Association Between Resilience and Psychological Morbidity in Parents of Critically Ill Children.
To determine whether parental resilience, measured at ICU admission, is associated with parent-reported symptoms of depression, anxiety, posttraumatic stress, and satisfaction with ICU care 3-5 weeks following ICU discharge. Planned prospective, observational study nested in a randomized comparative trial. PICUs and cardiac ICUs in two, free-standing metropolitan area children's hospitals. English- and Spanish-speaking parents whose children were younger than 18 years old and had anticipated ICU stay of greater than 24 hours or Pediatric Index of Mortality score of greater than or equal to 4 at the time of consent. All ICU admissions were screened for inclusion. Of 4,251 admissions reviewed, 1,360 were eligible. Five hundred families were approached and 382 enrolled. Two hundred thirty-two parents from 210 families with complete data were included in analysis. All participating parents completed the Connor-Davidson Resilience Scale at the time of consent and outcome measures 3-5 weeks after ICU discharge. All parents completed the Patient-Reported Outcome Measurement Information System Short Forms 8a for Depression and Anxiety, Impact of Event Scale-Revised for posttraumatic stress, and Pediatric Family Satisfaction-ICU 24 for parental satisfaction 3-5 weeks after ICU discharge. Higher parental resilience was associated with fewer symptoms of depression, anxiety, and posttraumatic stress in the final model (all p < 0.0001). Shorter length of stay, early mechanical ventilation, Latino ethnicity, and lower illness severity (both objective and parental perceptions) were associated with less morbidity in some or all measured mental health outcomes. Higher parental resilience is associated with fewer reported symptoms of anxiety, depression, and posttraumatic stress 3-5 weeks after ICU discharge. Parental resilience may impact parental post-ICU psychological morbidity. Measuring parental resilience could be one approach to identify parents at risk for post-ICU psychological morbidity. Future research into the impact of interventions designed to boost parental resilience is warranted.


Patient Characteristics and Treatment Outcome Associated with Protease Inhibitor (PI) use in the Asia-Pacific Region.
OBJECTIVES: Regimens containing protease inhibitors (PI) are less commonly used in developing countries due to high cost and less availability. We evaluated characteristics of patients initiating PI-based therapy according to previous antiretroviral (ARV) exposure; factors associated with initiating a PI-containing regimen using newer versus older PIs, and proportion of patients with detectable viral loads (VL) after initiating a PI-based regimen. METHODS: This analysis includes all patients who have initiated a PI-based regimen. ARV exposure was categorised: naïve (no previous ARV), 1st, 2nd, >/= 3rd switches; a switch was defined as starting or stopping any drug in a regimen. Newer PIs were defined as those approved by the US FDA after 1 January 2000. Detectable VL at 12 months was defined as VL >/= 400 copies/mL. Characteristics at PI initiation were evaluated. Logistic regression was used to determine factors associated with initiating a newer PI and detectable VL at 12 months after PI initiation. RESULTS: 1106 patients initiated PI-based therapy; of these, 618 (56%) were naïve patients. Overall, 22% (176) of patients had detectable VL at 12 months following the PI initiation. Being from a high income country (vs. mid/low income, OR = 1.80, p = 0.034) were more likely to be associated with detectable VL. CONCLUSION: The use of PIs in this cohort is dictated by accessibility and affordability issues particularly for the newer PIs. Short-term virological outcomes following PI-therapy in our cohort were good, and were associated with CD4 count at time of initiation.


Competence and ability.
It is nearly universally thought that the kind of decision-making competence that gives one a strong prima facie right to make one's own medical decisions essentially involves having an ability (or abilities) of some sort, or having a certain level or degree of ability (or abilities). When put under philosophical scrutiny, however, this kind of theory does not hold up. I will argue that being competent does not essentially involve abilities, and I will propose and defend a theory of decision-making competence according to which one is competent only if one possesses a certain kind of rationality in making treatment decisions.


Antibodies Reactive to Leptin in Adults with Type 2 Diabetes and Its Relationship with Clinical, Metabolic and Cardiovascular Risk Parameters.
Patients with obesity and type 2 diabetes (T2D) have shown alterations in the affinity of IgG anti-leptin antibodies which are possibly related to metabolic alterations. In the present exploratory study, we analyzed serum samples from adults with T2D classified by body mass index (BMI) and evaluated the relationship of IgG anti-leptin antibodies with body composition, metabolic and cardiovascular risk parameters. Serum IgG anti-leptin antibodies (total, free and immune complexes fractions) were measured by in-house ELISA. Body composition, metabolic biomarkers (glucose, glycated hemoglobin, lipid profile, insulin, leptin) and cardiometabolic risk indexes (AIP, HOMA-IR, HOMA-ß) were evaluated in one hundred T2D patients. Patients with T2D and obesity presented a decrease in the percentage of IgG anti-leptin immune complexes compared to patients with T2D and overweight (p < 0.0053). Negative correlations of IgG anti-leptin immune complexes with triglycerides (TG) (r=-0.412, p = 0.023) and VLDL-C (r=-0.611, p = 0.017) were found in normal weight T2D patients. Free IgG anti-leptin antibodies correlated positively with TC (r = 0.390, p = 0.032) and LDL-C (r = 0.458, p = 0.011) in overweight individuals with T2D. Finally, total IgG anti-leptin antibodies correlated positively with leptin hormone levels (r = 0.409, p = 0.024) and negatively with HOMA-IR (r =-0.459, p = 0.012) in T2D patients with obesity. The decrease of IgG anti-leptin immune complexes observed in patients with T2D and obesity suggests a reduction in antibody affinity to the hormone that may impact its transport and signaling, lipid, lipoprotein and insulin metabolism.


Diadenosine tetraphosphate binding protein from human HeLa cells: purification and characterization.
The ubiquitous dinucleotide P1,P4-di(adenosine-5') tetraphosphate (Ap4A) has been proposed to be involved in DNA replication and cell proliferation, DNA repair, platelet aggregation, and vascular tonus. A protein binding specifically to Ap4A is associated with a multiprotein form of DNA polymerase alpha (pol alpha 2) in HeLa cells. The Ap4A binding protein from HeLa cells has been purified to homogeneity starting from pol alpha 2 complex. The Ap4A binding protein is hydrophobic and is resolved from the pol alpha 2 complex by hydrophobic interaction chromatography on butyl-Sepharose and subsequently purified to homogeneity by chromatography on Mono-Q and Superose-12 FPLC columns. The Ap4A binding activity elutes as a single symmetrical peak upon gel filtration with a molecular mass of 200 kDa. Upon polyacrylamide gel electrophoresis under nondenaturing conditions, the purified protein migrates as a single protein of 200 kDa. Upon electrophoresis under denaturing conditions, the binding activity is resolved into two polypeptides of 45 and 22 kDa, designated as A1 and A2, respectively. A1 and A2 can be cross-linked using the homobifunctional cross-linking agent disuccinimidyl suberate. The cross-linked protein migrates as a single protein of 210 kDa on polyacrylamide gels under denaturing conditions, suggesting that these two polypeptides are subunits of a single protein. The purified protein binds Ap4A efficiently, and by Scatchard analysis, we have determined a dissociation constant of 0.25 microM, indicating high affinity of Ap4A binding protein to its ligand. ATP is not required for the binding activity. The nonionic detergent Triton X-100 is necessary for stabilizing the purified protein. Amino acid composition analysis indicates that A1 and A2 are distinct.


Ventral Striatum Functional Connectivity as a Predictor of Adolescent Depressive Disorder in a Longitudinal Community-Based Sample.
Previous studies have implicated aberrant reward processing in the pathogenesis of adolescent depression. However, no study has used functional connectivity within a distributed reward network, assessed using resting-state functional MRI (fMRI), to predict the onset of depression in adolescents. This study used reward network-based functional connectivity at baseline to predict depressive disorder at follow-up in a community sample of adolescents. A total of 637 children 6-12 years old underwent resting-state fMRI. Discovery and replication analyses tested intrinsic functional connectivity (iFC) among nodes of a putative reward network. Logistic regression tested whether striatal node strength, a measure of reward-related iFC, predicted onset of a depressive disorder at 3-year follow-up. Further analyses investigated the specificity of this prediction. Increased left ventral striatum node strength predicted increased risk for future depressive disorder (odds ratio=1.54, 95% CI=1.09-2.18), even after excluding participants who had depressive disorders at baseline (odds ratio=1.52, 95% CI=1.05-2.20). Among 11 reward-network nodes, only the left ventral striatum significantly predicted depression. Striatal node strength did not predict other common adolescent psychopathology, such as anxiety, attention deficit hyperactivity disorder, and substance use. Aberrant ventral striatum functional connectivity specifically predicts future risk for depressive disorder. This finding further emphasizes the need to understand how brain reward networks contribute to youth depression.


[Use of fluorescence-labelled cerebroside as a substrate for galactosylceramidase of human skin fibroblasts].
Possible use of the fluorescently labelled cerebroside, 1-O-(beta-D-galactosyl)-2-N-[6-(2-antroyl)hexanoyl]-4-sphingeni n (Gal-A-sphingenin) as a substrate for galactosylceramidase (GC) from human skin fibroblasts was investigated. Studies involving TLC and fluorimetric methods revealed enzymatic splitting of Gal-A-sphingenin whose degree correlated with the amount of the enzyme and incubation time. Some kinetic parameters of GC were determined, using Gal-A-sphingenin as substrate. It was shown that the values of specific activity of GC (1.6 nmol/mg protein/hr) and Km (0.025 mM) for Gal-A-sphingenin agree well with the corresponding values obtained with the use of the galactocerebroside as a natural substrate. In experiments with mixtures of Gal-A-sphingening and galactocerebroside used as substrates in different molar ratios, it was shown that the enzyme splits each of the substrates with equal velocity. The results of experiments with the enzyme samples from skin fibroblasts of healthy individuals and of patients with GM1-gangliosidosis (GM1-beta-D-galactosidase deficiency) suggest that Gal-A-sphingenin is a specific substrate for GC.


Getting ready for reading: a follow-up study of inner city second language learners at the end of Key Stage 1.
A previous study (Stuart, 1999) showed that early phoneme awareness and phonics teaching improved reading and spelling ability in inner-city schoolchildren in Key Stage 1, most of whom were learning English as a second language. The present study, a follow-up of these children at the end of Key Stage 1, addresses four main questions: (1) Are these improvements maintained to the end of Key Stage 1? (2) Are different patterns of cognitive process evident in the word recognition skills of phonics trained versus untrained children? (3) Do the phonics trained children now also show a significant advantage in reading comprehension? (4) Are there differences in amount of reading, in self-concept as readers and in oral vocabulary development between phonics trained and untrained children? Relationships between reading and spelling ages and Key Stage 1 SATs levels are also explored. Data are reported from 101 seven-year-olds (85 of whom were second language learners) remaining from the original 112 children reported on previously. Children were tested on four standardized tests of reading, spelling and vocabulary, and on a further six experimental tests of phoneme segmentation, grapheme-phoneme correspondence knowledge, regular, exception and nonword reading, author recognition and reading self-concept. Lasting influences of early phoneme awareness and phonics teaching on phoneme awareness, grapheme-phoneme correspondence knowledge, word reading and spelling were found. Part of the previously untrained group had now received structured phonics teaching, and were therefore treated as a third (late trained) group. Early and late-trained groups showed similar levels of attainment and similar cognitive processing patterns, which were different from the untrained group. However, there were no influences of training on reading comprehension, self-concept or oral vocabulary. Early phoneme awareness and phonics training efficiently accelerates the word recognition and spelling skills of first and second language learners alike. However, this is not sufficient to bootstrap the development of language comprehension in the second language learners. Further research is needed into the kinds of language teaching that will best develop their oral and written language comprehension.


Degenerate and non-degenerate two-photon absorption of coumarin dyes.
Two-photon absorption (2PA) spectroscopy is a robust bioimaging tool that depends on the determined cross-sections (σ2PA). The absorption of both photons occurs simultaneously with equivalent (degenerate) or different (non-degenerate) photon energies, D-2PA and ND-2PA, respectively. The former has been investigated experimentally and computationally for many systems, while the latter remains relatively unexplored computationally and limited experimentally. In this study, response theory using time-dependent density functional theory (TD-DFT) and the 2-state model (2SM) have been utilized to investigate σD-2PA and σND-2PA for the excitation to the lowest energy singlet state (S1) of coumarin, coumarin 6, coumarin 120, coumarin 307, and coumarin 343. Solvents involved were methanol (MeOH), chloroform (ClForm), and dimethylsulfoxide (DMSO), where the latter leads to the largest σ2PA. Values of σ2PA are largest for coumarin 6 and lowest for coumarin, which illustrates the effect of substituents. The 2SM clarifies how the largest cross-sections correspond to molecules with the largest transition dipole moments, μ01. In general, σD-2SM computations agree with σD-2PA. Moreover, σND-2SM are in qualitative agreement with σND-2PA with comparable enhancement relative to σD-2PA. Overall, σND-2PA are larger than σD-2PA where the increase is in the range of 22% to 49%, depending on the coumarin as well as the relative energies of the two photons. This work aids in future investigations into various fluorophores to understand their photophysical properties for ND-2PA.


Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non-muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?
It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.


Three-compartment T1 relaxation model for intracellular paramagnetic contrast agents.
The goal of this work was to elaborate a model describing the effective longitudinal relaxation rate constant R(1) for (1)H(2)O in three cellular compartments experiencing possible equilibrium water exchange, and to apply this model to explain the effective R(1) dependence on the overall concentration of a cell-internalized Gd(3+)-based contrast agent (CA). The model voxel comprises three compartments representing extracellular, cytoplasmic, and vesicular (e.g., endosomal, lysosomal) subcellular spaces. Relaxation parameters were simulated using a modified Bloch-McConnell equation including magnetization exchange between the three compartments. With the model, several possible scenarios for internalized CA distribution were evaluated. Relaxation parameters were calculated for contrast agent restricted to the cytoplasmic or vesicular compartments. The size or the number of CA-loaded vesicles was varied. The simulated data were then separately fitted with empirical mono- and biexponential inversion recovery expressions. The voxel CA-concentration dependencies of R(1) can be used to qualitatively and quantitatively understand a number of different experimental observations reported in the literature. Most important, the simulations reproduced the relaxivity "quenching" for cell-internalized contrast agent that has been observed.


A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Chromosome abnormality in early entrants.
A preliminary study was performed to estimate radiation dose in 10 individuals who had entered Hiroshima city one day after the explosion and worked around the hypocenter area for a week. The numbers of cells with chromosome aberrations differed in each subject, ranging from one to 18 (median: 11 abnormalities) in 500 metaphases of lymphocytes cultured for 48 hours with Phytohemagglutinin. Five individuals had more than 1.6 percent stable type aberrations and were estimated to have been exposed to 6-13 rad. The other five individuals and the controls were estimated to be less than two rad.


In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations.
Optimization of the in vivo performance of dosage forms in humans is essential in developing not only conventional formulations but also drug delivery system (DDS) formulations. Although animal experiments are still useful for these formulations, in silico approaches have become increasingly important for DDS formulations with regard to species-specific differences in physiology that can affect the in vivo performance of dosage forms between animals and humans. Furthermore, it is also important to couple in vitro characterizations with in silico models to predict in vivo performance in humans precisely. In this review article, I summarized in vitro-in silico approaches to predicting the in vivo performance of oral DDS formulations (amorphous solid dispersions, lipid-based formulations, nanosized formulations, cyclodextrins-based formulations, sustained release products, enteric coat products, and orally disintegrating tablets) and parenteral DDS formulations (cyclodextrins-based formulations, liposomes, and inhaled formulations).


Iron status is associated with carotid atherosclerotic plaques in middle-aged adults.
Although the iron-heart disease hypothesis is prevalent, the epidemiological findings are incongruent. The relationship of serum ferritin with early cardiovascular disease (CVD), particularly atherosclerosis, has not been evaluated extensively, particularly with accounting for inflammation. We examined this association in a case-control study of 124 age- and sex-matched pairs embedded in the population-based random sample (MONICA survey) in Southwest France, taking into account inflammation status. Cases had >or=2 carotid atherosclerotic plaques and controls had none. Inflammation was assessed using several markers, including serum alpha-1 acid glycoprotein (AGP) and high sensitivity C-reactive protein. There was an interaction of inflammation with group (case/control) for serum ferritin. In adults without elevated AGP, serum ferritin was significantly greater in atherosclerotic cases than in adults in the control group. In models adjusted for CVD risk factors, the odds of atherosclerosis increased with the increase in serum ferritin in individuals without elevated AGP; for every 10-microg/L increase in serum ferritin, the risk for atherosclerosis increased by 3% (odds ratio [95% CI]: 1.03 [1.01-1.06]). In conclusion, carotid atherosclerosis was positively associated with serum ferritin in individuals free from subclinical inflammation based on AGP. Further prospective and/or experimental studies are needed to corroborate the observed association of iron status with atherosclerosis.


Effects of Photons Irradiation on 18F-FET and 18F-DOPA Uptake by T98G Glioblastoma Cells.
The differential diagnosis between brain tumors recurrence and early neuroinflammation or late radionecrosis is still an unsolved problem. The new emerging magnetic resonance imaging, computed tomography, and positron emission tomography diagnostic modalities still lack sufficient accuracy. In the last years, a great effort has been made to develop radiotracers able to detect specific altered metabolic pathways or tumor receptor markers. Our research project aims to evaluate irradiation effects on radiopharmaceutical uptake and compare the kinetic of the fluorinate tracers. T98G glioblastoma cells were irradiated at doses of 2, 10, and 20 Gy with photons, and 18F-DOPA and 18F-FET tracer uptake was evaluated. Activity and cell viability at different incubation times were measured. 18F-FET and 18F-DOPA are accumulated via the LAT-1 transporter, but 18F-DOPA is further incorporated, whereas 18F-FET is not metabolized. Therefore, time-activity curves (TACs) tend to plateau with 18F-DOPA and to a rapid washout with 18F-FET. After irradiation, 18F-DOPA TAC resembles the 18F-FET pattern. 18F-DOPA activity peak we observed at 20 min might be fictitious, because earlier time points have not been evaluated, and a higher activity peak before 20 min cannot be excluded. In addition, the activity retained in the irradiated cells remains higher in comparison to the sham ones at all time points investigated. This aspect is similar in the 18F-FET TAC but less evident. Therefore, we can hypothesize the presence of a second intracellular compartment in addition to the amino acidic pool one governed by LAT-1, which could explain the progressive accumulation of 18F-DOPA in unirradiated cells.


Monoclonal Antibodies of a Diverse Isotype Induced by an O-Antigen Glycoconjugate Vaccine Mediate In Vitro and In Vivo Killing of African Invasive Nontyphoidal Salmonella.
Nontyphoidal Salmonella (NTS), particularly Salmonella enterica serovars Typhimurium and Enteritidis, is responsible for a major global burden of invasive disease with high associated case-fatality rates. We recently reported the development of a candidate O-antigen-CRM197 glycoconjugate vaccine against S. Typhimurium. Here, using a panel of mouse monoclonal antibodies generated by the vaccine, we examined the relative efficiency of different antibody isotypes specific for the O:4 antigen of S. Typhimurium to effect in vitro and in vivo killing of the invasive African S. Typhimurium strain D23580. All O:4-specific antibody isotypes could mediate cell-free killing and phagocytosis of S. Typhimurium by mouse blood cells. Opsonization of Salmonella with O:4-specific IgA, IgG1, IgG2a, and IgG2b, but not IgM, resulted in cell-dependent bacterial killing. At high concentrations, O:4-specific antibodies inhibited both cell-free complement-mediated and cell-dependent opsonophagocytic killing of S. Typhimurium in vitro. Using passive immunization in mice, the O:4-specific antibodies provided in vivo functional activity by decreasing the bacterial load in the blood and tissues, with IgG2a and IgG2b being the most effective isotypes. In conclusion, an O-antigen-CRM197 glycoconjugate vaccine can induce O-antigen-specific antibodies of different isotypes that exert in vitro and in vivo killing of S. Typhimurium.


The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen.
The three proteins that comprise anthrax toxin, edema factor (EF), lethal factor (LF), and protective antigen (PA), assemble at the mammalian cell surface into toxic complexes. After binding to its receptor, PA is proteolytically activated, yielding a carboxyl-terminal 63-kDa fragment (PA(63)) that coordinates assembly of the complexes, promotes their endocytosis, and translocates EF and LF to the cytosol. PA(63) spontaneously oligomerizes to form symmetric ring-shaped heptamers that are capable of binding three molecules of EF and/or LF as competing ligands. To determine whether binding of these ligands depends on oligomerization of PA(63), we prepared two oligomerization-deficient forms of this protein, each mutated on a different PA(63)-PA(63) contact face. In solution or when bound to receptors on Chinese hamster ovary K1 cells, neither mutant alone bound ligand, but a mixture of them did. After the two mutants were proteolytically activated and mixed with ligand in solution, a ternary complex was isolated containing one molecule of each protein. Thus EF and LF bind stably only to PA(63) dimers or higher order oligomers. These findings are relevant to the kinetics and pathways of assembly of anthrax toxin complexes.


Rapid non-genomic effects of corticosteroids and their role in the central stress response.
In response to a stressful encounter, the brain activates a comprehensive stress system that engages the organism in an adaptive response to the threatening situation. This stress system acts on multiple peripheral tissues and feeds back to the brain; one of its key players is the family of corticosteroid hormones. Corticosteroids affect brain functioning through both delayed, genomic and rapid, non-genomic mechanisms. The latter mode of action has long been known, but it is only in recent years that the physiological basis in the brain is beginning to be unravelled. We now know that corticosteroids exert rapid, non-genomic effects on the excitability and activation of neurons in (amongst others) the hypothalamus, hippocampus, amygdala and prefrontal cortex. In addition, corticosteroids affect cognition, adaptive behaviour and neuroendocrine output within minutes. Knowledge on the identity of the receptors and secondary pathways mediating the non-genomic effects of corticosteroids on a cellular level is accumulating. Interestingly, in many cases, an essential role for the 'classical' mineralocorticoid and glucocorticoid receptors in a novel membrane-associated mechanism is found. Here, we systematically review the recent literature on non-genomic actions of corticosteroids on neuronal activity and functioning in selected limbic brain targets. Further, we discuss the relevance of these permissive effects for cognition and neuroendocrine control, and the integration of this novel mode of action into the complex balanced pattern of stress effects in the brain.


Tearing: lacrimal obstructions.
Tearing disorders are relatively common. Comprehensive consideration of the entire tearing system can assist the diagnosis and treatment of tearing problems to improve, if not cure, the condition. The general symptom complaint of "tearing or a feeling of wetness/irritation" most commonly relates to a dry or irritated eye, which usually responds well to medical therapy or punctal occlusion. True tearing from a lacrimal obstruction, however, is usually treated surgically. With a thorough understanding of the anatomy and physiology most tearing problems can be systematically analyzed, diagnosed, and treated with a high degree of satisfaction to the patient and physician.


Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome.
Deletions or mutations in the gene encoding the basolateral chloride channel CLC-Kb (CLCNKB) cause classic Bartter syndrome (MIM 602023), which is characterized by hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism and hypercalciura. These patients are usually diagnosed during infancy or childhood due to failure to thrive and growth retardation. The purpose of this study was to investigate the underlying mutations in Japanese patients with classic Bartter syndrome. Seven Japanese patients from seven different families diagnosed as having classic Bartter syndrome were studied. Analysis of CLCNKB demonstrated a large deletion in two patients, a partial deletion in one patient and two mutations (DeltaL130 in exon 4 and W610X in exon 16) in the remaining four patients. DeltaL130 is a novel mutation, but W610X was previously reported in three unrelated Japanese patients. Six out of the seven patients were diagnosed due to typical characteristics of classic Bartter syndrome such as failure to thrive and poor weight gain however, one patient was asymptomatic with mild hypokalemia. In conclusion, we identified a novel mutation of the CLCNKB gene, DeltaL130. We did not determine whether the W610X mutation in our patients was from a common ancestor or if this mutation is frequent in Japan.


Cross-modulation interference with lateralization of mixed-modulated waveforms.
This study investigated the ability to use spatial information in mixed-modulated (MM) sounds containing concurrent frequency-modulated (FM) and amplitude-modulated (AM) sounds by exploring patterns of interference when different modulation types originated from different loci as may occur in a multisource acoustic field. Interaural delay thresholds were measured from 5 normal-hearing adults for an AM sound in the presence of interfering FM and vice versa as a function of interferer modulation rate. In addition, the effects of near versus remote interferer rates, and fixed versus randomized interferer interaural delay, were investigated. AM interfered with lateralization of FM at all modulation rates. However, the FM interfered with AM lateralization only when the FM rate was higher than the AM rate. This rate asymmetry was surprising given the prevalence of low-frequency dominance in lateralization, but was predicted by a cross-correlation model of binaural interaction. Effects were similar for fixed and randomized interferer interaural delays. The results suggest that in multisource environments, sources containing different modulation types significantly interfere with localization in complex ways that reveal interactions between modulation type and rate. These findings contribute to the understanding of auditory object formation and localization.


The faculty-to-faculty mentorship experience: a survey on challenges and recommendations for improvements.
Faculty at research institutions play a central role in advancing knowledge and careers, as well as promoting the well-being of students and colleagues in research environments. Mentorship from experienced peers has been touted as critical for enabling these myriad roles to allow faculty development, career progression, and satisfaction. However, there is little information available on who supports faculty and best ways to structure a faculty mentorship programme for early- and mid-career academics. In the interest of advocating for increased and enhanced faculty mentoring and mentoring programmes, we surveyed faculty around the world to gather data on whether and how they receive mentoring. We received responses from 457 early- and mid-career faculty and found that a substantial portion of respondents either reported having no mentor or a lack of a formal mentoring scheme. Qualitative responses on the quality of mentorship revealed that the most common complaints regarding mentorship included lack of mentor availability, unsatisfactory commitment to mentorship, and non-specific or non-actionable advice. On these suggestions, we identify a need for training for faculty mentors as well as strategies for individual mentors, departments, and institutions for funding and design of more intentional and supportive mentorship programmes for early- and mid-career faculty.


Case definition and classification of leukodystrophies and leukoencephalopathies.
An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.


An Inverse Relationship Between Age of Type 2 Diabetes Onset and Complication Risk and Mortality: The Impact of Youth-Onset Type 2 Diabetes.
This study compared the prevalence of complications in 354 patients with T2DM diagnosed between 15 and 30 years of age (T2DM15-30) with that in a duration-matched cohort of 1,062 patients diagnosed between 40 and 50 years (T2DM40-50). It also examined standardized mortality ratios (SMRs) according to diabetes age of onset in 15,238 patients covering a wider age-of-onset range. Complication status was assessed according to a standard protocol and extracted from our electronic database. Survival status was ascertained by data linkage with the Australian National Death Index. SMRs were calculated in comparison with the background Australian population and analyzed according to age of onset. After matching for duration, despite their younger age, T2DM15-30 had more severe albuminuria (P = 0.004) and neuropathy scores (P = 0.003). T2DM15-30 were as commonly affected by metabolic syndrome factors as T2DM40-50 but less frequently treated for hypertension and dyslipidemia (P < 0.0001). An inverse relationship between age of diabetes onset and SMR was seen, which was the highest for T2DM15-30 (3.4 [95% CI 2.7-4.2]). SMR plots adjusting for duration show that for those with T2DM15-30, SMR is the highest at any chronological age, with a peak SMR of more than 6 in early midlife. In contrast, mortality for older-onset groups approximates that of the background population. The negative effect of diabetes on morbidity and mortality is greatest for those diagnosed at a young age compared with T2DM of usual onset. These results highlight the growing imperative to direct attention toward young-onset T2DM and for effective interventions to be applied before middle age.


Erythrocyte destruction and protective immunity to Malaria: enhancement of the immune response by phenylhydrazine treatment.
Malaria infection is characterized by extensive destruction of erythrocytes. In addition, the surface membrane of parasitized erythrocytes becomes biochemically and antigenically modified. Thus during infection the host immune system is exposed to massive amounts of modified erythrocytes on a scale not normally considered in conventional immunological experiments. The haemocytoxic drug phenylhydrazine hydrochloride has been used to mimic, in otherwise normal animals, the effect of the modification and destruction of erythrocytes which occurs in malaria. The experiments demonstrated that protective immunity to Plasmodium berghei KSP11 infection in rats and mice is significantly enhanced by this treatment, that this effect generates memory, can be transferred with spleen cells, and can have both enhancing and suppressive action on the protective immune response.


[The student, the physician, and the teacher of medicine facing death and terminal patients].
The aim of this investigation was to study the feelings and attitudes of medical students, medical doctors and teachers of medicine facing death and terminal patients. An inquiry about death and terminal patient was applied to 81 pre-clinical students, 139 clinical students, 52 medical doctors and 54 teachers of the Faculty of Health Sciences. 303 responders showed interest in this subject (93%); 179 had problems in dealing with it (55%). Only 136 searched for information (41.7%) and 116 have difficulty in finding it (85.1%). Non-especialized sources of information were the most used ones (61.1%). Twenty medical doctors (38%) and 13 teachers (24%) discussed the subject more often with patients, 47 pre-clinical students (58%) did it with friends and 40 with relatives (49.4%); 36 teachers did it with health professionals (66.6%). 263 responders rarely think about their own death (80.7%), and 38 do it constantly (11.6%); 157 are afraid of thinking about their own death (52.2%). Eleven pre-clinical students (13.8%), ten clinical students (7.2%) and 4 medical doctors (7.4%) never thought of their own death. Before entering medical school, 136 responders had some kind of contact with corpses (41.8%). The interest about death did not change, after dealing with corpses in anatomy classes, to 321 responders (98.5%), the same happening with 236 individuals (96.3%) after necroscopy. During the clinical year 111 students (79.9%) worked with terminal patients. The authors suggest that formal education about death and terminal patient in medical schools, starting early in the medical course, as well as permanent attention to the theme by professionals, could modify the attitudes of students and medical doctors toward a better way in dealing with this subject.


Restriction and dependence to autonomy and freedom: transformation in adolescent heart transplant recipients.
The process of heart transplantation poses numerous challenges and adaptive tasks for paediatric patients and their families. Few studies have examined how the experience of transplant interacts with developmental transitions such as adolescence, a period of significant change, and adjustment in itself. We explored adolescent heart transplant recipients' and their parents' experience of transplant from the point at which their heart condition was diagnosed to several months after transplantation. We adopted a developmental focus, to consider how participants negotiated the tasks of adolescence in the context of their transplant experiences. A qualitative approach was used to interview five adolescent-parent dyads, who reported few post-transplant complications, and the data were analysed according to the principles of IPA. Our findings revealed transplant to be a transformative experience, with two themes marking a contrast between pre- and post-transplant states: "Restriction and Dependence" and "Autonomy and Freedom." The themes are considered in relation to adolescent development. We propose that clinicians working with paediatric heart transplant recipients and their families need to consider the particular developmental challenges faced by adolescent patients and view the attainment of developmental milestones alongside physical and psychological markers of successful adjustment.


Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+ T cells derived from patients with multiple sclerosis.
Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4(+) T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway--geranylgeranylation or farnesylation--is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease.


Enhancing the population of the encounter complex affects protein complex formation efficiency.
Optimal charge distribution is considered to be important for efficient formation of protein complexes. Electrostatic interactions guide encounter complex formation that precedes the formation of an active protein complex. However, disturbing the optimized distribution by introduction of extra charged patches on cytochrome c peroxidase does not lead to a reduction in productive encounters with its partner cytochrome c. To test whether a complex with a high population of encounter complex is more easily affected by suboptimal charge distribution, the interactions of cytochrome c mutant R13A with wild-type cytochrome c peroxidase and a variant with an additional negative patch were studied. The complex of the peroxidase and cytochrome c R13A was reported to have an encounter state population of 80%, compared to 30% for the wild-type cytochrome c. NMR analysis confirms the dynamic nature of the interaction and demonstrates that the mutant cytochrome c samples the introduced negative patch. Kinetic experiments show that productive complex formation is fivefold to sevenfold slower at moderate and high ionic strength values for cytochrome c R13A but the association rate is not affected by the additional negative patch on cytochrome c peroxidase, showing that the total charge on the protein surface can compensate for less optimal charge distribution. At low ionic strength (44 mm), the association with the mutant cytochrome c reaches the same high rates as found for wild-type cytochrome c, approaching the diffusion limit.


Measurement of the thermal relaxation time in agar-gelled water.
In this study, we presented an experiment to obtain the thermal relaxation time which is necessary to model heat conduction by the hyperbolic heat equation. This experiment was evaluated by finite element simulation to acquire reliably this parameter for biological tissue. Besides that, we measured the thermal relaxation time of agar-gelled water with 2% of concentration at 25°C. The average value of thermal relaxation time for the gel was 7.9630s with standard deviation of 1.4562.


[Obstructive Lung Disease:Point of Perioperative Management].
The respiratory disorder is classified into three types, "obstructive lung disease", "restrictive lung disease", and "mixed obstructive and restrictive lung disease". Chronic obstructive pulmonary disease (COPD) and bronchial asthma were represented by obstructive lung disease and the number of each patients was estimated over 5 millions. These are a condition commonly presented in older people who undergoing cardiovascular surgery and confers an increased risk of postoperative complications and mortality. It is necessary to understand perioperative management of patients with COPD and bronchial asthma.


Microstructural Investigation of Heat-Treated Ultra-High Performance Concrete for Optimum Production.
For optimum production of ultra-high performance concrete (UHPC), the material and microstructural properties of UHPC cured under various heat treatment (HT) conditions are studied. The effects of HT temperature and duration on the hydration reaction, microstructure, and mechanical properties of UHPC are investigated. Increasing HT temperature accelerates both cement hydration and pozzolanic reaction, but the latter is more significantly affected. This accelerated pozzolanic reaction in UHPC clearly enhances compressive strength. However, strength after the HT becomes stable as most of the hydration finishes during the HT period. Particularly, it was concluded that the mechanical benefit of the increased temperature and duration on the 28 day-strength is not noticeable when the HT temperature is above 60 °C (with a 48 h duration) or the HT duration is longer than 12 h (with 90 °C temperature). On the other hand, even with a minimal HT condition such as 1 day at 60 °C or 12 h at 90 °C, outstanding compressive strength of 179 MPa and flexural tensile strength of 49 MPa are achieved at 28 days. Microstructural investigation conducted herein suggests that portlandite content can be a good indicator for the mechanical performance of UHPC regardless of its HT curing conditions. These findings can contribute to reducing manufacturing energy consumption, cost, and environmental impact in the production of UHPC and be helpful for practitioners to better understand the effect of HT on UHPC and optimize its production.


Musculoskeletal Low Back Pain in School-aged Children: A Review.
Low back pain (LBP) in children and adolescents is a common problem. The differential diagnosis of LBP in this population is broad and different from that seen in the adult population. Most causes of LBP are musculoskeletal and benign in their clinical course. Clinicians should have an understanding of the relevant anatomy and the most commonly encountered etiologic factors of LBP in children and adolescents to provide effective care. Low back pain is rarely seen in youth before they reach school age. Subsequently, rates of LBP rise until age 18 years, at which age the prevalence of LBP is similar to that in adults. The differential diagnosis of LBP in this population is broad, and individual etiologic factors are most often associated with musculoskeletal overuse or trauma. Sinister etiologic factors are rare. The patient's history and physical examination are the foundation of evaluating a child with LBP. The indication for and timing of specific imaging or other studies will vary depending on the etiologic factor of concern. Most treatment of LBP in this population is centered on relative rest, rehabilitation, and identification of predisposing risk factors. Pharmacologic treatment may be used but is typically a brief course. Orthopedic, rheumatologic, and other subspecialty referrals may be considered when indicated, but most of these patients can be managed by a general pediatrician with a good understanding of the principles described in this article. Low back pain in children and adolescents is a common problem. It is most often nonspecific, musculoskeletal, and self-limiting. Pediatricians should recognize the importance of a proper history, physical examination, and general knowledge of the lumbar spine and pelvic anatomy relevant to the child in their evaluation with this presenting symptom.


Experimental study on seed light source coherence dependence of continuous-wave supercontinuum performance.
We experimentally compare output performance between laser beam (erbium fiber ring laser) and amplified spontaneous emission (ASE) beam (erbium fiber ASE) driven supercontinuums (SCs) in terms of seed beam temporal coherence. We control the degree of temporal coherence of the seed beams by using an optical filter to change their spectral linewidth. The random phase ASE driven SC is found to have better performance than the phase-correlated laser driven SC in terms of spectral smoothness and output power. Significantly high relative-intensity-noise in the output SCs is observed for both cases, i.e. the laser driven SC and the ASE driven SC irrespective of the seed beam temporal coherence due to the nonlinear amplification of quantum fluctuations both in the input pump beam and in the Raman scattering process.


Quantitative risk assessment of Vibrio parahaemolyticus in finfish: a model of raw horse mackerel consumption in Japan.
The aim of this study was to evaluate the effects of implemented control measures to reduce illness induced by Vibrio parahaemolyticus (V. parahaemolyticus) in horse mackerel (Trachurus japonicus), seafood that is commonly consumed raw in Japan. On the basis of currently available experimental and survey data, we constructed a quantitative risk model of V. parahaemolyticus in horse mackerel from harvest to consumption. In particular, the following factors were evaluated: bacterial growth at all stages, effects of washing the fish body and storage water, and bacterial transfer from the fish surface, gills, and intestine to fillets during preparation. New parameters of the beta-Poisson dose-response model were determined from all human feeding trials, some of which have been used for risk assessment by the U.S. Food and Drug Administration (USFDA). The probability of illness caused by V. parahaemolyticus was estimated using both the USFDA dose-response parameters and our parameters for each selected pathway of scenario alternatives: washing whole fish at landing, storage in contaminated water, high temperature during transportation, and washing fish during preparation. The last scenario (washing fish during preparation) was the most effective for reducing the risk of illness by about a factor of 10 compared to no washing at this stage. Risk of illness increased by 50% by exposure to increased temperature during transportation, according to our assumptions of duration and temperature. The other two scenarios did not significantly affect risk. The choice of dose-response parameters was not critical for evaluation of control measures.


Vulvovaginal hematomas complicating delivery. Rationale for drainage of the hematoma cavity.
To review the management of puerperal vulvovaginal hematomas and report on the use of closed system drainage in cases in which operative intervention was used. A retrospective review of medical records for a five-year period was conducted. The charts of all patients in whom puerperal vulvovaginal hematomas occurred were reviewed and data extracted regarding possible etiologic factors, details of delivery, characterization of the hematoma, surgical intervention and type of drain used. Also recorded was length of stay and postoperative complications. Eleven patients with hematomas were identified, for an incidence of 1/526. All patients received antibiotics; transfusion was required in eight patients. Drains were used in nine patients: Penrose in four and closed system drainage in five. All drains were brought through a separate site distant from the repair. There was one postoperative abscess, which resolved with wound care, resulting in no long-term morbidity. Puerperal vulvovaginal hematomas may be a life-threatening event. Review of the literature and our experience suggests that aggressive operative management and the use of drains are beneficial in the management of these patients. Closed system drainage may be an effective adjunct in the management of vulvovaginal hematomas.


Empowering patients: simplifying discharge instructions.
Patients who do not have enough information about their discharge plans have decreased treatment compliance, decreased patient safety, increased emergency department (ED) recidivism, and poor satisfaction. This project aimed to develop and implement a method to assess and improve patient understanding of treatment and discharge plan in the ED. The authors developed a questionnaire to assess patient knowledge using Centers for Medicare and Medicaid Services and Joint Commission recommendations, areas of communication deficits reported in other manuscripts, and ED staff and provider input. Responses from patient interviews were then scored against the medical record. Three trained scorers graded all responses, and inter-rater reliability was calculated using the kappa statistic.Baseline observations found that written discharge instructions were long and tedious, and important information was difficult to find. Based on initial patient scores, stakeholder interviews, and fishbone diagrams, the team developed a one-page simplified information page (SIP) targeted to inform patients their most relevant discharge instructions. Next, the SIP was tested on 118 patients to measure its effect on patient understanding. At the baseline study, no patients had complete understanding of their discharge instructions. The areas of lowest scores were medication instructions and indications to return to the ED. Implementation of the SIP resulted in statistically significant changes in score distribution across all questions assessed with the Wilcoxon signed-rank test. Interrater reliability between scorers was high (kappa=0.84). We incorporated the concept of the SIP to the cover page of our standard discharge instructions.Healthcare providers often spend valuable time educating their patients, and it is important to assess the effectiveness of this teaching to identify areas in which we may improve health literacy and patient understanding. This project has shown that a simple, easy-to-read, concise page developed with patient input significantly improved ED discharge instruction knowledge.


[Establishment of an animal model of prostate cancer metastasis to the lung traced by AsRed2].
To establish an animal model of prostate cancer (PCa) metastasis to the lung using PCa PR7 (PCa PC-3 cells stably expressing red fluorescent protein AsRed2) cell lines that can be monitored by in vivo fluorescence imaging technology. MTT and Transwell assay were used to compare the abilities of proliferation, migration and invasion of PC-3 and PR7 cells. Twenty BALB/c nude mice were equally randomized to 4 groups to receive tail vein injection of PR7 cell suspension at the concentration of 1 x 107/ml (group A), 2.5 x 107/ml (group B), 5 x 107/ml (group C) and 2.5 x 107/ml followed by the same dose 1 week later (group D). PCa metastasis to the lung was then monitored by in vivo fluorescence imaging technology at the end of 2, 4, 6 and 8 weeks. There were no statistically significant differences between PC-3 and PR7 cells in their abilities of proliferation, migration and invasion (P > 0.05). At the end of 4 weeks, lung metastasis was observed in 40% of the mice in group D, and at the end of 8 weeks, it was detected in 20% in group A, 60% in group B, 100% in group C, and 100% in group D, all confirmed by pathological examination. The animal model of PCa metastasis to the lung that can be monitored by in vivo fluorescence imaging technology was established successfully by tail vein injection of PR7 cells carrying red fluorescent protein.


Informal and formal care preferences and expected willingness of providing elderly care in Germany: protocol for a mixed-methods study.
In Germany, the number of elderly people in need of care is expected to increase from 2.4 million in 2015 to 3.2 million in 2030. The subsequent rise in demand for long-term care facilities is unlikely to be met by the current care structures and available staff. Additionally, many Germans still prefer to be cared for at home for as long as possible. In light of recent changes, such as increasing employment rates of women and growing geographical distances of family members, informal caregiving becomes more challenging in the future. The aim of this study is to explore preferences for informal and formal care services in the German general population, as well as the expected willingness of providing elderly care. A mixed-methods approach will be used to explore care preferences and expected willingness of providing elderly care in the German general population. A systematic literature review will be performed to provide an overview of the current academic literature on the topic. Qualitative interviews will be conducted with informal caregivers, care consultants and people with no prior caregiving experiences. A labelled discrete choice experiment will be designed and conducted to quantitatively measure the preferences for informal and formal care in the German general population. People between 18 and 65 years of age will be recruited in cooperation with a (regional) statutory health insurance (AOK Lower Saxony). A mixed multinomial logit regression model and a latent class finite mixture model will be used to analyse the data and test for subgroup differences in care preferences. The study has been approved by the Committee for Clinical Ethics of the Medical School in Hannover. Data will be treated confidential to ensure the participants' anonymity. The results will be discussed and disseminated to relevant stakeholders in the field. DRKS00012266.


Optimal enhancement configuration of silica nanoparticles for ultrasound imaging and automatic detection at conventional diagnostic frequencies.
To experimentally investigate the acoustical behavior of silica nanoparticles within conventional diagnostic ultrasound fields and to determine a suitable configuration, in terms of particle size and concentration, for their employment as targetable contrast agents. We also assessed the effectiveness of a novel method for automatic detection of targeted silica nanoparticles for future tissue typing applications. Silica nanospheres of variable size (160, 330, and 660 nm in diameter) and concentration (10¹⁰-10¹³ part/mL) were dispersed in different custom-designed agarose-based gel samples and imaged at 7.5 MHz with a conventional echograph linked to a research platform for radiofrequency signal acquisition. Off-line analysis included evaluation of backscattered ultrasound amplitude, image brightness, and nanoparticle automatic detection through radiofrequency signal processing. Amplitude of nanoparticle-backscattered signals linearly increased with particle number concentration, but image brightness did not show the same trend, because the logarithmic compression caused the reaching of a "plateau" where brightness remained almost constant for further increments in particle concentration. On the other hand, both backscatter amplitude and image brightness showed significant increments when particle diameter was increased. Taking into account particle size constraints for tumor targeting (pore size of tumor endothelium and trapping effects because of reticulo-endothelial system limit the dimension of effectively employable particles to less than 380 nm), a suitable compromise is represented by the employment of 330-nm silica nanospheres at a concentration of about 1 to 2 x 10¹¹ part/mL. These particles, in fact, showed the best combination of number concentration and diameter value to obtain an effective enhancement on conventional echographic images. Furthermore, also the sensitivity of the developed method for automatic nanoparticle detection had a maximum (72.8%) with 330-nm particles, whereas it was lower with both bigger and smaller particles (being equal to 64.1% and 17.5%, respectively). Silica nanoparticles at a diameter of about 330 nm are very promising contrast agents for ultrasound imaging and specific tumor targeting at conventional diagnostic frequencies, being in particular automatically detectable with high sensitivity already at low doses. Future studies will be carried out to assess the acoustic behavior of nanoparticles with different geometries/sizes and to improve sensitivity of the automatic detection algorithm.


Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.
Background: Cholangiocarcinoma is a highly lethal neoplasm for which the currently available chemotherapeutic agents are suboptimal. Numerous studies show that alterations in expression of genes related to mitotic spindle and mitotic checkpoint are involved in chromosomal instability and tumor progression in various malignancies. This study aimed to evaluate these genes in cholangiocarcinoma patients. Material and methods: Different public datasets were analyzed to examine the expression of 76 selected mitotic spindle checkpoint genes including Aurora Kinase A (AURKA) in cholangiocarcinoma. Afterwards, cell number counting, CCK-8 assay, and Caspase 3/7 assay were used to explore the antitumor effect of AURKA inhibitor Alisertib in vitro. In addition, xenograft model was used to evaluate the antitumor effect of Alisertib in vivo. Furthermore, siRNA mediated silencing of AURKA was used to verify the function of AURKA in cholangiocarcinoma. Results: Components of the mitotic spindle checkpoint, including AURKA, were broadly dysregulated in human cholangiocarcinoma. High AURKA mRNA expression was associated with poor survival in cholangiocarcinoma patients within different datasets. AURKA specific inhibitor Alisertib, inhibited cell growth, induced cell cycle arrest in G2/M phase, and promoted apoptosis in cholangiocarcinoma cell lines. Additionally, Alisertib also inhibited tumor growth in a cholangiocarcinoma xenograft mouse model. Furthermore, AURKA knockdown by siRNA recapitulated the antitumor effect of Alisertib. AURKA expression was also highly correlated with its interaction proteins Polo-like kinase 1(PLK1) and Targeting protein for xenopus kinesin-like protein2 (TPX2) in different cholangiocarcinoma datasets. Conclusions: Highly expressed AURKA confers poor outcomes in cholangiocarcinoma and may represent a rational therapeutic target.


Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways.
Liver fibrosis is the reversible deposition of extracellular matrix (ECM) and scar formation after liver damage by various stimuli. The interaction between NOX4/ROS and RhoA/ROCK1 in liver fibrosis is not yet clear. Ursolic acid (UA) is a traditional Chinese medicine with anti-fibrotic effects, but the molecular mechanism underlying these effects is still unclear. We investigated the interaction between NOX4/ROS and RhoA/ROCK1 during liver fibrosis and whether these molecules are targets for the anti-fibrotic effects of UA. First, we confirmed that UA reversed CCl4-induced liver fibrosis. In the NOX4 intervention and RhoA intervention groups, related experimental analyses confirmed the decrease in CCl4-induced liver fibrosis. Next, we determined that the expression of NOX4 and RhoA/ROCK1 was decreased in UA-treated liver fibrotic mice. Furthermore, RhoA/ROCK1 expression was decreased in the NOX4 intervention group, but there was no significant change in the expression of NOX4 in the RhoA intervention group. Finally, we found that liver fibrotic mice showed a decline in their microbiota diversity and abundance, a change in their microbiota composition, and a reduction in the number of potential beneficial bacteria. However, in UA-treated liver fibrotic mice, the microbiota dysbiosis was ameliorated. In conclusion, the NOX4/ROS and RhoA/ROCK1 signalling pathways are closely linked to the development of liver fibrosis. UA can reverse liver fibrosis by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, which may interact with each other.


Association between first-line antidepressant use and risk of dementia in older adults: a retrospective cohort study.
Prior studies suggested that antidepressant use is associated with an increased risk of dementia compared to no use, which is subject to confounding by indication. We aimed to compare the dementia risk among older adults with depression receiving first-line antidepressants (i.e., SSRI/SNRI) versus psychotherapy, which is also considered the first-line therapy for depression. This retrospective cohort study was conducted using the US Medical Expenditure Panel Survey from 2010 to 2019. We included adults aged ≥ 50 years diagnosed with depression who initiated SSRI/SNRI or psychotherapy. We excluded patients with a dementia diagnosis before the first record of SSRI/SNRI use or psychotherapy. The exposure was the patient's receipt of SSRI/SNRI (identified from self-report questionnaires) or psychotherapy (identified from the Outpatient Visits or Office-Based Medical Provider Visits files). The outcome was a new diagnosis of dementia within 2 years (i.e., survey panel period) identified using ICD-9/ICD-10 codes from the Medical Conditions file. Using a multivariable logistic regression model, we reported adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We also conducted subgroup analyses by patient sex, age group, race/ethnicity, severity of depression, combined use of other non-SSRI/SNRI antidepressants, and presence of underlying cognitive impairment. Among 2,710 eligible patients (mean age = 61 ± 8, female = 69%, White = 84%), 89% used SSRIs/SNRIs, and 11% received psychotherapy. The SSRI/SNRI users had a higher crude incidence of dementia than the psychotherapy group (16.4% vs. 11.8%), with an aOR of 1.36 (95% CI = 1.06-1.74). Subgroup analyses yielded similar findings as the main analyses, except no significant association for patients who were aged < 65 years (1.23, 95% CI = 0.93-1.62), male (1.34, 95% CI = 0.95-1.90), Black (0.76, 95% CI = 0.48-1.19), had a higher PHQ-2 (1.39, 95% CI = 0.90-2.15), and had underlying cognitive impairment (1.06, 95% CI = 0.80-1.42). Our findings suggested that older adults with depression receiving SSRIs/SNRIs were associated with an increased dementia risk compared to those receiving psychotherapy.


Prevalence of mutualism in a simple model of microbial coevolution.
Evolutionary transitions among ecological interactions are widely known, although their detailed dynamics remain absent for most population models. Adaptive dynamics has been used to illustrate how the parameters of population models might shift through evolution, but within an ecological regime. Here we use adaptive dynamics combined with a generalized logistic model of population dynamics to show that transitions of ecological interactions might appear as a consequence of evolution. To this purpose, we introduce a two-microbial toy model in which population parameters are determined by a bookkeeping of resources taken from (and excreted to) the environment, as well as from the byproducts of the other species. Despite its simplicity, this model exhibits all kinds of potential ecological transitions, some of which resemble those found in nature. Overall, the model shows a clear trend toward the emergence of mutualism.


Using nonlinear models in fMRI data analysis: model selection and activation detection.
There is an increasing interest in using physiologically plausible models in fMRI analysis. These models do raise new mathematical problems in terms of parameter estimation and interpretation of the measured data. In this paper, we show how to use physiological models to map and analyze brain activity from fMRI data. We describe a maximum likelihood parameter estimation algorithm and a statistical test that allow the following two actions: selecting the most statistically significant hemodynamic model for the measured data and deriving activation maps based on such model. Furthermore, as parameter estimation may leave much incertitude on the exact values of parameters, model identifiability characterization is a particular focus of our work. We applied these methods to different variations of the Balloon Model (Buxton, R.B., Wang, E.C., and Frank, L.R. 1998. Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn. Reson. Med. 39: 855-864; Buxton, R.B., Uludağ, K., Dubowitz, D.J., and Liu, T.T. 2004. Modelling the hemodynamic response to brain activation. NeuroImage 23: 220-233; Friston, K. J., Mechelli, A., Turner, R., and Price, C. J. 2000. Nonlinear responses in fMRI: the balloon model, volterra kernels, and other hemodynamics. NeuroImage 12: 466-477) in a visual perception checkerboard experiment. Our model selection proved that hemodynamic models better explain the BOLD response than linear convolution, in particular because they are able to capture some features like poststimulus undershoot or nonlinear effects. On the other hand, nonlinear and linear models are comparable when signals get noisier, which explains that activation maps obtained in both frameworks are comparable. The tools we have developed prove that statistical inference methods used in the framework of the General Linear Model might be generalized to nonlinear models.


Spike resonance properties in hippocampal O-LM cells are dependent on refractory dynamics.
During a wide variety of behaviors, hippocampal field potentials show significant power in the theta (4-12 Hz) frequency range and individual neurons commonly phase-lock with the 4-12 Hz field potential. The underlying cellular and network mechanisms that generate the theta rhythm, however, are poorly understood. Oriens-lacunosum moleculare (O-LM) interneurons have been implicated as crucial contributors to generating theta in local hippocampal circuits because of their unique axonal projections, slow synaptic kinetics and the fact that spikes are phase-locked to theta field potentials in vivo. We performed experiments in brain slice preparations from Long-Evans rats to investigate the ability of O-LM cells to generate phase-locked spike output in response to artificial synaptic inputs. We find that O-LM cells do not respond with any preference in spike output at theta frequencies when injected with broadband artificial synaptic inputs. However, when presented with frequency-modulated inputs, O-LM spike output shows the ability to phase-lock well to theta-modulated inputs, despite their strong low-pass profiles of subthreshold membrane impedance. This result was dependent on spike refractory dynamics and could be controlled by real-time manipulation of the postspike afterhyperpolarization. Finally, we show that the ability of O-LM cells to phase-lock well to theta-rich inputs is independent of the h-current, a membrane mechanism often implicated in the generation of theta frequency activity.


Murine pneumonia virus: seroepidemiological evidence of widespread human infection.
More than 75% of a random sample of adult human sera exhibited moderate to high murine pneumonia virus (PVM)-neutralizing activity. There was no correlation between PVM-neutralizing activity and respiratory syncytial virus or parainfluenza type 3 virus-neutralizing activities of the same sera. In children the proportion of sera with moderate to high titres increased with age, indicating early exposure to infection. Seroconversion (i.e. greater than fourfold increase in titre) was observed in four of 108 paired samples of previously undiagnosed respiratory infections. These observations suggest that the human population is frequently exposed to infection with PVM or an antigenically related virus. The sera of patients suffering from Paget's disease of bone tended to exhibit higher than normal PVM-neutralizing titres in comparison with the sera of patients with other bone diseases. Thus, PVM (or an antigenically related virus) resembles some other parainfluenza viruses in being circumstantially associated with Paget's disease of bone.


Peripheral and Central Contributions to Cortical Responses in Cochlear Implant Users.
The primary goal of this study was to describe relationships between peripheral and central electrophysiologic measures of auditory processing within individual cochlear implant (CI) users. The distinctiveness of neural excitation patterns resulting from the stimulation of different electrodes, referred to as 'spatial selectivity,' was evaluated. The hypothesis was that if central representations of spatial interactions differed across participants semi-independently of peripheral input, then the within-subject relationships between peripheral and central electrophysiologic measures of spatial selectivity would reflect those differences. Cross-subject differences attributable to processing central to the auditory nerve may help explain why peripheral electrophysiologic measures of spatial selectivity have not been found to correlate with speech perception. Eleven adults participated in this and a companion study. All were peri- or post-lingually deafened with more than 1 year of CI experience. Peripheral spatial selectivity was evaluated at 13 cochlear locations using 13 electrodes as probes to elicit electrically evoked compound action potentials (ECAPs). Masker electrodes were varied across the array for each probe electrode to derive channel-interaction functions. The same 13 electrodes were used to evaluate spatial selectivity represented at a cortical level. Electrode pairs were stimulated sequentially to elicit the auditory change complex (ACC), an obligatory cortical potential suggestive of discrimination. For each participant, the relationship between ECAP channel-interaction functions (quantified as channel-separation indices) and ACC N1-P2 amplitudes was modeled using the saturating exponential function y = a * (1-e). Both a and b coefficients were varied using a least-squares approach to optimize the fits. Electrophysiologic measures of spatial selectivity assessed at peripheral (ECAP) and central (ACC) levels varied across participants. The results indicate that differences in ACC amplitudes observed across participants for the same stimulus conditions were not solely the result of differences in peripheral excitation patterns. This finding supports the view that processing at multiple points along the auditory neural pathway from the periphery to the cortex may vary across individuals with different etiologies and auditory experiences. The distinctiveness of neural excitation resulting from electrical stimulation varies across CI recipients, and this variability was observed in both peripheral and cortical electrophysiologic measures. The ACC amplitude differences observed across participants were partially independent from differences in peripheral neural spatial selectivity. These findings are clinically relevant because they imply that there may be limits (1) to the predictive ability of peripheral measures and (2) in the extent to which improving the selectivity of electrical stimulation via programming options (e.g., current focusing/steering) will result in more specific central neural excitation patterns or will improve speech perception.


Overview of the interaction between chemotherapeutic agents and DNA.
Some chemotherapeutic agents, such as the antibiotics mitomycin and bleomycin, modify the structure of DNA by chemical reactions involving the formation or breakage of covalent bonds. Others interact with the macromolecule reversibly to form a transient complex which may be intercalative or nonintercalative in character. Techniques are available to probe the extent of perturbation of DNA structure produced by these drugs, and they reveal subtle differences between the effects of various ligands. In recent years bifunctional intercalating agents such as the quinoxaline antibiotics have been discovered; their binding to DNA is often tighter than seen with simple (monofunctional) intercalators and there is evidence for nucleotide sequence-selectivity. Footprinting experiments have been employed to identify preferred ligand-binding sites in natural DNA fragments (CpG sequences in the case of echinomycin) and have revealed that local perturbations of the helical structure can be propagated into DNA regions flanking the antibiotic-binding sites. Crystallographic evidence suggests that echinomycin and its congeners recognise GC base-pairs by hydrogen bonding between the carbonyl groups of alanine residues in the antibiotic and the 2-amino groups of guanine nucleotides in the minor groove of the DNA helix. Kinetic studies support the hypothesis that sequence-selective antibiotic molecules "shuffle" between different binding sites in the process of locating their optimal (preferred) sites.


The relevance of torsion to the mechanical derangement of the lumbar spine.
Cadaveric lumbar intervertebral joints were loaded simultaneously in torsion and compression, and load-deformation curves were obtained. These were repeated after each of the following structures were cut through in turn: the supra/interspinous ligaments, the apophyseal joint in compression, and the apophyseal joint in tension. From the differences in the curves, it was possible to deduce the role of each structure and of the intervertebral disc in resisting and limiting torsion. The results show that torsion of the lumbar spine is resisted primarily by the apophyseal joint that is in compression, although the intervertebral disc does play a major role. The capsular ligaments of the tension facet and the supra/interspinous ligaments are unimportant. The compression facet is the first of rotation in joints with nondegenerated intervertebral discs. Much greater angles are required to damage the intervertebral disc, so torsion seems unimportant in the etiology of disc degeneration and prolapse.


A DELLA in disguise: SPATULA restrains the growth of the developing Arabidopsis seedling.
The period following seedling emergence is a particularly vulnerable stage in the plant life cycle. In Arabidopsis thaliana, the phytochrome-interacting factor (PIF) subgroup of basic-helix-loop-helix transcription factors has a pivotal role in regulating growth during this early phase, integrating environmental and hormonal signals. We previously showed that SPATULA (SPT), a PIF homolog, regulates seed dormancy. In this article, we establish that unlike PIFs, which mainly promote hypocotyl elongation, SPT is a potent regulator of cotyledon expansion. Here, SPT acts in an analogous manner to the gibberellin-dependent DELLAs, REPRESSOR OF GA1-3 and GIBBERELLIC ACID INSENSITIVE, which restrain cotyledon expansion alongside SPT. However, although DELLAs are not required for SPT action, we demonstrate that SPT is subject to negative regulation by DELLAs. Cross-regulation of SPT by DELLAs ensures that SPT protein levels are limited when DELLAs are abundant but rise following DELLA depletion. This regulation provides a means to prevent excessive growth suppression that would result from the dual activity of SPT and DELLAs, yet maintain growth restraint under DELLA-depleted conditions. We present evidence that SPT and DELLAs regulate common gene targets and illustrate that the balance of SPT and DELLA action depends on light quality signals in the natural environment.


Different Evaluations Exist between Men with Erectile Dysfunction and Their Female Partners When Using Erectile Hardness Model: An Interesting, Observational, and Cross-Sectional Field Survey.
It is an interesting clinical phenomenon that when evaluating the erectile function of men with erectile dysfunction by couples, respectively, using the erectile hardness model, there will exist the evaluation difference between men and their female partners. This phenomenon reflects the problem of communication and cognition between husband and wife in ED patients. To explore the influencing factors associated with this clinical phenomenon, we conducted this interesting, observational, and cross-sectional field survey. We enrolled 385 couples from the andrology clinics of the first affiliated hospital of Anhui Medical University from December 2017 to December 2018. The demographic data of couples, the medical history, sexuality and the characteristics of ED, and anxiety and depression of the couples were collected through face-to-face interview and questionnaires. The couples were divided into two groups containing 238 couples and 147 couples, respectively. We divided couples into difference group including couples which have inconsistent evaluation results from touching the erectile hardness model and no difference group including couples which have consistent evaluation results from touching the erectile hardness model, respectively. The difference group where the couples share different evaluation results reported higher erectile hardness grade from men than from their female partners (male > female: 73.11% vs. male < female: 26.89%). The scores of IIEF-5 in difference group and no difference group are 13.43 ± 5.75 and 16.82 ± 8.23, respectively. The average grades evaluated from men and women in difference group are 2.79 ± 0.85 and 2.45 ± 0.63, respectively. The average grades evaluated from couples in no difference group are 3.02 ± 0.45. Through statistical comparison and logistic regression analysis, duration of ED > 16 months, seeking treatment from female, negative communication state, and depression from men are the relevant factors accounting for the different evaluation results. This phenomenon reflects the problem of communication and cognition between husband and wife in ED patients. As for couples with these risk factors, we cannot focus only on the oral medication which only restores the penile erectile function. More importantly, we must combine the sexual counseling and sexual knowledge education with the drug treatment. When the two treatments are tightly integrated, not only the penile erection but also the gap of couples can be restored which is the best result of the ED treatment.


The components of Drosophila histone chaperone dCAF-1 are required for the cell death phenotype associated with rbf1 mutation.
A Polycomb group protein, Posterior sex combs (Psc), was identified in a genetic screen designed to find factors that can specifically induce morphological defects in rbf1 mutant eyes. We discovered that rbf1 mutations enhance developmental phenotypes caused by Psc overexpression such as ectopic cell death and disorganized ommatidia. Our genetic analysis revealed that Psc-induced developmental defects are strongly influenced by CAF1p55, which is a shared component of several chromatin-associated complexes including a histone chaperone complex, chromatin assembly factor-1 (dCAF-1). Interestingly, the expression levels of dCAF-1 components, CAF1p105 and CAF1p180, are increased in rbf1 mutants, whereas the expression level of CAF1p55 itself remains relatively unchanged. We demonstrated that the increased levels of CAF1p105 and CAF1p180 are required for the hypersensitivity of rbf1 mutant cells to Psc-induced cell death and for the developmentally regulated cell death normally observed in rbf1 mutant eyes. We propose that Caf1p105 and Caf1p180 are important determinants of cell death sensitivity in rbf1 mutant cells and contribute to the genetic interaction between Psc and rbf1.


Nucleotide variation of seven genes in Drosophila kikkawai.
We examined levels and patterns of nucleotide variation in 21 strains of Drosophila kikkawai from Miyako island, Japan for the partial regions of the following seven nuclear genes: Adh, Ddc, esc, ksr, Pgi, su(f), and Tpi. The nucleotide variation at total sites (pi(t)) ranged from 0.0013 in the ksr, to 0.0173 in the Adh. The nucleotide divergence at total sites (K(t)) between D. kikkawai and D. lini ranged from 0.0286 in the Tpi to 0.0687 in the su(f). The levels of nucleotide polymorphism and divergence were heterogeneous among the investigated gene regions. The HKA test, which tests imbalance between the intra and interspecific nucleotide variation, showed that the intraspecific nucleotide variation in the Pgi region was much lower than the interspecific variation, while intraspecific variation in the Tpi region was only slightly lower than interspecific variation. The MK test showed an excess of low frequency replacement polymorphic changes in the Adh region, suggesting that most replacement mutations are deleterious. Fay and Wu's test detected an excess of newly arisen variants in the Ddc region. In total, four of the seven gene regions showed significant deviation from the neutrality.


Drug utilization: a regional approach.
A two-year Hospital Incentive Fund grant facilitated activities to improve drug utilization through a regional drug utilization evaluation involving 21 Ontario hospitals. While reporting on the development of a regional drug evaluation process, the authors identify areas where drug use, patient outcome and cost efficiency could be improved, and discuss the issues to be considered when developing such a process.


DSets-DBSCAN: A Parameter-Free Clustering Algorithm.
Clustering image pixels is an important image segmentation technique. While a large amount of clustering algorithms have been published and some of them generate impressive clustering results, their performance often depends heavily on user-specified parameters. This may be a problem in the practical tasks of data clustering and image segmentation. In order to remove the dependence of clustering results on user-specified parameters, we investigate the characteristics of existing clustering algorithms and present a parameter-free algorithm based on the DSets (dominant sets) and DBSCAN (Density-Based Spatial Clustering of Applications with Noise) algorithms. First, we apply histogram equalization to the pairwise similarity matrix of input data and make DSets clustering results independent of user-specified parameters. Then, we extend the clusters from DSets with DBSCAN, where the input parameters are determined based on the clusters from DSets automatically. By merging the merits of DSets and DBSCAN, our algorithm is able to generate the clusters of arbitrary shapes without any parameter input. In both the data clustering and image segmentation experiments, our parameter-free algorithm performs better than or comparably with other algorithms with careful parameter tuning.


Untargeted metabolomic profiling of urine from healthy dogs and dogs with chronic hepatic disease.
Chronic hepatic disease can present a diagnostic challenge with different etiologies being associated with similar clinical and laboratory findings. The histopathological assessment of a liver biopsy specimen is usually required in order to make a definitive diagnosis and the availability of non-invasive prognostic biomarkers is limited. The emerging science of metabolomics is used to detect changes in endogenous low molecular weight metabolites in biological samples and offers the possibility of identifying noninvasive markers of disease. The objective of this study was to investigate differences in the urine metabolome between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Stored urine samples from 10 healthy dogs, 10 dogs with chronic hepatitis, 6 dogs with hepatocellular carcinoma, and 5 dogs with a congenital portosystemic shunt were analyzed. The urine metabolome was analyzed by gas chromatography-quadrupole time of flight mass spectrometry and 220 known metabolites were identified. Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering between groups. Random forest analysis showed differences in the abundance of various metabolites including putrescine, gluconic acid, sorbitol, and valine. Based on univariate statistics, 37 metabolites were significantly different between groups. In, conclusion, the urine metabolome varies between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Further targeted assessment of these metabolites is needed to assess their diagnostic utility.


Surface enhanced Raman spectroscopy for microfluidic pillar arrayed separation chips.
Numerous studies have addressed the challenges of implementing miniaturized microfluidic platforms for chemical and biological separation applications. However, the integration of real time detection schemes capable of providing valuable sample information under continuous, ultra low volume flow regimes has not fully been addressed. In this report we present a chip based chromatography system comprising of a pillar array separation column followed by a reagent channel for passive mixing of a silver colloidal solution into the eluent stream to enable surface enhanced Raman spectroscopy (SERS) detection. Our design is the first integrated chip based microfluidic device to combine pressure driven separation capability with real time SERS detection. With this approach we demonstrate the ability to collect distinctive SERS spectra with or without complete resolution of chromatographic bands. Computational fluidic dynamic (CFD) simulations are used to model the diffusive mixing behaviour and velocity profiles of the two confluent streams in the microfluidic channels. We evaluate the SERS spectral band intensity and chromatographic efficiency of model analytes with respect to kinetic factors as well as signal acquisition rates. Additionally, we discuss the use of a pluronic modified silver colloidal solution as a means of eliminating contamination generally caused by nanoparticle adhesion to channel surfaces.


Visual presentation of novel objects and new spatial arrangements of objects differentially activates the medial temporal lobe subareas in humans.
A number of studies in rodents and monkeys report a distinction between the contributions of the hippocampus and perirhinal cortex to memory, such that the hippocampus is crucial for spatial memory whereas the perirhinal cortex has a pivotal role in perception and memory for visual objects. To determine if there is such a distinction in humans, we conducted a functional magnetic resonance imaging study to compare the medial temporal lobe responses to changes in object identity and spatial configurations of objects. We found evidence for the predicted distinction between hippocampal and perirhinal cortical activations, although part of the hippocampus was also activated by identification of novel objects. Additionally, an anterior-posterior activation gradient emerged inside the hippocampus and parahippocampal cortex. The anterior hippocampus, perirhinal cortex and anterior parahippocampal cortex are involved in perception of contextually novel objects, whereas the posterior hippocampus and posterior parahippocampal cortex are involved in processing of novel arrangements of familiar objects. These results demonstrate that there is a functional dissociation between processing of novel object identities and new spatial locations of objects among the subregions of medial temporal lobe structures in humans also.


Altered Somatosensory Cortical Activity Is Associated with Cortical Thickness in Adults with Cerebral Palsy: Multimodal Evidence from MEG/sMRI.
Somatosensory cortical activity is altered in individuals with cerebral palsy (CP). However, previous studies have focused on the lower extremities in children with CP and have given less attention to structural changes that may contribute to these alterations. We used a multimodal neuroimaging approach to investigate the relationship between somatosensory cortical activity and cortical thickness in 17 adults with CP (age = 32.8 ± 9.3 years) and 18 healthy adult controls (age = 30.7 ± 9.8 years). Participants performed a median nerve paired-pulse stimulation paradigm while undergoing magnetoencephalography (MEG) to investigate somatosensory cortical activity and sensory gating. Participants also underwent magnetic resonance imaging to evaluate cortical thickness within the area of the somatosensory cortex that generated the MEG response. We found that the somatosensory responses were attenuated in the adults with CP (P = 0.004). The adults with CP also hypergated the second stimulation (P = 0.030) and had decreased cortical thickness in the somatosensory cortex (P = 0.015). Finally, the strength of the somatosensory response was significantly correlated with the cortical thickness (P = 0.023). These findings demonstrate that the aberrant somatosensory cortical activity in adults with CP extends to the upper extremities and appears to be related to cortical thickness.


Increased release of glucuronoxylomannan antigen and induced phenotypic changes in Trichosporon asahii by repeated passage in mice.
Clinically important fungi such as Candida albicans and Cryptococcus neoformans are known to undergo phenotypic changes after repeated subculture or passages in vivo. However, there are no reports describing this phenomenon in Trichosporon species. This study investigated whether in-vivo passages of environmental isolates of Trichosporon asahii in mice changes their phenotype; three environmental isolates and 14 clinical isolates (from deep-seated infections) were used. The shape of the colony and cell type were observed, and the titre of glucuronoxylomannan (GXM) antigen and concentration of (1-->3)-beta-D-glucan were measured for each isolate. Changes in these features were also examined after three passages of the environmental isolates in mice. The shape of colonies and cell types were clearly different in environmental and clinical isolates. Furthermore, the clinical isolates released significantly higher levels of GXM antigen than environmental isolates (titre: log2 9.4 SD 0.7 versus log2 5.4 SD 1.4). The phenotype of passaged isolates was significantly different from the original environmental isolates with respect to the morphology of colonies and cell type and GXM release (titre: log2 10.0 SD 0.7 versus log2 5.4 SD 1.4). These results suggest that the phenotypic changes in T. asahii occur as a result of in-vivo passages. This process may allow a proportion of the fungal population to escape eradication by the host immune system, as GXM antigen is considered to protect the fungi against phagocytosis by polymorphonuclear leucocytes and monocytes in vivo.


Transcriptome sequencing and identification of cold tolerance genes in hardy Corylus species (C. heterophylla Fisch) floral buds.
The genus Corylus is an important woody species in Northeast China. Its products, hazelnuts, constitute one of the most important raw materials for the pastry and chocolate industry. However, limited genetic research has focused on Corylus because of the lack of genomic resources. The advent of high-throughput sequencing technologies provides a turning point for Corylus research. In the present study, we performed de novo transcriptome sequencing for the first time to produce a comprehensive database for the Corylus heterophylla Fisch floral buds. The C. heterophylla Fisch floral buds transcriptome was sequenced using the Illumina paired-end sequencing technology. We produced 28,930,890 raw reads and assembled them into 82,684 contigs. A total of 40,941 unigenes were identified, among which 30,549 were annotated in the NCBI Non-redundant (Nr) protein database and 18,581 were annotated in the Swiss-Prot database. Of these annotated unigenes, 25,311 and 10,514 unigenes were assigned to gene ontology (GO) categories and clusters of orthologous groups (COG), respectively. We could map 17,207 unigenes onto 128 pathways using the Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) database. Additionally, based on the transcriptome, we constructed a candidate cold tolerance gene set of C. heterophylla Fisch floral buds. The expression patterns of selected genes during four stages of cold acclimation suggested that these genes might be involved in different cold responsive stages in C. heterophylla Fisch floral buds. The transcriptome of C. heterophylla Fisch floral buds was deep sequenced, de novo assembled, and annotated, providing abundant data to better understand the C. heterophylla Fisch floral buds transcriptome. Candidate genes potentially involved in cold tolerance were identified, providing a material basis for future molecular mechanism analysis of C. heterophylla Fisch floral buds tolerant to cold stress.


[Informational characteristics of the impulse activity of cat sensomotor cortex neurons during elaboration of a defensive conditioned reflex].
Manifestations of the dynamics of defensive conditioning were studied in the cat sensorimotor cortical units. It has been shown that the process of learning is linked to the dynamics of the amount of total and useful information present in the evoked spike responses to a conditioned stimulus. As the pairings continue, the amount of useful information increases in reactions to conditioned or unconditioned stimuli and in the period preceding the conditioned stimulation.