MICROSCOPE Mission: Final Results of the Test of the Equivalence Principle.
The MICROSCOPE mission was designed to test the weak equivalence principle (WEP), stating the equality between the inertial and the gravitational masses, with a precision of 10^{-15} in terms of the Eötvös ratio η. Its experimental test consisted of comparing the accelerations undergone by two collocated test masses of different compositions as they orbited the Earth, by measuring the electrostatic forces required to keep them in equilibrium. This was done with ultrasensitive differential electrostatic accelerometers onboard a drag-free satellite. The mission lasted two and a half years, cumulating five months worth of science free-fall data, two-thirds with a pair of test masses of different compositions-titanium and platinum alloys-and the last third with a reference pair of test masses of the same composition-platinum. We summarize the data analysis, with an emphasis on the characterization of the systematic uncertainties due to thermal instabilities and on the correction of short-lived events which could mimic a WEP violation signal. We found no violation of the WEP, with the Eötvös parameter of the titanium and platinum pair constrained to η(Ti,Pt)=[-1.5±2.3(stat)±1.5(syst)]×10^{-15} at 1σ in statistical errors.


Computational Methods for Continuous Eye-Tracking Perimetry Based on Spatio-Temporal Integration and a Deep Recurrent Neural Network.
The measurement of retinal sensitivity at different visual field locations-perimetry-is a fundamental procedure in ophthalmology. The most common technique for this scope, the Standard Automated Perimetry, suffers from several issues that make it less suitable to test specific clinical populations: it can be tedious, it requires motor manual feedback, and requires from the patient high levels of compliance. Previous studies attempted to create user-friendlier alternatives to Standard Automated Perimetry by employing eye movements reaction times as a substitute for manual responses while keeping the fixed-grid stimuli presentation typical of Standard Automated Perimetry. This approach, however, does not take advantage of the high spatial and temporal resolution enabled by the use of eye-tracking. In this study, we introduce a novel eye-tracking method to perform high-resolution perimetry. This method is based on the continuous gaze-tracking of a stimulus moving along a pseudo-random walk interleaved with saccadic jumps. We then propose two computational methods to obtain visual field maps from the continuous gaze-tracking data: the first is based on the spatio-temporal integration of ocular positional deviations using the threshold free cluster enhancement (TFCE) algorithm; the second is based on using simulated visual field defects to train a deep recurrent neural network (RNN). These two methods have complementary qualities: the TFCE is neurophysiologically plausible and its output significantly correlates with Standard Automated Perimetry performed with the Humphrey Field Analyzer, while the RNN accuracy significantly outperformed the TFCE in reconstructing the simulated scotomas but did not translate as well to the clinical data from glaucoma patients. While both of these methods require further optimization, they show the potential for a more patient-friendly alternative to Standard Automated Perimetry.


Lineage-specific expansion of IFIT gene family: an insight into coevolution with IFN gene family.
In mammals, IFIT (Interferon [IFN]-induced proteins with Tetratricopeptide Repeat [TPR] motifs) family genes are involved in many cellular and viral processes, which are tightly related to mammalian IFN response. However, little is known about non-mammalian IFIT genes. In the present study, IFIT genes are identified in the genome databases from the jawed vertebrates including the cartilaginous elephant shark but not from non-vertebrates such as lancelet, sea squirt and acorn worm, suggesting that IFIT gene family originates from a vertebrate ancestor about 450 million years ago. IFIT family genes show conserved gene structure and gene arrangements. Phylogenetic analyses reveal that this gene family has expanded through lineage-specific and species-specific gene duplication. Interestingly, IFN gene family seem to share a common ancestor and a similar evolutionary mechanism; the function link of IFIT genes to IFN response is present early since the origin of both gene families, as evidenced by the finding that zebrafish IFIT genes are upregulated by fish IFNs, poly(I:C) and two transcription factors IRF3/IRF7, likely via the IFN-stimulated response elements (ISRE) within the promoters of vertebrate IFIT family genes. These coevolution features creates functional association of both family genes to fulfill a common biological process, which is likely selected by viral infection during evolution of vertebrates. Our results are helpful for understanding of evolution of vertebrate IFN system.


Measuring sperm movement within the female reproductive tract using Fourier analysis.
The adaptive significance of variation in sperm phenotype is still largely unknown, in part due to the difficulties of observing and measuring sperm movement in its natural, selective environment (i.e., within the female reproductive tract). Computer-assisted sperm analysis systems allow objective and accurate measurement of sperm velocity, but rely on being able to track individual sperm, and are therefore unable to measure sperm movement in species where sperm move in trains or bundles. Here we describe a newly developed computational method for measuring sperm movement using Fourier analysis to estimate sperm tail beat frequency. High-speed time-lapse videos of sperm movement within the female tract of the neriid fly Telostylinus angusticollis were recorded, and a map of beat frequencies generated by converting the periodic signal of an intensity versus time trace at each pixel to the frequency domain using the Fourier transform. We were able to detect small decreases in sperm tail beat frequency over time, indicating the method is sensitive enough to identify consistent differences in sperm movement. Fourier analysis can be applied to a wide range of species and contexts, and should therefore facilitate novel exploration of the causes and consequences of variation in sperm movement.


Altered function but not structure of the amygdala in nicotine-dependent individuals.
Tobacco use disorder is frequently comorbid with emotional disorders, each exerting reciprocal influence on the other. As an important hub for emotional processing, amygdala may also play a critical role in tobacco addiction. Therefore, we aimed to investigate the volume and spontaneous activity of the amygdala in nicotine-dependent individuals and their relationships with cigarette use. A total of 84 smokers (aged 22-54 years) and 41 nonsmokers (aged 26-56 years) were enrolled in the present study. 3D-T1 weighted images and resting-state fMRI images were acquired from all participants. We used ROI-wise volume, fractional amplitude of low frequency fluctuation (fALFF) and resting-state functional connectivity (FC) to assess structural and functional changes of the amygdala in the smokers. There was no significant difference between smokers and nonsmokers on amygdala volume (p > 0.05). When compared to nonsmokers, increased fALFF in the right amygdala was observed in smokers (p = 0.024). In addition, increased FC between the left amygdala and the right precuneus and decreased FC between the right amygdala and the right orbitofrontal cortex (OFC) was found in smokers. In smokers, these amygdala measures did not correlate with any measures of cigarette use. The results revealed that the amygdala function but not volume was affected in nicotine addiction. When considering the fALFF and FC results, we propose that the OFC top-down control may regulate the amygdala activity in nicotine addicts. The pattern of amygdala-based FC in smokers revealed in our study may provide new information about the brain circuitry of tobacco dependence.


Hormone-replacement therapy increases serum paraoxonase arylesterase activity in diabetic postmenopausal women.
The paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) in the blood and is low in patients with type 2 diabetes. Hormone-replacement therapy (HRT) can increase HDL cholesterol levels, but its effect on serum PON1 arylesterase activity is uncertain. The aim of the present study was to determine the effect of 6 months' HRT with conjugated equine estrogen and medroxyprogesterone acetate on serum PON1 arylesterase activity in postmenopausal women with type 2 diabetes. Serum PON1 activity was measured immediately before and at the end of the second arm of a randomized, placebo-controlled, crossover with washout study originally designed to test the effect of HRT on plasma lipids in diabetic postmenopausal women. Baseline serum PON1 arylesterase activity was significantly (P <.001) lower in the postmenopausal diabetic women (149 +/- 38 micromol/mL/min; n = 47) than values in healthy postmenopausal women (173 +/- 32 micromol/mL/min; n = 51). Serum PON1 activity increased (10%) significantly (P =.009) in diabetic women treated with HRT compared with placebo. A significant (P =.02) interaction between baseline PON1 activity and treatment indicated a greater increase in PON1 activity during HRT in women with lower baseline activities. At baseline, serum PON1 arylesterase activity was correlated significantly with plasma HDL cholesterol levels in diabetic women (r = 0.333, P =.01, n = 47), and the increase in serum PON1 activity was correlated significantly with the change in plasma HDL cholesterol during HRT (r = 0.659, P =.0001, n = 28). These data suggest that serum PON1 activity is abnormally low in postmenopausal women with type 2 diabetes and increases during HRT, particularly in women with lower baseline levels and in those who show a concomitant increase in HDL cholesterol.


Self-reported Black race predicts significant prostate cancer independent of clinical setting and clinical and socioeconomic risk factors.
Studies have linked Black race to prostate cancer (CaP) risk but most fail to account for established risk factors such as 5-ARI use, prostate volume, socioeconomic status, and hospital setting. We assess whether Black race remains associated with CaP and Gleason ≥3 + 4 CaP, after adjusting for clinical setting and socioeconomic and clinical factors at prostate biopsy, with a focus on men aged 40-54 years, who may be excluded from current screening guidelines. We recruited 564 men age 40-79 undergoing initial prostate biopsy for abnormal PSA or digital rectal examination (DRE) from three publicly funded and two private hospitals from 2009-2014. Univariate and multivariate analyses examined the associations between hospital type, race, West African Ancestry (WAA), clinical, and sociodemographic risk factors with CaP diagnosis and Gleason ≥3 + 4 CaP. Given changes in CaP screening recommendations, we also assess the multivariate analyses for men aged 40-54. Black and White men had similar age, BMI, and prostate volume. Black men had higher PSA (8.10 ng/mL vs. 5.63 ng/mL) and PSA density (0.22 ng/mL/cm3 vs. 0.15 ng/mL/cm3, all p < 0.001). Blacks had higher frequency of CaP (63.1% vs. 41.5%, p<0.001) and Gleason ≥3+4 CaP relative to Whites in both public (27.7% vs 11.6%, p<0.001) and private (48.4% vs 21.6%, p = 0.002) settings. In models adjusted for age, first degree family history, prostate volume, 5-ARI use, hospital type, income, marital and educational status, Black race was independently associated with overall CaP diagnosis (OR = 2.13, p = 0.002). There was a significant multiplicative interaction with Black race and abnormal DRE for Gleason ≥3 + 4 CaP (OR = 2.93, p = 0.01). WAA was not predictive of overall or significant CaP among Black men. Black race (OR = 5.66, p = 0.02) and family history (OR = 4.98, p = 0.01) were independently positively associated with overall CaP diagnosis for men aged 40 to 54. Black race is independently associated with CaP and Gleason ≥3+4 CaP after accounting for clinical and socioeconomic risk factors including clinical setting and WAA, and has a higher odds ratio of CaP diagnosis in younger men. Further investigation into optimizing screening in Black men aged 40 to 54 is warranted.


Exploring the symbol processing 'time interval' parametric constraint in a Belousov-Zhabotinsky operated chemical Turing machine.
Chemical reactions are powerful molecular recognition machines. This power has been recently harnessed to build actual instances of each class of experimentally realizable computing automata, using exclusively small-molecule chemistry (i.e. without requiring biomolecules). The most powerful of them, a programmable Turing machine, uses the Belousov-Zhabotinsky oscillatory chemistry, and accepts/rejects input sequences through a dual oscillatory and thermodynamic output signature. The time interval between the aliquots representing each letter of the input is the parameter that determines the time it takes to run the computation. Here, we investigate this critical performance parameter, and its effect not only on the computation speed, but also on the robustness of the accept/reject oscillatory and thermodynamic criteria. Our work demonstrates that the time interval is a non-trivial design parameter, whose choice should be made with great care. The guidelines we provide can be used in the optimization of the speed, robustness, and energy efficiency of chemical automata computations.


Novel biomarkers and prediction model for the pathological complete response to neoadjuvant treatment of triple-negative breast cancer.
Objective: To develop and validate a prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NCT) of triple-negative breast cancer (TNBC). Methods: We systematically searched Gene Expression Omnibus, ArrayExpress, and PubMed for the gene expression profiles of operable TNBC accessible to NCT. Molecular heterogeneity was detected with hierarchical clustering method, and the biological profiles of differentially expressed genes were investigated by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses, and Gene Set Enrichment Analysis (GSEA). Next, machine-learning algorithms including random-forest analysis and least absolute shrinkage and selection operator (LASSO) analysis were synchronously performed and, then, the intersected proportion of significant genes was undergone binary logistic regression to fulfill variables selection. The predictive response score (pRS) system was built as the product of the gene expression and coefficient obtained from the logistic analysis. Last, the cohorts were randomly divided in a 7:3 ratio into training cohort and validation cohort for the introduction of a robust model, and a nomogram was constructed with the independent predictors for pCR rate. Results: A total of 217 individuals from four cohort datasets (GSE32646, GSE25065, GSE25055, GSE21974) with complete clinicopathological information were included. Based on the microarray data, a six-gene panel (ATP4B, FBXO22, FCN2, RRP8, SMERK2, TET3) was identified. A robust nomogram, adopting pRS and clinical tumor size stage, was established and the performance was successively validated by calibration curves and receiver operating characteristic curves with the area under curve 0.704 and 0.756, respectively. Results of GSEA revealed that the biological processes including apoptosis, hypoxia, mTORC1 signaling and myogenesis, and oncogenic features of EGFR and RAF were in proactivity to attribute to an inferior response. Conclusions: This study provided a robust prediction model for pCR rate and revealed potential mechanisms of distinct response to NCT in TNBC, which were promising and warranted to further validate in the perspective.


Does current provision of undergraduate education prepare UK medical students in ENT? A systematic literature review.
To systematically identify and analyse all published literature relating to the provision of undergraduate education for preparedness in ear, nose and throat (ENT) surgery, as perceived by medical students and clinicians in the UK. Systematic literature review. 5 major databases were searched: MEDLINE, EMBASE, ERIC, Cochrane and Web of Science. The literature search was conducted from February to April 2015. Primary research or studies that report on the provision of undergraduate education for preparedness in ENT, from the perspective of medical students and clinicians in the UK. The timescale of searches was limited from 1999 onwards (ie, the past 15 years). The literature search was conducted by 2 independent reviewers. Search terms used involved the combination and variation of 5 key concepts, namely: medical student, clinician, ENT, undergraduate medical education and UK. A data extraction form was designed for and used in this study, based on guidelines provided by the UK National Health Service (NHS) Centre for Reviews and Dissemination. Textual narrative synthesis was used for data analysis. A total of 7 studies were included in the final review. 4 main themes were identified: confidence in managing patients, teaching delivery, student assessment and duration of rotations. A consistent finding in this review was that the majority of final year medical students and junior doctors did not feel adequately prepared to practise ENT. Important factors influencing preparedness in ENT included the duration of clinical rotations, the opportunity for hands-on learning and formal assessment. The findings of this review suggest the need for further development of the ENT undergraduate curricula across the UK. However, there is insufficient evidence from which to draw strong conclusions; this in itself is beneficial as it highlights a gap in the existing literature and supports the need for primary research.


Stopping smoking during pregnancy: are we on the right track?
Recent data suggest that although smoking during pregnancy has declined in North America, this has more to do with falling rates of smoking initiation among women of childbearing age than with increased rates of pregnancy-related smoking cessation. One possible explanation is poor exposure to effective stop-smoking strategies. Better information about women who smoke during pregnancy may help target these interventions more effectively. The study was a cross-sectional, self-administered survey of a consecutive sample of 916 (40.4% of eligible) women who delivered healthy babies in 1997-98 at a tertiary teaching hospital in Hamilton, Ontario. Our main focus was on health behaviours (smoking, drinking, eating, and exercise habits) before and during pregnancy; but we also included questions about the presence of (other) children and (other) smokers in the household, perceived health status, the subject's age and level of education, and whether or not the present pregnancy was planned. Factors associated with pregnancy-related smoking cessation were identified using multiple logistic regression. Respondents were better educated and healthier, but smoked at rates similar to women of childbearing age in Hamilton at the time of the survey. Two thirds of prior smokers or 20% of respondents overall continued to smoke during pregnancy. After adjustment for other factors, three factors were associated with ongoing smoking during pregnancy: having other smokers in the household; having other children in the household; and not having post-secondary education. Many pregnant smokers are not being reached by current stop-smoking strategies. New ways to help these women and their partners are needed.


Chap Stick acne.
We describe two patients with an unusual, limited form of acne manifest as a single row of large, open comedones along the entire cutaneous margin of the upper lip. The acne began after repetitive application to the lips of Chap Stick in one patient and petroleum jelly (Vaseline) in the other. It was treated successfully by eliminating the Chap Stick and petroleum jelly, respectively, as well as by microincision and expression of the comedones. Petrolatum, the major ingredient of Chap Stick, appears to be responsible for this type of acne.


Multisensor Inspection of Laser-Brazed Joints in the Automotive Industry.
Automobile laser brazing remains a complex process whose results are affected by several process variables that may result in nonacceptable welds. A multisensory customized inspection system is proposed, with two distinct non-destructive techniques: the potential drop method and eddy current testing. New probes were designed, simulated, produced, and experimentally validated in automobile's laser-brazed weld beads with artificially introduced defects. The numerical simulations allowed the development of a new four-point probe configuration in a non-conventional orthogonal shape demonstrating a superior performance in both simulation and experimental validation. The dedicated inspection system allowed the detection of porosities, cracks, and lack of bonding defects, demonstrating the redundancy and complementarity these two techniques provide.


Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy.
YiiP is a dimeric Zn(2+)/H(+) antiporter from Escherichia coli belonging to the cation diffusion facilitator family. We used cryoelectron microscopy to determine a 13-Å resolution structure of a YiiP homolog from Shewanella oneidensis within a lipid bilayer in the absence of Zn(2+). Starting from the X-ray structure in the presence of Zn(2+), we used molecular dynamics flexible fitting to build a model consistent with our map. Comparison of the structures suggests a conformational change that involves pivoting of a transmembrane, four-helix bundle (M1, M2, M4, and M5) relative to the M3-M6 helix pair. Although accessibility of transport sites in the X-ray model indicates that it represents an outward-facing state, our model is consistent with an inward-facing state, suggesting that the conformational change is relevant to the alternating access mechanism for transport. Molecular dynamics simulation of YiiP in a lipid environment was used to address the feasibility of this conformational change. Association of the C-terminal domains is the same in both states, and we speculate that this association is responsible for stabilizing the dimer that, in turn, may coordinate the rearrangement of the transmembrane helices.


TLR3 correlated with cervical lymph node metastasis in patients with papillary thyroid cancer.
Papillary thyroid cancer (PTC) is the most rapidly increasing endocrine malignancy worldwide. Although less aggressive than the majority malignancies, PTC exhibits extensive cervical lymph node metastasis in early stage of PTC. However, the underlying molecular mechanism of this early-metastasis remains unknown. Toll like receptors (TLRs) constitute a crucial component of the innate immune response to bacterial and viral pathogens. Emerging evidence suggests that TLRs play important roles in cancer progression, invasion and immune evasion, whereas whether TLRs have any role in PTC remains to be clarified. In this study, we found that TLR3 was present in both PTC specimen and various thyroid cancer cell lines. Further IHC analysis of 63 PTC patients revealed that TLR3 expression was associated with cervical metastasis, but not correlated with patients' TNM staging, extrathyroidal invasion. In addition, TLR3 promoted migration of K1 cells in vitro. Activation of TLR3 increased cancer stem cell marker and migration promoting CD44 expression in vitro, indicating that TLR3 might promote metastasis of PTC via modulating CD44 expression. Taken together, our data revealed that TLR3 is correlated with cervical metastasis of PTC and might be an essential prognostic indicator and target for PTC metastasis.


Oxidative stress augments toll-like receptor 8 mediated neutrophilic responses in healthy subjects.
Excessive oxidative stress has been reported to be generated in inflamed tissues and contribute to the pathogenesis of inflammatory lung diseases, exacerbations of which induced by viral infections are associated with toll-like receptor (TLR) activation. Among these receptors, TLR8 has been reported as a key receptor that recognizes single-strand RNA virus. However, it remains unknown whether TLR8 signaling is potentiated by oxidative stress. The aim of this study is to examine whether oxidative stress modulates TLR8 signaling in vitro. Human peripheral blood neutrophils were obtained from healthy non-smokers and stimulated with TLR 7/8 agonist imidazoquinoline resiquimod (R848) in the presence or absence of hydrogen peroxide (H2O2). Neutrophilic responses including cytokine release, superoxide production and chemotaxis were examined, and the signal transduction was also analyzed. Activation of TLR8, but not TLR7, augmented IL-8 release. The R848-augmented IL-8 release was significantly potentiated by pretreatment with H2O2 (p < 0.01), and N-acetyl-L-cysteine reversed this potentiation. The combination of H2O2 and R848 significantly potentiated NF-kB phosphorylation and IkBalpha degradation. The H2O2-potentiated IL-8 release was suppressed by MG-132, a proteosome inhibitor, and by dexamethasone. The expressions of TLR8, myeloid differentiation primary response gene 88 (MyD88), and tumor necrosis factor receptor-associated factor 6 (TRAF6) were not affected by H2O2. TLR8-mediated neutrophilic responses were markedly potentiated by oxidative stress, and the potentiation was mediated by enhanced NF-kB activation. These results suggest that oxidative stress might potentiate the neutrophilic inflammation during viral infection.


Experimental demonstration of wideband dispersion-compensated slow light by a chirped photonic crystal directional coupler.
We report on the fabrication and evaluation of a directional coupler consisting of two different chirped photonic crystal (PC) waveguides that can generate wideband, low dispersion slow light. The directional coupler was fabricated from a silicon-on-insulator PC slab with airhole diameter chirping. For both waveguides, we observed a group index of 60-80 near the photonic band edge and opposite dispersion characteristics. In the directional coupler, we evaluated a group index of 30-40 in a wavelength bandwidth of 32 nm. The experimental results agree with the theoretical relation between the group index and bandwidth.


Trilucent breast implants--a personal review of the current controversies (May 1999).
Trilucent ("Soya Bean") breast implants were marketed as a safe alternative to silicon implants. Following their use in the UK for the past four years, a reassessment of this has currently been announced (March 1999) and further implantation has been suspended by the Trilucent company in conjunction with the MDA (Medical Devices Agency). This has been the result of some reports of adverse reactions to the triglyceride filling material when the implant ruptures. All patients with trilucent implants were advised to return to their respective surgeons for review and advice. A personal review has been undertaken by the author of this paper. The results obtained are discussed. The majority of patients were concerned, but were happy with cosmetic results, and did not at present wish their implants removed. None appeared as yet to have had serious complications that could be attributed to the implants.


[Estimation of platelet counts and their morphological parameters in patients infected by borrelia burgdorferi].
Platelet counts and their morphologic parameters in patients with Lyme borreliosis before and after antibiotic therapy (4 weeks of treatment) were estimated. 30 patients aged 17-60, x = 41 were evaluated: 7 with Erythema migrans, 3 patients with neuroborreliosis in the from Lymphocytic meningitis and 20 ones with Lyme arthritis. Control group consisted of 19 healthy persons aged 34-52, x = 43. Hematologic analyser Coulter MAXM was used for testing PLT, MPV, PCT and PDW. The results indicated that patients with Lyme boreliosis have decreasing platelet count with simultaneously increasing their volume in comparison with healthy control. It may result from the involement of platelets in defense mechanisms of infected host. The decrease of platelet count after the antibiotic treatment in comparison with the control group may be the reflection of influence of antibiotic treatment on thrombopoesis.


Studies of thyrotropin-releasing hormone (TRH)-induced defecation in cats.
In unanesthetized cats, defecation produced by thyrotropin-releasing hormone (TRH) was investigated after its injection into the cerebral ventricle (ICV) through chronically implanted cannulae. TRH injected in doses from 0.1 to 1.0 mg into the cerebral ventricle evoked defecation which was not dose-dependent. The antimuscarinic drug, atropine, the ganglionic blocker, mecamylamine, the alpha and beta adrenergic blocking agents, yohimbine and propranolol, the dopamine antagonist, chlorpromazine, the 5-hydroxytryptamine antagonist, methysergide, and the antihistamine, antazoline, all injected into the cerebral ventricle had virtually no effect on the defecation evoked by TRH injected similarly. In cats pretreated with ICV reserpine, 5,6-dihydroxytryptamine and hemicholinium-3, the defecation induced by ICV TRH was not significantly changed. On the other hand, in cats pretreated with ICV 6-hydroxydopamine, the defecation caused by ICV TRH was potentiated. Therefore, it is concluded that TRH-induced defecation could not be related to central catecholaminergic, 5-hydroxytryptaminergic and cholinergic receptors, but rather to central TRH sites in the cat.


N-acetylneuraminic acid concentrations in human milk oligosaccharides and glycoproteins during lactation.
Human milk contains a variety of N-acetylneuraminic acid (NANA)-containing oligosaccharides, but the expected range of intake of sialic acid in this form by infants fed human milk is unknown. Two quite different amounts have been reported: 120 mg/liter in pooled, mature human milk (1) and 1400 mg/liter in the milk of a single woman on the 1st day of lactation (2). The normal range of NANA intake in human milk glycoproteins likewise does not appear to have been analyzed previously. Data presented here indicate that both human milk oligosaccharide and glycoprotein NANA decline exponentially over the first 2 months of lactation, decreasing little thereafter. During the first 2 months of lactation, milk from women delivering at term cannot be distinguished from that of women delivering significantly before term (less than 32 wks gestation) with regard to oligosaccharide and glycoprotein NANA. The parallel decrease of sialic acid in these fractions suggests a relationship between sialydation of human milk oligosaccharides and glycoproteins. Human milk NANA concentrations are discussed with regard to reports that exogenous administration of NANA can increase cerebral and cerebellar concentrations of NANA in glycoproteins and gangliosides, and produce long term changes in behavior in rats.


The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases.
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K⁺ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the "evolutionary" Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel-specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies.


The 5' upstream region of mPer1 gene contains two promoters and is responsible for circadian oscillation.
The mPer1 gene is assumed to be a key molecule in the regulation and functioning of the mammalian circadian clock, which is based on the oscillation generated by a transcription-(post)translation feedback loop of a set of clock genes [1]. Robust circadian oscillation and acute light-elicited induction of mPer1 mRNA expression have been observed in the suprachiasmatic nucleus (SCN), the mammalian circadian center [2] [3]. To investigate the mechanism underlying the complex regulation of mPer1 expression, we isolated and characterized the 5' upstream region of the mPer1 gene. Unexpectedly, we identified two promoters, each followed by alternative first exons of mPer1. Consistent with the presence of multiple E-boxes in the promoters, exon-specific in situ hybridization of the SCN established that both promoters function in circadian oscillation and in light-induction of mPer1 expression. Transgenic mice carrying the 5' upstream region of the mPer1 gene fused to the luciferase gene demonstrated that a DNA fragment carrying both promoter regions is sufficient to elicit striking circadian oscillation in the SCN and responsiveness to light. Moreover, luminescence in the SCN accurately mirrored the mPer1 transcriptional activity. These transgenic mice will be very useful for monitoring clock-specific mPer1 expression in intact organisms and to follow the circadian clock in real time.


Assessment of maternal cerebral blood flow velocity by transcranial Doppler ultrasound before delivery and in the early postpartum period.
This prospective observational study aimed to identify the effects of labor on cerebral hemodynamics by measuring the middle cerebral artery (MCA) blood flow velocity by transcranial Doppler ultrasound (TCD), and the related factors just before delivery and within the 24 h after delivery. The study included 35 healthy pregnant women with a gestational age of >37 weeks who were in labor and a control group including healthy, age-matched, nonpregnant women (n = 24). Demographic characteristics and significant clinical information of pregnant women were recorded. The MCA blood flow velocity was assessed by TCD just before and within 24 h after delivery. The parameters assessed by TCD were mean cerebral blood flow velocity (MCBFV), peak systolic velocity (PSV), pulsatility index (PI), resistance index (RI), and systolic/diastolic ratio. There was no significant difference between the pregnant and nonpregnant women regarding age (27 ± 5 years versus 28 ± 7 years; p = .751). The MCBFV, PSV, PI, and RI showed a significant increase within the 24 h after delivery as compared with those before delivery. Comparison of the pregnant women with the control group in terms of the values of all parameters related to the MCA blood flow velocity revealed that the values that were significantly low before delivery reached to the level of the control group after delivery Conclusion: The findings of this study demonstrated that the blood flow velocity of the MCA decreased during the late pregnancy period and increased in the early postpartum period to the level similar to that of the nonpregnant group.


Environmental quality predicts optimal egg size in the wild.
Parents can maximize their reproductive success by balancing the trade-off between investment per offspring and fecundity. According to theory, environmental quality influences the relationship between investment per offspring and offspring fitness, such that well-provisioned offspring fare better when environmental quality is lower. A major prediction of classic theory, then, is that optimal investment per offspring will increase as environmental quality decreases. To test this prediction, we release over 30,000 juvenile Atlantic salmon (Salmo salar) into eight wild stream environments, and we monitor subsequent growth and survival of juveniles. We estimate the shape of the relationship between investment per offspring (egg size) and offspring fitness in each stream. We find that optimal egg size is greater when the quality of the stream environment is lower (as estimated by a composite index of habitat quality). Across streams, the mean size of stream gravel and the mean amount of incident sunlight are the most important individual predictors of optimal egg size. Within streams, juveniles recaptured in stream subsections that featured larger gravels and greater levels of sunlight also grew relatively quickly, an association that complements our cross-stream analyses. This study provides the first empirical verification that environmental quality alters the relationship between investment per offspring and offspring fitness, such that optimal investment per offspring increases as environmental quality decreases.


Human RAD18 interacts with ubiquitylated chromatin components and facilitates RAD9 recruitment to DNA double strand breaks.
RAD18 is an ubiquitin ligase involved in replicative damage bypass and DNA double-strand break (DSB) repair processes. We found that RPA is required for the dynamic pattern of RAD18 localization during the cell cycle, and for accumulation of RAD18 at sites of γ-irradiation-induced DNA damage. In addition, RAD18 colocalizes with chromatin-associated conjugated ubiquitin and ubiquitylated H2A throughout the cell cycle and following irradiation. This localization pattern depends on the presence of an intact, ubiquitin-binding Zinc finger domain. Using a biochemical approach, we show that RAD18 directly binds to ubiquitylated H2A and several other unknown ubiquitylated chromatin components. This interaction also depends on the RAD18 Zinc finger, and increases upon the induction of DSBs by γ-irradiation. Intriguingly, RAD18 does not always colocalize with regions that show enhanced H2A ubiquitylation. In human female primary fibroblasts, where one of the two X chromosomes is inactivated to equalize X-chromosomal gene expression between male (XY) and female (XX) cells, this inactive X is enriched for ubiquitylated H2A, but only rarely accumulates RAD18. This indicates that the binding of RAD18 to ubiquitylated H2A is context-dependent. Regarding the functional relevance of RAD18 localization at DSBs, we found that RAD18 is required for recruitment of RAD9, one of the components of the 9-1-1 checkpoint complex, to these sites. Recruitment of RAD9 requires the functions of the RING and Zinc finger domains of RAD18. Together, our data indicate that association of RAD18 with DSBs through ubiquitylated H2A and other ubiquitylated chromatin components allows recruitment of RAD9, which may function directly in DSB repair, independent of downstream activation of the checkpoint kinases CHK1 and CHK2.


A longitudinal examination of parent-reported emotional-behavioral functioning of children with mild to moderate chronic kidney disease.
Children with mild to moderate chronic kidney disease (CKD) are at increased risk for deficits in neurocognition. Less is known about how CKD affects emotional-behavioral functioning in this population. Parent ratings of emotional-behavioral functioning at baseline and over time were examined for 845 children with mild to moderate CKD using the Behavior Assessment System for Children, Second Edition Parent Rating Scales (BASC-2 PRS). Associations with demographic and disease-related predictors were also examined. Children with mild to moderate CKD had parent-reported emotional-behavioral functioning largely within normal limits, at baseline and over time. The proportion with T-scores at least 1 SD above the mean was 24% for Internalizing Problems and 28% for Attention Problems. A greater proportion of participants scored lower than expected (worse) on scales measuring adaptive skills (25%). Persistent hypertension predicted attention problems (β = 1.59, 95% CI = 0.24 to 2.94, p < 0.02) and suggested worse behavioral symptoms (β = 1.36, 95% CI = - 0.01 to 2.73, p = 0.05). Participants with proteinuria at baseline, but not at follow-up, had fewer attention problems than participants whose proteinuria had not resolved (β = - 3.48, CI = - 6.79 to - 0.17, p < 0.04). Glomerular diagnosis was related to fewer (β = - 2.68, 95% CI = - 4.93 to - 0.42, p < 0.02) internalizing problems. Although children with CKD generally have average emotional-behavioral parent ratings, a notable percentage of the population may be at risk for problems with attention and adaptive behavior. Providers working with this population should facilitate psychosocial referrals when indicated.


Molecular characterization of recombinant T1, a non-allergenic periwinkle (Catharanthus roseus) protein, with sequence similarity to the Bet v 1 plant allergen family.
More than 25% of the population suffer from Type I allergy, an IgE-mediated hypersensitivity disease. Allergens with homology to the major birch ( Betula verrucosa ) pollen allergen, Bet v 1, belong to the most potent elicitors of IgE-mediated allergies. T1, a cytokinin-inducible cytoplasmic periwinkle ( Catharanthus roseus ) protein, with significant sequence similarity to members of the Bet v 1 plant allergen family, was expressed in Escherichia coli. Recombinant T1 (rT1) did not react with IgE antibodies from allergic patients, and failed to induce basophil histamine release and immediate-type skin reactions in Bet v 1-allergic patients. Antibodies raised against purified rT1 could be used for in situ localization of natural T1 by immunogold electron microscopy, but did not cross-react with most of the Bet v 1-related allergens. CD analysis showed significant differences regarding secondary structure and thermal denaturation behaviour between rT1 and recombinant Bet v 1, suggesting that these structural differences are responsible for the different allergenicity of the proteins. T1 represents a non-allergenic member of the Bet v 1 family that may be used to study structural requirements of allergenicity and to engineer hypo-allergenic plants by replacing Bet v 1-related allergens for primary prevention of allergy.


Shape Universality Classes in the Random Sequential Adsorption of Nonspherical Particles.
Random sequential adsorption (RSA) of particles of a particular shape is used in a large variety of contexts to model particle aggregation and jamming. A key feature of these models is the observed algebraic time dependence of the asymptotic jamming coverage ∼t^{-ν} as t→∞. However, the exact value of the exponent ν is not known apart from the simplest case of the RSA of monodisperse spheres adsorbed on a line (Renyi's seminal "car parking problem"), where ν=1 can be derived analytically. Empirical simulation studies have conjectured on a case-by-case basis that for general nonspherical particles, ν=1/(d+d[over ˜]), where d denotes the dimension of the domain, and d[over ˜] the number of orientational degrees of freedom of a particle. Here, we solve this long-standing problem analytically for the d=1 case-the "Paris car parking problem." We prove, in particular, that the scaling exponent depends on the particle shape, contrary to the original conjecture and, remarkably, falls into two universality classes: (i) ν=1/(1+d[over ˜]/2) for shapes with a smooth contact distance, e.g., ellipsoids, and (ii) ν=1/(1+d[over ˜]) for shapes with a singular contact distance, e.g., spherocylinders and polyhedra. The exact solution explains, in particular, why many empirically observed scalings fall in between these two limits.


Testicular sex cord-stromal tumor in a boy with 2q37 deletion syndrome.
2q37 deletion syndrome is a rare congenital disorder that is characterized by facial dysmorphism, obesity, vascular and skeletal malformations, and a variable degree of intellectual disability. To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at chromosome 2q37. However, it remains elusive whether 2q37 deletion per se or other genetic factors, such as copy number variations (CNVs), may confer the risk for the tumorigenic condition. We report a two-year-old Japanese boy with 2q37 deletion syndrome who exhibited the typical facial appearance, coarctation of the aorta, and a global developmental delay, while lacking the symptoms of brachydactyly and obesity. He developed a sex cord-stromal tumor of the right testis at three months of age. The array comparative genome hybridization analysis identified an 8.2-Mb deletion at 2q37.1 (chr2:234,275,216-242,674,807) and it further revealed two additional CNVs: duplications at 1p36.33-p36.32 (chr1:834,101-2,567,832) and 20p12.3 (chr20:5,425,762-5,593,096). The quantitative PCRs confirmed the heterozygous deletion of HDAC4 at 2q37.3 and duplications of DVL1 at 1q36 and GPCPD1 at 20p12.3. This study describes the unique phenotypes in a boy with 2q37 deletion and additional CNVs at 1p36.33-p36.32 and 20p12.3. The data provide evidence that the phenotypic variations and unusual complications of 2q37 deletion syndrome are not simply explained by the deleted size or genes located at 2q37, but that external CNVs may account at least in part for their variant phenotypes. Accumulating the CNV data for chromosomal disorders will be beneficial for understanding the genetic effects of concurrent CNVs on the syndromic phenotypes and rare complications.


Nutraceutical Potential of Grape (Vitis vinifera L.) Seed Oil in Oxidative Stress, Inflammation, Obesity and Metabolic Alterations.
Vitis vinifera L. (grapevine) is a perennial plant of the Vitaceae family that is widely used to produce grapes and wines. Grape seed oil is rich in fatty acids such as linoleic acid (65-75%), vitamin E (50 mg), and phytosterols in addition to phenolic compounds, such as catechins (414 mg), epicatechins (130.4 mg), and gallic acid (77 µg), shows promise as a nutritional compound and is outstanding as a therapeutic substance with active properties for health, detected mainly by in vitro studies, as well as some in vivo studies. The benefits of consuming this oil include modulating the expression of antioxidant enzymes, anti-atherosclerotic and anti-inflammatory effects, and protection against oxidative cell damage and some types of cancer. However, experimental findings confirm that therapeutic functions remain scarce; thus, more studies are needed to determine the mechanisms of action involved in the indicated therapeutic qualities.


Metabolic flux measurements across portal drained viscera, liver, kidney and hindquarter in mice.
A method was developed to measure metabolic fluxes across either portally-drained viscera (PDV) and liver or kidney and hindquarter (HQ) in anesthetized mice. The method includes a primed-constant infusion of ketamine-medetomidine anaesthesia to stabilize the mice for the surgical procedures. For measurement of metabolic fluxes across PDV and liver, blood sampling catheters were inserted in the carotid artery, portal vein and hepatic vein and infusion catheters in the jugular vein and mesenteric vein. For measurement of metabolic flux across kidney and HQ, blood sampling catheters were inserted in the carotid artery, renal vein and caval vein and infusion catheters in the jugular vein and abdominal aorta. 14C-PAH was infused to enable plasma flow measurement using an indicator dilution method. In addition, we developed a blood sampling procedure without waste of blood. We measured plasma flow and metabolic fluxes across PDV, liver, kidney and HQ. Mean plasma flow in post-absorptive mice was: PDV: 0.9+/-0.2, liver: 1.2+/-0.3, kidney: 1.0+/-0.1, HQ: 1.1+/-0.3 ml/10 g body weight (b.w.)/min. Significant glutamine release by the HQ and uptake of glutamine by the kidney and PDV was observed. In PDV, citrulline is produced from glutamine and is in turn used by the kidney for the production of arginine. In conclusion, the described model enables measurement of metabolic fluxes across PDV, liver, kidney and HQ in mice. The availability of such a small animal model allows the potential for measuring metabolic parameters in transgenic and knockout mice, and therefore may lead to an important refinement in metabolic research.


Mating system and recombination affect molecular evolution in four Triticeae species.
Mating systems and recombination are thought to have a deep impact on the organization and evolution of genomes. Because of the decline in effective population size and the interference between linked loci, the efficacy of selection is expected to be reduced in regions with low recombination rates and in the whole genome of self-fertilizing species. At the molecular level, relaxed selection is expected to result in changes in the rate of protein evolution and the pattern of codon bias. It is increasingly recognized that recombination also affects non-selective processes such as the biased gene conversion towards GC alleles (bGC). Like selection, this kind of meiotic drive in favour of GC over AT alleles is expected to be reduced in weakly recombining regions and genomes. Here, we investigated the effect of mating system and recombination on molecular evolution in four Triticeae species: two outcrossers (Secale cereale and Aegilops speltoides) and two selfers (Triticum urartu and Triticum monococcum). We found that GC content, possibly driven by bGC, is affected by mating system and recombination as theoretically predicted. Selection efficacy, however, is only weakly affected by mating system and recombination. We investigated the possible reasons for this discrepancy. A surprising one is that, in outcrossing lineages, selection efficacy could be reduced because of high substitution rates in favour of GC alleles. Outcrossers, but not selfers, would thus suffer from a 'GC-induced' genetic load. This result sheds new light on the evolution of mating systems.


Computer-controlled endoscopic performance assessment system.
We have devised an advanced computer-controlled system (ADEPT) for the objective evaluation of endoscopic task performance. The system's hardware consists of a dual gimbal mechanism that accepts a variety of 5.0-mm standard endoscopic instruments for manipulation in a precisely mapped and enclosed work space. The target object consists of a sprung base plate incorporating various tasks. It is covered by a sprung perforated transparent top plate that has to be moved and held in the correct position by the operator to gain access to the various tasks. Standard video endoscope equipment provides the visual interface between the operator and the target-instrument field. Different target modules can be used, and the level of task difficulty can be adjusted by varying the manipulation, elevation, and azimuth angles. The system's software is designed to (a) prompt the surgeon with the information necessary to perform the task, (b) collect and collate data on performance during execution of specified tasks, and (c) save the data for future analysis. The system was alpha and beta tested to ensure that all functions operated correctly.


Novel approaches to control of bacterial infections in animals.
Bacterial infections of poultry remain of great importance world-wide in terms of economic effects and public health. They include infections caused by Salmonella, Escherichia coli, Campylobacter and Pasteurella. Through the introduction of rigid hygienic measures it is possible to breed and rear poultry free of these pathogens. However, the cost to the industry would be prohibitive and economically disastrous. Biological measures have been introduced albeit in a relatively empirical way. Antibiotic therapy and prophylaxis is used extensively with the associated problems of development of resistance. Killed vaccines are used but are not usually very effective. Live vaccines are increasingly becoming acceptable and studies are under way to increase our understanding of the pathogenesis of these infections so that vaccine development may become less empirical. Work with live vaccines to be used against Salmonella has shown that they may be administered orally to newly-hatched chicks. The vaccine strain colonises the gut extensively and prevents re-infection by other Salmonella strains by a genus-specific mechanism which is similar to that which occurs during down-regulation of bacterial growth in stationary-phase nutrient broth cultures. The mechanism of this phenomenon is currently being studied. This approach may also be applied to control Campylobacter infections. Bacteria of the Pasteurella group and E. coli may produce septicaemic infections in poultry. Recent work with K1+ E. coli infections in mice has shown that virulent bacteriophages may be used to treat or prevent septicaemias and meningitides. This work has been extrapolated to chickens with a similar degree of success and it suggests that some infections of this sort in animals and man may be amenable to this approach. In-bred lines of chickens have been found to vary greatly in their susceptibility to systemic Salmonella infections. This is probably mediated by one gene and the effect is dominant and not linked to sex or MHC. The mouse natural resistance gene (NrampI) does not appear to contribute greatly to this effect. Differences in the extent of gut colonisation by Salmonella in in-bred and out-bred lines can also be detected. These results are very exciting and open up opportunities for disease control for the future.


Hybrid particle-field molecular dynamics simulations for dense polymer systems.
We propose a theoretical scheme for a hybrid simulation technique where self-consistent field theory and molecular dynamics simulation are combined (MD-SCF). We describe the detail of the main implementation issues on the evaluation of a smooth three-dimensional spatial density distribution and its special gradient based on the positions of particles. The treatments of our multiscale model system on an atomic scale or on a specific coarse-grained scale are carefully discussed. We perform a series of test simulations on this hybrid model system and compare the structural correlations on the atomic scale with those of classical MD simulations. The results are very encouraging and open a way to an efficient strategy that possess the main advantages common to the SCF and the atomistic approaches, while avoiding the disadvantages of each of the treatments.


Estimation of individual beneficial and adverse effects of intensive glucose control for patients with type 2 diabetes.
Intensive glucose control reduces the risk of vascular complications while increasing the risk of severe hypoglycaemia at a group level. We sought to estimate individual beneficial and adverse effects of intensive glucose control in patients with type 2 diabetes. We performed a post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, a randomised controlled trial evaluating standard vs intensive glucose control (HbA1c target ≤6.5% [48 mmol/mol]). In 11,140 participants, we estimated the individual 5 year absolute risk reduction (ARR) for the composite outcome of major micro- and macrovascular events and absolute risk increase (ARI) for severe hypoglycaemia for intensive vs standard glucose control. Predictions were based on competing risks models including clinical characteristics and randomised treatment. Based on these models, 76% of patients had a substantial estimated 5 year ARR for major vascular events (>1%, 5 year number-needed-to-benefit [NNTB5] <100) and 1% had a small ARR (<0.5%, NNTB5 >200). Similarly, 36% of patients had a substantial estimated ARI for severe hypoglycaemia (5 year number-needed-to-harm [NNTH5] <100) and 29% had a small ARI (NNTH5 >200). When assigning similar or half the weight to severe hypoglycaemia compared with a major vascular event, net benefit was positive in 85% or 99% of patients, respectively. Limiting intensive treatment to the 85% patient subgroup had no significant effect on the overall incidence of major vascular events and severe hypoglycaemia compared with treating all patients. Taking account of the effects of intensive glucose control on major micro- and macrovascular events and severe hypoglycaemia for individual patients, the estimated net benefit was positive in the majority of the participants in the ADVANCE trial. The estimated individual effects can inform treatment decisions once individual weights assigned to positive and adverse effects have been specified. ClinicalTrials.gov NCT00145925.


AIDS-related MR hyperintensity of the basal ganglia.
Our goal was to describe the MR imaging appearance and clinical pathologic correlates of bilateral basal ganglia hyperintensity in acquired immunodeficiency syndrome (AIDS). Medical records and laboratory data were reviewed retrospectively in nine cases of bilateral basal ganglia hyperintensity on long-repetition-time MR images. Opportunistic infections of the central nervous system were excluded by clinical and laboratory data. Postmortem neuropathologic examination was obtained in two cases. All patients presented acutely with new seizures or changes in mental status. A history of drug abuse was elicited in seven of the nine remaining patients. Renal failure was present in six cases. Symmetric bilateral caudate and putamen hyperintensity on T2-weighted images was found in all cases with variable extension to the surrounding white matter, thalamus, and brain stem. Postmortem neuropathologic examination in two cases revealed numerous microinfarcts in a distribution similar to the MR signal abnormalities. The MR appearance of basal ganglia hyperintensity in this series of AIDS patients represents ischemic tissue injury. We propose that this clinicopathologic entity is precipitated by the combined effects of human immunodeficiency virus infection and drug use, particularly cocaine and/or associated toxic contaminants.


Counterion influence on chemical shifts in strychnine salts.
The highly toxic plant alkaloid strychnine is often isolated in the form of the anion salt of its protonated tertiary amine. Here, we characterize the relative influence of different counterions on (1)H and (13)C chemical shifts in several strychnine salts in D2O, methanol-d4 (CD3OD), and chloroform-d (CDCl3) solvents. In organic solvents but not in water, substantial variation in chemical shifts of protons near the tertiary amine was observed among different salts. These secondary shifts reveal differences in the way each anion influences electronic structure within the protonated amine. The distributions of secondary shifts allow salts to be easily distinguished from each other as well as from the free base form. Slight concentration dependence in chemical shifts of some protons near the amine was observed for two salts in CDCl3, but this effect is small compared with the influence of the counterion. Distinct chemical shifts in different salt forms of the same compound may be useful as chemical forensic signatures for source attribution and sample matching of alkaloids such as strychnine and possibly other organic acid and base salts.


Influence of molecular weight on ion-transport properties of polymeric ionic liquids.
We report the results of atomistic molecular dynamics simulations on polymerized 1-butyl-3-vinylimidazolium-hexafluorophosphate ionic liquids, studying the influence of the polymer molecular weight on the ion mobilities and the mechanisms underlying ion transport, including ion-association dynamics, ion hopping, and ion-polymer coordinations. With an increase in polymer molecular weight, the diffusivity of the hexafluorophosphate (PF6-) counterion decreases and plateaus above seven repeat units. The diffusivity is seen to correlate well with the ion-association structural relaxation time for pure ionic liquids, but becomes more correlated with ion-association lifetimes for larger molecular weight polymers. By analyzing the diffusivity of ions based on coordination structure, we unearth a transport mechanism in which the PF6- moves by "climbing the ladder" while associated with four polymeric cations from two different polymers.


Identification of Aloe-derived natural products as prospective lead scaffolds for SARS-CoV-2 main protease (Mpro) inhibitors.
In the past two years, the COVID-19 pandemic has caused over 5 million deaths and 250 million infections worldwide. Despite successful vaccination efforts and emergency approval of small molecule therapies, a diverse range of antivirals is still needed to combat the inevitable resistance that will arise from new SARS-CoV-2 variants. The main protease of SARS-CoV-2 (Mpro) is an attractive drug target due to the clinical success of protease inhibitors against other viruses, such as HIV and HCV. However, in order to combat resistance, various chemical scaffolds need to be identified that have the potential to be developed into potent inhibitors. To this end, we screened a high-content protease inhibitor library against Mproin vitro, in order to identify structurally diverse compounds that could be further developed into antiviral leads. Our high-content screening efforts retrieved 27 hits each with > 50% inhibition in our Mpro FRET assay. Of these, four of the top inhibitor compounds were chosen for follow-up due to their potency and drugability (Lipinski's rules of five criteria): anacardic acid, aloesin, aloeresin D, and TCID. Further analysis via dose response curves revealed IC50 values of 6.8 μM, 38.9 μM, 125.3 μM, and 138.0 μM for each compound, respectively. Molecular docking studies demonstrated that the four inhibitors bound at the catalytic active site of Mpro with varying binding energies (-7.5 to -5.6 kcal/mol). Furthermore, Mpro FRET assay kinetic studies demonstrated that Mpro catalysis is better represented by a sigmoidal Hill model than the standard Michaelis-Menten hyperbola, indicating substantial cooperativity of the active enzyme dimer. This result suggests that the dimerization interface could be an attractive target for allosteric inhibitors. In conclusion, we identified two closely-related natural product compounds from the Aloe plant (aloesin and aloeresin D) that may serve as novel scaffolds for Mpro inhibitor design and additionally confirmed the strongly cooperative kinetics of Mpro proteolysis. These results further advance our knowledge of structure-function relationships in Mpro and offer new molecular scaffolds for inhibitor design.


Positive pressure ventilation: what is the real cost?
Positive pressure ventilation is a radical departure from the physiology of breathing spontaneously. The immediate physiological consequences of positive pressure ventilation such as haemodynamic changes are recognized, studied, and understood. There are other significant physiological interactions which are less obvious, more insidious, and may only produce complications if ventilation is prolonged. The interaction of positive pressure with airway resistance and alveolar compliance affects distribution of gas flow within the lung. The result is a wide range of ventilation efficacy throughout different areas of the lung, but the pressure differentials between alveolus and interstitium also influence capillary perfusion. The hydrostatic forces across the capillaries associated with the effects of raised venous pressures compound these changes resulting in interstitial fluid sequestration. This is increased by impaired lymphatic drainage which is secondary to raised intrathoracic pressure but also influenced by raised central venous pressure. Ventilation and PEEP promulgate further physiological derangement. In theory, avoiding these physiological disturbances in a rested lung may be better for the lung and other organs. An alternative to positive pressure ventilation might be to investigate oxygen supplementation of a physiologically neutral and rested lung. Abandoning heroic ventilation would be a massive departure from current practice but might be a more rationale approach to future practice.


The effect of caregiving on women in families with Duchenne/Becker muscular dystrophy.
Duchenne/Becker muscular dystrophy (DBMD) is a disorder of progressive muscle weakness that causes an increasing need for assistance with activities of daily living. Our objective was to assess the psychosocial health and contributing factors among female caregivers in families with DBMD. We conducted a survey of adult women among families with DBMD in the United States (US) from June 2006 through January 2007, collecting data related to the care recipient, perception of caregiving demands, personal factors, and socio-ecologic factors. Life satisfaction, stress, and distress were assessed as outcomes. Existing validated instruments were used when available. We received responses from 1238 women who were caring for someone with DBMD, 24.2% of whom were caring for two or more people with DBMD. Caregivers were more likely to be married/cohabitating than women in the general US population, and a high level of resiliency was reported by 89.3% of caregivers. However, the rate of serious psychological distress was significantly higher among caregivers than among the general population. Likewise, 46.4% reported a high level of stress, and only 61.7% reported that they were satisfied with their life. A high level of caregiving demands based on the Zarit Burden Interview (ZBI) was reported by 50.4% of caregivers. The post-ambulatory phase of DBMD was associated with decreased social support and increased ZBI scores. In multivariate logistic regression modelling, life satisfaction was dependent on high social support, high resiliency, high income, and form of DBMD. Distress and high stress were predicted by low resiliency, low social support, and low income. Employment outside of the home was also a predictor of high stress. Interventions focused on resiliency and social support are likely to improve the quality of life of DBMD caregivers, and perhaps caregivers of children with other disabilities or special health care needs as well.


Occult chorioretinal anastomosis in age-related macular degeneration: a prospective study by optical coherence tomography.
To investigate macular optical coherence tomography (OCT) features in patients with chorioretinal anastomosis (CRA) and drusen, as well as their correlation with the Gass occult-CRA hypothesis. Prospective observational case series. setting: Tertiary ophthalmic referral center. study population: All patients with biomicroscopic evidence of CRA and drusen consecutively evaluated between February 2003 and March 2004. observation procedures: Third-generation OCT evaluation and stereoscopic angiographic studies. main outcome measures: Macular morphologic features at baseline and at 12 weeks. Twenty eyes with CRA and drusen were identified in 11 patients, seven women (63.6%) and four men (36.4%) ranging in age from 69 to 82 years (median, 79 years). Focal elevation of the retinal pigment epithelium was seen in eyes with stage 1 (pre-clinical) CRA. Small hyperreflective signals at the level of the elevated retinal pigment epithelium were seen in stage 2 CRA. In stage 3 CRA, a hyperreflective "mound" at the level of the elevated retinal pigment epithelium was seen in association with a thickened retina. In stage 4 CRA sub-retinal pigment epithelium fluid accumulation was present, and complete disorganization of the macular region was observed in stage 5 CRA. Macular changes were observed in eight eyes (40%) at follow-up, with all but one CRA lesion progressing one stage. Morphologic features and changes demonstrated by OCT suggest that fibrovascular detachment of the retinal pigment epithelium followed by development of occult CRA are the initial events occurring in eyes with CRA in age-related macular degeneration. Our findings may support the evolutionary CRA staging system proposed by Gass.


The Brain's Reward Response Occurs Even Without Actual Reward!
What if the brain's response to reward occurs even when there is no reward? Wouldn't that be a further concern for people prone to problem gambling and other forms of addiction, like those related to eating? Electroencephalography was employed to investigate this possibility using probabilistic feedback manipulations and measures of known event-related potentials (ERPs) related to reward processing. We tested the hypothesis-that reward-based ERPs would occur even in the absence of a tangible reward and when manipulations on expectation are implicit. The well-known P300 response potential was a key focus, and was assessed in non-gambling volunteer undergraduates on a task involving experimentally-manipulated probabilities of positive or negative feedback comprising three trial types-80, 50, or 20% positive feedback. A feedback stimulus (F1) followed a guess response between two possible outcomes (implicit win/loss), and then a second feedback stimulus (F2) was presented to confirm an alleged 'win' or 'loss' (explicit win/loss). Results revealed that amplitude of the P300 in F1-locked data (implicit manipulation) was larger (more positive) on average for feedback outcomes that were manipulated to be less likely than expected. The effect is pronounced after increased time on task (later trials), even though the majority of participants were not explicitly aware of our probability manipulations. For the explicit effects in F2-locked data, no meaningful or significant effects were observed. These findings point to the existence of proposed success-response mechanisms that operate not only explicitly but also with implicit manipulations that do not involve any direct indication of a win or loss, and are not associated with tangible rewards. Thus, there seems to be a non-explicit form of perception (we call 'implicit') associated with an internal experience of wins/losses (in the absence of actual rewards or losses) that can be measured in associated brain processes. The potential significance of these findings is discussed in terms of implications for problem gambling.


Functional implications of long non-coding RNAs in the pancreatic islets of Langerhans.
Type-2 diabetes (T2D) is a complex disease characterized by insulin resistance in target tissues and impaired insulin release from pancreatic beta cells. As central tissue of glucose homeostasis, the pancreatic islet continues to be an important focus of research to understand the pathophysiology of the disease. The increased access to human pancreatic islets has resulted in improved knowledge of islet function, and together with advances in RNA sequencing and related technologies, revealed the transcriptional and epigenetic landscape of human islet cells. The discovery of thousands of long non-coding RNA (lncRNA) transcripts highly enriched in the pancreatic islet and/or specifically expressed in the beta-cells, points to yet another layer of gene regulation of many hitherto unknown mechanistic principles governing islet cell functions. Here we review fundamental islet physiology and propose functional implications of the lncRNAs in islet development and endocrine cell functions. We also take into account important differences between rodent and human islets in terms of morphology and function, and suggest how species-specific lncRNAs may partly influence gene regulation to define the unique phenotypic identity of an organism and the functions of its constituent cells. The implication of primate-specific lncRNAs will be far-reaching in all aspects of diabetes research, but most importantly in the identification and development of novel targets to improve pancreatic islet cell functions as a therapeutic approach to treat T2D.


Doping Approaches for Organic Semiconductors.
Electronic doping in organic materials has remained an elusive concept for several decades. It drew considerable attention in the early days in the quest for organic materials with high electrical conductivity, paving the way for the pioneering work on pristine organic semiconductors (OSCs) and their eventual use in a plethora of applications. Despite this early trend, however, recent strides in the field of organic electronics have been made hand in hand with the development and use of dopants to the point that are now ubiquitous. Here, we give an overview of all important advances in the area of doping of organic semiconductors and their applications. We first review the relevant literature with particular focus on the physical processes involved, discussing established mechanisms but also newly proposed theories. We then continue with a comprehensive summary of the most widely studied dopants to date, placing particular emphasis on the chemical strategies toward the synthesis of molecules with improved functionality. The processing routes toward doped organic films and the important doping-processing-nanostructure relationships, are also discussed. We conclude the review by highlighting how doping can enhance the operating characteristics of various organic devices.


Developmental bisphenol S toxicity in two freshwater animal models.
Freshwater animals are exposed to anthropogenic contaminants and are biomonitors of water quality and models of the deleterious impacts of exposure. Sponges, such as Ephydatia muelleri, constantly pump water and are effective indicators of water-soluble contaminants. Zebrafish (Danio rerio), native to Southeast Asia, live in the water column and feed at the water-sediment interface and are exposed to both water-soluble and insoluble contaminants. While sponges and zebrafish diverged ∼700 million years ago, they share common genetic elements, and their response to contaminants can be predictive to a wide-range of animals. An emerging contaminant, bisphenol S, was tested to evaluate its toxicity during development. The toxicity and mechanism(s) of action of BPS is not well known. Water-borne exposures to BPS caused differing hatching rates, morphological changes, and shared gene expression changes of toxicologically-relevant genes. This study shows that BPS causes similarly adverse developmental impacts pointing to some overlapping mechanisms of action.


Trichosporon porosum comb. nov., an anamorphic basidiomycetous yeast inhabiting soil, related to the loubieri/laibachii group of species that assimilate hemicelluloses and phenolic compounds.
Several isolates representing the genus Trichosporon were collected over a 6-year period from soils in The Netherlands. Based on classical growth tests with carbon and nitrogen compounds these were identical. Three of these (CBS 8396, CBS 8397 and CBS 8522) were subjected to molecular analysis of the D1/D2 region of the large subunit of rDNA. This confirmed that the three strains were identical, yet distinct from other members of the genus. Conspecificity was demonstrated with the type strain (CBS 2040) of Apiotrichum porosum Stautz (1931), with the exception that A. porosum, which had been isolated from exudate of a yew tree, differed morphologically from the soil strains. Based on the identity of DNA base sequences, morphology was not considered to be an adequate parameter to separate otherwise identical strains into two genera. Therefore, the new combination Trichosporon porosum is presented. Based on molecular sequence analysis, T. porosum may be related to T. sporotrichoides, within a weakly related clade that includes species such as Trichosporon laibachii and Trichosporon loubieri. The strains of T. porosum degrade phenolic compounds and hemicelluloses, which are characteristics with potential ecological importance in soil habitats. Characters distinguishing the nine species of the laibachii/loubieri group of species were listed. These include traditionally used tests as well as assimilation patterns of some aliphatic and phenolic compounds. Based on these tests, species such as Trichosporon multisporum and T. laibachii could be separated.


Patient knowledge and information concerning medication on discharge from hospital.
This study aimed to establish whether patients had sufficient knowledge and information concerning their medications on discharge from hospital. The purpose was also to identify who educated and provided patients with information and in what form it came. The study was carried out in five medical wards of a large teaching hospital, where patients were interviewed on the morning of discharge. By using a medication checklist the findings of this study appeared to indicate that the patients interviewed had relatively little knowledge or information regarding their discharge medications. However, overall their knowledge and information concerning their discharge medications had improved in relation to that of their admission medications. Despite this finding, there remains a definite need for structured medication teaching programmes with appropriate assessment of patients needs on admission to hospital.


Recombinant alpha-interferon enhances tumor targeting of an antimelanoma monoclonal antibody in vivo.
To determine whether recombinant human alpha-interferon (rIFN alpha A) could enhance tumor uptake of an antimelanoma monoclonal antibody (Mab) 96.5 in vivo, groups of nude mice bearing P97 antigen-positive human melanoma subcutaneous xenografts were given i.m. injections of normal saline or rIFN alpha A daily for 10 days. On day 7, mice received either 5 micrograms of 111In-labeled Mab 96.5 or irrelevant 111In-labeled subclass-matched or non-subclass-matched control Mabs. Animals were killed 72 h later and the percent injected dose per gram (%ID/g) in tumor and normal organs was determined. There was a significant (p less than 0.001) increase in 96.5 in tumors of IFN-treated mice compared to saline-treated mice and mice receiving irrelevant Mabs. There was also a significantly increased uptake of 96.5 in blood, heart, lung, kidney, and muscle of IFN-treated vs. control mice (p less than 0.05). This finding was most likely due to increased antigen shedding since significant differences in %ID/g were not observed between IFN-treated and control mice bearing antigen-negative tumors. Furthermore, P97 content in tumor and tissues of IFN-treated mice bearing melanoma xenografts was significantly higher than in mice without tumors. In summary, IFN enhanced targeting of 96.5 via an antigen-specific mechanism. These data confirm and extend previous studies in other tumor systems, and suggest that clinical trials of Mabs plus IFN might be useful in overcoming poor Mab localization that occurs as a result of antigenic heterogeneity in humans.


Nonuniqueness of magnetic fields and energy derivatives in spin-polarized density functional theory.
The effect of the recently uncovered nonuniqueness of the external magnetic field B(r) corresponding to a given pair of density n(r) and spin density n(s)(r) on the derivative of the energy functional of spin-polarized density functional theory, and its implications for the definition of chemical reactivity descriptors, is examined. For ground states, the nonuniqueness of B(r) implies the nondifferentiability of the energy functional E(v,B)[n,n(s)] with respect to n(s)(r). It is shown, on the other hand, that this nonuniqueness allows the existence of the one-sided derivatives of E(v,B)[n,n(s)] with respect to n(s)(r). Although the N-electron ground state can always be obtained from the minimization of E(v,B)[n,n(s)] without any constraint on the spin number N(s)=integraln(s)(r)dr, the Lagrange multiplier mu(s) associated with the fixation of N(s) does not vanish even for ground states. Mu(s) is identified as the left- or right-side derivative of the total energy with respect to N(s), which justifies the interpretation of mu(s) as a (spin) chemical potential. This is relevant not only for the spin-polarized generalization of conceptual density functional theory, the spin chemical potential being one of the elementary reactivity descriptors, but also for the extension of the thermodynamical analogy of density functional theory for the spin-polarized case. For higher-order reactivity indices, B(r)'s nonuniqueness has similar implications as for mu(s), leading to a split of the indices with respect to N(s) into one-sided reactivity descriptors.


Widespread occurrence of anti-troponin T crossreactive components in non-muscle cells.
Using a monoclonal antibody generated against striated muscle troponin T, we previously noted the presence of crossreactive components in smooth muscle and non-muscle cells. Since the presence of troponin T in tissues other than striated muscle is controversial, we sought to establish the nature of the crossreaction and to determine the extent of its occurrence. For this study, indirect immunofluorescence microscopy and immunoblot analyses were performed. Crossreactive material was found in diverse cells from the animal, plant and fungal kingdoms. On the basis of morphological distributions, both microtubule-associated and non-microtubule-associated components were revealed. Microtubule-associated components of animal cell lines included a 35 X 10(3) Mr protein, similar in electrophoretic mobility to skeletal troponin T (37 X 10(3) Mr). Reactive components of comparable mobility were observed in immunoblots of brain and cerebellar homogenates. Filamentous staining was observed in a variety of mammalian cells in culture and in cells of vertebrate tissues. Chick cerebellar tissue showed reactions in the neurites of the molecular layer and granule cell bodies. In the plant kingdom, examination of the onion root-tip cells indicated an association of crossreactive components with interphase cortical microtubules, preprophase bands, the mitotic spindle and phragmoplast microtubules. In the fungal kingdom, both interphase and mitotic spindle microtubules in a cellular slime mould were reactive. Non-microtubule-associated components were observed in the centrosphere regions of mitotic sea-urchin eggs, in mitotic and interphase plasmodia of Physarum polycephalum, and in trichocysts and basal bodies of Paramecium tetraurelia. In all systems examined, the troponin T crossreactive components were located in regions or on structures of possible Ca2+ or calmodulin activity, suggesting a possible functional similarity to troponin T.


The divergence of major histocompatibility complex class I genes in Sciurus aberti.
Major histocompatibility complex (MHC) class I genes encode cell surface molecules that bind and present immunogenic peptides to cytolytic T lymphocytes. We have developed a model using the MHC (Scab) of tassel-eared squirrels, Sciurus aberti, to investigate the evolution of MHC genes in subspecies that have been effectively isolated in comparable, if not identical, environments. Class I cDNAs from single S. aberti aberti and S. aberti kaibabensis squirrels were cloned and sequenced. These two cDNA transcripts differed by nucleotide substitutions that were predominantly located in codons impacting the peptide binding site, and nonsynonymous substitutions exceeded synonymous substitutions at these sites. These sequences also differed by the insertion of two amino acids in a beta-strand adjacent to position 45 in pocket B of the peptide binding site that may result in a deeper pocket with altered peptide specificity. This indel is present in additional Scab class I sequences, and class I sequences in five subspecies carry identically sized insertions. Phylogenetic analyses of exons 2, 3, and 4 with neighbor-joining and maximum parsimony methods depict that Scab class I sequences diverged at a point intermediate between murid class I sequences and class I sequences of primates, carnivores, and artiodactyls. The relative relatedness of Scab class I sequences to those in the latter group appears to be founded in relative similarities in exons 2 and 3, which encode the peptide binding site. These results bring into question the use of a single model for rodent class I sequences. Moreover, they demonstrate that the inclusion of exons 2 and 3 in phylogenetic analyses of class I may obscure true phylogenetic relationships, perhaps due to convergence through strong selective pressure.


Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study.
Patients with elevated serum triglyceride (TG) levels often have elevations in non-high-density lipoprotein cholesterol (non-HDL-C) levels as well. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has identified non-HDL-C as a secondary therapeutic target in these patients, but treatment goals may not be reached with statin monotherapy alone. This study evaluated the effects on non-HDL-C and other variables of adding prescription omega-3-acid ethyl esters (P-OM3; Lovaza, formerly Omacor [Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey]) to stable statin therapy in patients with persistent hypertriglyceridemia. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adults who had received > or = 8 weeks of stable statin therapy and had mean fasting TG levels > or = 200 and < 500 mg/dL and mean low-density lipoprotein cholesterol levels < or = 10% above their NCEP ATP III goal. The study regimen consisted of an initial 8 weeks of open-label simvastatin 40 mg/d and dietary counseling, followed by 8 weeks of randomized treatment with double-blind P-OM3 4 g/d plus simvastatin 40 mg/d or placebo plus simvastatin 40 mg/d. The main outcome measure was the percent change in non-HDL-C from baseline to the end of treatment. The evaluable population included 254 patients, of whom 57.5% (146) were male and 95.7% (243) were white. The mean (SD) age of the population was 59.8 (10.4) years, and the mean weight was 92.0 (19.6) kg. At the end of treatment, the median percent change in non-HDL-C was significantly greater with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001). P-OM3 plus simvastatin was associated with significant reductions in TG (29.5% vs 6.3%) and very-low-density lipoprotein cholesterol (27.5% vs 7.2%), a significant increase in high-density lipoprotein cholesterol (HDL-C) (3.4% vs -1.2%), and a significant reduction in the total cholesterol:HDL-C ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo). Adverse events (AEs) reported by > or= 1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were nasopharyngitis (4 [3.3%]), upper respiratory tract infection (4 [3.3%]), diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. In these adult, mainly white patients with persistent hypertriglyceridemia, P-OM3 plus simvastatin and dietary counseling improved non-HDL-C and other lipid and lipoprotein parameters to a greater extent than simvastatin alone.


CRISPR/Cas9-Mediated Knock-Out of the MtCLE35 Gene Highlights Its Key Role in the Control of Symbiotic Nodule Numbers under High-Nitrate Conditions.
Legume plants have the ability to establish a symbiotic relationship with soil bacteria known as rhizobia. The legume-rhizobium symbiosis results in the formation of symbiotic root nodules, where rhizobia fix atmospheric nitrogen. A host plant controls the number of symbiotic nodules to meet its nitrogen demands. CLE (CLAVATA3/EMBRYO SURROUNDING REGION) peptides produced in the root in response to rhizobial inoculation and/or nitrate have been shown to control the number of symbiotic nodules. Previously, the MtCLE35 gene was found to be upregulated by rhizobia and nitrate treatment in Medicago truncatula, which systemically inhibited nodulation when overexpressed. In this study, we obtained several knock-out lines in which the MtCLE35 gene was mutated using the CRISPR/Cas9-mediated system. M. truncatula lines with the MtCLE35 gene knocked out produced increased numbers of nodules in the presence of nitrate in comparison to wild-type plants. Moreover, in the presence of nitrate, the expression levels of two other nodulation-related MtCLE genes, MtCLE12 and MtCLE13, were reduced in rhizobia-inoculated roots, whereas no significant difference in MtCLE35 gene expression was observed between nitrate-treated and rhizobia-inoculated control roots. Together, these findings suggest the key role of MtCLE35 in the number of nodule numbers under high-nitrate conditions, under which the expression levels of other nodulation-related MtCLE genes are reduced.


Neurology clerkship goals and their effect on learning and satisfaction.
To define medical student goals in the neurology clerkship and explore the association between goal setting and student performance, clerkship satisfaction, self-directed learning (SDL), and interest in neurology. A 4-year prospective study of consecutive second- to fourth-year medical students rotating through a required 4-week neurology clerkship was conducted. A goal-generating cohort (first 2 years) was enrolled to describe the breadth of student-derived goals. A goal-evaluating cohort (second 2 years) was used to evaluate the frequency of goal achievement and assess associations with performance (e.g., National Board of Medical Examiners [NBME], examination), satisfaction, and SDL behaviors (both based on 5-point Likert scale). Of 440 evaluable students, 201 were goal-generating and 239 goal-evaluating. The top 3 goals were (1) improvement in neurologic examination, (2) understanding neurologic disease, and (3) deriving a differential diagnosis. More than 90% (n = 216/239) of students reported achieving goals. Achievers reported significantly higher clerkship satisfaction (4.2 ± 0.8 vs. 2.8 ± 1.0, p < 0.0001), greater interest in neurology (71% vs. 35%, p = 0.001), and higher observed tendency toward SDL (4.5 ± 0.5 vs. 4.1 ± 0.8, p < 0.0001). After adjusting for age and training, NBME scores were 1.7 points higher in achievers (95% confidence interval 0.1-3.2, p = 0.04). Students consistently generated similar goals for a required neurology clerkship. Goal achievers had better adjusted standardized test scores, higher satisfaction, and greater tendency toward SDL. This student-generated, goal-setting program may be particularly appealing to clinicians, educators, and researchers seeking resource-lean mechanisms to improve student experience and performance in the clinical clerkships.


The CLOSER (CLarifying Vaginal Atrophy's Impact On SEx and Relationships) survey: implications of vaginal discomfort in postmenopausal women and in male partners.
Postmenopausal vaginal atrophy (VA) is a chronic condition with symptoms that include vaginal dryness, soreness, itching, burning, and dyspareunia. The CLarifying Vaginal Atrophy's Impact On SEx and Relationships survey evaluated the impact of VA on the physical and emotional aspects of sexual relationships between postmenopausal women and their male partners. Four thousand one hundred females and 4,100 males representing the United Kingdom, Finland, Norway, Sweden, Denmark, Italy, France, Canada, and the United States were surveyed. Assessments included: (i) talking about VA and its symptoms; (ii) the impact of VA on intimacy, relationships, and women's self-esteem; (iii) talking about VA and erectile dysfunction (ED); and (iv) the impact of local estrogen therapy (LET) on intimacy and relationships. Descriptive data on the impact of VA. Twenty-eight percent of women did not tell their partners when they first encountered vaginal discomfort, mainly because they felt "it was just a natural part of growing older" (52%) or because of "embarrassment" (21%). Eighty-two percent of males wanted their partner to share their experiences with VA; males were also more comfortable discussing VA than females (68% vs. 58%, respectively). Having sex less often (women: 58%, men: 61%), less satisfying sex (women: 49%, men: 28%), and putting off having sex (women: 35%, men: 14%) were the main effects of VA. Intimacy avoidance was attributed to painful sex (women: 55%, men: 61%) and women's reduced sexual desire (women: 46%, men: 43%). Discussions about vaginal discomfort and ED were generally limited to partners and healthcare providers (HCPs). LET use resulted in less painful sex (women: 62%, men: 59%) and more satisfying sex (women: 47%, men: 49%). VA has an adverse emotional and physical impact on postmenopausal women and their partners. These findings may encourage more open communication about VA between couples and their HCPs.


[Glycogen phosphorylase of skeletal muscles].
A review is given on the affinity modification of pyridoxal phosphate and AMP-binding sites as well as on the chemical modification of essential amino acid residues of phosphorylase (histidine residue of the substrate-binding site and cysteine residue of the coenzyme-binding site). The role of allosteric effectors (AMP and glucose-6-phosphate) and functionally important centers of the protein in conformational transitions of rabbit muscle phosphorylase b is discussed. The kinetic properties of rabbit and bovine muscle phosphorylase are compared. Bovine muscle phosphorylase is shown to be a partly phosphorylated form of the enzyme. Some peculiarities of the pH-dependence of kinetic behaviour of the hybrid form of the bovine muscle enzyme are discussed.


Cardiac Resynchronization Therapy for Improving Non-Uniform Thickening of Left Ventricular Wall: Assessment by Quantitative Gated Myocardial Perfusion SPECT.
Cardiac resynchronization therapy (CRT) improves cardiac dyssynchrony in heart failure patients with a wide QRS electrocardiogram (ECG). Assessment of left ventricular (LV) dyssynchrony using echocardiography or other imaging modalities is important to predict CRT effectiveness. In this study, we retrospectively evaluated cardiac nuclear imaging of ECG-gated myocardial perfusion single-photon emission computed tomography (SPECT) with 99mTc-sestamibi for CRT candidate (n = 120) with severe heart failure and wide QRS (> 120 msec) in ECG. To analyze LV non-uniformity, we used the quantitative gated SPECT (QGS) software to calculate changes in regional LV wall thickness during a cardiac cycle (i.e., wall thickening scores). Cardiac events (heart failure, ventricular arrhythmias and cardiac death) after CRT during 38 ± 22 (SD) months were also evaluated. In 97 of 120 patients who underwent QGS before and 6 months after CRT, CRT homogenized non-uniform wall thickening between septal and lateral of the LV especially in CRT responders. This observation was indicated as increase in the lateral deflection (XWT) of wall thickening scores before CRT and its decrease after CRT. In 120 patients with QGS before CRT, the larger XWT before CRT (≥ 16.5) predicted better prognoses after CRT. This finding was similarly observed even in patients with narrower baseline QRS (≤ 140 msec; n = 41 of 120), who usually have less benefits from CRT. In conclusion, CRT improved non-uniformity of wall thickening between the LV septal and lateral regions evaluated using QGS, which is predictive of better prognosis in the chronic phase after CRT.


A new in vitro assay for quantitation of chemotherapy-induced mucositis.
Patients receiving high-dose chemotherapy (HD-CT) are at risk of severe mucositis. Most prevention studies evaluate the degree of mucositis on clinical, and therefore subjective, measurements. The aim of this study was to develop an objective in vitro assay of chemotherapy-induced mucositis. Twelve patients with locally advanced breast carcinoma received HD-CT followed by peripheral stem cell reinfusion. Before and twice weekly after HD-CT, the mucosa was evaluated by an oral washing, a buccal smear and the World Health Organization (WHO) toxicity grading; furthermore, blood leucocyte levels were determined. For the oral washings, the percentage of viable epithelial cells was determined by trypan blue dye exclusion and leucocytes were counted by fluorescence microscopy after incubation with acridine orange. Maturity of buccal cells was assessed by staining buccal smears for morphology according to Papanicolaou (Whitacker D and Williams V, 1994). Eight healthy volunteers served as controls. The mean percentage (+/- s.e.m.) of viable oral epithelial cells was stable in controls (44 +/- 2%). In patients, they increased after HD-CT, which was significant after day 7 compared with pretreatment (P < or = 0.05). In addition, a shift from mature to immature epithelial cells in buccal smears was observed. Oral leucocyte levels were closely correlated with the blood leucocyte counts. The WHO score followed the results of these other evaluations with some delay. The viability of buccal cells obtained by oral washings increases after HD-CT. This is possibly because of desquamation of the upper oral mucosa layer, with a shift from mature to more immature cells. These data can be quantitated, and this assay may therefore be useful in studies aimed at prevention of mucositis.