Increased synthesis of poly(ADP-ribose) in isolated liver nuclei from autoimmune NZB/NZW mice.
The synthesis and degradation of poly(ADP-ribose) were investigated in isolated liver nuclei from autoimmune NZB/W mice and four strains of normal mice. Compared to normal mice the maximum levels of incorporation of [3H]NAD into poly(ADP-ribose) were increased about 2-fold in the autoimmune mice. The kinetics of incorporation suggested that this change was due to an increase in the activity of the polymerase rather than a decrease in the level of degradative enzymes. Thus there may be a connection between autoimmunity and poly(ADP-ribose) metabolism.


Lack of association of presenilin-1 intron-8 polymorphism with neuropathological features of Alzheimer's disease.
Over 45 mutations within the coding region of presenilin-1 (PS-1) are associated with an autosomal dominant form of Alzheimer's disease. Recently allele 1 of a polymorphism within intron-8 was reported to be in disequilibrium with Alzheimer's disease in a group of patients with sporadic Alzheimer's disease. This association has been replicated in some, but not all, studies. To determine whether the PS-1 intronic polymorphism is overrepresented in Alzheimer's disease in an autopsy-proven series, and to examine whether allele 1 is associated with a specific neuropathological phenotype, polymerase chain reaction based technique was used to assess the genotype in 85 cases of Alzheimer's disease. The resulting genotypes were compared with age of onset, duration of illness, and quantitative neuropathological measures of Abeta(total), Abeta(1-40), Abeta(1-42), neurofibrillary tangle number and neuron number. The 1/1 genotype did not associate with any differences in the clinical or neuropathological phenotype. These data suggest that the PS-1 intron-8 polymorphism does not strongly impact the clinical or neuropathologic features of Alzheimer's disease.


Effects of nitrilotriacetic acid on the induction of gene mutations and sister-chromatid exchanges by insoluble chromium compounds.
The influence of nitrilotriacetic acid trisodium salt (NTA) on the mutagenic and clastogenic activity of several water-insoluble or poorly soluble chromium compounds was determined by means of the Salmonella/microsome assay (plate test on TA100 strain) and the sister-chromatid exchange (SCE) test in mammalian cell cultures (CHO line). NTA in itself did not induce gene mutations nor did it increase the frequency of SCE. Cr(VI) compounds (Pb, Ba, Zn, Sr and Ca chromates) and an industrial Cr(VI) pigment, chromium orange (containing PbCrO4 PbO), were inactive or scarcely active mutagens in the Salmonella/microsome test when dissolved in water, but they were increasingly mutagenic when solubilized by 0.5 N NaOH or NTA (10 or 100 mg/ml). Also, the mutagenic activity of Cr(VI), contaminating an industrial Cr(III) pigment (chromite), was slightly enhanced by NTA. Mutagenicity of chromates was correlated with the amounts of Cr(VI) solubilized by NTA or alkali, as determined by the colorimetric reaction with diphenylcarbazide and atomic absorption spectrophotometry, and was decreased by incubation with microsomes, due to reduction of Cr(VI) to the genetically inactive Cr(III) form. In the SCE assay, the insoluble or poorly soluble Ba, Zn, Sr and Ca chromates and the insoluble Cr(VI) pigments zinc yellow (containing ZnCrO4 Zn(OH2], chromium yellow and molybdenum orange (both containing PbCrO4) were directly clastogenic due to cellular endocytosis taking place in prolonged treatments, and NTA significantly increased their chromosome-damaging activity.


Pylons ablaze: Examining the role of 5G COVID-19 conspiracy beliefs and support for violence.
Amid increased acts of violence against telecommunication engineers and property, this pre-registered study (N = 601 Britons) investigated the association between beliefs in 5G COVID-19 conspiracy theories and the justification and willingness to use violence. Findings revealed that belief in 5G COVID-19 conspiracy theories was positively correlated with state anger, which in turn, was associated with a greater justification of real-life and hypothetical violence in response to an alleged link between 5G mobile technology and COVID-19, alongside a greater intent to engage in similar behaviours in the future. Moreover, these associations were strongest for those highest in paranoia. Furthermore, we show that these patterns are not specific to 5G conspiratorial beliefs: General conspiracy mentality was positively associated with justification and willingness for general violence, an effect mediated by heightened state anger, especially for those most paranoid in the case of justification of violence. Such research provides novel evidence on why and when conspiracy beliefs may justify the use of violence.


Molecular mechanisms of phagocytic uptake in mammalian cells.
Phagocytosis is a highly conserved, complex process that has evolved to counter the constant threat posed by pathogens, effete cells and debris. Classically defined as a mechanism for internalising and destroying particles greater than 0.5 mum in size, it is a receptor-mediated, actin-driven process. The best-studied phagocytic receptors are the opsono-receptors, FcgammaR and CR3. Phagocytic uptake involves actin dynamics including polymerisation, bundling, contraction, severing and depolymerisation of actin filaments. Recent evidence points to the importance of membrane remodelling during phagocytosis, both in terms of changes in lipid composition and delivery of new membrane to the sites of particle binding. Here we review the molecular mechanisms of phagocytic uptake and some of the strategies developed by microbial pathogens to manipulate this process.


Association of Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis With Marked Improvement in Health-Related Quality of Life.
To quantify the magnitude, domains, and duration of change in health-related quality of life (HRQoL) in patients with systemic sclerosis (SSc) who underwent autologous hematopoietic stem cell transplantation (HSCT) as compared to SSc patients with similar characteristics who did not undergo autologous HSCT. The study was designed as a retrospective study comparing SSc patients who underwent autologous HSCT and SSc patients who met the criteria for transplantation but were treated with conventional care. Outcomes included scores on the 36-item Short Form (SF-36) health survey and the Health Assessment Questionnaire (HAQ) and its disease-specific symptom scales. Differences in scores between the groups were compared using linear models, adjusting for baseline scores and inverse probability of treatment and censoring weights. In total, 41 SSc patients who underwent autologous HSCT and 65 SSc patients treated with conventional care were compared. In marginal linear weighted models, the SF-36 physical component summary score was a mean ± SEM 7.02 ± 1.94 points higher at the first annual visit (P = 0.001) and 14.40 ± 6.16 points higher at the seventh annual visit (P = 0.03) in patients treated with autologous HSCT compared to the conventional care group. HAQ scores were significantly better in the autologous HSCT group compared to the conventional care group during follow-up (mean ± SEM difference from baseline -0.57 ± 0.13 [P < 0.001] at the first annual visit and -0.94 ± 0.49 [P = 0.07] at the seventh annual visit). There were no differences in the SF-36 mental component summary scores between the 2 groups either at baseline or during follow-up. This study provides robust complementary HRQoL data, including overall and event-free survival data, to expand on the standard repertoire of biomedical variables, thus potentially supporting the physical benefits of autologous HSCT in patients with SSc.


Role of plasma membrane phospholipids in the uptake and release of transferrin and its iron by reticulocytes.
The involvement of membrane phospholipids in the utilization of transferrin-bound iron by reticulocytes was investigated using [59Fe]- and [125I]-labelled transferrin and rabbit reticulocytes which had been incubated with phospholipase A. Transferrin and iron uptake and release were all inhibited by phospholipase A which produced a marked decrease in the relative abundance of phosphatidylcholine and phosphatidylethanolamine and equivalent increases in their lyso-compounds in the reticulocyte plasma membrane. There was a close correlation between the iron uptake rate and the rate and amount of transferrin uptake and the amount of the lysophospholipids in the membrane. Incubation of the cells with exogenous lysophosphatidylethanolamine or lysophosphatidylcholine also produced inhibition of iron and transferrin uptake. The reduced uptake produced by phospholipase A could be reversed if the lyso-compounds were removed by fatty acid-free bovine serum albumin or by reincubation in medium 199. Treatment with phospholipase A was shown to increase the amount of transferrin bound by specific receptors on the reticulocyte membrane but to inhibit the entry of transferrin into the cells. The present investigation provides evidence that the phospholipid composition of the cell membrane influences the interaction of transferrin with its receptors, the processes of endocytosis and exocytosis whereby transferrin enters and leaves the cells, and the mechanism by which iron is mobilized between its binding to transferrin and incorporation into heme. In addition, the results indicate that phosphatidylethanolamine is present in the outer half of the lipid bilayer of reticulocyte membrane.


Accurate measurement of female genital tract fluid dilution in cervicovaginal lavage samples.
An ion chromatographic method with conductivity detection for the precise and accurate analysis of lithium ions in phosphate-buffered saline, used as a cervicovaginal lavage (CVL) fluid, was developed and validated. The lithium ion dilution factor during the CVL is used to calculate the volume of cervicovaginal fluid (CVF) collected. Initial CVL Li(+) concentrations of 1mM and 10mM were evaluated. The method is robust, practical, and afforded an accurate measurement (5% of the measurement, or better) at 24μL of vaginal fluid simulant collected per mL of CVL fluid, as low as 5μLmL(-1) using 10mM Li(+) with a measurement accuracy of 6.7%. Ion chromatograms of real-world CVL samples collected in vivo from common animal models (sheep and pig-tailed macaque) and a human volunteer demonstrate that the analysis is interference-free. The method is readily transferrable and should enable the accurate measurement of CVF volume collected during CVLs benefitting a broad range of research disciplines, including pharmacokinetic, pharmacodynamic, metabolomic, and microbiome studies.


Demonstration of thermal dissipation of absorbed quanta during energy-dependent quenching of chlorophyll fluorescence in photosynthetic membranes.
When plant leaves or chloroplasts are exposed to illumination that exceeds their photosynthetic capacity, photoprotective mechanisms such as described by the energy-dependent (non-photochemical) quenching of chlorophyll fluorescence are involved. The protective action is attributed to an increased rate constant for thermal dissipation of absorbed quanta. We applied photoacoustic spectroscopy to monitor thermal dissipation in spinach thylakoid membranes together with simultaneous measurement of chlorophyll fluorescence in the presence of inhibitors of opposite action on the formation of delta pH across the thylakoid membrane (tentoxin and nigericin/valinomycin). A linear relationship between the appearance of fluorescence quenching during formation of the delta pH and the reciprocal variation of thermal dissipation was demonstrated. Dicyclohexylcarbodiimide, which is known to prevent protonation of the minor light-harvesting complexes of photosystem II, significantly reduced the formation of fluorescence quenching and the concurrent increase in thermal dissipation. However, the addition of exogenous ascorbate to activate the xanthophyll de-epoxidase increased non-photochemical fluorescence quenching without affecting the measured thermal dissipation. It is concluded that a portion of energy-dependent fluorescence quenching that is independent of de-epoxidase activity can be readily measured by photoacoustic spectroscopy as an increase in thermal deactivation processes.


The twisting maneuver for fluoroscopic-guided removal of nonpalpable tunneled central venous access catheter cuffs.
The present report describes an alternative technique for the detection of nonpalpable polyester cuffs during the removal of tunneled central venous catheters. By twisting the external segment of the tunneled catheter in obese patients or those with severe edema, fluoroscopy can easily confirm the estimated site of the hidden cuff.


High-throughput virtual screening and preclinical analysis identifies CB-1, a novel potent dual B-Raf/c-Raf inhibitor, effective against wild and mutant variants of B-Raf expression in colorectal carcinoma.
Paradoxical Raf activation via Raf dimerization is a major drawback of wild/mutant B-Raf inhibitors. Herein, we report that CB-1 a novel, potent B-Raf/c-Raf dual inhibitor, effective against colon cancer cells, irrespective of their genetic status. High-throughput virtual screening of the ChemBridge library against wild B-Raf (B-RafWT), mutant B-Raf (B-RafV600E), and c-Raf was performed using an automated protocol with the AutoDock-VINA. Caco-2 and HT-29 cells were used. Of the 23,365 compounds screened computationally, CB-1 showed the highest binding energy towards B-RafWT with a ΔGbinding score of - 13.0 kcal/mol. The compound was also predicted to be effective against B-RafV600E and c-Raf molecules with ΔGbinding energies of - 10.6 and - 10.1 kcal/mol, respectively. The compound inhibited B-RafWT, B-RafV600E and c-Raf kinases with IC50 values of 27.13, 51.70, and 40.23 nM, respectively. The GI50 value of CB-1 was 247.9 nM in B-RafWT-expressing Caco-2 cells and 352.4 nM in B-RafV600E-expressing HT-29 cells. Dose-dependent increases in total apoptosis and G1 cell cycle phase arrest was observed in CB-1-treated colon cancer cells. The compound decreased B-Raf expression in both wild and mutant colon cancer cells. CB-1, a novel, potent dual B-Raf/c-Raf inhibitor was effective against colon cancer cells bearing wild-type and mutant variants of B-Raf expression.


Late diagnosis of HIV in 2022: Why so little change?
The proportion of people who are diagnosed late is a key metric to measure the public health response to HIV. But this percentage remains stubbornly high in nearly every country. Delays in accessing antiretroviral therapy affects both (i) individual health, due to a higher risk of mortality, and (ii) population-based health, due to continued risk of transmission. Despite huge efforts to increase testing, late diagnosis continues to be an indication of a public health failure. This short review includes community perspectives on why late diagnosis continues and how it may be reduced. We discuss both structural barriers that prevent people from testing earlier and personal reasons why some people still refuse testing when offered. We note that late diagnosis is reported in all countries and in all demographic groups and that sex, gender, age, and sexuality all affect these rates. However, even in groups with high HIV awareness, such as in gay and bisexual men in the UK, more than one in three people with HIV continue to be diagnosed late. Fears and prejudice about HIV based on outdated information are still common among both health workers and people using health services. For example, testing is still not offered in primary or emergency care settings, and even free testing might not be accepted if someone fears the outcome might jeopardize their resident status, employment, relationship, or health. In addition to developing targeted projects to reach the highest-risk groups, a positive mainstream public campaign could make testing more acceptable at a broad population level across all demographics. This could challenge and repair the media campaigns from the 1980s that still contribute to the stigma that frightens people away from testing now. We hope that an effective approach in one country might also help others.


Ontogenesis of hepatocyte respiration processes in relation to rat liver cytochrome P450-dependent monooxygenase system.
The study aimed to evaluate the effect of age on the activity of the cytochrome P450-dependent monooxygenase system and on cellular respiration processes in Wistar rats aged 0.5, 1, 2, 4, 8, 12, 20, and 28 months. The following parameters were determined: cytochrome P450 content, cytochrome b5 content, NADPH-cytochrome P450 reductase activity, and NADH-cytochrome b5 reductase activity, succinate dehydrogenase (SDH) activity, and lactate dehydrogenase (LDH) activity. In the study, cytochrome P450 content increased in the first month of life, which was accompanied by increases in SDH and LDH activities. In the subsequent months, SDH activity decreased, whereas LDH activity increased to reach the maximum in month eight and then decreased. Cytochrome b5 content showed a decreasing tendency throughout the experiment. NADH-cytochrome b5 reductase activity showed only slight deviations in individual age groups.


Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression.
Under cellular distress, multiple facets of normal homeostatic signaling are altered or disrupted. In the context of the immune landscape, external and internal stressors normally promote the expression of natural killer group 2 member D (NKG2D) ligands that allow for the targeted recognition and killing of cells by NKG2D receptor-bearing effector populations. The presence or absence of NKG2D ligands can heavily influence disease progression and impact the accessibility of immunotherapy options. In cancer, tumor cells are known to have distinct regulatory mechanisms for NKG2D ligands that are directly associated with tumor progression and maintenance. Therefore, understanding the regulation of NKG2D ligands in cancer will allow for targeted therapeutic endeavors aimed at exploiting the stress response pathway. In this review, we summarize the current understanding of regulatory mechanisms controlling the induction and repression of NKG2D ligands in cancer. Additionally, we highlight current therapeutic endeavors targeting NKG2D ligand expression and offer our perspective on considerations to further enhance the field of NKG2D ligand biology.


Influence of tea and coffee beverages on prostacyclin synthesis by the rat aorta.
Influences of 2.5 and 5% (w/v) aqueous tea and coffee beverages administered ad lib. to rats for two weeks on PGI2 synthesis by the rat thoracic aorta in vitro were investigated using a rat platelet antiaggregatory bioassay and HPLC methods. The 2.5% beverages did not affect PGI2 synthesis; however, the 5% beverages significantly decreased PGI2 synthesis. The observed decreases were significantly abolished in presence of exogenous arachidonic acid suggesting a beverage-induced inhibition of precursor release. The ability of the beverages to inhibit PGI2 synthesis may partly contribute towards better understanding of the biochemical mechanisms underlying some of the beverages-induced actions in vivo.


Ozone therapy in the management and prevention of caries.
The purpose of this article was to assess the effectiveness of ozone therapy in the management and prevention of caries, reviewing clinical and in vitro studies. Ozone has proven to be effective against gram-negative and gram-positive bacteria, viruses, and fungi. In dentistry, most of the published articles are based on ozone's antimicrobial effects and the treatment of caries. Most of the clinical studies reported ozone to be a promising alternative to conventional methods for caries management. However, a few studies have shown ozone to be insufficient for preventing caries and reducing microorganisms in open occlusal carious lesions. Ozone might be a useful tool to reduce and control oral infectious microorganisms in dental plaque and dental cavity. However, the results of in vitro studies are controversial; while some researchers reported that ozone therapy had a minimal or no effect on the viability of microorganisms, others suggested ozone to be highly effective in killing both gram-positive and gram-negative oral microorganisms. Therefore, more evidence is required before ozone can be accepted as an alternative to present methods for the management and prevention of caries.


Considerations in the selection of surgical gloves for tape wound closure.
One of the reasons that tape closure of wounds is rarely used in the emergency department is that it is difficult for the emergency physician wearing powdered, latex gloves to handle skin closure tapes. Because the skin closure tapes adhere aggressively to powdered latex gloves, it is difficult for the emergency physician to separate the tape from his glove and apply the tape to the skin. The advent of a new powder free glove allows the emergency physician to handle the tapes and accomplish tape wound closure.


[Tolerance and short-term results of the systematic laparotomy-chemotherapy-radiotherapy sequence in Hodgkin's disease in adults].
Twenty five cases of Hodgkin disease were treated by chemotherapy and radiotherapy after staging laparotomy. The safety and the utility of staging laparotomy are discussed. Staging laparotomy seems to be usefull in stage II with involvement of at least three lymphatic territories and in stage III.


Induction of cholinergic expression in developing spinal cord cultures.
The induction of choline acetyltransferase (ChAT) by cAMP derivatives was studied in dissociated spinal cord cultures. Dibutyryl cAMP (dbcAMP) and 8-bromo cAMP (1 mM) produced a 2-3-fold stimulation of ChAT activity in developing cultures whereas 8-bromo cGMP had no effect. A phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine, also increased (2-fold) ChAT activity in immature cultures. Significant elevations in ChAT were detected after 2 h incubation with dbcAMP. Maximum enzyme induction was observed 24 h after dbcAMP supplementation to the culture medium. Developmental studies revealed that ChAT could be induced on days 2-16 in culture. The largest induction of ChAT activity was observed on day 7 in culture. After day 19, when control enzyme activity attained levels of mature cultures, cAMP-mediated ChAT induction was no longer observed. Cycloheximide and actinomycin D blocked ChAT induction whereas basal enzyme activity remained unaffected. Culture protein content was not changed after 1-day exposure to dbcAMP. 125I-Tetanus toxin fixation after dbcAMP treatment revealed a 20% decrease from control in neuronal surface during days 7-9 in culture. These data indicated that cAMP derivatives produced a rapid increase in cholinergic expression during a specific period of development in spinal cord cultures. There appears to be specificity to this effect, as total neuronal surface does not respond in the same manner as ChAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of chitosan malate on viability and cytoskeletal structures morphology of Caco-2 cells.
The aim of this work was to evaluate the effects of the treatment with chitosan malate (CM) on viability of Caco-2 cells and on the morphology and the integrity of their cytoskeletal structures (microtubules, microfilaments). Cytotoxicity of CM, both as a solution and as microparticles obtained by spray drying, was evaluated by using the reduction of MTT reagent; microtubule and microfilaments organization of Caco-2 cells treated with CM solution was examined with immunofluorescence techniques in monolayers fixed with the glutaraldehyde-borohydride method. CM as a solution displayed a concentration-dependent cytotoxicity towards Caco-2 cells, with viability percentages of 5 ± 2%, 7 ± 3% and 31 ± 15% at 15, 10 and 5mg/mL, respectively, while at 2.5mg/mL or less cell viability was 90% or higher. CM microparticles also produced a remarkable cytotoxic effect (cell viability 84 ± 17%, 16 ± 8% and 5 ± 6% after treatment with 1, 5 and 10mg CM per well, respectively), resulting more toxic than CM solution. Microtubules pattern of Caco-2 cells, which is a network regularly arranged around the nucleus, appeared deeply modified by CM treatment in a concentration-dependent way, with progressive microtubule changes in length and spatial disposition and deposition of fluorescent aggregates at the periphery of the cells. Furthermore, after treatment with 5-15mg/mL CM, remarkable alterations of actin organization were observed, with a progressive disruption of the network of stress fibers and the appearance of actin aggregates inside the cell cytoplasm. In conclusion, viability and the cytoskeletal pattern of Caco-2 cells are modified by treatment with CM at high concentrations, which might be locally reached in vivo after application of drug-loaded chitosan microparticles onto mucosal cells.


Serological evidences for a membrane structure related to human beta 2-microglobulin expressed by certain earthworm leukocytes.
Indirect immunofluorescence performed with 2 polyclonal and 4 monoclonal antibodies directed against human beta 2-microglobulin (beta 2m) revealed the presence of a beta 2m-like determinant on the membrane of a subpopulation of earthworm leukocytes classified as weakly adherent acidophils. Two out of the 4 monoclonal antibodies were found to bind to 15% of the earthworm leukocytes. Similar results were obtained with antibodies specific for beta 2m and isolated by affinity chromatography from either polyclonal antiserum or anti-beta 2m hybridoma supernatant. Additional binding inhibition and competition experiments strengthened the results and suggested that the homology between the structure present on earthworm leukocytes and human beta 2m may be restricted to only one major determinant. The existence of a beta 2m-like molecule in earthworms may provide important clues for understanding protein evolution and basic immune mechanisms.


Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.
Aging and senescence impact CD4 T helper cell (Th) subset differentiation during influenza infection. In the lungs of infected aged mice, there were significantly greater percentages of Th cells expressing the transcription factor FoxP3, indicative of regulatory CD4 T cells (Treg), when compared to young. TGF-beta levels, which drive FoxP3 expression, were also higher in the bronchoalveolar lavage of aged mice and blocking TGF-beta reduced the percentage of FoxP3+ Th in aged lungs during influenza infection. Since TGF-beta can be the product of senescent cells, these were targeted by treatment with senolytic drugs. Treatment of aged mice with senolytics prior to influenza infection restored the differentiation of Th cells in those aged mice to a more youthful phenotype with fewer Th cells expressing FoxP3. In addition, treatment with senolytic drugs induced differentiation of aged Th toward a healing Type 2 phenotype, which promotes a return to homeostasis. These results suggest that senescent cells, via production of cytokines such as TGF-beta, have a significant impact on Th differentiation.


Long-range detection of acoustic vibrations by speckle tracking.
When a rough surface is illuminated by a laser beam, it scatters the light, producing a random interference pattern also known as speckle pattern. By imaging the speckle pattern with a line-scan CCD, we are able to measure the acoustic vibrations of a scattering surface, which can be up to 300 m distant. We also show that our instrument can be used as a laser microphone capable of detecting ambient sound such as a human voice.


Regulators of gene expression in Enteric Neural Crest Cells are putative Hirschsprung disease genes.
The enteric nervous system (ENS) is required for peristalsis of the gut and is derived from Enteric Neural Crest Cells (ENCCs). During ENS development, the RET receptor tyrosine kinase plays a critical role in the proliferation and survival of ENCCs, their migration along the developing gut, and differentiation into enteric neurons. Mutations in RET and its ligand GDNF cause Hirschsprung disease (HSCR), a complex genetic disorder in which ENCCs fail to colonize variable lengths of the distal bowel. To identify key regulators of ENCCs and the pathways underlying RET signaling, gene expression profiles of untreated and GDNF-treated ENCCs from E14.5 mouse embryos were generated. ENCCs express genes that are involved in both early and late neuronal development, whereas GDNF treatment induced neuronal maturation. Predicted regulators of gene expression in ENCCs include the known HSCR genes Ret and Sox10, as well as Bdnf, App and Mapk10. The regulatory overlap and functional interactions between these genes were used to construct a regulatory network that is underlying ENS development and connects to known HSCR genes. In addition, the adenosine receptor A2a (Adora2a) and neuropeptide Y receptor Y2 (Npy2r) were identified as possible regulators of terminal neuronal differentiation in GDNF-treated ENCCs. The human orthologue of Npy2r maps to the HSCR susceptibility locus 4q31.3-q32.3, suggesting a role for NPY2R both in ENS development and in HSCR.


Prevalence of Hypothyroidism in Children and Adolescents of Fars Province (Southern Iran): A Nationwide Prescription Study, 2018-2019.
Hypothyroidism is the most common hormonal deficiency worldwide; however, there is limited data about its prevalence in the children and adolescents of the Middle East. The prevalence of hypothyroidism were calculated by dividing the number of patients purchasing levothyroxine in 1397 Solar-Hijri year (Correlate with March 2018-February 2019) by the population at risk (per 10000 persons). Data were collected from the Iran health insurance organization registration records and family physician databases of health vice-chancellor of Shiraz University of Medical Sciences. The present study shows that the prevalence of levothyroxine treated population aged under 18 years is 13 in 10000 in the Fars province and it is more common in females (17 in 10000 in females versus 9 in 10000 in males). This study also revealed that the prevalence of hypothyroidism was different in various age groups and increased in older children and adolescents after pubertal ages. Also, an increase in the female: male ratio of prevalence was more obvious during and after puberty. Our study showed that the prevalence of congenital hypothyroidism was 3/10000 in southern Iran. Also, the prevalence of hypothyroidism in children and adolescents was totally 13/10000 population, and this prevalence increased in older age and female gender. This prevalence was close to the data from iodine sufficient areas in Europe and the United States.


Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system.
Pirfenidone (PFD) is an orally available synthetic drug which has been approved for the treatment of idiopathic pulmonary fibrosis. In addition to its anti-fibrotic properties, PFD also exerts anti-tumor effects in cancer models by inducing alterations in the tumor microenvironment. Here, we demonstrate that PFD reduces proliferation, 2D- and 3D-migration as well as colony formation of the non-small-cell lung carcinoma (NSCLC) cells. On a molecular level, we show that PFD on the one hand interacts with plasminogen activator inhibitor-1 (PAI-1; Kd of 46.2±11.3nM) and affects its inhibitory potency, but on the other hand it also increases PAI-1 expression; in both cases consequently leading to the reduction of urokinase (uPA) activity. Finally, we report that the effect of PFD on 2D-migration of NSCLC cells depends on PAI-1 expression and thus on the activity of the uPA system whereas the PFD-induced changes in cancer cell proliferation, 3D-migration and colony formation are PAI-1 independent. To conclude, a direct interference of PFD with the uPA-PAI-1 system may deregulate pericellular proteolytic activity and thereby influence the stability of the tumor blood vessels and the matrix architecture within tumor stroma.


The coevolution of Euphydryas chalcedona butterflies and their larval host plants : II. Maternal and host plant effects on larval growth, development, and food-use efficiency.
The effects of foodplant species and maternal food type on larval growth, development, and digestive parameters were examined for larvae from an oligophagous colony of Euphydryas chalcedona butterflies. Broods of larvae from areas containing two different foodplants, Diplacus aurantiacus and Scrophularia californica, were divided. One group was fed their "native" host and their siblings were fed the other species. Growth and digestion parameters were measured from hatching until larvae entered diapause.Larvae that fed on Scrophularia grew faster and larger, and suffered lower mortality than their siblings that fed on Diplacus. Growth and digestion indices for larvae from the two maternal-host types did not indicate genetically mediated differences in food-use efficiency; Scrophularia was more digestible than Diplacus to all larvae. Larvae showed a strong feeding preference for Scrophularia, regardless of previous food or presumed maternal-host type. However, larvae that had been reared on Diplacus ate more Diplacus than larvae that had been reared on Scrophularia. In addition, all larvae were capable of increasing gut pH when fed Diplacus. Thus, the effect of previous feeding experience on host utilization and preference by larvae was more significant than the effect of the presumed maternal-host type.


Partially unspliced and fully spliced ELF3 mRNA, including a new Alu element in human breast cancer.
Using modified representational difference analysis, a DNA fragment (GC3) was isolated as a difference between a breast cancer and a normal cell line from the same patient. GC3 proved to be a fragment of intron 7 of the ELF3 gene, an ets family transcription factor, amplified in the breast cancer cell line. Using genomic walking technology, a new Alu (Alu(kwd)) was found downstream of GC3 in an antisense position between nt 8762 and nt 8763 within intron 8 of the ELF3 gene. This ELF3 intron fragment(GC3) was expressed in human breast cancer cell lines and four of six breast cancer tissues, but not in matched normal cell lines and tissues. Similarly, Alu(kwd) was also found in the same breast cancer cell lines and five of eight other breast cancer tissues, but not in matched normal cell lines and tissue. This was confirmed by RNase and DNase digestion analysis. Moreover, GC3 and Alu(kwd) were detected in both the nuclear and cytoplasmic RNA fractions of breast cancer cell lines. The finding of cytoplasmic intron retention was verified with northern blotting and the 5' and 3' rapid amplification cDNA ends procedure (5' and 3'RACE) to search for cDNA sequences in RNA from these cancer cell lines. Partially unspliced ELF3 mRNA and fully spliced ELF3 mRNA was found in the same breast cancer cell line. Partially unspliced ELF3 mRNA contained introns 4-7 without any nucleotide mutation at intron/exon splice junction borders. Fully spliced 1959 bp ELF3 mRNA showed a different 5'UTR from the published ELF3 mRNA, and was predicted to encode a 371 amino acid protein sharing 98% homology with the ELF3 protein sequence. This is the first report of intron retention of ELF3 as well as the pathological appearance of both spliced and unspliced cytoplasmic ELF3 mRNA in human breast cancer cells.


Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin αV β3.
The bidirectional force transmission process of integrin through the cell membrane is still not well understood. Several possible mechanisms have been discussed in literature on the basis of experimental data, and in this study, we investigate these mechanisms by free and steered molecular dynamics simulations. For the first time, constant velocity pulling on the complete integrin molecule inside a dipalmitoyl-phosphatidylcholine membrane is conducted. From the results, the most likely mechanism for inside-out and outside-in signaling is the switchblade model with further separation of the transmembrane helices.


Interdialytic weight gain is less with the Mediterranean type of diet in hemodialysis patients.
Interdialytic weight gain is an important prognostic factor in dialysis patients. Different eating patterns may affect interdialytic weight gain. The goal was to assess the effect of the Mediterranean type of diet on interdialytic weight gain of chronic hemodialysis patients. This study had a cross-sectional design. Four hospital-based satellite hemodialysis units in different cities in Turkey. A total of 702 patients (279 women, 423 men; mean age, 47.8 +/- 15.5 years) were included in the study. They were grouped according to the hemodialysis centers: Alanya-Izmir (group 1, n = 194) and Ankara-Adana (group 2, n = 508). Group 1 patients were consuming a Mediterranean type of diet, whereas group 2 patients had a diet rich in protein and carbohydrates. All of the patients were under the same dialysis and treatment protocols. The demographic data, the medications, interdialytic weight gains, and laboratory data such as serum albumin, C-reactive protein, hemoglobin, hematocrit, serum iron binding capacity, ferritin, and parathyroid hormone during the last 3 months for each patient were recorded. The interdialytic weight gain differences between the groups were compared using the Student t-test and the Mann-Whitney U test. When the two groups were compared according to age, sex, blood pressure, serum albumin, hematocrit, and parathyroid hormone levels, there was no statistically significant difference. Mean interdialytic weight gain for group 1 and group 2 was 2.47 +/- 0.94 kg and 3.08 +/- 0.94 kg, respectively (P < .001). When the two groups were compared according to their iron requirements, group 1 showed an increased requirement for doses of iron and erythropoietin (P < .001 and P < .001, respectively). A Mediterranean-type diet, rich in seafood and vegetables, was associated with less interdialytic weight gain compared with a diet rich in protein and carbohydrates. Although all of our patients had the same diet education and treatment protocols, the geographic region and culture influenced their compliance to diet and their therapeutic outcomes.


Regional mapping of early childhood risk for mental disorders in an Australian population sample.
Population-level profiles of risk for later childhood mental disorders have been identified in patterns of early developmental vulnerabilities using Australian Early Developmental Census. We sought to demonstrate the geographical distribution of these early childhood risk profiles for mental illness, to inform policy decisions for place-sensitive provision of health and allied services. Using geographic information system techniques, we mapped the regional percentage of children at highest risk for mental disorders across the state of New South Wales (NSW), according to Local Government Areas, for 82 891 children in the NSW Child Development Study. A high proportion (>10%) of children at risk of later mental disorders were located in regional and socioeconomically disadvantaged areas, with a few metropolitan regions showing similarly high proportions of the population at risk. These findings highlight the potential to identify place-sensitive needs for early intervention and prevention programs for emerging mental health problems in children.


Factor IX-deficient plasma spiked with N9-GP behaves similarly to N9-GP post-administration clinical samples in N9-GP ELISA and FIX activity assays.
Evaluation of assay performance with new modified coagulation factors, such as N9-GP, may require testing of different assays and assay conditions. Validation of assays used for clinical monitoring of haemophilia B patients is challenging due to limited availability of blood samples from patients exposed to these new agents. The aim of the study is to investigate correlations between assays measuring N9-GP concentration and factor IX (FIX) activity, and to evaluate whether in vitro FIX-deficient plasma samples spiked with N9-GP and in vivo post-administration samples from patients exposed to N9-GP perform similarly in these assays. In vitro samples, prepared by adding N9-GP to FIX-deficient plasma, were compared to samples from haemophilia B patients participating in the phase 3 paradigm 2(™) clinical trial (in vivo samples), in assays measuring N9-GP concentration (ELISA) and FIX activity (one-stage clotting assay and chromogenic assay). The results of the FIX activity assays and ELISAs were compared and analysed to determine the similarity between the in vitro and in vivo sample analyses. Regression analysis demonstrated a linear relationship between N9-GP concentration and FIX activity. Furthermore, there was no significant difference between the regression lines for the in vitro and in vivo sample analyses. The one-stage clot assay using SynthAFax and the chromogenic assay show promise for use in measuring FIX activity in haemophilia B patients treated with N9-GP. Since in vitro and in vivo samples performed similarly in these assays, N9-GP-spiked FIX-deficient plasma could be used as controls in routine measurements of N9-GP activity in haemophilia B patients.


The Immp2l mutation causes age-dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment.
Reactive oxygen species are implicated in age-associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2-like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age-associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria-targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age-matched normal control mice or SkQ1-treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4-hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age-associated neurodegeneration.


Peanut alkaline lipase.
Peanut alkaline lipase, (glycerol ester hydrolase EC 22.214.171.124), pH optimum 8.5, was isolated from acetone powders prepared from developing and germinated peanut seed (arachis hypogaea L. var. NC-2). Enzyme activity/seed increased in successive developmental stages. The course of the hydrolytic reaction was linear with regard to enzyme concentration and all times tested up to periods exceeding 60 min. Km for the reaction was determined to be 2.6 times 10-4M. Molecular weight of peanut lipase, as estimated by Sephadex gel filtration and sodium dodecyl sulfate gel electrophoresis, was ca. 55,000.


Use of Paramedian Forehead Flap in an Octogenarian:A Case Report.
Increase in life expectancy has led to increased number of octogenarian and nonagenarians population. These old people have increased chances of developing skin tumours like slow growing basal cell carcinoma on the sun exposed parts of body. Many a times surgeons all over the world are bit conservative in managing these elderly patients and compromise on cosmetic aspects due to very advanced age of these patients. This report is about an 87-year-old female with BCC of nasal dorsum who underwent a major surgical procedure to maintain facial aesthetics.


Heel ultrasound in women after long-term ERT compared with bone densities in the forearm, spine and hip.
To compare heel ultrasound values with bone densities at different measurement sites as determined by single photon absorptiometry (SPA) and dual-energy X-ray absorptiometry (DXA) in long-term users of estrogen replacement therapy (ERT), we analyzed data from 30 users of estradiol implants (mean duration of treatment 16 years) and 32 non-users, comprising 28 complete age-matched pairs. The precision errors in vivo of ultrasound measurements were 0.18%, 1.3% and 1.5% for speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index, respectively. In the controls, ultrasound parameters correlated well with values from SPA and DXA measurements (r = 0.51-0.63, p < 0.004). In long-term users of ERT, however, measurements with ultrasound did not correlate with DXA in the spine and hip (r = 0.01-0.31, NS) but correlated well with SPA in the forearm (r = 0.47-0.66, p < 0.009). Implant users, compared with non-users, had small and just significantly different values when measured by ultrasound (at most 12%, p = 0.03-0.04) but significantly higher bone mineral densities (18%-25%, p = 0.0001-0.01) in the forearm, spine and hip when measured by SPA or DXA. Data indicated that a substantial proportion of long-term users of estrogen may be non-responders concerning the effect of estrogen on bone qualities expressed in heel ultrasound values. In a multivariate regression analysis the effect of increasing age and increasing treatment duration were both negative for the ultrasound parameters.(ABSTRACT TRUNCATED AT 250 WORDS)


Lasers, Microneedling, and Platelet-Rich Plasma for Skin Rejuvenation and Repair.
Skin resurfacing for the purpose of rejuvenation and repair continues to evolve with the development of noninvasive or minimally invasive surgical substitutes. Advances in laser therapy, microneedling, and platelet-rich plasma have reinvigorated research in wound repair and regenerative science. An overall positive clinical response toward the use of platelet-rich plasma as an adjuvant to fractional photothermolysis and percutaneous collagen induction is observed. Its effect on post-treatment adverse symptoms, erythema, edema, crusting, and clinical outcomes in rejuvenation are summarized in this article. The lack of identifiable complications and convenience of treatment provides a positive outlook for future use and investigations.


The effect of image quality on the assessment of child abuse photographs.
Although child abuse pediatricians are frequently asked to evaluate risk of abuse based on photographs, the effect of photographic quality on this process is presently unknown. Photographs of abused children are often taken by professionals without photographic training, and quality varies widely. This article reports the first study of the effect of image quality on clinical assessment from photographs. A total of 120 images depicting 60 cutaneous lesions were selected for the study. Paired images of single lesions varied in quality of focus, exposure, or framing. Seventy medical and nursing professionals were recruited from the Internet listservs focusing on child abuse. Subjects evaluated the images for quality (1-9 scale), opined if the image was "inadequate for interpretation," and answered a clinical question about the type of lesion displayed. Accuracy was defined as concordance between the subject and the live examiner's written documentation. Adequacy was defined as the proportion of subjects that did not indicate that the photograph was inadequate for interpretation. Mean accuracy among subjects was 64% and ranged from 35% to 84%. Accuracy was not predicted by subject profession, experience, or self-rated computer skill. Image quality and adequacy were independently associated with increased accuracy. Higher-quality images improved accuracy. An examiner's impression that an image is adequate did not guarantee an accurate interpretation. Reliance on photographs alone is not sufficiently accurate in the assessment of cutaneous trauma.


Structural dynamics of GaN microcrystals in Evolutionary Selection Selective Area Growth probed by X-ray microdiffraction.
A method to grow high quality, single crystalline semiconductor material irrespective of the substrate would allow a cost-effective improvement to functionality and performance of optoelectronic devices. Recently, a novel type of substrate-insensitive growth process called Evolutionary Selection Selective Area Growth (ES-SAG) has been proposed. Here we report the use of X-ray microdiffraction to study the structural properties of GaN microcrystals grown by ES-SAG. Utilizing high resolution in both direct and reciprocal spaces, we have unraveled structural dynamics of GaN microcrystals in growth structures of different dimensions. It has been found that the geometric proportions of the growth constrictions play an important role: 2.6 μm and 4.5 μm wide growth tunnels favor the evolutionary selection mechanism, contrary to the case of 8.6 μm growth tunnels. It was also found that GaN microcrystal ensembles are dominated by slight tensile strain irrespective of growth tunnel shape.


Perioperative point-of-care ultrasound for diagnosis of acute lower extremity arterial thrombosis after total hip arthroplasty revision: a case report.
Acute arterial thrombosis after hip arthroplasty is a rare event associated with potentially catastrophic complications. Early clinical diagnosis of progressive limb ischemia is often difficult in the immediate postoperative period because of residual neuraxial blockade and the nonspecific nature of signs. We describe the use of point-of-care ultrasound (POCUS) in the postanesthesia care unit (PACU) to diagnose this complication early and facilitate timely intervention. A 78-yr-old female patient underwent elective right hip revision arthroplasty under spinal anesthesia and postoperatively had an absent dorsalis pedis pulse on her operative leg as screened by an audible-only Doppler. No obvious clinical symptoms were present as the patient was still under subarachnoidal blockade. A bedside POCUS vascular evaluation was performed in the PACU and showed an absence of blood flow in the superficial femoral artery, expediting the confirmation of a surgical emergency. The patient underwent a successful open thrombectomy and made an uneventful postoperative recovery. Our case report highlights the novel use and impact of bedside POCUS to assess the presence or absence of distal limb arterial blood flow and, in this case, the level of arterial occlusion.


Exposure to endocrine-disrupting metals and serum estrogen levels among US women.
Multiple factors could affect estrogen levels in the body; however, the impact of exposure to endocrine-disrupting chemicals on estrogen levels in humans remains inconclusive. This cross-sectional study was to assess the association between blood levels of endocrine-disrupting metals (including cadmium, lead, and mercury) and serum estradiol levels in 1618 women (aged ≥ 20 years) who participated in the 2013-2016 National Health and Nutrition Examination Survey. Using multiple general linear models, we estimated percent changes of estradiol levels in association with blood metal concentrations. Age-specific analysis was further conducted. The median level of blood cadmium, lead, and mercury was 0.31 µg/L (range: 0.07-7.23), 0.76 µg/dL (0.11-12.80), and 0.73 µg/L (0.20-36.90), respectively, and the median estradiol level was 31.10 pg/mL (range: 2.12-523.00) among women aged 20-80 years. After adjusting for potential confounders, a 10 % increase in blood cadmium and lead levels was associated with 1.43 % (95 % CI: 0.50, 2.37) increased levels and 1.45 % (- 2.17, - 0.11) decreased levels of estrogen, respectively, in the total study population. When stratified by age, the positive association with cadmium was only seen in women aged 20-49 years [1.47 % (0.39, 2.56) increased estradiol] and the inverse association with lead was seen among women aged 50-80 years [3.40 % (- 4.78, - 2.00) decreased estradiol]. Mercury was not significantly associated with estrogen levels. Our study demonstrates a potential relationship between exposure to endocrine-disrupting cadmium and lead and serum estrogen levels in US women. Age-specific associations were observed. Prospective and mechanistic studies are warranted to further explore these interactions and the associated reproductive toxicities.


A review of meibomian gland structure, function, and contact lens wear.
To provide a balanced literature review of the studies that have evaluated the effect of contact lenses on meibomian gland (MG) health. A PubMed.gov literature search was conducted on or before May 15, 2021. No other time constraints were applied. Search terms included the following: "meibomian gland(s)" plus "contact lens(es)" or "meibography" plus "contact lens(es)". Only full text articles written in English were considered. The reference lists of recovered papers were used to identify articles missed during the primary search. Included articles were required to discuss the impact of contact lenses on MG morphology or function and were graded according to the level of evidence presented. The literature indicates that contact lenses impact MG function; however, the data are equivocal regarding contact lenses inducing MG structural changes. The literature likewise indicates that the mechanism(s) by which contact lenses impact the MGs are likely multifactorial. Recent data suggests that MGs may have some plasticity. Detected differences between studies likely stem from varied populations evaluated, study designs, and the duration of the evaluation periods. With this literature review finding conflicting relationships between MG health and contact lens use, future longitudinal studies with standardized clinical MG assessments are needed to determine the true impact of contact lenses on MG health. Until these data are obtained, contact lens wearers should undergo a full MG evaluation, especially because recent data suggest that MG treatments may restore MG structure and function.


Evaluation of the effect of probiotic lozenges in the treatment of recurrent aphthous stomatitis: a randomized, controlled clinical trial.
The study aimed to explore the effectiveness of probiotics in the treatment of minor recurrent aphthous stomatitis (RAS). We performed a randomized, controlled clinical study. Sixty adult (group A) and 60 children patients (group B) with diagnosis of minor RAS were included. Both groups were divided into two subgroups; AI and BI (test subgroups) and AII and BII (control subgroups). For test subgroups, probiotic lozenges were consecutively administered twice daily, for 5 days. The size and pain level of ulcers were recorded on treatment days 0, 3, and 5. The outbreak frequency of RAS within 6 months was investigated for all subgroups. Compared with baseline, an improvement was evident for all subgroups. However, for effectiveness in pain reduction, a statistically significant difference in favor of AI was observed for all evaluation periods when compared with control subgroup. Regarding effectiveness in ulcer size reduction, a statistically significant difference in favor of BI was observed at day 5 when compared with control subgroup. No significant difference was observed in the effectiveness index between subgroups AI and BI (test subgroups) except in effectiveness in pain reduction at day 3. The outbreak frequency decreased significantly in subgroup BI. Topical application of probiotics decreased pain intensity and accelerates RAS healing. The effectiveness in pain reduction is more evident in adult patients while acceleration of healing is more evident in children. Probiotics could be a well-tolerated, topical therapeutic agent in the treatment of minor RAS. ClinicalTrials.gov ID: NCT04383236.


Race, ovarian responsiveness, and live birth after in vitro fertilization.
To determine if ovarian responsiveness to gonadotropin stimulation differs by race/ethnicity and whether this predicts live birth rates (LBRs) in non-White patients undergoing in vitro fertilization (IVF). Retrospective cohort study. Academic infertility center. White, Asian, Black, and Hispanic patients undergoing ovarian stimulation for IVF. Self-reported race and ethnicity. The primary outcome was ovarian sensitivity index (OSI), defined as (the number of oocytes retrieved ÷ total gonadotropin dose) × 1,000 as a measure of ovarian responsiveness, adjusting for age, body mass index, infertility diagnosis, and cycle number. Secondary outcomes included live birth and clinical pregnancy after first retrievals, adjusting for age, infertility diagnosis, and history of fibroids, as well as miscarriage rate per clinical pregnancy, adjusting for age, body mass index, infertility diagnosis, duration of infertility, history of fibroids, and use of preimplantation genetic testing for aneuploidy. The primary analysis of OSI included 3,360 (70.2%) retrievals from White patients, 704 (14.7%) retrievals from Asian patients, 553 (11.6%) retrievals from Black patients, and 168 (3.5%) retrievals from Hispanic patients. Black and Hispanic patients had higher OSIs than White patients after accounting for those with multiple retrievals and adjusting for confounders (6.08 in Black and 6.27 in Hispanic, compared with 5.25 in White). There was no difference in OSI between Asian and White patients. The pregnancy outcomes analyses included 2,299 retrievals. Despite greater ovarian responsiveness, Black and Hispanic patients had lower LBRs compared with White patients, although these differences were not statistically significant after adjusting for confounders (adjusted odds ratio, 0.83; 95% confidence interval [CI], 0.63-1.09, for Black; adjusted odds ratio, 0.93; 95% CI, 0.61-1.43, for Hispanic). Ovarian sensitivity index was modestly predictive of live birth in White and Asian patients but not in Black (area under the curve, 0.51; 95% CI, 0.38-0.64) and Hispanic (area under the curve, 0.50; 95% CI, 0.37-0.63) patients. Black and Hispanic patients have higher ovarian responsiveness to stimulation during IVF but do not experience a consequent increase in LBR. Factors beyond differences in responsiveness to ovarian stimulation need to be explored to address the racial/ethnic disparity established in prior literature.


Focal cortical resections for the treatment of extratemporal epilepsy in children.
Epilepsy in children is a common and disabling disorder. Approximately 10% to 20% of patients who develop seizures will have medically intractable epilepsy. This group of patients may be candidates for epilepsy surgery. Unlike adults, epilepsy in children frequently arises in extratemporal sites. The surgical treatment of this extratemporal epilepsy is discussed in this article.


Potentiating effects of oxygen in lungs damaged by methylcyclopentadienyl manganese tricarbonyl, cadmium chloride, oleic acid, and antitumor drugs.
The intraperitoneal administration of methylcyclopentadienyl manganese tricarbonyl (MMT) and cyclophosphamide, exposure to an aerosol of cadmium chloride, intravenous administration of oleic acid, and intratracheal instillation of bleomycin to young female BALB/c mice or CD/CR rats result in acute lung injury. Pulmonary morphology and lung collagen content were examined in animals treated with these chemicals alone or in combination with an elevated oxygen concentration (80%) in the inspired air. In mice, the development of fibrosis could be significantly enhanced if animals treated with MMT, cadmium chloride, cyclophosphamide, or bleomycin were exposed to 80% oxygen immediately following exposure to these agents. In rats only cyclophosphamide- and bleomycin-induced acute lung injury was potentiated by hyperoxia, resulting in significant enhancement of lung collagen content. The pathogenesis responsible for this differential species response of pulmonary injury to hyperoxia remains to be investigated.


Induction of circulating tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients.
Fever is frequently observed in cancer patients treated with high-dose recombinant human interleukin-2 (rIL-2). The preincubation of rIL-2 with polymyxin B, an antibiotic that inhibits the biologic effects of endotoxins, did not diminish the pyrogenicity of IL-2 in New Zealand rabbits, indicating that IL-2-induced fever is not due to contaminating endotoxins. In contrast to interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon alpha, which cause fever through their effects on arachidonic acid metabolism in the hypothalamus, IL-2 was unable to induce prostaglandin E2 synthesis in hypothalamic cells or fibroblasts in vitro, suggesting that IL-2 is not intrinsically pyrogenic. To determine if IL-2-induced fever is mediated indirectly through the generation of pyrogenic cytokines, culture supernatants from IL-2-stimulated human peripheral blood mononuclear cells were screened for the presence of pyrogens by direct injection into rabbits and by measuring the amounts of IL-1 alpha, IL-1 beta, and TNF alpha by specific radioimmunoassays (RIA). All three cytokines were readily detected by RIA in these supernatants, which in turn caused fever when injected into rabbits. Furthermore, in six of six cancer patients treated with rIL-2, elevated levels of TNF alpha were detected in the plasma by RIA 2 hr after IL-2 administration. Plasma TNF levels increased from pretreatment values of 14 +/- 7 to 765 +/- 150 pg/ml 2 hr after an IL-2 injection. These results strongly implicate IL-2-induced pyrogenic cytokines, in particular TNF alpha, as a major cause of the fever and possibly other aspects of the acute-phase response associated with IL-2 therapy.


[Liver transplantation with living donor : current aspects, perspectives and significance in Germany].
More than 20 years ago living donor liver transplantation was introduced into clinical practice. Specifics of this method were developed initially for children and later on for adults particularly in regions where a liver transplantation program using deceased donors was not readily available. The most sensitive aspect of living donation, namely the danger to a healthy relative in order to perform the transplantation is immanent in the system and, thus, it is definitively a secondary option as compared to deceased organ donation. Following worldwide initial euphoria the numbers have markedly decreased in the western world since the start of the new millennium. In Asian countries in particular, much work has been done to optimize the procedure so that the donor safety and the outcome quality for the recipient have been impressively demonstrated in large patient populations. There is still a severe donor organ shortage and the option to allocate an optimal (partial) organ on an individual basis by living donation has given new impact to the discussion about a further rise in the profile of living donations here as well. The new version of the German transplantation legislation implemented in summer 2012 requires a number of conditions with respect to insurance for living donors. The current state and perspectives are presented here.


Association Between Physician Empathy and Difficult Patient Encounters: a Cross-Sectional Study.
Physicians frequently experience patients as difficult. Our study explores whether more empathetic physicians experience fewer patient encounters as difficult. To investigate the association between physician empathy and difficult patient encounters (DPEs). Cross-sectional study. Participants were 18 generalist physicians with 3-8 years of experience. The investigation was conducted from August-September 2018 and April-May 2019 at six healthcare facilities. Based on the Jefferson Scale of Empathy (JSE) scores, we classified physicians into low and high empathy groups. The physicians completed the Difficult Doctor-Patient Relationship Questionnaire-10 (DDPRQ-10) after each patient visit. Scores ≥ 31 on the DDPRQ-10 indicated DPEs. We implemented multilevel mixed-effects logistic regression models to examine the association between physicians' empathy and DPE, adjusting for patient-level covariates (age, sex, history of mental disorders) and with physician-level clustering. The median JSE score was 114 (range: 96-126), and physicians with JSE scores 96-113 and 114-126 were assigned to low and high empathy groups, respectively (n = 8 and 10 each); 240 and 344 patients were examined by physicians in the low and high empathy groups, respectively. Among low empathy physicians, 23% of encounters were considered difficulty, compared to 11% among high empathy groups (OR: 0.37; 95% CI = 0.19-0.72, p = 0.004). JSE scores and DDPRQ-10 scores were negatively correlated (r = -0.22, p < 0.01). Empathetic physicians were less likely to experience encounters as difficult. Empathy appears to be an important component of physician perception of encounter difficulty.


Automatic Cancer Cell Taxonomy Using an Ensemble of Deep Neural Networks.
Microscopic image-based analysis has been intensively performed for pathological studies and diagnosis of diseases. However, mis-authentication of cell lines due to misjudgments by pathologists has been recognized as a serious problem. To address this problem, we propose a deep-learning-based approach for the automatic taxonomy of cancer cell types. A total of 889 bright-field microscopic images of four cancer cell lines were acquired using a benchtop microscope. Individual cells were further segmented and augmented to increase the image dataset. Afterward, deep transfer learning was adopted to accelerate the classification of cancer types. Experiments revealed that the deep-learning-based methods outperformed traditional machine-learning-based methods. Moreover, the Wilcoxon signed-rank test showed that deep ensemble approaches outperformed individual deep-learning-based models (p < 0.001) and were in effect to achieve the classification accuracy up to 97.735%. Additional investigation with the Wilcoxon signed-rank test was conducted to consider various network design choices, such as the type of optimizer, type of learning rate scheduler, degree of fine-tuning, and use of data augmentation. Finally, it was found that the using data augmentation and updating all the weights of a network during fine-tuning improve the overall performance of individual convolutional neural network models.


Enrichment of short-chain organic acids transferred to submicron sea spray aerosols.
Organic acids, considered to be a substantial component of the marine carbon cycle, can enter the atmosphere through sea spray aerosol (SSA) and further affect the climate. Despite their importance, the distribution and mixing state of organic acids in SSA over the marine boundary layer are poorly understood and therefore need more investigation. Here, we have used ion chromatography (IC) in anion mode to measure short-chain organic acids concentrations in SSA collected throughout a custom-made SSA simulation chamber. The enrichment behavior and morphology of monocarboxylic acids (MAs, C1-8) and dicarboxylic acids (DAs) in submicron SSA were studied in seawater. We found that with MAs addition, the number concentration and mass concentration of SSA particles decreased gradually for C5-8 MAs, whereas they weakly varied with DAs addition due to the fact that carboxyl groups at both ends of DAs increased the surface tension of seawater. Moreover, the target compounds in submicron SSA displayed a surface activity-dependent enrichment behavior, where seawater with stronger surface activity, such as that containing MAs with >5 carbons, was more enriched in SSA in comparison to seawater with weaker surface activity. MAs with chain length <5 carbons were slightly enriched in SSA, whereas the enrichment factor (EF) of C5-8 MAs further increased with increasing chain length. These findings are of utmost importance in further understanding and quantifying the contribution of organic matter to SSA, which is crucial for assessing the atmosphere feedback of the marine carbon cycle. MAIN FINDING OF THE WORK: Surface tension of seawater is the key factor affecting the enrichment of short-chain organic acids in SSA.


Cervical brachytherapy utilizing ring applicator: comparison of standard and conformal loading.
Afterloading high-dose-rate brachytherapy (HDR) treatment of cervical cancer with cross-sectional imaging and three-dimensional (3D) reconstruction offers opportunities for individualized conformal treatment planning rather than fixed point-A dosimetry. Between June 2003 and September 2004, 15 patients with FIGO Stage 1B-4A cervical carcinoma, median age 56 years, were treated with radical external-beam radiotherapy to pelvis, including paraortic nodes if positive on staging investigations. Fourteen patients received concurrent cisplatin chemotherapy. All patients received HDR brachytherapy administered by intrauterine tube and ring applicator. Clinical target volume (CTV) and organs at risk (OAR)--rectum, bladder, and small bowel--were outlined from postinsertion CT planning scans. Planning target volume (PTV) was derived by use of 2-mm to 3-mm 3D expansion. A standard plan was produced that delivered 6 Gy to point A, and a second plan delivered 6 Gy to PTV. Constraints were defined for the OAR: bladder, 6 Gy; rectum, 5 Gy; and small bowel, 5 Gy. Dosimetric comparison was performed by use of the Baltas conformal index (COIN). Mean COIN values were 0.39 for conformal plans and 0.33 for standard plans (p = 0.001); mean D95 values were 4.79 Gy and 4.50 Gy, respectively. The majority of patients achieved a plan closer to ideal for coverage of PTV, with minimization of radiation received by normal tissues for conformal loading measured by COIN compared with fixed point-A prescription that used the cervical ring applicator.


Limbic system participates in mediating the effects of general anesthetics.
In a previous study, we reported that inactivation of the medial septum or the hippocampus by muscimol, a GABA(A) receptor agonist, potentiated the effects of a general anesthetic. In this study, we further investigated whether other structures that are connected to the septohippocampal system are involved in mediating general anesthesia. In freely behaving rats, muscimol (0.25 microg) or saline was infused intracerebrally into one of four areas-the supramammillary area (SUM), nucleus accumbens (NAC), ventral pallidum (VP), and ventral tegmental area (VTA)-and righting, pain, and EEG responses were recorded following either halothane or sodium pentobarbital, representing inhalational and injectable general anesthetic, respectively. The effect of halothane (2%) or pentobarbital (20 mg/kg i.p.) in abolishing the righting, pain response, or low-voltage neocortical activity was enhanced, and the initial behavioral hyperactivity (delirium) was reduced, after muscimol as compared to after saline infusion in SUM, NAC, VP, and VTA. EEGs in the hippocampus and the sensorimotor cortex following halothane or pentobarbital showed increased delta, and decreased hippocampal theta and gamma waves after muscimol infusion as compared to saline infusion in SUM, NAC, VP, and VTA. By contrast, infusion of muscimol in the median raphe increased locomotion and did not significantly alter the behavioral or EEG effects of halothane or pentobarbital. It is suggested that structures that activate the limbic cortices (MS, SUM, and VTA but not the median raphe) or mediate the output of the hippocampus (NAC and VP) normally participate in maintaining consciousness and inactivation of these structures potentiates the response to a general anesthetic.


Does a suggested diagnosis in a general practitioners' referral question impact diagnostic reasoning: an experimental study.
Diagnostic errors are a major cause of preventable patient harm. Studies suggest that presenting inaccurate diagnostic suggestions can cause errors in physicians' diagnostic reasoning processes. It is common practice for general practitioners (GPs) to suggest a diagnosis when referring a patient to secondary care. However, it remains unclear via which underlying processes this practice can impact diagnostic performance. This study therefore examined the effect of a diagnostic suggestion in a GP's referral letter to the emergency department on the diagnostic performance of medical interns. Medical interns diagnosed six clinical cases formatted as GP referral letters in a randomized within-subjects experiment. They diagnosed two referral letters stating a main complaint without a diagnostic suggestion (control), two stating a correct suggestion, and two stating an incorrect suggestion. The referral question and case order were randomized. We analysed the effect of the referral question on interns' diagnostic accuracy, number of differential diagnoses, confidence, and time taken to diagnose. Forty-four medical interns participated. Interns considered more diagnoses in their differential without a suggested diagnosis (M = 1.85, SD = 1.09) than with a suggested diagnosis, independent of whether this suggestion was correct (M = 1.52, SD = 0.96, d = 0.32) or incorrect ((M = 1.42, SD = 0.97, d = 0.41), χ2(2) =7.6, p = 0.022). The diagnostic suggestion did not influence diagnostic accuracy (χ2(2) = 1.446, p = 0.486), confidence, (χ2(2) = 0.058, p = 0.971) or time to diagnose (χ2(2) = 3.128, p = 0.209). A diagnostic suggestion in a GPs referral letter did not influence subsequent diagnostic accuracy, confidence, or time to diagnose for medical interns. However, a correct or incorrect suggestion reduced the number of diagnoses considered. It is important for healthcare providers and teachers to be aware of this phenomenon, as fostering a broad differential could support learning. Future research is necessary to examine whether these findings generalize to other healthcare workers, such as more experienced specialists or triage nurses, whose decisions might affect the diagnostic process later on. The study protocol was preregistered and is available online at Open Science Framework ( https://osf.io/7de5g ).


Association between urinary symptom severity and white matter plaque distribution in women with multiple sclerosis.
Multiple sclerosis (MS) is characterized by demyelinated white matter plaque throughout the central nervous system. Plaque involvement in regions that regulate micturition may be associated with urinary symptom severity in patients with MS. The aim of this prospective study is to investigate the relationship between cerebral plaque volume (PV), location, and urinary symptoms in women with MS. We conducted a case-control pilot study of women with MS undergoing routine yearly brain MRI. Women were administered the American Urologic Association-Symptom Index (AUA-SI) and divided into two groups: severe urinary symptoms (AUA-SI ≥20) and mild symptoms (AUA-SI ≤7). PV and location in the brain were determined using a validated automated white matter lesion segmentation algorithm. This study of 36 women found that the median total PV did not differ between groups. Women with severe urinary symptoms had larger median PV in the left frontal lobe (LFL) and right limbic lobe (RLL) compared with women with mild urinary symptoms. Within the RLL, women with severe symptoms had a larger median PV in the right cingulate gyrus (RCG). There was a moderate correlation between LFL lesion volume and RLL lesion volume with the AUA emptying subscore; however, these regions did not correlate with the storage subscore. This preliminary study found urinary symptom severity in women with MS is associated with PV in the RCG and LFL, and not total cerebral PV. These findings may explain why disease burden alone is not a predictor of severity or type of voiding dysfunction in patients with MS.


Is Dysphagia Under Diagnosed or is Normal Swallowing More Variable than We Think? Reported Swallowing Problems in People Aged 18-65 Years.
Dysphagia prevalence in younger community dwelling adults and across nations is sparse. We investigated the prevalence of swallowing problems in an unselected cohort of people aged 18-65 years. The EAT-10 Assessment Tool was converted into an anonymized online survey. Invitations were e-mailed to author contacts and onwards dispersal encouraged. Analysis was performed using non-parametric test for group comparison (Mann-Whitney U) and Spearman's rho correlation. From March 2014 to October 2017: 2054 responses (32 reported ages outside of 18-65 or undeclared) from Africa, Asia, Australasia/Oceania, Europe, and North and South America. Responses: 1,648 female, 364 male, (10 reported as both), median age 34, (range 18-65, mean 37.12, SD 12.40) years. Total EAT-10 scores: median 0 (range 0-36, mean 1.57, SD 3.49). EAT-10 score ≥ 3 (337) median 5 (range 3-36, mean 7.02 SD 5.91). Median age 36 (range 19-65, mean 37.81, SD 13.21) years. Declared sex was not statistically significantly associated with non-pathological vs. pathological EAT-10 score (p = 0.665). Female scores (median 0.00, mean 1.56, SD 3.338) were significantly higher than for males (median 0.00, mean 1.62, SD 4.161): U (Nfemale = 1648, Nmale = 364) = 275,420.000, z = - 2.677, p = 0.007. Age and EAT-10 score were not associated: females rs = - 0.043, p = 0.079, N = 1648, males rs = - 0.003, p = 0.952, N = 364. Considerable impact on people: "I take ages to eat a main course … This is embarrassing and I often leave food even though I am still hungry." (no diagnosis, EAT-10 = 17). Concerns regarding swallowing exist in people undiagnosed with dysphagia, who may feel uncomfortable seeking professional help. Dysphagia may be under reported resulting in a hidden population. Subtle changes are currently seen as subtle markers of COVID-19. Further work is required to ensure that what is an essentially normal swallow does not become medicalized.


Implication of thermally conductive nanodiamond-interspersed graphite nanoplatelet hybrids in thermoset composites with superior thermal management capability.
Novel hybrid nanofillers composed of nanodiamond-attached graphite nanoplatelets (ND@GNPs) were designed and employed to toughen the epoxy (EP) matrix for fabricating superior thermal conductive and physically robust thermoset nanocomposites for electronics and auto industries. The hybrid nanofiller was covalently bonded by 4,4'-diphenylmethane diisocyanate and it provided distinct enhancement in thermal conductivity and dynamic storage modulus of the EP/ND@GNPs nanocomposites attributing to the unique nanostructure of ND@GNPs that can form strong interfacial interaction with EP matrix, thus restrict the EP molecular motions. The EP/ND@GNPs20 presented a thermal conductivity of 2.48 W · m-1 · K-1 and dynamic storage modulus of 5.6 GPa. The presence of ND particles not only can enhance heat transfer efficiency but also improve the interfacial interaction between ND and EP matrix, which can directly affect physical properties of the EP composites.


Tuning structural and mechanical properties of two-dimensional molecular crystals: the roles of carbon side chains.
A key requirement for the future applicability of molecular electronics devices is a resilience of their properties to mechanical deformation. At present, however, there is no fundamental understanding of the origins of mechanical properties of molecular films. Here we use quinacridone, which possesses flexible carbon side chains, as a model molecular system to address this issue. Eight molecular configurations with different molecular coverage are identified by scanning tunneling microscopy. Theoretical calculations reveal quantitatively the roles of different molecule-molecule and molecule-substrate interactions and predict the observed sequence of configurations. Remarkably, we find that a single Young's modulus applies for all configurations, the magnitude of which is controlled by side chain length, suggesting a versatile avenue for tuning not only the physical and chemical properties of molecular films but also their elastic properties.


Mercury in the open Mediterranean: evidence of contamination?
In relation to the previously observed higher Hg concentrations in the tissues of certain Mediterranean fish (e.g. mackerel and tuna) compared with the same species in the Atlantic, the evidence for anomolously high Hg contamination of the Mediterranean has been examined. Four aspects have been addressed: the reliability of analytical measurements; the paucity of data on Hg in the Mediterranean and other oceanic areas; the actual levels of Hg in truly open-ocean waters; and ecological factors which may play a role in the enrichment of Hg in Mediterranean fish. Recent evidence suggests that former measurements of Hg in sea water are inadequate, and overestimate the concentrations of Hg in oceanic waters. Even today, intercalibration studies suggest that there are serious problems in the determination of Hg at the levels present in open oceans. A comparison of the most recent reliable data indicates that Mediterranean open-ocean waters are not enriched in Hg relative to the North Atlantic or other open-ocean areas. Similarly, no evidence exists for Hg anomalies in deep-ocean sediments in the Mediterranean, although it is apparent that localised coastal anomalies do occur as a result of natural and anthropogenic Hg sources. Generally, there is a severe lack of data on total Hg concentrations in truly open-ocean environments, and virtually no data on alkyl forms of Hg. Geographic comparisons of Hg in plankton and small pelagic fish do not indicate the presence of higher Hg concentrations in the Mediterranean Sea compared with oceanic regimes. Since these lower trophic species serve as a source of food for larger predaceous fish, e.g. tuna, the origin of the high Hg content in top-level predators is difficult to explain by evoking solely food chain relationships. In trying to resolve the question of why high Hg concentrations are found in certain Mediterranean fish, future studies should include an examination of the alkyl as well as inorganic forms of Hg, and ecological factors such as growth rates and feeding regime.


Nutrition knowledge, attitudes, and fat consumption.
A questionnaire on nutrition knowledge, attitudes, and consumption of foods contributing highly to fat in the diet of United Kingdom residents was completed by 210 subjects. Personal attitudes were found to be good predictors of consumption and much more important than perceived social pressure from other persons. Women, subjects in the 26- to 45-year age group, and those of higher socioeconomic class tended to have more negative attitudes toward consumption of such foods. Nutrition knowledge was not found to relate to attitudes or to consumption of the foods.


Genomic full-length sequence of the HLA-A*24:233 allele, identified by full-length group-specific sequencing.
Genomic full-length sequence of HLA-A*24:233 was identified by group-specific sequencing in a Chinese individual.


EUS-guided FNAC in intra-abdominal lesions: Technique of tissue acquisition, ancillary testing, pearls and perils, and prospects.
Endoscopic ultrasound enables visualization of lesions within and in the vicinity of the gastrointestinal tract. Endoscopic ultrasound guided fine needle aspiration cytology (EUS-FNAC) helps in targeting various luminal and extraluminal lesions both diagnostically and therapeutically. Various intra-abdominal organs amenable to EUS-FNA include the gastrointestinal tract (GIT), pancreas, kidney, adrenal gland, liver, bile duct, gallbladder, spleen, and lymph nodes. EUS-FNAC is mostly done for pancreatic and intra-abdominal lymph nodal lesions. In the present review, we have discussed various aspects of EUS-FNAC.


A clinically relevant method to screen for hepatic steatosis in overweight adolescents: a cross sectional study.
To develop a screening algorithm to detect hepatic steatosis in overweight and obese adolescents. We performed a cross sectional study of 129 overweight adolescents 13-18 yrs. The primary outcome, hepatic steatosis was defined as an intracellular triglyceride content > 5.5 mg/g and quantified using (1)H-magenetic resonance spectroscopy. Primary predictor variables included, alanine and aspartate transaminases (ALT/AST) and features of the metabolic syndrome. Hepatic steatosis was present in 33% of overweight and obese adolescents. Adolescents with hepatic steatosis were more likely to be boys (adjusted OR: 4.8; 95% CI: 2.5-10.5), display a higher waist circumference (111 ± 12 vs 100 ± 13 cm, p < 0.001) and have metabolic syndrome (adjusted OR: 5.1; 95% CI: 1.6-16.4). Serum ALT predicted hepatic steatosis in boys (AUC: 0.82; 95% CI: 0.70-0.95; p < 0.001) but not girls (AUC = 0.63; 95% CI: 0.46-0.75, p = 0.16). An ALT >20 U/L, combined with the presence of metabolic syndrome, male gender and an elevated waist circumference provided the best model (AUC 0.85) with high sensitivity (72%) and specificity (82%) and positive and negative predictive values of 61% and 89% respectively. Serum transaminases provide modest predictive value for hepatic steatosis in youth. The ALT threshold for predicting hepatic steatosis is significantly lower than current clinical thresholds for predicting non-alcoholic fatty liver disease. The addition of ALT, presence of the metabolic syndrome and male gender significant improve the ability to predict hepatic steatosis.


Subclinical hypothyroidism in older individuals.
Subclinical hypothyroidism, which is defined as a thyroid-stimulating hormone concentration higher than the reference range (generally 4·5 mIU/L or higher) with normal free thyroxine concentrations, is frequently found in older individuals. International guidelines differ in recommendations for management of subclinical hypothyroidism in older individuals. We assessed published data during the past decade on the clinical significance and treatment of subclinical hypothyroidism in individuals aged 65 years and older. Meta-analyses, randomised clinical trials, and cohort studies are discussed in this narrative Review. Studies showed no significantly increased incidence in adverse cardiovascular, musculoskeletal, or cognitive outcomes in individuals aged 65 years or older when serum thyroid-stimulating hormone concentration was 4·5-7·0 mIU/L versus a euthyroid group. Moreover, in older individuals with subclinical hypothyroidism, symptoms of hypothyroidism and cardiac and bone parameters did not improve after levothyroxine treatment. These data suggest that treatment with levothyroxine should be considered for individuals aged 65 years or older with subclinical hypothyroidism when thyroid-stimulating hormone concentration is persistently 7 mIU/L or higher and to not initiate treatment with thyroid-stimulating hormone concentrations of less than 7 mIU/L. Levothyroxine doses should be personalised according to age, comorbidities, and life expectancy.


Molecular variability elicits a tunable switch with discrete neuromodulatory response phenotypes.
Recent single cell studies show extensive molecular variability underlying cellular responses. We evaluated the impact of molecular variability in the expression of cell signaling components and ion channels on electrophysiological excitability and neuromodulation. We employed a computational approach that integrated neuropeptide receptor-mediated signaling with electrophysiology. We simulated a population of neurons in which expression levels of a neuropeptide receptor and multiple ion channels were simultaneously varied within a physiological range. We analyzed the effects of variation on the electrophysiological response to a neuropeptide stimulus. Our results revealed distinct response patterns associated with low versus high receptor levels. Neurons with low receptor levels showed increased excitability and neurons with high receptor levels showed reduced excitability. These response patterns were separated by a narrow receptor level range forming a separatrix. The position of this separatrix was dependent on the expression levels of multiple ion channels. To assess the relative contributions of receptor and ion channel levels to the response profiles, we categorized the responses into six phenotypes based on response kinetics and magnitude. We applied several multivariate statistical approaches and found that receptor and channel expression levels influence the neuromodulation response phenotype through a complex though systematic mapping. Our analyses extended our understanding of how cellular responses to neuromodulation vary as a function of molecular expression. Our study showed that receptor expression and biophysical state interact with distinct relative contributions to neuronal excitability.


Recently reported sightings of ball lightning: observations collected by correspondence and Russian and Ukrainian sightings.
The observations in the first section of this paper were sent to John Abrahamson in response to the publication of a recent paper on ball lightning, with the correspondents either reading the original paper, or reports of it in popular science articles. A selection of the cases has been made, including those which showed interesting detail possibly useful in debating ball lightning mechanisms. Any inserted text within parenthesis is the observer's response to follow-up queries from J.A. The age of the observer (where noted) is that at the time of the observation. Three observations (1 q-s) did not show motion independent of their surroundings, but have been included because of their other similarities to ball lightning. It is interesting to note the high proportion (greater than 0.5) of scientifically or technically trained observers in this collection. The data presented in the second section of this paper come from both letters and interviews. Our interview questionnaire consisted of 46 questions and was mostly carried out in quiet conditions. Observations in 2 a, e, h, l, m, q-t were corrected during several (two or three) interviews. Heading each observation case we note the most unusual property of the object. Ball lightning appears in Russia and the Ukraine usually in summer (June-August), and more rarely in spring (March-May), or autumn (September-November). It appears usually during the daytime, 13:00-17:00 h, when most summer thunderstorms take place. Observers in their descriptions usually use the term "morning" to describe the period from 06:00 to 11:00 h, "daytime" for 12:00-18:00 h, and "evening" for 19:00-21:00 h. The term "time' means the local time, and sometimes it is difficult to compare it with the local geographic time due to frequent official state summer-winter time changes. The decree time in Russia can in general differ from the geographic time by 1-2 h.


Induction of cytochrome P-450 mRNA in rainbow trout: in vitro translation and immunodetection.
The time course of induction of the rainbow trout microsomal hepatic monooxygenase (MO) system was examined by determination of levels of mRNA and corresponding levels of catalytic activity. Animals were pretreated with beta-naphthoflavone (beta-NF, ip, 100 mg/kg) and terminated at 0, 2, 6, 18, and 48 hr postinjection. Levels of mRNA were determined by immunoprecipitation of in vitro translation products. Levels of mRNA coding for the cytochrome P-450 LM4b isozyme were maximally increased (13-fold) at 18 hr and had decreased almost to pretreatment levels by 48 hr post-treatment. This was in contrast to the catalytic activity in which ethoxyresorufin-O-deethylase (EROD) and ethoxycoumarin-O-deethylase (ECOD) were significantly elevated at both 18 hr (25- and 5-fold, respectively) and 48 hr (46- and 8-fold, respectively). Pretreatment with beta-NF (ip, 100 mg/kg) or 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB, ip, 150 mg/kg) for 18 hr resulted in significant differences in levels of mRNA in only the beta-NF-treated group. The LM2 P-450 isozyme could not be detected by immunoprecipitation with anti-LM2 IgG in trout treated with these same inducers. The results suggest a difference between the time course of induction of the mRNA for cytochrome P-450 LM4b isozyme and the induction of catalytic activity. Under the detection system utilized, the results suggest that the phenobarbital-like inducer, 6-CB, does not induce cytochrome activity nor does it induce the mRNA for cytochrome P-450 LM4b isozyme.


Intralymphatic mRNA vaccine induces CD8 T-cell responses that inhibit the growth of mucosally located tumours.
The lack of appropriate mouse models is likely one of the reasons of a limited translational success rate of therapeutic vaccines against cervical cancer, as rapidly growing ectopic tumours are commonly used for preclinical studies. In this work, we demonstrate that the tumour microenvironment of TC-1 tumours differs significantly depending on the anatomical location of tumour lesions (i.e. subcutaneously, in the lungs and in the genital tract). Our data demonstrate that E7-TriMix mRNA vaccine-induced CD8(+) T lymphocytes migrate into the tumour nest and control tumour growth, although they do not express mucosa-associated markers such as CD103 or CD49a. We additionally show that despite the presence of the antigen-specific T cells in the tumour lesions, the therapeutic outcomes in the genital tract model remain limited. Here, we report that such a hostile tumour microenvironment can be reversed by cisplatin treatment, leading to a complete regression of clinically relevant tumours when combined with mRNA immunization. We thereby demonstrate the necessity of utilizing clinically relevant models for preclinical evaluation of anticancer therapies and the importance of a simultaneous combination of anticancer immune response induction with targeting of tumour environment.


Natural genetic variation in the pheromone production of C. elegans.
From bacterial quorum sensing to human language, communication is essential for social interactions. Nematodes produce and sense pheromones to communicate among individuals and respond to environmental changes. These signals are encoded by different types and mixtures of ascarosides, whose modular structures further enhance the diversity of this nematode pheromone language. Interspecific and intraspecific differences in this ascaroside pheromone language have been described previously, but the genetic basis and molecular mechanisms underlying the variation remain largely unknown. Here, we analyzed natural variation in the production of 44 ascarosides across 95 wild Caenorhabditis elegans strains using high-performance liquid chromatography coupled to high-resolution mass spectrometry. We discovered wild strains defective in the production of specific subsets of ascarosides (e.g., the aggregation pheromone icas#9) or short- and medium-chain ascarosides, as well as inversely correlated patterns between the production of two major classes of ascarosides. We investigated genetic variants that are significantly associated with the natural differences in the composition of the pheromone bouquet, including rare genetic variants in key enzymes participating in ascaroside biosynthesis, such as the peroxisomal 3-ketoacyl-CoA thiolase, daf-22, and the carboxylesterase cest-3. Genome-wide association mappings revealed genomic loci harboring common variants that affect ascaroside profiles. Our study yields a valuable dataset for investigating the genetic mechanisms underlying the evolution of chemical communication.


The Na(+)-HCO3- cotransporter operates with a coupling ratio of 2 HCO3- to 1 Na+ in isolated rabbit renal proximal tubule.
All the relevant literature reports indicate that net rates of salt and water absorption and cell membrane potentials (Vb) are lower, but intracellular Na+ concentration is higher in rabbit renal proximal tubule in vitro than in rat proximal tubule in vivo. Since the different driving forces should influence basolateral Na(+)-HCO3- cotransport we have studied the operation of the cotransporter in isolated rabbit renal proximal tubule in vitro with special emphasis on the stoichiometry of flux coupling (q). Using conventional and ion-selective intracellular microelectrodes three series of experiments were performed: (a) we determined the Vb response to a 2:1 reduction of bath HCO3- or Na+ concentration, (b) we determined initial efflux rates of HCO3- or Na+ ions in response to a sudden 10:1 reduction of bath HCO3- concentration, and (c) we collapsed the tubules and determined electrochemical driving forces of Na+ and HCO3- across the basolateral cell membrane under conditions approaching zero net flux in the control state in the presence of Ba2+- and in Cl(-)-free solutions. All measurements concurrently yielded a coupling ratio of approximately two HCO3- ions to one Na+ ion (q = 2). This result contrasts with the ratio q = 3, which we have previously observed in similar experiments on rat renal proximal tubule in vivo [Yoshitomi et al. (1985) Pflügers Arch 405:360] and which was also observed on rabbit renal basolateral cell membrane vesicles in vitro [Soleimani et al. (1987) J Clin Invest 79:1276].(ABSTRACT TRUNCATED AT 250 WORDS)