reduces the phosphatidylcholine production by inhibiting the methyl-transferase I and II, and the reduction of phosphatidylcholine production inhibits leukotriene release.


Simultaneous azo-coupling method for steroid acetate hydrolyzing enzyme.
A simultaneous azo-coupling method for histochemical localization of steroid acetate hydrolyzing enzyme is described. It is based on the observation that d-equilenin, a natural oestrogenic steroid hormone, forms deeply coloured insoluble reaction products with diazonium salts under reaction conditions suitable for histochemical purposes. An acetate at position 3 of d-equilenin is rapidly hydrolysed by tissue esterase and the liberated d-equilenin couples with a diazonium salt to form a coloured precipitate. Steroid acetate hydrolyzing enzyme activity was observed in various tissues of the rat; a comparison with nonspecific esterase activity using alpha-naphthyl acetate as substrate suggested that steroid acetate hydrolyzing enzyme activity represents the activity of one or several isozymes of classical nonspecific esterase. This conclusion has also been drawn previously from biochemical studies using esters of other steroids.


A patient with ectopic cortisol production derived from malignant testicular masses.
A 65-year-old man presented to an oncology clinic with bilateral testicular masses, lower extremity edema, and cushingoid appearance. Measurements of serum cortisol and adrenocorticotropic hormone levels, testicular ultrasound and abdominal CT scans, and review of histopathology to identify the cellular origin of the ectopic cortisol production. Cushing syndrome was diagnosed on the basis of a markedly elevated 24-hour urine free cortisol level and classic cushingoid features. The etiology of Cushing syndrome was determined to be an adrenocortical carcinoma arising from testicular adrenal rest cells. Nevertheless, the possibility of a malignant Leydig cell tumor with ectopic cortisol production could not be excluded. Mitotane and metyrapone were used to decrease cortisol production. Excess mineralocorticoid activity was blocked with spironolactone; sodium retention was also managed with sodium restriction and diuretics. Despite initial success with this regimen, the patient died as a result of tumor progression and complications of poorly controlled hypercortisolism.


Gold-catalyzed four-component multifunctionalization of alkynes.
The alkyne unit is a versatile building block in organic synthesis and the development of selective multifunctionalization of alkynes is an important object of research in this field. Herein, we report an interesting gold-catalyzed, four-component reaction that achieves the oxo-arylfluorination or oxo-arylalkenylation of internal aromatic or aliphatic alkynes, efficiently breaking a carbon-carbon triple bond and forming four new chemical bonds. The reaction divergence can be controlled by site-directing functional groups in the alkynes; the presence of a phosphonate unit favors the oxo-arylfluorination, while the carboxylate motif benefits oxo-arylalkenylation. This reaction is enabled by an Au(I)/Au(III) redox coupling process using Selectfluor as both an oxidant and a fluorinating reagent. A wide range of structurally diverse α,α-disubstituted ketones, and tri- or tetra-substituted unsaturated ketones have been prepared in synthetically valuable yields and with excellent chemo-, regio- and stereoselectivity. The gram-scale preparation and late-stage application of complex alkynes have further enhanced their synthetic value.


Intercostal insertion of Veress needle for canine laparoscopic procedures: a cadaver study.
To record and compare the frequency of organ penetration after insertion of a Veress needle (VN) in 6 different intercostal spaces (ICS) for creation of pneumoperitoneum in canine cadavers. Descriptive study. Canine cadavers (n = 15). In 15 cadavers positioned in dorsal recumbency, VN insertion in the right and left 8th-10th ICS was performed, the abdomen insufflated, and VN position and any visceral penetration recorded. The frequency of viscus penetration was assessed in all insertion sites. In cadavers, the right 9th ICS was associated with the lowest number of organ penetrations after VN insertion. In cadavers, the position associated with the lowest frequency of penetrating any intraabdominal structure was the 9th ICSon the right side.


Electrochemically assisted deposition of strontium modified magnesium phosphate on titanium surfaces.
Electrochemically assisted deposition was utilized to produce ceramic coatings on the basis of magnesium ammonium phosphate (struvite) on corundum-blasted titanium surfaces. By the addition of defined concentrations of strontium nitrate to the coating electrolyte Sr(2+) ions were successfully incorporated into the struvite matrix. By variation of deposition parameters it was possible to fabricate coatings with different kinetics of Sr(2+) into physiological media, whereas the release of therapeutically relevant strontium doses could be sustained over several weeks. Morphological and crystallographic examinations of the immersed coatings revealed that the degradation of struvite and the release of Sr(2+) ions were accompanied by a transformation of the coating to a calcium phosphate based phase similar to low-crystalline hydroxyapatite. These findings showed that strontium doped struvite coatings may provide a promising degradable coating system for the local application of strontium or other biologically active metal ions in the implant-bone interface.


Challenges in the diagnostic and therapeutic approach to nephrolithiasis.
The incidence of renal stones is rising along with the costs and morbidity associated with this condition. With careful evaluation and management, the great majority of recurrent stones are preventable. The cornerstone of this evaluation remains the 24-h urine collection. This review details the physiological rationale for commonly requested urine studies and details how these results should guide therapy with special emphasis on recent advances in the understanding of risk factors for stone disease. Challenges associated with the complicated patient will be addressed. Long-term follow-up and repeated evaluations are effective at preventing recurrent stones and increasing patient satisfaction. There is growing appreciation of the complexity of dietary risks for stone disease, and traditional risk-factors such as dietary oxalate must be reevaluated. The key to stone prevention is the individualization of therapy to specific patient risk factors with a recognition that these factors can change over time leading to a need for alterations in preventive therapies.


Association between serum estradiol level, sex hormone binding globulin level, and bone mineral density in middle-aged postmenopausal women.
Changes in sex hormones are thought to play an important role in bone health in postmenopausal women. Our aim in this study was to evaluate the association between levels of estradiol (E2), which is the most potent endogenous estrogen, and sex hormone binding globulin (SHBG) and bone mineral density (BMD) among postmenopausal women, 40-59 years of age. Using data from the National Health and Nutrition Examination Survey 2013-2016, we performed weighted multivariable linear regression models to evaluate the associations between serum levels of E2 and SHBG and lumbar BMD. A weighted generalized additive model and smooth curve fitting were used to address potential nonlinearity. A total of 608 postmenopausal women were included in the analysis. The serum E2 level was positively associated with lumbar BMD, after adjusting for other covariates (β 0.65; 95% confidence interval (CI) 0.38-0.93). An inverted U-shaped association between the serum E2 level and lumbar BMD was further identified, with the point of inflection at an E2 level of 70 pg/mL. There was no significant association between the SHBG level and lumbar BMD (β 0.01; 95% CI - 0.30 to 0.31). However, the association between these two variables was U-shaped, with the point of inflection at an SHBG level of 65 nmol/L. Based on our findings, it may be beneficial to appropriately increase serum E2 levels to promote bone health in postmenopausal women with low estrogen levels. Considering the inverted U-shaped association, an excessive E2 level may be harmful to BMD. In addition, increasing the SHBG level to within the normal range (65-144 nmol/L) may be considered.


Determinants of access of frail, community-residing older adults to geriatricians in Ontario.
Little is known about determinants of access to community-based geriatricians. The Geriatric 5Ms™ describe geriatricians' core competencies and inform referrals to specialists for older adults with complex needs. We explored the association of the Geriatric 5Ms™ and other characteristics with outpatient access to geriatricians by home care (HC) clients. This was a population-based, retrospective cohort study of frail community-dwelling HC clients (≥60 years) with complex needs (n = 196,444). Health assessment information was linked to health services data in Ontario, Canada, 2012-2015. Multivariable generalized estimating equations were used to identify characteristics associated with geriatrician contact (≥1 visit in 90 days post-HC admission), including derived Geriatric 5Ms™ score, and predisposing, enabling, and need factors obtained from clinical assessments. Only 5.2% of the cohort had outpatient geriatrician contact in Ontario, Canada. Derived Geriatric 5Ms™ score was associated with higher odds of contact, but the model had modest discriminatory power (c-statistic = 0.67). In the broader multivariable model, based on empirically included factors and adjusted for regional differences, age, worsening of decision-making, dementia, hallucinations, Parkinsonism, osteoporosis, and caregiver distress/institutionalization risk were associated with higher odds of geriatrician contact. Female sex, difficulties accessing home, impaired locomotion, recovery potential, hemiplegia/hemiparesis, and cancer, were associated with lower odds of contact. This model had good discriminatory power (c-statistic = 0.77). Few frail, community-dwelling older adults receiving HC had any outpatient geriatrician contact. While the derived Geriatric 5Ms™ score was associated with contact, a broader empirical model performed better than the Geriatric 5Ms™ in predicting contact with an outpatient geriatrician. Contact was mainly driven by conditions common in older adults, but evidence suggests that geriatricians are not evaluating the most medically complex and unstable older adults in the community. These findings suggest a need to re-examine the referral process for geriatricians and the allocation of limited specialized resources.


Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease.
Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.


[Influence of raw material on storage behaviour of potato chips (author's transl)].
The influence of storage duration on the lipid and fatty acid content of potato tubers and on the concentration of volatile aroma substances in potato chips were studied. An increase in the unsaturated fatty acids of potato tubers was found during the first months of storage. The higher lipid content of early maturing varieties as compared with late maturing ones may be explained by decreased physiological maturity of these potatoes. Among the aroma substances the constituents hexanal, pentanal, and pentane are possible important indicators for the rancidity of potato chips. Relationships between differing storage conditions of chips and their reeping quality were indicated by volatile aroma substances, especially hexanal.


Rates of glaucoma medication utilization among persons with primary open-angle glaucoma, 1992 to 2002.
To determine the percentage of Medicare beneficiaries with primary open-angle glaucoma (POAG) treated medically or surgically, utilization rates for each major class of glaucoma medication, and factors influencing treatment. Longitudinal observational study using data from the Medicare Current Beneficiary Survey (MCBS). Persons age 65 and older with POAG, 1992 to 2002 (N = 6446). By using MCBS data merged with Medicare claims, rates of medical and surgical treatment for participants with POAG were determined. Logistic analysis was used to assess factors associated with use of care. Receipt/nonreceipt of medical or surgical therapy in a year and rates of drug utilization by class and of surgery by type among persons who did not receive medical therapy in a year. On average from 1992 to 2002, 27.4% of persons diagnosed with POAG received no medical or surgical treatment. Rates of nonuse increased by 3% annually (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02-1.05). Beneficiaries with Medicaid were 43% more likely not to receive care for POAG in a year (OR, 1.43; 95% CI, 1.20-1.70). Hispanic, Asian, and beneficiaries of other race/ethnicity were less likely to receive treatment than were whites. Use of beta-blockers and miotics decreased, but utilization rates increased substantially for alpha-agonists, combination beta-blocker-carbonic anhydrase inhibitors, and especially prostaglandin analogs. Despite availability of more efficacious glaucoma medication classes with few side effects and findings of clinical trials underscoring the importance of intraocular pressure reduction in POAG patients, many patients with POAG continue to go untreated.


A phorbol ester-binding protein is required downstream of Rab5 in endosome fusion.
Previous observations indicate that a zinc and phorbol ester binding factor is necessary for endosome fusion. To further characterize the role of this factor in the process, we used an in vitro endosome fusion assay supplemented with recombinant Rab5 proteins. Both zinc depletion and addition of calphostin C, an inhibitor of protein kinase C, inhibited endosome fusion in the presence of active Rab5. Addition of the phorbol ester PMA (phorbol 12-myristate 13-acetate) reversed the inhibition of endosome fusion caused by a Rab5 negative mutant. Moreover, PMA stimulated fusion in the presence of Rab5 immunodepleted cytosol. These results suggest that the phorbol ester binding protein is acting downstream of Rab5 in endosome fusion.


Absolute eosinophil count correlates with temperature and CD4 count independently of HIV infection among tuberculosis patients.
To determine clinical correlates of the peripheral absolute eosinophil count (AEC) among bacteriologically confirmed TB patients in Uganda. We evaluated data of bacteriologically confirmed adult TB patients who had a peripheral blood AEC measurement at the National TB Treatment Center in Uganda during a cross-sectional study. We performed linear regression analysis for correlates of log-transformed AEC. We included 235 patients in this analysis with a median (interquartile range, IQR) age of 31 (24-39) years. 60.4% were male, and 33.6% had TB/HIV co-infection. In a multivariable linear regression model that controlled for age, residence type, HIV status, weight loss, anorexia, body mass index, CD8+ T-cell count, haemoglobin level and TB bacillary load, males had a 47.0% higher AEC than females (adjusted coefficient (R2 ) = 0.385, 95% confidence interval (CI) 0.012-0.759 P = 0.043). Also, a 1 °C raise in temperature resulted in an 11.5% decrease in the AEC (R2 = -0.122 95% CI (-0.233 to -0.011) P = 0.031) while a 1 cell/mm3 increase in the CD4+ T-cell count resulted in a 0.10% increase in the AEC (R2 = 0.001 95% CI (0.000-0.001) P = 0.032). The AEC was higher among males than females, consistent with the normal population distribution of AEC among Ugandans. The AEC was weakly but positively correlated with the CD4 count and negatively correlated with temperature.


Spin polarization of electrons by nonmagnetic heterostructures: the basics of spin optics.
We propose to use the lateral interface between two regions with different strengths of the spin-orbit interaction(s) to spin polarize the electrons in gated two-dimensional semiconductor heterostructures. For a beam with a nonzero angle of incidence, the transmitted electrons will split into two spin polarization components propagating at different angles. We analyze the refraction at such an interface and outline the basic schemes for filtration and control of the electron spin.


Multiple sclerosis lesions that impair memory map to a connected memory circuit.
Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.


Cardiovascular mortality in patients with advanced chronic kidney disease with and without diabetes: a nationwide cohort study.
Cardiovascular mortality and the impact of cardiac risk factors in advanced chronic kidney disease (CKD) remain poorly investigated. We examined the risk of cardiovascular mortality in patients with advanced CKD with and without diabetes as well as the impact of albuminuria, plasma hemoglobin, and plasma low-density lipoprotein (LDL) cholesterol levels. In a Danish nationwide registry-based cohort study, we identified persons aged ≥ 18 years with an estimated glomerular filtration rate < 30 mL/min/1.73m2 between 2002 and 2018. Patients with advanced CKD were age- and sex-matched with four individuals from the general Danish population. Cause-specific Cox regression models were used to estimate the 1-year risk of cardiovascular mortality standardized to the distribution of risk factors in the cohort. We included 138,583 patients with advanced CKD of whom 32,698 had diabetes. The standardized 1-year risk of cardiovascular mortality was 9.8% (95% CI 9.6-10.0) and 7.4% (95% CI 7.3-7.5) for patients with and without diabetes, respectively, versus 3.1% (95% CI 3.1-3.1) in the matched cohort. 1-year cardiovascular mortality risks were 1.1- to 2.8-fold higher for patients with diabetes compared with those without diabetes across the range of advanced CKD stages and age groups. Albuminuria and anemia were associated with increased cardiovascular mortality risk regardless of diabetes status. LDL-cholesterol was inversely associated with cardiovascular mortality risk in patients without diabetes, while there was no clear association in patients with diabetes. Diabetes, albuminuria, and anemia remained important risk factors of cardiovascular mortality whereas our data suggest a limitation of LDL-cholesterol as a predictor of cardiovascular mortality in advanced CKD.


High prevalence of vitamin D deficiency in HIV-infected individuals in comparison with the general population across Punjab province, Pakistan.
The status of vitamin D in individuals infected with human immunodeficiency virus (HIV), particularly in naïve as well as treated patients, has never been reported in the Pakistani population. A cross-sectional study was performed to measure vitamin D in individuals infected with HIV living in various districts of the Punjab, Pakistan. 1000 persons attending various treatment centers of the Punjab were screened for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), and Syphilis. Total 398 patients met inclusion criteria and vitamin D level was measured in respective cases by using enzyme-linked immunosorbent assay (ELISA) technique. 232 samples from the healthy population were also included in present research. Demographic history and clinical parameters regarding HIV disease were evaluated. Comparison of variables was done to find out the link between vitamin D levels and characteristics of HIV infected persons and comparison to that of healthy individuals was performed. Among 398 HIV patients vitamin D deficiency and insufficiency was found among 15 % and 39 % while majority of the control participants had sufficient levels of vitamin D (78 %). Most of the HIV infected individuals were males (68.6 %) and had age between 24 and 47 years (67.8 %). A significant relationship was found for vitamin D level, lifestyle and CD4 count among HIV + ve non acquired immunodeficiency syndrome (AIDS) subjects (95 % CI; p < 0.001, p = 0.09). For HIV + ve AIDS patients vitamin D had a significant relationship with lifestyle along with HIV viral load and CD4 count. Hypovitaminosis D prevails among the HIV infected population of Punjab, Pakistan.


Cuspal movement and microleakage in premolar teeth restored with resin-based filling materials cured using a 'soft-start' polymerisation protocol.
To investigate the effect of polymerisation shrinkage strain of four posterior filling materials on cuspal movement, degree of conversion (DC) and cervical gingival microleakage of mesio-occlusal-distal (MOD) restorations placed incrementally in maxillary premolar teeth using a 'soft-start' polymerisation protocol. Forty sound extracted upper premolar teeth were subjected to standardised preparation of a large MOD cavity before restoration. A 'soft-start' polymerisation curing regimen was used and each posterior filling material was placed in eight increments with the appropriate bonding system. A twin channel deflection measuring gauge allowed a measurement of individual cusp deflections at each stage of polymerisation. Restored teeth were thermocycled before immersion in a 0.2% basic fuchsin dye for 24h. After sagittal sectioning of the restored teeth in a mesio-distal plane, the sectioned restorations were examined to assess cervical microleakage. The DC was also assessed using a diffuse-reflectance accessory on a Fourier transform infra-red spectrophotometer. A significant increase in cuspal movement recorded for Z100 (20.06+/-4.71) compared with Filtek Z250 (16.52+/-3.26), P60 (14.23+/-3.71) and Admira (11.11+/-2.47). No significant reduction in cuspal movement was identified when compared with a previous study [6] where a full-intensity standard polymerisation protocol was employed. No significant differences were also identified between the materials when the cervical gingival microleakage scores or DC were examined for the 'soft-start' compared with the standard polymerisation protocol. Although material type remained a significant factor, the use of a 'soft-start' polymerization compared with a standard curing regime did not offer any significant reduction in associated cuspal movement, DC or gingival microleakage at the cervical dentine cavosurface margin of the cavities restored with the resin-based filling materials.


Potential use of vegetable proteins to reduce Brazil nut oil oxidation in microparticle systems.
Brazil nut oil is mostly composed of unsaturated fatty acids, some of which are associated with decreased incidence of cardiovascular diseases. Vegetable proteins have been increasingly used as wall material for partial replacement of carbohydrates and whey proteins. In order to create an oil preservation method, Brazil nut oil was encapsulated with three different types of vegetable protein concentrates and gum arabic (GA): rice (RPC + GA); pea (PPC + GA); and soy (SPC + GA) .For this purpose, vegetable protein concentrates were characterized, and after the drying process the physicochemical characteristics of the microparticles were evaluated. The most stable emulsion, after seven days of evaluation, was composed of RPC + GA. RPC + GA. This treatment was also more stable based on the shelf life assessments. We concluded that RCP microparticles were the best option for encapsulating Brazil nut oil in comparison with the other particles evaluated. In addition, the product obtained is potentially capable of being included in various processed foods.


Control strategies to manage trade-offs during microbial production.
When engineering microbes to overproduce a target molecule, engineers face multiple layers of trade-offs to allocate limited cellular resources between the target pathway and native cellular systems. These trade-offs arise from limited free ribosomes during translation, competition for metabolic precursors, as well as the negative relationship between production and growth rate. To achieve high production performance, microbes need to spontaneously make decisions in the dynamic and heterogeneous fermentation environment. In this review, we discuss recent advances in microbial control strategies that are used to manage these trade-offs and to improve microbial production. This review focuses on design principles and compares different implementations, with the hope to provide guidelines to future microbial engineering.


Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy.
Clinical genome editing is emerging for rare disease treatment, but one of the major limitations is the targeting of CRISPR editors' delivery. We delivered base editors to the retinal pigmented epithelium (RPE) in the mouse eye using silica nanocapsules (SNCs) as a treatment for retinal degeneration. Leber congenital amaurosis type 16 (LCA16) is a rare pediatric blindness caused by point mutations in the KCNJ13 gene, a loss of function inwardly rectifying potassium channel (Kir7.1) in the RPE. SNCs carrying adenine base editor 8e (ABE8e) mRNA and sgRNA precisely and efficiently corrected the KCNJ13W53X/W53X mutation. Editing in both patient fibroblasts (47%) and human induced pluripotent stem cell-derived RPE (LCA16-iPSC-RPE) (17%) showed minimal off-target editing. We detected functional Kir7.1 channels in the edited LCA16-iPSC-RPE. In the LCA16 mouse model (Kcnj13W53X/+ΔR), RPE cells targeted SNC delivery of ABE8e mRNA preserved normal vision, measured by full-field electroretinogram (ERG). Moreover, multifocal ERG confirmed the topographic measure of electrical activity primarily originating from the edited retinal area at the injection site. Preserved retina structure after treatment was established by optical coherence tomography (OCT). This preclinical validation of targeted ion channel functional rescue, a challenge for pharmacological and genomic interventions, reinforced the effectiveness of nonviral genome-editing therapy for rare inherited disorders.


Computed tomography demonstration of cholecystogastric fistula.
Cholecystogastric fistula is a rare complication of chronic cholecystitis or long-standing cholelithiasis. It results from the gradual erosion of the approximated, chronically inflamed wall of the gall bladder and stomach with fistulous tract formation. The present case describes the direct visualization of a cholecystogastric fistula by computed tomography in a patient without prior biliary system complaints.


Population pharmacokinetic study of gentamicin and a Bayesian approach in patients with renal impairment.
A population pharmacokinetic study was conducted on a total of 70 patients receiving gentamicin therapy. The patients included those with normal renal function and those with varying degrees of renal impairment. The parameters studied were the apparent volume of distribution and the plasma clearance of gentamicin. The interindividual variability and the residual variability of those parameters in the different subpopulations were studied according to a statistical model that assumed log normal distribution. Use of the one-way ANOVA test revealed statistically significant differences (P = 0.004) in the population plasma clearance of gentamicin in patients below and above 50 years of age. A linear relationship was established between the plasma clearance of gentamicin and the creatinine clearance in those patients. At the same time, the coefficient of variation of the Clp increased progressively in patients with renal impairment, varying between 28.98% in patients with a ClCR greater than 100 ml/min and 76.53% in patients with a ClCR between 20 and 60 ml/min. The results obtained in the population study were later applied to drug monitoring in 23 patients with varying degrees of renal function and who received gentamicin therapy with different doses. The residual variability of the population allowed us to calculate a weighting factor (FF) between the experimental and the population data using Bayesian fitting. The weighting factor was 0.89 in patients with normal renal function and 0.80 in patients with renal impairment. Statistical comparison of the pharmacokinetic parameters obtained from the populational data, non-linear regression and the Bayesian method using revealed differences in the values for the apparent volume of distribution obtained with the two methods.(ABSTRACT TRUNCATED AT 250 WORDS)


Ocular motor and sensory function in Parkinson's disease.
To evaluate the effect of dopaminergic medication and deep brain stimulation on ocular function in Parkinson's disease (PD) and to measure vision-related quality of life in subjects with PD. Prospective, comparative case series. Twenty-seven PD and 16 control subjects were recruited. Visual acuity, ocular motor function, convergence, and vision-related quality of life using the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) were measured. Visual sensory and motor measurements were obtained during the on and off states of PD dopaminergic treatment. Convergence ability and vision-related quality of life. The PD subjects had a mean age of 58.8 years; 30% were female. Their mean duration of PD was 10.9 ± 6.8 years. The control subjects had a mean age of 61.6 years; 56% were female. There was no difference in visual acuity, contrast sensitivity, or color vision of the PD subjects in their on state compared with controls. Convergence amplitudes measured with base-out prism were significantly poorer in PD subjects in their on state compared with controls (24.1 ± 8 Δ vs. 14.8 ± 10.3 Δ; P = 0.003). The mean composite VFQ-25 score was significantly worse in the PD subjects compared with the controls (87.1 ± 8.69 vs. 96.6 ± 3.05; P = 0.0001). Comparing the PD subjects in their on with their off states, there was no difference in distance exodeviation, near exodeviation, or ocular ductions. Mean convergence amplitudes and near point of convergence were better in the on state compared with the off state: 14.8 ± 10.3 Δ versus 10.7 ± 9.0 Δ (P = 0.0006) and 13.1 ± 9.1 cm versus 18.1 ± 12.2 cm (P = 0.002), respectively. Convergence ability is significantly poorer in PD subjects in both the on and off states compared with controls, but improves significantly with systemic dopaminergic treatment. Ocular motor function in PD subjects fluctuates in response to treatment, which complicates ophthalmic management. Parkinson's disease subjects have a significant reduction in vision-related quality of life, especially with near activities, that is not associated with visual acuity. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


High level of aphidicolin resistance with multiple mutations in mouse FM3A cell mutants.
Spontaneous mutants of mouse FM3A cells (AC1, AC2, and AC3), highly resistant to aphidicolin (3000-, 2500-, and 300-fold increase in resistance, respectively), were isolated by multistep selection. The DNA synthesizing activity in permeabilized cells of all three mutants was substantially resistant to aphidicolin, like that in intact cells. The DNA polymerase activity in nuclear extracts in AC1 and AC3, but not AC2, was resistant to aphidicolin. Partially purified DNA polymerase alpha from AC3, but not from AC1 or AC2, showed resistance to aphidicolin. The apparent Ki value for aphidicolin of AC3 polymerase alpha was three to four times that of the enzyme from the parent cells, but the apparent Km values of the enzyme for dCTP and dTTP were normal. All the mutants showed cross-resistance to both arabinofuranosyladenine and arabinofuranosylcytosine. The AC3 mutant had expanded deoxyribonucleoside triphosphate pools. On two-dimensional polyacrylamide gel electrophoresis, AC1 gave a new protein (mol wt 40 kDa). The aphidicolin-resistance trait was reversible in AC2, unlike in AC1 and AC3. These results show that in mammalian cells there are at least two mechanisms of aphidicolin-resistance that involve an altered DNA polymerase alpha that is resistant to aphidicolin and simultaneous expansion of the four DNA-precursor pools.


Interleukin 2 induces synthesis of polypeptides in an interleukin 2-dependent cell line by transcription and translation.
Interleukin 2 (IL 2) is a lymphocyte growth factor capable of inducing the rapid growth of antigen- or mitogen-stimulated T cells. To understand the molecular mechanisms of IL 2 action, we studied the synthesis of cellular polypeptides induced by IL 2. For a homogeneous cell population responsive to IL 2, we used a murine clone of natural killer-like cells, NK 7, which is strictly dependent on exogenous IL 2 for cell viability and growth. NK 7 cells were first kept in culture without IL 2 for 6 h and then labeled for 3 h with [14C]leucine in the presence or absence of 100 U/ml recombinant human IL 2. Analysis of the cellular polypeptides by two dimensional gel electrophoresis and autoradiography revealed that the addition of IL 2 to IL 2-starved NK 7 cells specifically increased the levels of at least ten polypeptides (designated from molecular weight as p94a, p94b, p52, p51a, p51b, p48.5, p36, p34.5, p25.5, and p23). The increases of p52, p25.5, and p23 were inhibited by 5 micrograms/ml actinomycin D, whereas the other seven were virtually unaffected by the drug.


Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutational burden (TMB) is closely associated with the efficacy and response rate of immunotherapy. However, its roles in ACC were not investigated. Using somatic mutations data of 92 ACC samples in TCGA database, we calculated their TMB values by the 'maftools' package in R software (Ver 3.6.3). To explore the roles of TMB in ICIs therapy, we have addressed this issue from three perspectives. First, the effects of TMB levels on tumor immune microenvironment (TIM) were analyzed through CIBERSORT algorithm, ssGSEA method and TIMER web server. Second, we investigated the expressive correlations between TMB level and five pivotal immune checkpoints based on Pearson coefficient. Third, the difference in TIDE score between high- and low-TMB groups was compared. The prognostic value of TMB was also evaluated. Besides, GSEA was performed to determine the changes in the activities of signaling pathways caused by TMB. TMB values in ACC samples were not high. The average of total mutation counts in each sample was only 21.5. High TMB could lead metabolic reprogramming and poor survival outcomes. However, it was unable to affect the infiltration levels of lymphocytes, and failed to facilitate the activities of immune-related pathways. Regarding immune checkpoints (ICs), only PD-L1 upregulation could result in a good prognosis, and TMB level did not correlate with the expressions of other ICs except for LAG3. There was no significant difference in TIDE score between high- and low-TMB groups. Combining the present results and previous study, we speculated that inadequate stimulation for neoantigens formation, intrinsic immune-resistance and special genomic alterations were three possible reasons for TMB limiting functions in TIM and ICIs. Besides, TMB was toughly applied in clinical practice due to its high cost of determination and non-universal definition of high TMB. TMB presents limiting effects on prediction for ICIs efficacy and prognostic assessment for ACC patients.


Measurement of total occlusal convergence of 3 different tooth preparations in 4 different planes by dental students.
Total occlusal convergence of crown preparation is an important didactic and clinical concept in dental education. The purpose of this study was to compare the discrepancy between the total occlusal convergence of dental students' typodont crown preparations and the ideal range (4 to 10 degrees) in 3 different regions of the mouth and in 4 different planes of the teeth. The dental students of the Class of 2012 at Harvard School of Dental Medicine were asked to prepare typodont teeth for crowns on 3 different teeth, the maxillary left central incisor (ceramic), mandibular left first molar (complete metal), and mandibular left first premolar (metal ceramic), during their third year preclinical summative examination and the Comprehensive Clinical Examination in their fourth year. Eighteen students prepared 3 teeth in their third and fourth years, whereas 19 students participated only in their fourth year, for a total of 55 sets of 3 teeth. By using custom fit die bases to reproduce the position, a novel procedure of measuring each tooth was accomplished in 4 different planes: the faciolingual, mesiodistal, mesiofacial-distolingual, and mesiolingual-distofacial. The total occlusal convergence of each image was measured with a computer screen protractor. The gingival 2 mm of the axial wall was used to determine the taper of each wall. Linear mixed model analysis was used to estimate and compare the total occlusal convergences of different teeth and planes (α=.05). Bonferroni corrections were used to adjust for post hoc multiple comparisons. The mean total occlusal convergence varied by tooth and plane (2-way interaction; P<.001). For the first molar, dental students excessively tapered in all 4 planes; the model-predicted 99% CIs for the total occlusal convergence were as follows: faciolingual (12.7, 19.4), mesiodistal (14.0, 19.3), mesiofacial-distolingual (13,4, 19.4), and mesiolingual-distofacial (13.7, 19.1). For the central incisor, 99% CIs for the total occlusal convergence were (15.9, 24.4) for the faciolingual measurement, providing strong evidence of excessive tapering, and (4.1, 8.0) for the mesiodistal measurement, which was within the ideal total occlusal convergence range. The mesiofacial-distolingual and mesiolingual-distofacial planes in the central incisor and all 4 planes in the first premolar had mean total occlusal convergences that exceeded 10 degrees; however, excessive tapering could not be statistically established, because their CIs included values within the ideal range. The present study found significant evidence of excessive tapering in a study comparing the total occlusal convergence values of crown preparations with those of the ideal preparation for 3 different teeth in 4 different planes. The total occlusal convergence for the molar preparations had the highest mean values.


Developmental origins of adult diseases and neurotoxicity: epidemiological and experimental studies.
To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers at this symposium presented their research results on different neurotoxic chemicals relating to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to inorganic mercury and methylmercury, and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-dose human equivalent gestational lead exposure produces late-onset obesity only in male mice that is associated with neurodegeneration. Didima de Groot presented results on prenatal exposure of rats to methylazoxymethanol and discussed the results in light of the etiology of western Pacific amyotrophic lateral sclerosis and Parkinson-dementia complex. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following acute 24 h exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment. The results indicate that developmental neurotoxicity results in permanent changes, thus emphasizing the need to prevent such toxicity.


Duodenal ulcer healing and acid secretory responses to modified sham feeding and pentagastrin stimulation.
The effect of duodenal ulcer healing on the acid secretory responses to modified sham feeding and maximal pentagastrin stimulation has been studied in 17 patients treated successfully with ranitidine (n = 9) and sucralfate (n = 8). Parietal cell sensitivity was calculated as the ratio of the modified sham feeding response to the peak pentagastrin response, expressed as a percentage. Ulcer healing after sucralfate therapy resulted in significant falls in modified sham feeding stimulated acid output (P less than 0.02), from 9.4 (1.8-17.0) (median + range) to 3.7 (0.2-9.4) mmol/h; in peak acid output (P less than 0.05) from 42.8 (23.0-61.4) to 27.7 (7.2-51.0) mmol/h; and in the parietal cell sensitivity (P less than 0.05) from 19.2 (4.4-42.6) to 14.3 (2.8-19.7)%. No significant falls in any of these parameters were noted following ulcer healing with ranitidine. Duodenal ulcer healing with sucralfate results in decreased acid secretory responses to vagal and pentagastrin stimulation.


Omission bias and decision making in pulmonary and critical care medicine.
Pulmonary and critical care physicians routinely make complex decisions, but little is known about cognitive aspects of this process. Omission bias and status quo bias are well-described cognitive biases that can cause lay decision makers to prefer inaction that preserves the status quo even when changing the status quo through action is more likely to lead to the best outcomes. It is unknown if these biases influence trained decision makers such as pulmonologists. To determine whether omission bias and status quo bias influence the medical decisions of pulmonologists. The study was a randomized controlled trial conducted within a cross-sectional survey of pulmonologists' opinions about the relevance of various factors in pulmonary and critical care decision making. We designed case vignettes that presented patient information with an associated patient management choice. The status quo state and the action/omission distinction were varied in two forms of otherwise identical vignettes. One form of each case vignette pair (A and B) was administered randomly to each prospective respondent during the first mailing of the opinion survey. Five hundred pulmonologists selected randomly from the membership of the American College of Chest Physicians. There were 125 respondents, including 59 for form A and 66 form B (enrollment rate, 25%). In vignettes involving evaluation of pulmonary embolism and treatment of septic shock, respondents were more likely to choose a suboptimal management strategy when an omission option was present that allowed preservation of the status quo (71% vs 53%, p = 0.048; 50% vs 29%, p = 0.016, respectively). In a vignette involving a hypothetical clinical trial and the decision to prescribe tube feeding, the omission option was not significantly associated with the decision to prescribe tube feeding (54% vs 50%, p = 0.67). Pulmonary and critical care decisions are susceptible to the influence of omission and status quo bias. Because of the great number of decisions that are made each day involving choices between maintaining or changing the status quo, this finding could have far-reaching implications for patient outcomes, cost-effectiveness, resource utilization, clinical practice variability, and medical errors.


Benzodiazepine effects on flicker sensitivity: role of stimulus frequency and size.
1. Benzodiazepines (BZDs) impair sensitivity to temporally modulated visual stimuli (flicker). Critical flicker-fusion frequency (CFF) is commonly used as a measure of this effect, but it only measures sensitivity to a narrow range of frequencies, usually above 25 Hz. Are other frequencies more sensitive to the effects of BZDs? 2. Flicker sensitivity at 1, 2, 4, 8, 16, and 32 Hz was measured for 1 degrees and 5 degrees stimuli before and 50 to 100 minutes after triazolam (0.25 mg), lorazepam (1.0 mg) and placebo. Drug effects on CFF were also measured. 3. Both BZDs significantly impaired overall flicker sensitivity. Triazolam produced 50% more impairment than lorazepam. CFF was significantly impaired by triazolam. BZD effects did not vary with stimulus size. 4. Significantly greater BZD-induced impairment of flicker sensitivity occurred at 16 Hz than at 1, 2, 4, or 32 Hz. 5. The magnitude of BZD effects on flicker sensitivity vary with the temporal frequency of the stimulus. BZD effects are greatest for 8-16 Hz stimuli.


Measurement of family-centred care: translation, adaptation and validation of the Measure of Processes of Care (MPOC-56 and -20) for use in Japan.
The Measure of Processes of Care (MPOC) that was developed in Canada is a widely used quantitative measure of parents' perceptions of the extent to which family-centred care is conducted. The purpose of this study was to assess the validity and reliability of the Japanese version of the MPOC. The translation of the MPOC was performed according to international standards for translation of questionnaires. The Canadian validation procedures were followed, consisting of concurrent validity, construct validity and test-retest reliability. The Japanese version of the MPOC was completed by 261 families with children receiving rehabilitation services. The Japanese version of the MPOC showed adequate internal consistency with Cronbach's alpha, varying between 0.76 and 0.94. The construct validity was examined with confirmative analysis of each scale structure. Correlations between the MPOC scale scores and satisfaction questions scores were positive, and that to a question about parents' stress was negative. For test-retest reliability, the intraclass correlation coefficients were between 0.76 and 0.89. The Japanese version of the MPOC has good psychometric properties and can be recommended for evaluation of the processes of child rehabilitation in Japan.


Gangliosides of the starfish Aphelasterias japonica, evidence for a new linkage between two N-glycolylneuraminic acid residues through the hydroxy group of the glycolic acid residue.
Mono- and disialogangliosides containing glucose, galactose and sialic acids were isolated from the total lipid extract of hepatopancreas of the starfish Aphelasterias japonica. Their structures were elucidated by total and partial acid hydrolysis, trideuteriomethylation analysis, neuraminidase treatment, chromium trioxide oxidation, methanolysis and periodate oxidation. The monosialoganglioside was identified as 8-O-methyl-N-glycolylneuraminosyl-alpha-(2-3)-galactosyl-beta-(1- 4)-glucosyl-beta-(1-1)-ceramide. The disialoganglioside has the additional N-glycolylneuraminic acid or its 8-O-methyl derivative residue at the subterminal position to which the terminal sialic acid residue is linked through the hydroxy group of the glycolic acid unit. The long-chain bases were found to be mixtures of phytosphingosines with both branched and linear chains, and the fatty acids were shown to be mixtures of normal and alpha-hydroxy fatty acids, the latter amounted to about 90% of the fatty-acid mixtures. The composition of the lipid moieties of the gangliosides was determined by GLC and GLC-MS.


Low-/high-density lipoprotein cholesterol ratio and carotid plaques in patients with coronary heart disease: a Chinese cohort study.
Evidence on the relationship between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and carotid plaques remains limited. This study aimed to examine the association between LDL-C/HDL-C and carotid plaques in participants with coronary heart disease (CHD) and to further explore the extent to which a healthy lifestyle reduces the risk of LDL-C/HDL-C-related carotid plaques. This large-scale and multi-centre retrospective study included 9426 CHD patients (aged 35-75 years) between January 1, 2014 and September 30, 2020. The LDL-C/HDL-C values were converted to the following tertiles: lowest (< 2.15), middle (2.15-3), and highest (> 3). Healthy lifestyle-related factors referred to whether or not the participant was a non-smoker and non-drinker. Participants were divided into an unfavourable group (those who did not adhere to healthy lifestyle factors), intermediate (only one unhealthy factor), and favourable (neither of the two unhealthy factors). Logistic regression was used for statistical analyses. Of the 9426 participants, 6989 (74.15%) CHD patients had carotid plaques. After adjustment for confounders, each unit increase in the LDL-C/HDL-C was significantly associated with carotid plaques (OR: 1.61; 95%CI: 1.43-1.84; P < 0.001). Multivariate logistic regression revealed that carotid plaques risk for the highest tertile (> 3) was 1.18 times that of the lowest quartile (< 2.15). Compared with an unfavourable lifestyle, an intermediate or a favourable lifestyle was associated with a significant 30% (OR: 0.70; 95%CI: 0.64-0.78; P < 0.001) or 67% (OR: 0.33; 95%CI: 0.29-0.37; P < 0.001) reduction in carotid plaques risk, respectively, among CHD patients with high LDL-C/HDL-C. There were significantly additive and multiplicative interactions between lifestyle and LDL-C/HDL-C with regards to carotid plaques. A high LDL-C/HDL-C is associated with a risk of carotid plaques developing in CHD patients. Adhering to a healthy lifestyle has additive beneficial effects on reducing the risk of carotid plaques, especially in relation to the highest LDL-C/HDL-C.


In-silico screening using flexible ligand binding pockets: a molecular dynamics-based approach.
In-silico screening of flexible ligands against flexible ligand binding pockets (LBP) is an emerging approach in structure-based drug discovery. Here, we describe a molecular dynamics (MD) based docking approach to investigate the influence on the high-throughput in-silico screening of small molecules against flexible ligand binding pockets. In our approach, an ensemble of 51 energetically favorable structures of the LBP of human estrogen receptor alpha (hERalpha) were collected from 3 ns MD simulations. In-silico screening of 3500 endocrine disrupting compounds against these flexible ligand binding pockets resulted in thousands of ER-ligand complexes of which 582 compounds were unique. Detailed analysis of MD generated structures showed that only 17 of the LBP residues significantly contribute to the overall binding pocket flexibility. Using the flexible LBP conformations generated, we have identified 32 compounds that bind better to the flexible ligand-binding pockets compared to the crystal structure. These compounds, though chemically divergent, are structurally similar to the natural hormone. Our MD-based approach in conjunction with grid-based distributed computing could be applied routinely for in-silico screening of large databases against any given target.


Primary diffuse leptomeningeal gliomatosis as a rare cause of pain in cervical spine.
Primary diffuse leptomeningeal gliomatosis (PDLG) is a very rare neuro-oncological disease, with only 90 cases of PDLG described in medical literature so far. We present a case report of a 56-years-old female patient, who was originally hospitalized due to cervical spine pain lasting several months. Despite complex diagnostics and treatment, the neurological state of the patient progressively deteriorated. Patient died 10 months after the first reported symptom. Postmortem pathological findings resulted in the diagnosis of PDLG. Affection of the cervical spine in early stages of PDLG is rare and has been described in only six patients so far. PDLG is a fatal neuro-oncological disease and it must be kept in mind in the differential diagnosis of persistent back pain syndromes.


Isolation and propagation of colon cancer stem cells.
The design of tissue culture conditions that faithfully reproduce the characteristics of cells in their native environment remains one of the main challenges of cancer stem cell (CSC) biology. Here we describe a detailed methodology for the isolation and expansion of both human colon CSCs and mouse intestinal adenoma together with a brief differentiation and coculture method that proved to be valuable to study the concept of CSCs plasticity.


A three-compartment model of the hemodynamic response and oxygen delivery to brain.
We describe a mathematical model linking changes in cerebral blood flow, blood volume and the blood oxygenation state in response to stimulation. The model has three compartments to take into account the fact that the cerebral blood flow and volume as measured concurrently using laser Doppler flowmetry and optical imaging spectroscopy have contributions from the arterial, capillary as well as the venous compartments of the vasculature. It is an extension to previous one-compartment hemodynamic models which assume that the measured blood volume changes are from the venous compartment only. An important assumption of the model is that the tissue oxygen concentration is a time varying state variable of the system and is driven by the changes in metabolic demand resulting from changes in neural activity. The model takes into account the pre-capillary oxygen diffusion by flexibly allowing the saturation of the arterial compartment to be less than unity. Simulations are used to explore the sensitivity of the model and to optimise the parameters for experimental data. We conclude that the three-compartment model was better than the one-compartment model at capturing the hemodynamics of the response to changes in neural activation following stimulation.


Correlation between Serum 25-Hydroxy Vitamin D Levels and the Severity of Acne Vulgaris: A Systematic Review.
Vitamin D is thought to play a role in the pathogenesis of acne, and its levels can change in patients with acne vulgaris. Several studies have revealed that serum 25-hydroxy vitamin D levels tend to be low and statistically significant in acne vulgaris patients. However, the relationship between vitamin D levels and acne severity is still poorly understood. This study aims to identify the correlation between serum 25-hydroxy vitamin D levels and the severity of acne vulgaris. This systematic review study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline based on several studies taken from the PubMed, PMC, Semantic Scholar, and ResearchGate databases until June 2021. Full-text case-control, randomized controlled trial, or cross-sectional study in English or Indonesian language reporting on the serum 25-hydroxy vitamin D levels and the severity of acne vulgaris on human participants were included. From a total of 401 studies, 10 studies met the criteria. Almost all studies (8 of 10) revealed lower serum 25-hydroxy vitamin D levels as the acne severity progresses, although 2 of them were not statistically significant. The evidence of an inverse correlation between serum 25-hydroxy vitamin D levels and the severity of acne vulgaris suggests the need for screening of vitamin D levels in acne patients and offers a new prospect in the field of acne prevention and treatment.